Case Reports

The circulation of cerebrospinal fluid (CSF) is crucial for maintaining homeostasis for the optimal functioning of the multiple complex activities of the brain and spinal cord, including the disposal of metabolic waste products of brain and spinal cord activity into the cerebral venous drainage. Throughout the brain, the arachnoid mater forms small outpouchings or diverticula that penetrate the dura mater and communicate with the dural venous sinuses. These outpuchings are called arachnoid granulations or arachnoid villi, and most are found within the dural sinuses, primarily in the transverse sinuses and superior sagittal sinus, but can occasionally be seen extending into the inner table of the calvarium.^1,2

wekituuistec

The amount of arachnoid granulations seen in bone, particularly around the superior sagittal sinus, may increase with age.² Arachnoid granulations are generally small but the largest ones can be seen on gross examination during intracranial procedures or autopsy.³ Magnetic resonance imaging (MRI) can detect arachnoid granulations, which are characterized as T1 hypointense and T2 hyperintense (CSF isointense), well-circumscribed, small, nonenhancing masses within the dural sinuses or in the diploic space (Figure 1). Even small arachnoid granulations < 1 mm in length can be detected.²

Smaller arachnoid granulations have been described histologically as entirely covered by a dural membrane, thus creating a subdural space that separates the body of the arachnoid granulation from the lumen of the accompanying venous sinus.⁴ However, larger arachnoid granulations may not be completely covered by a dural membrane, thus creating a point of contact between the arachnoid granulation and the venous sinus.⁴ Larger arachnoid granulations are normally filled with CSF, and their signal characteristics are similar to CSF on imaging.^5,6 Arachnoid granulations also often contain vessels draining into the adjacent venous sinus.^5,6

When larger arachnoid granulations are present, they may permit the protrusion of herniated brain tissue. There has been an increasing number of reports of these brain herniations into arachnoid granulations (BHAGs) in the literature.^7-10 While these herniations have been associated with nonspecific neurologic symptoms like tinnitus and idiopathic intracranial hypertension, their true clinical significance remains undetermined.^10,11 This article presents 5 cases of BHAG, discusses their clinical presentations and image findings, and reviews the current literature.

Case 1

A 30-year-old male with a history of multiple traumatic brain injuries presented for evaluation of seizures. The patient described the semiology of the seizures as a bright, colorful light in his right visual field, followed by loss of vision, then loss of awareness and full body convulsion. The semiology of this patient’s seizures was consistent with left temporo-occipital lobe seizure. The only abnormality seen in the brain MRI was the herniation of brain parenchyma originating from the occipital lobe into the transverse sinus, presumably through an arachnoid granulation (Figure 1). An electroencephalogram (EEG) was unremarkable, though the semiology of the seizure historically described by the patient was localized to the area of BHAG. The patient is currently taking antiseizure medications and has experienced no additional seizures.

Case 2

spuuujirenauocrecebresheclospemiwatecleticlalacrofrefranebriswamafrowiga

A male aged 53 years with a history of peripheral artery disease presented with a 6-month history of headaches and dizziness. The patient reported the onset of visual aura to his right visual field, starting as a fingernail-sized scintillating kaleidoscope light that would gradually increase in size to a round shape with fading kaleidoscope colors. This episode would last for a few minutes and was immediately followed by a headache. There was no alteration of consciousness during visual aura, although sometimes the patient would have right-sided scalp tingling. These episodes were often unprovoked, but occasionally triggered by bright lights. A single routine EEG was unremarkable. The patient reported headaches without aura, but not aura without headaches, which made occipital lobe seizure less likely. MRI demonstrated a small herniation of brain parenchyma into the inner table of the left occipital bone (Figure 2). The patient was diagnosed with migraine with aura, and the semiology of the visual aura corresponded to the location of the herniation in the left occipital region.

Case 3

thegohubauososwotisibawridawegogihinechubroniwelashipheketauamamokubreketushithavephijibrujotobrelolaprohuthusovasweboclo

A 77-year-old male with a history of left ear diving injury presented with left-sided asymmetric hearing loss and word recognition difficulty for several years. MRI obtained as part of his work-up to evaluate for possible schwannoma of the eighth left cranial nerve instead demonstrated an incidental right cerebellar herniation within an arachnoid granulation into the diploic space of the occipital bone (Figure 3). The BHAG for this patient appeared to be an incidental finding unrelated to his asymmetric hearing loss.

Case 4

hekispanophikishuleclopamigicrutacraprewihusiphogestilepapuchislufrinuvacospatuvubewremitoswahotrobritrodri

A male aged 62 years with a history of metastatic esophageal cancer, substance abuse, and a prior presumed alcohol withdrawal seizure underwent an MRI for evaluation of brain metastasis after presenting to the hospital with confusion 1 day after starting chemotherapy (Figure 4). Nine years prior, the patient had an isolated generalized tonic-clonic seizure approximately 72 hours following a period of alcohol cessation. The MRI demonstrated an incidental left parasagittal herniation of left parietal lobe tissue through an arachnoid granulation into the superior sagittal sinus, in addition to metastatic brain lesions. An EEG showed mild encephalopathy without evidence of seizures. It was determined that the patient's confusion was most likely due to toxic-metabolic encephalopathy from chemotherapy.

Case 5

gebretaspauicrosaslukogokephatrushophispiswustupuswisluvibroshodr

A 51-year-old male presented with worsening headache severity and frequency. He had a history of chronic headaches for about 20 years that occurred annually, but were now occurring twice weekly. The headaches often started with a left eye visual aura followed by pressure in the left eye, left frontal region, and left ear, with at times a cervicogenic component. No cervical spine imaging was available. An MRI revealed 2 small adjacent areas of cerebellar herniation into arachnoid granulations in the left occipital bone (Figure 5).

Arachnoid granulations appear very early in life, although they are uncommon before age 2 years.² Classically, they have been understood to act as 1-way valves permitting the outflow of CSF from the subarachnoid space to the dural venous sinuses. However, increasing evidence shows they may only play a minor role in that process.¹² The structure of arachnoid granulations is being reexamined. A recent microscopy study demonstrated structural heterogeneity with a fine, porous lining that permits flow.¹³ Additionally, associated immune components in the microenvironment suggests that arachnoid granulations may function similarly to lymph nodes as part of a central nervous system lymphatic network.¹³ Evidence is lacking for arachnoid granulations being the primary route of CSF outflow, and newer models include CSF exit pathways along the cranial nerves and drainage through lymphatics within the dura mater.¹²

New MRI systems have demonstrated that the prevalence of arachnoid granulations increases with age. One study found that all subjects in the aged 40 years cohort had detectable arachnoid granulations on images obtained with a 3T MRI system, with the main site being the superior sagittal sinus.² The prevalence increased until age 40 years and then noticeably decreased. Not only did the prevalence increase in this pattern, but the total number of detectable arachnoid granulations followed a similar pattern.² In addition, the detectable arachnoid granulations tend to be larger in older patients. Arachnoid granulations are very common in adults, but little is known about when and why brain tissue herniates through these structures.

This case series illustrates how a small amount of adult cerebral or cerebellar matter in large arachnoid granulations can herniate into the dural sinuses and diploic space. Although arachnoid granulations extending into the dural sinuses and diploic space are a relatively common finding on MRI,BHAGs are rare in these locations.^1,2,8 Improved spatial resolution afforded by newer high-field scanners with thinner sections, such as very thin (1 mm) T1- and heavily T2-weighted 3 dimensional sequences may lead to increased detection of BHAG. Some of these herniations are small and may be easily missed or confused for normal arachnoid granulations on 3 to 5 mm thickness MRIs.

Despite increased recognition, it is still uncertain to what degree these herniations contribute to the clinical presentations. Associated neurologic symptoms may include seizures, headaches, tinnitus, syncope, and increased intracranial pressure.^7-10

Three cases presented in this article demonstrated abnormal signals adjacent to the herniated brain, presumably due to dysplasia of gliotic tissue. In 1 study, parenchymal signal and structural changes occurred in about one-half of the reported BHAG, all of which were cerebellar herniations.⁷ In Case 1, the herniation and adjacent abnormal MRI signal corresponded to localization of the seizure semiology as obtained from patient history, strongly suggesting the BHAG played a role in the presentation. Signal abnormality accompanying an adjacent BHAG may suggest a higher likelihood that the BHAG has clinical relevance. However, the patient in Case 2 had a visual aura that corresponded to the BHAG location, so a signal abnormality may not be necessary for a patient to develop symptoms. Case 1 also included a history of documented traumatic brain injuries, suggesting that perhaps head trauma may facilitate BHAG development. Regardless, there is likely also a congenital component to their formation, as BHAG has been observed in the pediatric population.¹⁴

The patient's asymmetric left-sided hearing loss in Case 3 appeared unrelated to the BHAG as its location was in the contralateral cerebellar region and did not correspond to the patient’s clinical findings. The patient in Case 4 had a limited history regarding localization details of their prior presumed alcohol withdrawal seizure, such as head movements, eye deviation, or lateralized onset of convulsions. Given this limited data, it is unclear whether their prior seizure could have been related to BHAG or not. The patient in case 5 reported worsening headaches on the left side of his head, which corresponded to BHAG occurring on the left side. However, given that the increased T2 signal occurred in the left cerebellar hemisphere with BHAG in the left occipital bone, the occipital cortex was not involved. In this case, the BHAG would not explain the patient’s visual aura as such a lesion would have been expected in the right occipital cortex rather than its actual location in this patient’s left cerebellar hemisphere.

CONCLUSIONS

Understanding the clinical impact of brain herniations is important because they are probably more common than previously thought. Improved MRI capabilities suggest that more BHAG will be detected moving forward as radiologists interpret images with higher resolution and thinner slices. Until its significance is fully understood, BHAG will continue to complicate the diagnosis of patients with neurologic complaints whose brain MRIs and EEGs are otherwise unremarkable.

drophawulusateluwuphuslospaneueslerawrorujap

There have been no cases of surgical BHAG intervention and pathology analysis that would help determine their clinical significance. A related entity, temporal lobe encephalocele, has been linked to focal temporal lobe epilepsy, which has demonstrated significant symptom improvement following surgical correction.¹⁵ However, encephaloceles have been distinguished from BHAG in part because they do not necessarily herniate through an arachnoid granulation.⁸ BHAG has only begun to be characterized in detail over the last decade, so more research is needed to understand how it develops and what clinical significance it truly holds.

The circulation of cerebrospinal fluid (CSF) is crucial for maintaining homeostasis for the optimal functioning of the multiple complex activities of the brain and spinal cord, including the disposal of metabolic waste products of brain and spinal cord activity into the cerebral venous drainage. Throughout the brain, the arachnoid mater forms small outpouchings or diverticula that penetrate the dura mater and communicate with the dural venous sinuses. These outpuchings are called arachnoid granulations or arachnoid villi, and most are found within the dural sinuses, primarily in the transverse sinuses and superior sagittal sinus, but can occasionally be seen extending into the inner table of the calvarium.^1,2

wekituuistec

The amount of arachnoid granulations seen in bone, particularly around the superior sagittal sinus, may increase with age.² Arachnoid granulations are generally small but the largest ones can be seen on gross examination during intracranial procedures or autopsy.³ Magnetic resonance imaging (MRI) can detect arachnoid granulations, which are characterized as T1 hypointense and T2 hyperintense (CSF isointense), well-circumscribed, small, nonenhancing masses within the dural sinuses or in the diploic space (Figure 1). Even small arachnoid granulations < 1 mm in length can be detected.²

Smaller arachnoid granulations have been described histologically as entirely covered by a dural membrane, thus creating a subdural space that separates the body of the arachnoid granulation from the lumen of the accompanying venous sinus.⁴ However, larger arachnoid granulations may not be completely covered by a dural membrane, thus creating a point of contact between the arachnoid granulation and the venous sinus.⁴ Larger arachnoid granulations are normally filled with CSF, and their signal characteristics are similar to CSF on imaging.^5,6 Arachnoid granulations also often contain vessels draining into the adjacent venous sinus.^5,6

When larger arachnoid granulations are present, they may permit the protrusion of herniated brain tissue. There has been an increasing number of reports of these brain herniations into arachnoid granulations (BHAGs) in the literature.^7-10 While these herniations have been associated with nonspecific neurologic symptoms like tinnitus and idiopathic intracranial hypertension, their true clinical significance remains undetermined.^10,11 This article presents 5 cases of BHAG, discusses their clinical presentations and image findings, and reviews the current literature.

Case 1

A 30-year-old male with a history of multiple traumatic brain injuries presented for evaluation of seizures. The patient described the semiology of the seizures as a bright, colorful light in his right visual field, followed by loss of vision, then loss of awareness and full body convulsion. The semiology of this patient’s seizures was consistent with left temporo-occipital lobe seizure. The only abnormality seen in the brain MRI was the herniation of brain parenchyma originating from the occipital lobe into the transverse sinus, presumably through an arachnoid granulation (Figure 1). An electroencephalogram (EEG) was unremarkable, though the semiology of the seizure historically described by the patient was localized to the area of BHAG. The patient is currently taking antiseizure medications and has experienced no additional seizures.

Case 2

spuuujirenauocrecebresheclospemiwatecleticlalacrofrefranebriswamafrowiga

A male aged 53 years with a history of peripheral artery disease presented with a 6-month history of headaches and dizziness. The patient reported the onset of visual aura to his right visual field, starting as a fingernail-sized scintillating kaleidoscope light that would gradually increase in size to a round shape with fading kaleidoscope colors. This episode would last for a few minutes and was immediately followed by a headache. There was no alteration of consciousness during visual aura, although sometimes the patient would have right-sided scalp tingling. These episodes were often unprovoked, but occasionally triggered by bright lights. A single routine EEG was unremarkable. The patient reported headaches without aura, but not aura without headaches, which made occipital lobe seizure less likely. MRI demonstrated a small herniation of brain parenchyma into the inner table of the left occipital bone (Figure 2). The patient was diagnosed with migraine with aura, and the semiology of the visual aura corresponded to the location of the herniation in the left occipital region.

Case 3

thegohubauososwotisibawridawegogihinechubroniwelashipheketauamamokubreketushithavephijibrujotobrelolaprohuthusovasweboclo

A 77-year-old male with a history of left ear diving injury presented with left-sided asymmetric hearing loss and word recognition difficulty for several years. MRI obtained as part of his work-up to evaluate for possible schwannoma of the eighth left cranial nerve instead demonstrated an incidental right cerebellar herniation within an arachnoid granulation into the diploic space of the occipital bone (Figure 3). The BHAG for this patient appeared to be an incidental finding unrelated to his asymmetric hearing loss.

Case 4

hekispanophikishuleclopamigicrutacraprewihusiphogestilepapuchislufrinuvacospatuvubewremitoswahotrobritrodri

A male aged 62 years with a history of metastatic esophageal cancer, substance abuse, and a prior presumed alcohol withdrawal seizure underwent an MRI for evaluation of brain metastasis after presenting to the hospital with confusion 1 day after starting chemotherapy (Figure 4). Nine years prior, the patient had an isolated generalized tonic-clonic seizure approximately 72 hours following a period of alcohol cessation. The MRI demonstrated an incidental left parasagittal herniation of left parietal lobe tissue through an arachnoid granulation into the superior sagittal sinus, in addition to metastatic brain lesions. An EEG showed mild encephalopathy without evidence of seizures. It was determined that the patient's confusion was most likely due to toxic-metabolic encephalopathy from chemotherapy.

Case 5

gebretaspauicrosaslukogokephatrushophispiswustupuswisluvibroshodr

A 51-year-old male presented with worsening headache severity and frequency. He had a history of chronic headaches for about 20 years that occurred annually, but were now occurring twice weekly. The headaches often started with a left eye visual aura followed by pressure in the left eye, left frontal region, and left ear, with at times a cervicogenic component. No cervical spine imaging was available. An MRI revealed 2 small adjacent areas of cerebellar herniation into arachnoid granulations in the left occipital bone (Figure 5).

Arachnoid granulations appear very early in life, although they are uncommon before age 2 years.² Classically, they have been understood to act as 1-way valves permitting the outflow of CSF from the subarachnoid space to the dural venous sinuses. However, increasing evidence shows they may only play a minor role in that process.¹² The structure of arachnoid granulations is being reexamined. A recent microscopy study demonstrated structural heterogeneity with a fine, porous lining that permits flow.¹³ Additionally, associated immune components in the microenvironment suggests that arachnoid granulations may function similarly to lymph nodes as part of a central nervous system lymphatic network.¹³ Evidence is lacking for arachnoid granulations being the primary route of CSF outflow, and newer models include CSF exit pathways along the cranial nerves and drainage through lymphatics within the dura mater.¹²

New MRI systems have demonstrated that the prevalence of arachnoid granulations increases with age. One study found that all subjects in the aged 40 years cohort had detectable arachnoid granulations on images obtained with a 3T MRI system, with the main site being the superior sagittal sinus.² The prevalence increased until age 40 years and then noticeably decreased. Not only did the prevalence increase in this pattern, but the total number of detectable arachnoid granulations followed a similar pattern.² In addition, the detectable arachnoid granulations tend to be larger in older patients. Arachnoid granulations are very common in adults, but little is known about when and why brain tissue herniates through these structures.

This case series illustrates how a small amount of adult cerebral or cerebellar matter in large arachnoid granulations can herniate into the dural sinuses and diploic space. Although arachnoid granulations extending into the dural sinuses and diploic space are a relatively common finding on MRI,BHAGs are rare in these locations.^1,2,8 Improved spatial resolution afforded by newer high-field scanners with thinner sections, such as very thin (1 mm) T1- and heavily T2-weighted 3 dimensional sequences may lead to increased detection of BHAG. Some of these herniations are small and may be easily missed or confused for normal arachnoid granulations on 3 to 5 mm thickness MRIs.

Despite increased recognition, it is still uncertain to what degree these herniations contribute to the clinical presentations. Associated neurologic symptoms may include seizures, headaches, tinnitus, syncope, and increased intracranial pressure.^7-10

Three cases presented in this article demonstrated abnormal signals adjacent to the herniated brain, presumably due to dysplasia of gliotic tissue. In 1 study, parenchymal signal and structural changes occurred in about one-half of the reported BHAG, all of which were cerebellar herniations.⁷ In Case 1, the herniation and adjacent abnormal MRI signal corresponded to localization of the seizure semiology as obtained from patient history, strongly suggesting the BHAG played a role in the presentation. Signal abnormality accompanying an adjacent BHAG may suggest a higher likelihood that the BHAG has clinical relevance. However, the patient in Case 2 had a visual aura that corresponded to the BHAG location, so a signal abnormality may not be necessary for a patient to develop symptoms. Case 1 also included a history of documented traumatic brain injuries, suggesting that perhaps head trauma may facilitate BHAG development. Regardless, there is likely also a congenital component to their formation, as BHAG has been observed in the pediatric population.¹⁴

The patient's asymmetric left-sided hearing loss in Case 3 appeared unrelated to the BHAG as its location was in the contralateral cerebellar region and did not correspond to the patient’s clinical findings. The patient in Case 4 had a limited history regarding localization details of their prior presumed alcohol withdrawal seizure, such as head movements, eye deviation, or lateralized onset of convulsions. Given this limited data, it is unclear whether their prior seizure could have been related to BHAG or not. The patient in case 5 reported worsening headaches on the left side of his head, which corresponded to BHAG occurring on the left side. However, given that the increased T2 signal occurred in the left cerebellar hemisphere with BHAG in the left occipital bone, the occipital cortex was not involved. In this case, the BHAG would not explain the patient’s visual aura as such a lesion would have been expected in the right occipital cortex rather than its actual location in this patient’s left cerebellar hemisphere.

CONCLUSIONS

Understanding the clinical impact of brain herniations is important because they are probably more common than previously thought. Improved MRI capabilities suggest that more BHAG will be detected moving forward as radiologists interpret images with higher resolution and thinner slices. Until its significance is fully understood, BHAG will continue to complicate the diagnosis of patients with neurologic complaints whose brain MRIs and EEGs are otherwise unremarkable.

drophawulusateluwuphuslospaneueslerawrorujap

There have been no cases of surgical BHAG intervention and pathology analysis that would help determine their clinical significance. A related entity, temporal lobe encephalocele, has been linked to focal temporal lobe epilepsy, which has demonstrated significant symptom improvement following surgical correction.¹⁵ However, encephaloceles have been distinguished from BHAG in part because they do not necessarily herniate through an arachnoid granulation.⁸ BHAG has only begun to be characterized in detail over the last decade, so more research is needed to understand how it develops and what clinical significance it truly holds.

The circulation of cerebrospinal fluid (CSF) is crucial for maintaining homeostasis for the optimal functioning of the multiple complex activities of the brain and spinal cord, including the disposal of metabolic waste products of brain and spinal cord activity into the cerebral venous drainage. Throughout the brain, the arachnoid mater forms small outpouchings or diverticula that penetrate the dura mater and communicate with the dural venous sinuses. These outpuchings are called arachnoid granulations or arachnoid villi, and most are found within the dural sinuses, primarily in the transverse sinuses and superior sagittal sinus, but can occasionally be seen extending into the inner table of the calvarium.^1,2

wekituuistec

The amount of arachnoid granulations seen in bone, particularly around the superior sagittal sinus, may increase with age.² Arachnoid granulations are generally small but the largest ones can be seen on gross examination during intracranial procedures or autopsy.³ Magnetic resonance imaging (MRI) can detect arachnoid granulations, which are characterized as T1 hypointense and T2 hyperintense (CSF isointense), well-circumscribed, small, nonenhancing masses within the dural sinuses or in the diploic space (Figure 1). Even small arachnoid granulations < 1 mm in length can be detected.²

Smaller arachnoid granulations have been described histologically as entirely covered by a dural membrane, thus creating a subdural space that separates the body of the arachnoid granulation from the lumen of the accompanying venous sinus.⁴ However, larger arachnoid granulations may not be completely covered by a dural membrane, thus creating a point of contact between the arachnoid granulation and the venous sinus.⁴ Larger arachnoid granulations are normally filled with CSF, and their signal characteristics are similar to CSF on imaging.^5,6 Arachnoid granulations also often contain vessels draining into the adjacent venous sinus.^5,6

When larger arachnoid granulations are present, they may permit the protrusion of herniated brain tissue. There has been an increasing number of reports of these brain herniations into arachnoid granulations (BHAGs) in the literature.^7-10 While these herniations have been associated with nonspecific neurologic symptoms like tinnitus and idiopathic intracranial hypertension, their true clinical significance remains undetermined.^10,11 This article presents 5 cases of BHAG, discusses their clinical presentations and image findings, and reviews the current literature.

Case 1

A 30-year-old male with a history of multiple traumatic brain injuries presented for evaluation of seizures. The patient described the semiology of the seizures as a bright, colorful light in his right visual field, followed by loss of vision, then loss of awareness and full body convulsion. The semiology of this patient’s seizures was consistent with left temporo-occipital lobe seizure. The only abnormality seen in the brain MRI was the herniation of brain parenchyma originating from the occipital lobe into the transverse sinus, presumably through an arachnoid granulation (Figure 1). An electroencephalogram (EEG) was unremarkable, though the semiology of the seizure historically described by the patient was localized to the area of BHAG. The patient is currently taking antiseizure medications and has experienced no additional seizures.

Case 2

spuuujirenauocrecebresheclospemiwatecleticlalacrofrefranebriswamafrowiga

A male aged 53 years with a history of peripheral artery disease presented with a 6-month history of headaches and dizziness. The patient reported the onset of visual aura to his right visual field, starting as a fingernail-sized scintillating kaleidoscope light that would gradually increase in size to a round shape with fading kaleidoscope colors. This episode would last for a few minutes and was immediately followed by a headache. There was no alteration of consciousness during visual aura, although sometimes the patient would have right-sided scalp tingling. These episodes were often unprovoked, but occasionally triggered by bright lights. A single routine EEG was unremarkable. The patient reported headaches without aura, but not aura without headaches, which made occipital lobe seizure less likely. MRI demonstrated a small herniation of brain parenchyma into the inner table of the left occipital bone (Figure 2). The patient was diagnosed with migraine with aura, and the semiology of the visual aura corresponded to the location of the herniation in the left occipital region.

Case 3

thegohubauososwotisibawridawegogihinechubroniwelashipheketauamamokubreketushithavephijibrujotobrelolaprohuthusovasweboclo

A 77-year-old male with a history of left ear diving injury presented with left-sided asymmetric hearing loss and word recognition difficulty for several years. MRI obtained as part of his work-up to evaluate for possible schwannoma of the eighth left cranial nerve instead demonstrated an incidental right cerebellar herniation within an arachnoid granulation into the diploic space of the occipital bone (Figure 3). The BHAG for this patient appeared to be an incidental finding unrelated to his asymmetric hearing loss.

Case 4

hekispanophikishuleclopamigicrutacraprewihusiphogestilepapuchislufrinuvacospatuvubewremitoswahotrobritrodri

A male aged 62 years with a history of metastatic esophageal cancer, substance abuse, and a prior presumed alcohol withdrawal seizure underwent an MRI for evaluation of brain metastasis after presenting to the hospital with confusion 1 day after starting chemotherapy (Figure 4). Nine years prior, the patient had an isolated generalized tonic-clonic seizure approximately 72 hours following a period of alcohol cessation. The MRI demonstrated an incidental left parasagittal herniation of left parietal lobe tissue through an arachnoid granulation into the superior sagittal sinus, in addition to metastatic brain lesions. An EEG showed mild encephalopathy without evidence of seizures. It was determined that the patient's confusion was most likely due to toxic-metabolic encephalopathy from chemotherapy.

Case 5

gebretaspauicrosaslukogokephatrushophispiswustupuswisluvibroshodr

A 51-year-old male presented with worsening headache severity and frequency. He had a history of chronic headaches for about 20 years that occurred annually, but were now occurring twice weekly. The headaches often started with a left eye visual aura followed by pressure in the left eye, left frontal region, and left ear, with at times a cervicogenic component. No cervical spine imaging was available. An MRI revealed 2 small adjacent areas of cerebellar herniation into arachnoid granulations in the left occipital bone (Figure 5).

Arachnoid granulations appear very early in life, although they are uncommon before age 2 years.² Classically, they have been understood to act as 1-way valves permitting the outflow of CSF from the subarachnoid space to the dural venous sinuses. However, increasing evidence shows they may only play a minor role in that process.¹² The structure of arachnoid granulations is being reexamined. A recent microscopy study demonstrated structural heterogeneity with a fine, porous lining that permits flow.¹³ Additionally, associated immune components in the microenvironment suggests that arachnoid granulations may function similarly to lymph nodes as part of a central nervous system lymphatic network.¹³ Evidence is lacking for arachnoid granulations being the primary route of CSF outflow, and newer models include CSF exit pathways along the cranial nerves and drainage through lymphatics within the dura mater.¹²

New MRI systems have demonstrated that the prevalence of arachnoid granulations increases with age. One study found that all subjects in the aged 40 years cohort had detectable arachnoid granulations on images obtained with a 3T MRI system, with the main site being the superior sagittal sinus.² The prevalence increased until age 40 years and then noticeably decreased. Not only did the prevalence increase in this pattern, but the total number of detectable arachnoid granulations followed a similar pattern.² In addition, the detectable arachnoid granulations tend to be larger in older patients. Arachnoid granulations are very common in adults, but little is known about when and why brain tissue herniates through these structures.

This case series illustrates how a small amount of adult cerebral or cerebellar matter in large arachnoid granulations can herniate into the dural sinuses and diploic space. Although arachnoid granulations extending into the dural sinuses and diploic space are a relatively common finding on MRI,BHAGs are rare in these locations.^1,2,8 Improved spatial resolution afforded by newer high-field scanners with thinner sections, such as very thin (1 mm) T1- and heavily T2-weighted 3 dimensional sequences may lead to increased detection of BHAG. Some of these herniations are small and may be easily missed or confused for normal arachnoid granulations on 3 to 5 mm thickness MRIs.

Despite increased recognition, it is still uncertain to what degree these herniations contribute to the clinical presentations. Associated neurologic symptoms may include seizures, headaches, tinnitus, syncope, and increased intracranial pressure.^7-10

Three cases presented in this article demonstrated abnormal signals adjacent to the herniated brain, presumably due to dysplasia of gliotic tissue. In 1 study, parenchymal signal and structural changes occurred in about one-half of the reported BHAG, all of which were cerebellar herniations.⁷ In Case 1, the herniation and adjacent abnormal MRI signal corresponded to localization of the seizure semiology as obtained from patient history, strongly suggesting the BHAG played a role in the presentation. Signal abnormality accompanying an adjacent BHAG may suggest a higher likelihood that the BHAG has clinical relevance. However, the patient in Case 2 had a visual aura that corresponded to the BHAG location, so a signal abnormality may not be necessary for a patient to develop symptoms. Case 1 also included a history of documented traumatic brain injuries, suggesting that perhaps head trauma may facilitate BHAG development. Regardless, there is likely also a congenital component to their formation, as BHAG has been observed in the pediatric population.¹⁴

The patient's asymmetric left-sided hearing loss in Case 3 appeared unrelated to the BHAG as its location was in the contralateral cerebellar region and did not correspond to the patient’s clinical findings. The patient in Case 4 had a limited history regarding localization details of their prior presumed alcohol withdrawal seizure, such as head movements, eye deviation, or lateralized onset of convulsions. Given this limited data, it is unclear whether their prior seizure could have been related to BHAG or not. The patient in case 5 reported worsening headaches on the left side of his head, which corresponded to BHAG occurring on the left side. However, given that the increased T2 signal occurred in the left cerebellar hemisphere with BHAG in the left occipital bone, the occipital cortex was not involved. In this case, the BHAG would not explain the patient’s visual aura as such a lesion would have been expected in the right occipital cortex rather than its actual location in this patient’s left cerebellar hemisphere.

CONCLUSIONS

Understanding the clinical impact of brain herniations is important because they are probably more common than previously thought. Improved MRI capabilities suggest that more BHAG will be detected moving forward as radiologists interpret images with higher resolution and thinner slices. Until its significance is fully understood, BHAG will continue to complicate the diagnosis of patients with neurologic complaints whose brain MRIs and EEGs are otherwise unremarkable.

drophawulusateluwuphuslospaneueslerawrorujap

There have been no cases of surgical BHAG intervention and pathology analysis that would help determine their clinical significance. A related entity, temporal lobe encephalocele, has been linked to focal temporal lobe epilepsy, which has demonstrated significant symptom improvement following surgical correction.¹⁵ However, encephaloceles have been distinguished from BHAG in part because they do not necessarily herniate through an arachnoid granulation.⁸ BHAG has only begun to be characterized in detail over the last decade, so more research is needed to understand how it develops and what clinical significance it truly holds.

Allergic rhinoconjunctivitis causes onerous symptoms of sneezing, rhinorrhea, postnasal drip, nasal congestion, and itchy, watery eyes. It is a common condition that affects 10% to 25% of the US population and up to 23% of military members with increased symptoms during deployments.^1-3 Allergen immunotherapy (AIT), commonly known as allergy shots, is an effective treatment for allergic rhinoconjunctivitis, especially for patients whose symptoms are not controlled by allergy medications.⁴ Many military personnel who would like to receive AIT cannot continue with their immunotherapy because of frequent moves, deployments, and temporary duty assignments. This case report highlights the difficulty of managing AIT in the Military Health System.

Case Presentation

A 34-year-old active-duty US Air Force male surgeon with a medical history of allergic rhinoconjunctivitis was referred to the allergy clinic for evaluation and consideration of AIT. His symptoms included rhinorrhea, sneezing, nasal congestion, and itchy, watery eyes. The symptoms had been present for several years, occurring predominantly in the spring and fall, but also perennially when exposed to animals such as cats, dogs, and horses. The patient was raised on a ranch where he was exposed to these animals.

The patient had prior skin testing at the University of Nebraska Medical Center (UNMC) for aeroallergens and was positive for trees, grasses, weeds, molds, dust mites, cats, dogs, and horses. He received AIT at UNMC with great success for18 months. Regrettably, the patient discontinued AIT following a military move to Keesler Air Force Base in Mississippi. The patient’s examination was notable for injected conjunctiva, nasal mucosa edema, and a cobblestone throat. His symptoms were not alleviated with oral cetirizine and nasal fluticasone.

dasiherurawenavuphutechodrineswejunuspestospechauotrachebrurogimecroshochishewucaprapubrethetoceuugeshaphemephuhibuswekospiphoshotrophetra

His skin testing was positive for trees, weeds, mold, cats, dogs, dust mites, and horsehair (Table). The risks and benefits of AIT were discussed with the patient, who elected to proceed with restarting AIT and received counseling on aeroallergen avoidance. The patient was unable to continue AIT at Keesler Medical Center because of a military deployment.

Discussion

There are several barriers to receiving AIT for active-duty patients with allergies. Due to previous skin test extracts, our patient had become desensitized to them. Though he had received aeroallergen immunotherapy with success for 18 months, the patients had to restart the build up phase of AIT due to a military-related move.

For patients to benefit from AIT, they must build up and maintain their immunotherapy injections for at least 3 to 5 years.⁴ The build-up period of immunotherapy lasts about 3 to 4 months. Patients typically receive weekly injections until they reach a maintenance immunotherapy dose of 0.5 mL of a 1:1 concentration ratio.⁴

Frequent deployments or temporary duty assignments are other barriers to AIT for active-duty patients. AIT is not usually given on deployments or temporary duty assignments unless the patient is located near a major military medical center. The US Air Force and Army operate allergy extender clinics at smaller bases and overseas locations to facilitate the maintenance of immunotherapy for military patients. Primary care physicians act as allergy extenders. These smaller allergy clinics are supervised by regional allergists at major military medical centers via telehealth and electronic/telephonic communication. These allergy clinics are not more widely available because there are not enough allergists and allergy medical technicians.

Allergen immunotherapy is not standardized, meaning civilian allergists use different aeroallergen immunotherapy formulations. While AIT is standardized in the US military through the Extract Laboratory Management System (ELMS), many active-duty patients are evaluated by civilian allergists in the TRICARE system who do not use ELMS, and when they move, AIT is not maintained.

Because up to 25% of active-duty personnel suffer from allergic rhinoconjunctivitis and AIT is not administered in many deployed settings, this issue could affect mission readiness and capabilities.^3-6 These personnel may suffer from frequent and severe nasal and ocular allergy symptoms without being able to continue AIT. There is the potential for adverse effects on the military missions because of these impaired military personnel.^5,6

Potential steps to improve the availability of allergen immunotherapy in the deployed setting include training deployed physicians, medical technicians, and other health care practitioners in administering and treating AIT so deployed personnel can receive therapy. Additionally, AIT should be standardized and ordered via the ELMS. Civilian allergists should be highly encouraged to use ELMS. This would create standardization of AIT for all active-duty allergy patients. The allergy extender system could be expanded to all military treatment facilities to provide easy access to allergen immunotherapy. The US Navy has the fewest allergists and allergy extenders, and would need to expand its network of allergy extenders to provide AIT at its health care facilities.

Conclusions

We present an active-duty servicemember with allergic rhinoconjunctivitis to trees, grasses, weeds, cats, dogs, dust mites, mold, and horses who had intermittent therapy that was interrupted by deployments. Our case highlights the difficulty of managing AIT in the military health system due to frequent moves, deployments, and temporary duty assignments. We also suggest steps that could help expand AIT for military personnel, including those deployed internationally.

Allergic rhinoconjunctivitis causes onerous symptoms of sneezing, rhinorrhea, postnasal drip, nasal congestion, and itchy, watery eyes. It is a common condition that affects 10% to 25% of the US population and up to 23% of military members with increased symptoms during deployments.^1-3 Allergen immunotherapy (AIT), commonly known as allergy shots, is an effective treatment for allergic rhinoconjunctivitis, especially for patients whose symptoms are not controlled by allergy medications.⁴ Many military personnel who would like to receive AIT cannot continue with their immunotherapy because of frequent moves, deployments, and temporary duty assignments. This case report highlights the difficulty of managing AIT in the Military Health System.

Case Presentation

A 34-year-old active-duty US Air Force male surgeon with a medical history of allergic rhinoconjunctivitis was referred to the allergy clinic for evaluation and consideration of AIT. His symptoms included rhinorrhea, sneezing, nasal congestion, and itchy, watery eyes. The symptoms had been present for several years, occurring predominantly in the spring and fall, but also perennially when exposed to animals such as cats, dogs, and horses. The patient was raised on a ranch where he was exposed to these animals.

The patient had prior skin testing at the University of Nebraska Medical Center (UNMC) for aeroallergens and was positive for trees, grasses, weeds, molds, dust mites, cats, dogs, and horses. He received AIT at UNMC with great success for18 months. Regrettably, the patient discontinued AIT following a military move to Keesler Air Force Base in Mississippi. The patient’s examination was notable for injected conjunctiva, nasal mucosa edema, and a cobblestone throat. His symptoms were not alleviated with oral cetirizine and nasal fluticasone.

dasiherurawenavuphutechodrineswejunuspestospechauotrachebrurogimecroshochishewucaprapubrethetoceuugeshaphemephuhibuswekospiphoshotrophetra

His skin testing was positive for trees, weeds, mold, cats, dogs, dust mites, and horsehair (Table). The risks and benefits of AIT were discussed with the patient, who elected to proceed with restarting AIT and received counseling on aeroallergen avoidance. The patient was unable to continue AIT at Keesler Medical Center because of a military deployment.

Discussion

There are several barriers to receiving AIT for active-duty patients with allergies. Due to previous skin test extracts, our patient had become desensitized to them. Though he had received aeroallergen immunotherapy with success for 18 months, the patients had to restart the build up phase of AIT due to a military-related move.

For patients to benefit from AIT, they must build up and maintain their immunotherapy injections for at least 3 to 5 years.⁴ The build-up period of immunotherapy lasts about 3 to 4 months. Patients typically receive weekly injections until they reach a maintenance immunotherapy dose of 0.5 mL of a 1:1 concentration ratio.⁴

Frequent deployments or temporary duty assignments are other barriers to AIT for active-duty patients. AIT is not usually given on deployments or temporary duty assignments unless the patient is located near a major military medical center. The US Air Force and Army operate allergy extender clinics at smaller bases and overseas locations to facilitate the maintenance of immunotherapy for military patients. Primary care physicians act as allergy extenders. These smaller allergy clinics are supervised by regional allergists at major military medical centers via telehealth and electronic/telephonic communication. These allergy clinics are not more widely available because there are not enough allergists and allergy medical technicians.

Allergen immunotherapy is not standardized, meaning civilian allergists use different aeroallergen immunotherapy formulations. While AIT is standardized in the US military through the Extract Laboratory Management System (ELMS), many active-duty patients are evaluated by civilian allergists in the TRICARE system who do not use ELMS, and when they move, AIT is not maintained.

Because up to 25% of active-duty personnel suffer from allergic rhinoconjunctivitis and AIT is not administered in many deployed settings, this issue could affect mission readiness and capabilities.^3-6 These personnel may suffer from frequent and severe nasal and ocular allergy symptoms without being able to continue AIT. There is the potential for adverse effects on the military missions because of these impaired military personnel.^5,6

Potential steps to improve the availability of allergen immunotherapy in the deployed setting include training deployed physicians, medical technicians, and other health care practitioners in administering and treating AIT so deployed personnel can receive therapy. Additionally, AIT should be standardized and ordered via the ELMS. Civilian allergists should be highly encouraged to use ELMS. This would create standardization of AIT for all active-duty allergy patients. The allergy extender system could be expanded to all military treatment facilities to provide easy access to allergen immunotherapy. The US Navy has the fewest allergists and allergy extenders, and would need to expand its network of allergy extenders to provide AIT at its health care facilities.

Conclusions

We present an active-duty servicemember with allergic rhinoconjunctivitis to trees, grasses, weeds, cats, dogs, dust mites, mold, and horses who had intermittent therapy that was interrupted by deployments. Our case highlights the difficulty of managing AIT in the military health system due to frequent moves, deployments, and temporary duty assignments. We also suggest steps that could help expand AIT for military personnel, including those deployed internationally.

Allergic rhinoconjunctivitis causes onerous symptoms of sneezing, rhinorrhea, postnasal drip, nasal congestion, and itchy, watery eyes. It is a common condition that affects 10% to 25% of the US population and up to 23% of military members with increased symptoms during deployments.^1-3 Allergen immunotherapy (AIT), commonly known as allergy shots, is an effective treatment for allergic rhinoconjunctivitis, especially for patients whose symptoms are not controlled by allergy medications.⁴ Many military personnel who would like to receive AIT cannot continue with their immunotherapy because of frequent moves, deployments, and temporary duty assignments. This case report highlights the difficulty of managing AIT in the Military Health System.

Case Presentation

A 34-year-old active-duty US Air Force male surgeon with a medical history of allergic rhinoconjunctivitis was referred to the allergy clinic for evaluation and consideration of AIT. His symptoms included rhinorrhea, sneezing, nasal congestion, and itchy, watery eyes. The symptoms had been present for several years, occurring predominantly in the spring and fall, but also perennially when exposed to animals such as cats, dogs, and horses. The patient was raised on a ranch where he was exposed to these animals.

The patient had prior skin testing at the University of Nebraska Medical Center (UNMC) for aeroallergens and was positive for trees, grasses, weeds, molds, dust mites, cats, dogs, and horses. He received AIT at UNMC with great success for18 months. Regrettably, the patient discontinued AIT following a military move to Keesler Air Force Base in Mississippi. The patient’s examination was notable for injected conjunctiva, nasal mucosa edema, and a cobblestone throat. His symptoms were not alleviated with oral cetirizine and nasal fluticasone.

dasiherurawenavuphutechodrineswejunuspestospechauotrachebrurogimecroshochishewucaprapubrethetoceuugeshaphemephuhibuswekospiphoshotrophetra

His skin testing was positive for trees, weeds, mold, cats, dogs, dust mites, and horsehair (Table). The risks and benefits of AIT were discussed with the patient, who elected to proceed with restarting AIT and received counseling on aeroallergen avoidance. The patient was unable to continue AIT at Keesler Medical Center because of a military deployment.

Discussion

There are several barriers to receiving AIT for active-duty patients with allergies. Due to previous skin test extracts, our patient had become desensitized to them. Though he had received aeroallergen immunotherapy with success for 18 months, the patients had to restart the build up phase of AIT due to a military-related move.

For patients to benefit from AIT, they must build up and maintain their immunotherapy injections for at least 3 to 5 years.⁴ The build-up period of immunotherapy lasts about 3 to 4 months. Patients typically receive weekly injections until they reach a maintenance immunotherapy dose of 0.5 mL of a 1:1 concentration ratio.⁴

Frequent deployments or temporary duty assignments are other barriers to AIT for active-duty patients. AIT is not usually given on deployments or temporary duty assignments unless the patient is located near a major military medical center. The US Air Force and Army operate allergy extender clinics at smaller bases and overseas locations to facilitate the maintenance of immunotherapy for military patients. Primary care physicians act as allergy extenders. These smaller allergy clinics are supervised by regional allergists at major military medical centers via telehealth and electronic/telephonic communication. These allergy clinics are not more widely available because there are not enough allergists and allergy medical technicians.

Allergen immunotherapy is not standardized, meaning civilian allergists use different aeroallergen immunotherapy formulations. While AIT is standardized in the US military through the Extract Laboratory Management System (ELMS), many active-duty patients are evaluated by civilian allergists in the TRICARE system who do not use ELMS, and when they move, AIT is not maintained.

Because up to 25% of active-duty personnel suffer from allergic rhinoconjunctivitis and AIT is not administered in many deployed settings, this issue could affect mission readiness and capabilities.^3-6 These personnel may suffer from frequent and severe nasal and ocular allergy symptoms without being able to continue AIT. There is the potential for adverse effects on the military missions because of these impaired military personnel.^5,6

Potential steps to improve the availability of allergen immunotherapy in the deployed setting include training deployed physicians, medical technicians, and other health care practitioners in administering and treating AIT so deployed personnel can receive therapy. Additionally, AIT should be standardized and ordered via the ELMS. Civilian allergists should be highly encouraged to use ELMS. This would create standardization of AIT for all active-duty allergy patients. The allergy extender system could be expanded to all military treatment facilities to provide easy access to allergen immunotherapy. The US Navy has the fewest allergists and allergy extenders, and would need to expand its network of allergy extenders to provide AIT at its health care facilities.

Conclusions

We present an active-duty servicemember with allergic rhinoconjunctivitis to trees, grasses, weeds, cats, dogs, dust mites, mold, and horses who had intermittent therapy that was interrupted by deployments. Our case highlights the difficulty of managing AIT in the military health system due to frequent moves, deployments, and temporary duty assignments. We also suggest steps that could help expand AIT for military personnel, including those deployed internationally.

Rosai Dorfman disease (RDD) is a rare non-Langerhans cell histiocytosis first described in 1965 by Destombes and again in 1969 by Rosai and Dorfman to depict patients who presented with massive cervical lymphadenopathy.¹ The classification for histiocytosis was revised in 2016 based on new insights into the pathologic, genetic, and molecular features of RDD.^2,3 Now, RDD is listed under the R group, which includes familial, sporadic, classical (nodal), extranodal RDD, and other noncutaneous, non-Langerhans cell histiocytosis.³ Cutaneous RDD is classified under the C group and typically presents as painless papules, plaques, or nodules without significant lymphadenopathy, or systemic symptoms usually seen in the presentation of RDD.⁴

The etiology of RDD is poorly understood, although an underlying infectious or genetic component is suspected.⁵ Several pathogens—including human herpesvirus 6, parvovirus B19, Epstein-Barr virus, cytomegalovirus, Brucella, and Klebsiella—have all been investigated. A link to kinase mutations has been described in nodal and extranodal RDD; however, the molecular profile of cutaneous RDD remains unknown.² Histologic findings for RDD typically include cells that are S100 positive, CD68 positive, and CD163 positive, and CD1a and langerin (CD207) negative, thus excluding Langerhans cell histiocytosis.² The hallmark finding of RDD is emperipolesis, which results from “histiocyte-mediated phagocytosis of intact lymphocytes and other immune cells.”⁶ Immunoglobulin G (Ig) G4-positive plasma cells are also common, but the significance of this finding is controversial. We present a case of a patient with recurrent RDD within a right medial thigh lipoma and include a literature review to explore the significance of histologic findings and various treatment options in the setting of emerging treatment and diagnostic criteria.

Case Presentation

A 56-year-old African American male was evaluated in the rheumatology clinic at the Central Texas Veterans Affairs Medical Center in Temple, Texas, in 2022 for a cutaneous mass of his right medial thigh. The patient previously reported the onset of a right medial thigh mass in 2005 after he had been deployed in Iraq for about 1 year. A biopsy of the mass from 2005 showed infiltration of plasma cells, lymphocytes, and histiocytes and occasional neutrophils with noted reactivity of S100 protein and CD163, but not CD1a. The patient’s original biopsy report from March 2005 was obtained secondhand from an addendum to a Dermatology Consult note. Surgical excision of the mass was not performed until 2012 and systemic therapy was not initiated.

figure_1.png

In 2021, the mass recurred and gradually increased in size, prompting a second surgical removal. Pathology results from the 2021 mass showed a lipoma with areas of fibrosis with a mixed inflammatory cell infiltrate, including abundant lymphocytes, plasma cells, occasional hemosiderin-laden histiocytes, and clusters of enlarged histiocytes with foamy to pale eosinophilic, finely granular cytoplasm, and large, round, vesicular nuclei with prominent nucleoli. Emperipolesis was also present (Figure 1).

figure_2.png

Special immunohistochemical staining showed most of the lymphocytes were CD20 positive B-cells with a minority of CD3 positive T-cells. Histiocytes were CD163 positive and CD68 positive with patchy reactivity for S100 protein. The plasma cells were CD138 positive. There were > 125 IgG4-positive plasma cells present in a single high-powered field and the overall IgG4:IgG plasma cell ratio was > 40%. Pertinent imaging included a whole-body positron emission tomography/computed tomography (PET/CT) hypermetabolic activity scan of a small right femoral lymph node (9 mm) and nearby medial right femoral lymph node (13 mm) (Figure 2A). A well-defined mass in the medial aspect of the right thigh (2.5 cm x 3.2 cm x 3.9 cm) and a cutaneous/subcutaneous lesion of the anterior medial aspect of the proximal right thigh superior to the mass (2.9 cm) were also evident on imaging (Figure 2B). Each area of hypermetabolic activity had decreased in size and activity when compared to a previous PET/CT obtained 1 month earlier. There was no evidence of skeletal malignancy. A physical examination did not reveal any other soft tissue masses, palpable lymphadenopathy, or areas of skin involvement. Given the patient’s reassuring imaging findings and a lack of any new physical examination findings, no systemic therapy was initiated, and following shared decision making, the patient agreed to a period of watchful waiting. 

RDD is rare with a prevalence of 1:200,000. It has been reported that multisystem involvement occurs in 19% of cases and the prognosis of RDD correlates with the number of extranodal systems involved in the disease process.⁷ Although sporadic RDD is usually self-limited with favorable outcomes, it is estimated that 10% of patients may die of RDD due to direct complications, infections, and amyloidosis.^2,7 RDD commonly affects young male children and young adults with a mean age of 20 years and has a higher incidence among African American children.^2,7,8 Although patients with RDD present bilateral, painless cervical lymphadenopathy in 90% of cases, about 43% of patients with RDD and associated adenopathy present with ≥ 1 site of extranodal involvement, and only 23% of patients with RDD present with isolated extranodal sites without adenopathy.⁹ As was the case with our patient, the most common extranodal sites are found in the skin and soft tissue (16%).^6,9 However, histopathologic diagnosis of RDD in a lipoma is exceedingly rare. We found only 1 other case report of a patient with a history of multiple lipomas who developed a new solitary nodule that was excised and demonstrated RDD upon immunohistochemical staining.⁴ There has been no documented association between multiple lipomas and RDD.⁴

Histologically, RDD is often characterized by emperipolesis (the presence of an intact cell within the cytoplasm of anther cell) and a mixed cell infiltrate that includes S100 positive histiocytes, mononuclear cells, plasma cells, and lymphocytes.¹⁰ Despite these shared histologic features among the various phenotypes of RDD, other type-specific characteristics may also be present. When compared to nodal RDD, extranodal disease tends to demonstrate a lack of nodal architecture, more fibrosis and collagen deposition, fewer RDD cells, a lower degree of emperipolesis, and alternating pale (histiocyte rich) and dark (lymphocyte rich) regions with notable polygonal histiocytes arranged in a storiform pattern.^5,10

Our patient’s histology showed an overall IgG4:IgG plasma cell ratio > 40%. RDD frequently presents with IgG4-positive plasma cells, which has confounded the diagnosis of IgG4-related diseases and hyper-IgG4 disease.¹¹ Given this association, the Histiocyte Society revised classification recommends that all cases of RDD be evaluated for IgG4-positive cell infiltration.^2,3 Further discussion on this matter was recently provided after an expert panel published a consensus statement in 2015 detailing the evaluation of IgG4. The panel advocates for stricter terminology and criteria on this issue, advises that isolated IgG4-positive plasma cells are nonspecific, and states that the diagnosis of IgG4 disease should be based on careful judgment and correlation with the clinical scenario and supportive findings.¹² Therefore, while IgG4 positivity continues to be misleading in RDD cases, further evaluation for IgG4 disease is recommended. 

Sporadic RDD is usually self-limited with a reported remission rate of up to 50%, according to a case series of 80 patients with RDD.¹³ This leads to the recommendation of a period of watchful monitoring in patients with limited disease.¹³ In patients with unifocal extranodal disease, surgical excision has shown positive remission results; however, local recurrence of soft tissue lesions can occur at a rate of 21.4% to 51%.¹⁴ Although initiation of systemic therapy should be considered in patients with recurrent disease, there is currently no standardized regimen or medication of choice for treatment. Treatment with steroids, including prednisone 40 to 70 mg daily or dexamethasone 8 to 20 mg daily, have been shown to be effective in reducing the nodal size and symptoms, especially in cases of nonresectable multifocal extranodal disease of the central nervous system, bone, and orbital.^7,15,16 However, cases of orbital, tracheal, renal, or soft tissue RDD have reported failure in treatment with steroids.^17,18

According to the consensus recommendations for the treatment of RDD released in 2018, treatment with chemotherapy has shown mixed results. Anthracycline and alkylating agents have shown minimal efficacy, but combination regimens with vinca alkaloids, methotrexate, and 6-mercaptopurine have helped patients experience remission.^19,20 Due to the rarity of RDD and lack of clinical trials, the exact efficacy of these treatment regimens remains unknown and is largely limited to case reports described within the medical literature. Treatment with nucleoside analogs, such as cladribine 2.1 to 5 mg/m² or clofarabine 25 mg/m² per day for 5 days every 28 days for 6 months, have shown promising results and helped achieve complete remission in patients with refractory or recurrent RDD.^7,21-23 Immunomodulator therapies including TNF-α inhibitor, such as thalidomide and lenalidomide, have also shown to be effective, particularly in patients with refractory disease.^24,25 Low-dose thalidomide (100 mg daily) was effective for cases of refractory cutaneous RDD, though no standard dosing regimen exists. Lenalidomide has shown to be effective in patients with multiple refractory nodal or bone RDD, but is associated with more complications given that it is more myelosuppressive than thalidomide.⁷ Radiotherapy has also been initiated in patients with refractory soft tissue disease or persistent symptoms after resection and in patients who are not candidates for surgery or systemic therapy, though no standard doses of radiotherapy have been established.^7,26,27

Conclusions

RDD is a rare histiocytic disorder that presents in a wide range of age groups, different locations in the body, and with variable disease behavior. Multidisciplinary management of the disease and research for mutations and microenvironment of RDD is needed to better understand its clinicopathological nature and improve targeted novel therapies.

Acknowledgments

The authors thank Veterans Affairs Central Texas Health Care Section Chief of Rheumatology, Swastika Jha, MD, for her guidance in this case and Bo Wang, MD, for his preparation of the pathological specimens. 

Rosai Dorfman disease (RDD) is a rare non-Langerhans cell histiocytosis first described in 1965 by Destombes and again in 1969 by Rosai and Dorfman to depict patients who presented with massive cervical lymphadenopathy.¹ The classification for histiocytosis was revised in 2016 based on new insights into the pathologic, genetic, and molecular features of RDD.^2,3 Now, RDD is listed under the R group, which includes familial, sporadic, classical (nodal), extranodal RDD, and other noncutaneous, non-Langerhans cell histiocytosis.³ Cutaneous RDD is classified under the C group and typically presents as painless papules, plaques, or nodules without significant lymphadenopathy, or systemic symptoms usually seen in the presentation of RDD.⁴

The etiology of RDD is poorly understood, although an underlying infectious or genetic component is suspected.⁵ Several pathogens—including human herpesvirus 6, parvovirus B19, Epstein-Barr virus, cytomegalovirus, Brucella, and Klebsiella—have all been investigated. A link to kinase mutations has been described in nodal and extranodal RDD; however, the molecular profile of cutaneous RDD remains unknown.² Histologic findings for RDD typically include cells that are S100 positive, CD68 positive, and CD163 positive, and CD1a and langerin (CD207) negative, thus excluding Langerhans cell histiocytosis.² The hallmark finding of RDD is emperipolesis, which results from “histiocyte-mediated phagocytosis of intact lymphocytes and other immune cells.”⁶ Immunoglobulin G (Ig) G4-positive plasma cells are also common, but the significance of this finding is controversial. We present a case of a patient with recurrent RDD within a right medial thigh lipoma and include a literature review to explore the significance of histologic findings and various treatment options in the setting of emerging treatment and diagnostic criteria.

Case Presentation

A 56-year-old African American male was evaluated in the rheumatology clinic at the Central Texas Veterans Affairs Medical Center in Temple, Texas, in 2022 for a cutaneous mass of his right medial thigh. The patient previously reported the onset of a right medial thigh mass in 2005 after he had been deployed in Iraq for about 1 year. A biopsy of the mass from 2005 showed infiltration of plasma cells, lymphocytes, and histiocytes and occasional neutrophils with noted reactivity of S100 protein and CD163, but not CD1a. The patient’s original biopsy report from March 2005 was obtained secondhand from an addendum to a Dermatology Consult note. Surgical excision of the mass was not performed until 2012 and systemic therapy was not initiated.

figure_1.png

In 2021, the mass recurred and gradually increased in size, prompting a second surgical removal. Pathology results from the 2021 mass showed a lipoma with areas of fibrosis with a mixed inflammatory cell infiltrate, including abundant lymphocytes, plasma cells, occasional hemosiderin-laden histiocytes, and clusters of enlarged histiocytes with foamy to pale eosinophilic, finely granular cytoplasm, and large, round, vesicular nuclei with prominent nucleoli. Emperipolesis was also present (Figure 1).

figure_2.png

Special immunohistochemical staining showed most of the lymphocytes were CD20 positive B-cells with a minority of CD3 positive T-cells. Histiocytes were CD163 positive and CD68 positive with patchy reactivity for S100 protein. The plasma cells were CD138 positive. There were > 125 IgG4-positive plasma cells present in a single high-powered field and the overall IgG4:IgG plasma cell ratio was > 40%. Pertinent imaging included a whole-body positron emission tomography/computed tomography (PET/CT) hypermetabolic activity scan of a small right femoral lymph node (9 mm) and nearby medial right femoral lymph node (13 mm) (Figure 2A). A well-defined mass in the medial aspect of the right thigh (2.5 cm x 3.2 cm x 3.9 cm) and a cutaneous/subcutaneous lesion of the anterior medial aspect of the proximal right thigh superior to the mass (2.9 cm) were also evident on imaging (Figure 2B). Each area of hypermetabolic activity had decreased in size and activity when compared to a previous PET/CT obtained 1 month earlier. There was no evidence of skeletal malignancy. A physical examination did not reveal any other soft tissue masses, palpable lymphadenopathy, or areas of skin involvement. Given the patient’s reassuring imaging findings and a lack of any new physical examination findings, no systemic therapy was initiated, and following shared decision making, the patient agreed to a period of watchful waiting. 

RDD is rare with a prevalence of 1:200,000. It has been reported that multisystem involvement occurs in 19% of cases and the prognosis of RDD correlates with the number of extranodal systems involved in the disease process.⁷ Although sporadic RDD is usually self-limited with favorable outcomes, it is estimated that 10% of patients may die of RDD due to direct complications, infections, and amyloidosis.^2,7 RDD commonly affects young male children and young adults with a mean age of 20 years and has a higher incidence among African American children.^2,7,8 Although patients with RDD present bilateral, painless cervical lymphadenopathy in 90% of cases, about 43% of patients with RDD and associated adenopathy present with ≥ 1 site of extranodal involvement, and only 23% of patients with RDD present with isolated extranodal sites without adenopathy.⁹ As was the case with our patient, the most common extranodal sites are found in the skin and soft tissue (16%).^6,9 However, histopathologic diagnosis of RDD in a lipoma is exceedingly rare. We found only 1 other case report of a patient with a history of multiple lipomas who developed a new solitary nodule that was excised and demonstrated RDD upon immunohistochemical staining.⁴ There has been no documented association between multiple lipomas and RDD.⁴

Histologically, RDD is often characterized by emperipolesis (the presence of an intact cell within the cytoplasm of anther cell) and a mixed cell infiltrate that includes S100 positive histiocytes, mononuclear cells, plasma cells, and lymphocytes.¹⁰ Despite these shared histologic features among the various phenotypes of RDD, other type-specific characteristics may also be present. When compared to nodal RDD, extranodal disease tends to demonstrate a lack of nodal architecture, more fibrosis and collagen deposition, fewer RDD cells, a lower degree of emperipolesis, and alternating pale (histiocyte rich) and dark (lymphocyte rich) regions with notable polygonal histiocytes arranged in a storiform pattern.^5,10

Our patient’s histology showed an overall IgG4:IgG plasma cell ratio > 40%. RDD frequently presents with IgG4-positive plasma cells, which has confounded the diagnosis of IgG4-related diseases and hyper-IgG4 disease.¹¹ Given this association, the Histiocyte Society revised classification recommends that all cases of RDD be evaluated for IgG4-positive cell infiltration.^2,3 Further discussion on this matter was recently provided after an expert panel published a consensus statement in 2015 detailing the evaluation of IgG4. The panel advocates for stricter terminology and criteria on this issue, advises that isolated IgG4-positive plasma cells are nonspecific, and states that the diagnosis of IgG4 disease should be based on careful judgment and correlation with the clinical scenario and supportive findings.¹² Therefore, while IgG4 positivity continues to be misleading in RDD cases, further evaluation for IgG4 disease is recommended. 

Sporadic RDD is usually self-limited with a reported remission rate of up to 50%, according to a case series of 80 patients with RDD.¹³ This leads to the recommendation of a period of watchful monitoring in patients with limited disease.¹³ In patients with unifocal extranodal disease, surgical excision has shown positive remission results; however, local recurrence of soft tissue lesions can occur at a rate of 21.4% to 51%.¹⁴ Although initiation of systemic therapy should be considered in patients with recurrent disease, there is currently no standardized regimen or medication of choice for treatment. Treatment with steroids, including prednisone 40 to 70 mg daily or dexamethasone 8 to 20 mg daily, have been shown to be effective in reducing the nodal size and symptoms, especially in cases of nonresectable multifocal extranodal disease of the central nervous system, bone, and orbital.^7,15,16 However, cases of orbital, tracheal, renal, or soft tissue RDD have reported failure in treatment with steroids.^17,18

According to the consensus recommendations for the treatment of RDD released in 2018, treatment with chemotherapy has shown mixed results. Anthracycline and alkylating agents have shown minimal efficacy, but combination regimens with vinca alkaloids, methotrexate, and 6-mercaptopurine have helped patients experience remission.^19,20 Due to the rarity of RDD and lack of clinical trials, the exact efficacy of these treatment regimens remains unknown and is largely limited to case reports described within the medical literature. Treatment with nucleoside analogs, such as cladribine 2.1 to 5 mg/m² or clofarabine 25 mg/m² per day for 5 days every 28 days for 6 months, have shown promising results and helped achieve complete remission in patients with refractory or recurrent RDD.^7,21-23 Immunomodulator therapies including TNF-α inhibitor, such as thalidomide and lenalidomide, have also shown to be effective, particularly in patients with refractory disease.^24,25 Low-dose thalidomide (100 mg daily) was effective for cases of refractory cutaneous RDD, though no standard dosing regimen exists. Lenalidomide has shown to be effective in patients with multiple refractory nodal or bone RDD, but is associated with more complications given that it is more myelosuppressive than thalidomide.⁷ Radiotherapy has also been initiated in patients with refractory soft tissue disease or persistent symptoms after resection and in patients who are not candidates for surgery or systemic therapy, though no standard doses of radiotherapy have been established.^7,26,27

Conclusions

RDD is a rare histiocytic disorder that presents in a wide range of age groups, different locations in the body, and with variable disease behavior. Multidisciplinary management of the disease and research for mutations and microenvironment of RDD is needed to better understand its clinicopathological nature and improve targeted novel therapies.

Acknowledgments

The authors thank Veterans Affairs Central Texas Health Care Section Chief of Rheumatology, Swastika Jha, MD, for her guidance in this case and Bo Wang, MD, for his preparation of the pathological specimens. 

Rosai Dorfman disease (RDD) is a rare non-Langerhans cell histiocytosis first described in 1965 by Destombes and again in 1969 by Rosai and Dorfman to depict patients who presented with massive cervical lymphadenopathy.¹ The classification for histiocytosis was revised in 2016 based on new insights into the pathologic, genetic, and molecular features of RDD.^2,3 Now, RDD is listed under the R group, which includes familial, sporadic, classical (nodal), extranodal RDD, and other noncutaneous, non-Langerhans cell histiocytosis.³ Cutaneous RDD is classified under the C group and typically presents as painless papules, plaques, or nodules without significant lymphadenopathy, or systemic symptoms usually seen in the presentation of RDD.⁴

The etiology of RDD is poorly understood, although an underlying infectious or genetic component is suspected.⁵ Several pathogens—including human herpesvirus 6, parvovirus B19, Epstein-Barr virus, cytomegalovirus, Brucella, and Klebsiella—have all been investigated. A link to kinase mutations has been described in nodal and extranodal RDD; however, the molecular profile of cutaneous RDD remains unknown.² Histologic findings for RDD typically include cells that are S100 positive, CD68 positive, and CD163 positive, and CD1a and langerin (CD207) negative, thus excluding Langerhans cell histiocytosis.² The hallmark finding of RDD is emperipolesis, which results from “histiocyte-mediated phagocytosis of intact lymphocytes and other immune cells.”⁶ Immunoglobulin G (Ig) G4-positive plasma cells are also common, but the significance of this finding is controversial. We present a case of a patient with recurrent RDD within a right medial thigh lipoma and include a literature review to explore the significance of histologic findings and various treatment options in the setting of emerging treatment and diagnostic criteria.

Case Presentation

A 56-year-old African American male was evaluated in the rheumatology clinic at the Central Texas Veterans Affairs Medical Center in Temple, Texas, in 2022 for a cutaneous mass of his right medial thigh. The patient previously reported the onset of a right medial thigh mass in 2005 after he had been deployed in Iraq for about 1 year. A biopsy of the mass from 2005 showed infiltration of plasma cells, lymphocytes, and histiocytes and occasional neutrophils with noted reactivity of S100 protein and CD163, but not CD1a. The patient’s original biopsy report from March 2005 was obtained secondhand from an addendum to a Dermatology Consult note. Surgical excision of the mass was not performed until 2012 and systemic therapy was not initiated.

figure_1.png

In 2021, the mass recurred and gradually increased in size, prompting a second surgical removal. Pathology results from the 2021 mass showed a lipoma with areas of fibrosis with a mixed inflammatory cell infiltrate, including abundant lymphocytes, plasma cells, occasional hemosiderin-laden histiocytes, and clusters of enlarged histiocytes with foamy to pale eosinophilic, finely granular cytoplasm, and large, round, vesicular nuclei with prominent nucleoli. Emperipolesis was also present (Figure 1).

figure_2.png

Special immunohistochemical staining showed most of the lymphocytes were CD20 positive B-cells with a minority of CD3 positive T-cells. Histiocytes were CD163 positive and CD68 positive with patchy reactivity for S100 protein. The plasma cells were CD138 positive. There were > 125 IgG4-positive plasma cells present in a single high-powered field and the overall IgG4:IgG plasma cell ratio was > 40%. Pertinent imaging included a whole-body positron emission tomography/computed tomography (PET/CT) hypermetabolic activity scan of a small right femoral lymph node (9 mm) and nearby medial right femoral lymph node (13 mm) (Figure 2A). A well-defined mass in the medial aspect of the right thigh (2.5 cm x 3.2 cm x 3.9 cm) and a cutaneous/subcutaneous lesion of the anterior medial aspect of the proximal right thigh superior to the mass (2.9 cm) were also evident on imaging (Figure 2B). Each area of hypermetabolic activity had decreased in size and activity when compared to a previous PET/CT obtained 1 month earlier. There was no evidence of skeletal malignancy. A physical examination did not reveal any other soft tissue masses, palpable lymphadenopathy, or areas of skin involvement. Given the patient’s reassuring imaging findings and a lack of any new physical examination findings, no systemic therapy was initiated, and following shared decision making, the patient agreed to a period of watchful waiting. 

RDD is rare with a prevalence of 1:200,000. It has been reported that multisystem involvement occurs in 19% of cases and the prognosis of RDD correlates with the number of extranodal systems involved in the disease process.⁷ Although sporadic RDD is usually self-limited with favorable outcomes, it is estimated that 10% of patients may die of RDD due to direct complications, infections, and amyloidosis.^2,7 RDD commonly affects young male children and young adults with a mean age of 20 years and has a higher incidence among African American children.^2,7,8 Although patients with RDD present bilateral, painless cervical lymphadenopathy in 90% of cases, about 43% of patients with RDD and associated adenopathy present with ≥ 1 site of extranodal involvement, and only 23% of patients with RDD present with isolated extranodal sites without adenopathy.⁹ As was the case with our patient, the most common extranodal sites are found in the skin and soft tissue (16%).^6,9 However, histopathologic diagnosis of RDD in a lipoma is exceedingly rare. We found only 1 other case report of a patient with a history of multiple lipomas who developed a new solitary nodule that was excised and demonstrated RDD upon immunohistochemical staining.⁴ There has been no documented association between multiple lipomas and RDD.⁴

Histologically, RDD is often characterized by emperipolesis (the presence of an intact cell within the cytoplasm of anther cell) and a mixed cell infiltrate that includes S100 positive histiocytes, mononuclear cells, plasma cells, and lymphocytes.¹⁰ Despite these shared histologic features among the various phenotypes of RDD, other type-specific characteristics may also be present. When compared to nodal RDD, extranodal disease tends to demonstrate a lack of nodal architecture, more fibrosis and collagen deposition, fewer RDD cells, a lower degree of emperipolesis, and alternating pale (histiocyte rich) and dark (lymphocyte rich) regions with notable polygonal histiocytes arranged in a storiform pattern.^5,10

Our patient’s histology showed an overall IgG4:IgG plasma cell ratio > 40%. RDD frequently presents with IgG4-positive plasma cells, which has confounded the diagnosis of IgG4-related diseases and hyper-IgG4 disease.¹¹ Given this association, the Histiocyte Society revised classification recommends that all cases of RDD be evaluated for IgG4-positive cell infiltration.^2,3 Further discussion on this matter was recently provided after an expert panel published a consensus statement in 2015 detailing the evaluation of IgG4. The panel advocates for stricter terminology and criteria on this issue, advises that isolated IgG4-positive plasma cells are nonspecific, and states that the diagnosis of IgG4 disease should be based on careful judgment and correlation with the clinical scenario and supportive findings.¹² Therefore, while IgG4 positivity continues to be misleading in RDD cases, further evaluation for IgG4 disease is recommended. 

Sporadic RDD is usually self-limited with a reported remission rate of up to 50%, according to a case series of 80 patients with RDD.¹³ This leads to the recommendation of a period of watchful monitoring in patients with limited disease.¹³ In patients with unifocal extranodal disease, surgical excision has shown positive remission results; however, local recurrence of soft tissue lesions can occur at a rate of 21.4% to 51%.¹⁴ Although initiation of systemic therapy should be considered in patients with recurrent disease, there is currently no standardized regimen or medication of choice for treatment. Treatment with steroids, including prednisone 40 to 70 mg daily or dexamethasone 8 to 20 mg daily, have been shown to be effective in reducing the nodal size and symptoms, especially in cases of nonresectable multifocal extranodal disease of the central nervous system, bone, and orbital.^7,15,16 However, cases of orbital, tracheal, renal, or soft tissue RDD have reported failure in treatment with steroids.^17,18

According to the consensus recommendations for the treatment of RDD released in 2018, treatment with chemotherapy has shown mixed results. Anthracycline and alkylating agents have shown minimal efficacy, but combination regimens with vinca alkaloids, methotrexate, and 6-mercaptopurine have helped patients experience remission.^19,20 Due to the rarity of RDD and lack of clinical trials, the exact efficacy of these treatment regimens remains unknown and is largely limited to case reports described within the medical literature. Treatment with nucleoside analogs, such as cladribine 2.1 to 5 mg/m² or clofarabine 25 mg/m² per day for 5 days every 28 days for 6 months, have shown promising results and helped achieve complete remission in patients with refractory or recurrent RDD.^7,21-23 Immunomodulator therapies including TNF-α inhibitor, such as thalidomide and lenalidomide, have also shown to be effective, particularly in patients with refractory disease.^24,25 Low-dose thalidomide (100 mg daily) was effective for cases of refractory cutaneous RDD, though no standard dosing regimen exists. Lenalidomide has shown to be effective in patients with multiple refractory nodal or bone RDD, but is associated with more complications given that it is more myelosuppressive than thalidomide.⁷ Radiotherapy has also been initiated in patients with refractory soft tissue disease or persistent symptoms after resection and in patients who are not candidates for surgery or systemic therapy, though no standard doses of radiotherapy have been established.^7,26,27

Conclusions

RDD is a rare histiocytic disorder that presents in a wide range of age groups, different locations in the body, and with variable disease behavior. Multidisciplinary management of the disease and research for mutations and microenvironment of RDD is needed to better understand its clinicopathological nature and improve targeted novel therapies.

Acknowledgments

The authors thank Veterans Affairs Central Texas Health Care Section Chief of Rheumatology, Swastika Jha, MD, for her guidance in this case and Bo Wang, MD, for his preparation of the pathological specimens. 

High-grade B-cell lymphomas (HGBCLs) are aggressive lymphoproliferative disorders (LPDs) that require fluorescence in-situ hybridization to identify gene rearrangements within MYC and BCL2 and/or BCL6 oncogenes. Traditionally referred to as double-hit or triple-hit lymphomas, HGBCL is a newer entity in the 2016 updated World Health Organization classification of lymphoid neoplasms.¹ More than 90% of patients with HGBCL present with advanced clinical features, such as central nervous system involvement, leukocytosis, or lactose dehydrogenase (LDH) greater than 3 times the upper limit of normal. Treatment outcomes with aggressive multiagent chemotherapy combined with anti-CD20–targeted therapy are generally worse for patients with double-hit disease, especially among frail patients with advanced age. Patients with underlying autoimmune and rheumatologic conditions, such as rheumatoid arthritis (RA), are at higher risk for developing LPDs. These include highly aggressive subtypes of non-Hodgkin lymphoma, such as HGBCL, likely due to cascading events secondary to chronic inflammation and/or immunosuppressive medications. These immunodeficiency-associated LPDs often express positivity for Epstein-Barr virus-encoded small RNA (EBER).

We present a case of double-hit HGBCL that was EBER negative with MYC and BCL6 rearrangements in an older veteran with RA managed with methotrexate. An excellent sustained response was observed for the patient’s stage IV double-hit HGBCL disease within 4 weeks of methotrexate discontinuation. To our knowledge, this is the first reported response to methotrexate discontinuation for a patient with HGBCL.

CASE PRESENTATION

A male veteran aged 81 years presented to the Raymond G. Murphy Veterans Affairs Medical Center (RGMVAMC) in Albuquerque, New Mexico, with an unintentional 25-pound weight loss over 18 months. Pertinent history included RA managed with methotrexate 15 mg weekly for 6 years and a previous remote seizure. The patients prior prostate cancer was treated with radiation at the time of diagnosis and ongoing androgen deprivation therapy. Initial workup with chest X-ray and chest computed tomography (CT) indicated loculated left pleural fluid collection with a suspected splenic tumor.

figure_1.png

A positron-emission tomography (PET)/CT was ordered given his history of prostate cancer, which showed potential splenic and sternal metastases with corresponding fludeoxyglucose F18 uptake (Figure 1A). Biopsy was not pursued due to the potential for splenic hemorrhage. Based on the patient’s RA and methotrexate use, the collection of findings was initially thought to represent a non-Hodgkin lymphoma, with knowledge that metastatic prostate cancer refractory to androgen deprivation therapy was possible. Because he was unable to undergo a splenic biopsy, an observation strategy involving repeat PET/CT every 6 months was started.

The surveillance PET/CT 6 months later conveyed worsened disease burden with increased avidity in the manubrium (Figure 1B). The patient’s case was discussed at the RGMVAMC tumor board, and the recommendation was to continue with surveillance follow-up imaging because image-guided biopsy might not definitively yield a diagnosis. Repeat PET/CT3 months later indicated continued worsening of disease (Figure 1C) with a rapidly enlarging hypermetabolic mass in the manubrium that extended anteriorly into the subcutaneous tissues and encased the bilateral anterior jugular veins. On physical examination, this sternal mass had become painful and was clearly evident. Additionally, increased avidity in multiple upper abdominal and retroperitoneal lymph nodes was observed.

figure_2.png

Interventional radiology was consulted to assist with a percutaneous fine-needle aspiration of the manubrial mass, which revealed a dense aggregate of large, atypical lymphocytes confirmed to be of B-cell origin (CD20 and PAX5 positive) (Figure 2). The atypical B cells demonstrated co-expression of BCL6, BCL2, MUM1, and MYC but were negative for CD30 and EBER by in situ hybridization. The overall morphologic and immunophenotypic findings were consistent with a large B-cell lymphoma. Fluorescent in-situ hybridization identified the presence of MYC and BCL6 gene rearrangements, and the mass was consequently best classified as a double-hit HGBCL.

Given the patient’s history of long-term methotrexate use, we thought the HGBCL may have reflected an immunodeficiency-associated LPD, although the immunophenotype was not classic because of the CD30 and EBER negativity. With the known toxicity and poor treatment outcomes of aggressive multiagent chemotherapy for patients with double-hit HGBCL—particularly in the older adult population—methotrexate was discontinued on a trial basis.

A PET/CT was completed 4 weeks after methotrexate was discontinued due to concerns about managing an HGBCL without chemotherapy or anti-CD20–directed therapy. The updated PET/CT showed significant improvement with marked reduction in avidity of his manubrial lesion (Figure 1D). Three months after methotrexate discontinuation, the patient remained in partial remission for his double-hit HGBCL, as evidenced by no findings of sternal mass on repeat examinations with continued decrease in hypermetabolic findings on PET/CT. The patient's RA symptoms rebounded, and rheumatology colleagues prescribed sulfasalazine and periodic steroid tapers to help control his inflammatory arthritis. Fourteen months after discontinuation of methotrexate, the patient died after developing pneumonia, which led to multisystemic organ failure.

DISCUSSION

HGBCL with MYC and BCL2 and/or BCL6 rearrangements is an aggressive LPD.¹ A definitive diagnosis requires collection of morphologic and immunophenotypic evaluations of suspicious tissue. Approximately 60% of patients with HGBCL have translocations in MYC and BCL2, 20% have MYC and BCL6 translocations, and the remaining 20% have MYC, BCL2 and BCL6 translocations (triple-hit disease).¹

The MYC and BCL gene rearrangements are thought to synergistically drive tumorigenesis, leading to accelerated lymphoma progression and a lesser response to standard multiagent chemotherapy than seen in diffuse large B-cell lymphoma.^1-3 Consequently, there have been several attempts to increase treatment efficacy with intense chemotherapy regimens, namely DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab), or by adding targeted agents, such as ibrutinib and venetoclax to a standard R-CHOP (rituximab with reduced cyclophosphamide, doxorubicin, vincristine, and prednisone) backbone.^4-7 Though the standard choice of therapy for fit patients harboring HGBCL remains controversial, these aggressive regimens at standard doses are typically difficult to tolerate for patients aged > 80 years.

table.png

Patients with immunosuppression are at higher risk for developing LPDs, including aggressive B-cell non-Hodgkin lymphomas such as diffuse large B-cell lymphoma. These patients are frequently classified into 2 groups: those with underlying autoimmune conditions (RA-associated LPDs), or those who have undergone solid-organ or allogeneic hematopoietic stem-cell transplants, which drives the development of posttransplant LPDs (Table).^8-11 Both types of LPDs are often EBER positive, indicating some association with Epstein-Barr virus infection driven by ongoing immunosuppression, with knowledge that this finding is not absolute and is less frequent among patients with autoimmune conditions than those with posttransplant LPD.^8,12

For indolent and early-stage aggressive LPDs, reduction of immunosuppression is a reasonable frontline treatment. In fact, Tokuyama and colleagues reported a previous case in which an methotrexate-associated EBER-positive early-stage diffuse large B-cell lymphoma responded well to methotrexate withdrawal.¹³ For advanced, aggressive LPDs associated with immunosuppression, a combination strategy of reducing immunosuppression and initiating a standard multiagent systemic therapy such as with R-CHOP is more common. Reducing immunosuppression without adding systemic anticancer therapy can certainly be considered in patients with EBER-negative LPDs; however, there is less evidence supporting this approach in the literature.

A case series of patients with EBER-positive double-hit HGBCL has been described previously, and response rates were low despite aggressive treatment.¹⁴ The current case differs from that case series in 2 ways. First, our patient did not have EBER-positive disease despite having an HGBCL associated with RA and methotrexate use. Second, our patient had a very rapid and excellent partial response simply with methotrexate discontinuation. Aggressive treatment was considered initially; however, given the patient’s age and performance status, reduction of immunosuppression alone was considered the frontline approach.

This case indicates that methotrexate withdrawal may lead to remission in patients with double-hit lymphoma, even without clear signs of Epstein-Barr virus infection being present. We are not sure why our patient with EBER-negative HGBCL responded differently to methotrexate withdrawal than the patients in the aforementioned case series with EBER-positive disease; nevertheless, a short trial of methotrexate withdrawal with repeat imaging 4 to 8 weeks after discontinuation seems reasonable for patients who are older, frail, and seemingly not fit for more aggressive treatment.

CONCLUSIONS

For our older patient with RA and biopsy-proven, stage IV EBER-negative HGBCL bearing MYC and BCL6 rearrangements (double hit), discontinuation of methotrexate led to a rapid and sustained marked response. Reducing immunosuppression should be considered for patients with LPDs associated with autoimmune conditions or immunosuppressive medications, regardless of additional multiagent systemic therapy administration. In older patients who are frail with aggressive B-cell lymphomas, a short trial of methotrexate withdrawal with quick interval imaging is a reasonable frontline option, regardless of EBER status.

High-grade B-cell lymphomas (HGBCLs) are aggressive lymphoproliferative disorders (LPDs) that require fluorescence in-situ hybridization to identify gene rearrangements within MYC and BCL2 and/or BCL6 oncogenes. Traditionally referred to as double-hit or triple-hit lymphomas, HGBCL is a newer entity in the 2016 updated World Health Organization classification of lymphoid neoplasms.¹ More than 90% of patients with HGBCL present with advanced clinical features, such as central nervous system involvement, leukocytosis, or lactose dehydrogenase (LDH) greater than 3 times the upper limit of normal. Treatment outcomes with aggressive multiagent chemotherapy combined with anti-CD20–targeted therapy are generally worse for patients with double-hit disease, especially among frail patients with advanced age. Patients with underlying autoimmune and rheumatologic conditions, such as rheumatoid arthritis (RA), are at higher risk for developing LPDs. These include highly aggressive subtypes of non-Hodgkin lymphoma, such as HGBCL, likely due to cascading events secondary to chronic inflammation and/or immunosuppressive medications. These immunodeficiency-associated LPDs often express positivity for Epstein-Barr virus-encoded small RNA (EBER).

We present a case of double-hit HGBCL that was EBER negative with MYC and BCL6 rearrangements in an older veteran with RA managed with methotrexate. An excellent sustained response was observed for the patient’s stage IV double-hit HGBCL disease within 4 weeks of methotrexate discontinuation. To our knowledge, this is the first reported response to methotrexate discontinuation for a patient with HGBCL.

CASE PRESENTATION

A male veteran aged 81 years presented to the Raymond G. Murphy Veterans Affairs Medical Center (RGMVAMC) in Albuquerque, New Mexico, with an unintentional 25-pound weight loss over 18 months. Pertinent history included RA managed with methotrexate 15 mg weekly for 6 years and a previous remote seizure. The patients prior prostate cancer was treated with radiation at the time of diagnosis and ongoing androgen deprivation therapy. Initial workup with chest X-ray and chest computed tomography (CT) indicated loculated left pleural fluid collection with a suspected splenic tumor.

figure_1.png

A positron-emission tomography (PET)/CT was ordered given his history of prostate cancer, which showed potential splenic and sternal metastases with corresponding fludeoxyglucose F18 uptake (Figure 1A). Biopsy was not pursued due to the potential for splenic hemorrhage. Based on the patient’s RA and methotrexate use, the collection of findings was initially thought to represent a non-Hodgkin lymphoma, with knowledge that metastatic prostate cancer refractory to androgen deprivation therapy was possible. Because he was unable to undergo a splenic biopsy, an observation strategy involving repeat PET/CT every 6 months was started.

The surveillance PET/CT 6 months later conveyed worsened disease burden with increased avidity in the manubrium (Figure 1B). The patient’s case was discussed at the RGMVAMC tumor board, and the recommendation was to continue with surveillance follow-up imaging because image-guided biopsy might not definitively yield a diagnosis. Repeat PET/CT3 months later indicated continued worsening of disease (Figure 1C) with a rapidly enlarging hypermetabolic mass in the manubrium that extended anteriorly into the subcutaneous tissues and encased the bilateral anterior jugular veins. On physical examination, this sternal mass had become painful and was clearly evident. Additionally, increased avidity in multiple upper abdominal and retroperitoneal lymph nodes was observed.

figure_2.png

Interventional radiology was consulted to assist with a percutaneous fine-needle aspiration of the manubrial mass, which revealed a dense aggregate of large, atypical lymphocytes confirmed to be of B-cell origin (CD20 and PAX5 positive) (Figure 2). The atypical B cells demonstrated co-expression of BCL6, BCL2, MUM1, and MYC but were negative for CD30 and EBER by in situ hybridization. The overall morphologic and immunophenotypic findings were consistent with a large B-cell lymphoma. Fluorescent in-situ hybridization identified the presence of MYC and BCL6 gene rearrangements, and the mass was consequently best classified as a double-hit HGBCL.

Given the patient’s history of long-term methotrexate use, we thought the HGBCL may have reflected an immunodeficiency-associated LPD, although the immunophenotype was not classic because of the CD30 and EBER negativity. With the known toxicity and poor treatment outcomes of aggressive multiagent chemotherapy for patients with double-hit HGBCL—particularly in the older adult population—methotrexate was discontinued on a trial basis.

A PET/CT was completed 4 weeks after methotrexate was discontinued due to concerns about managing an HGBCL without chemotherapy or anti-CD20–directed therapy. The updated PET/CT showed significant improvement with marked reduction in avidity of his manubrial lesion (Figure 1D). Three months after methotrexate discontinuation, the patient remained in partial remission for his double-hit HGBCL, as evidenced by no findings of sternal mass on repeat examinations with continued decrease in hypermetabolic findings on PET/CT. The patient's RA symptoms rebounded, and rheumatology colleagues prescribed sulfasalazine and periodic steroid tapers to help control his inflammatory arthritis. Fourteen months after discontinuation of methotrexate, the patient died after developing pneumonia, which led to multisystemic organ failure.

DISCUSSION

HGBCL with MYC and BCL2 and/or BCL6 rearrangements is an aggressive LPD.¹ A definitive diagnosis requires collection of morphologic and immunophenotypic evaluations of suspicious tissue. Approximately 60% of patients with HGBCL have translocations in MYC and BCL2, 20% have MYC and BCL6 translocations, and the remaining 20% have MYC, BCL2 and BCL6 translocations (triple-hit disease).¹

The MYC and BCL gene rearrangements are thought to synergistically drive tumorigenesis, leading to accelerated lymphoma progression and a lesser response to standard multiagent chemotherapy than seen in diffuse large B-cell lymphoma.^1-3 Consequently, there have been several attempts to increase treatment efficacy with intense chemotherapy regimens, namely DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab), or by adding targeted agents, such as ibrutinib and venetoclax to a standard R-CHOP (rituximab with reduced cyclophosphamide, doxorubicin, vincristine, and prednisone) backbone.^4-7 Though the standard choice of therapy for fit patients harboring HGBCL remains controversial, these aggressive regimens at standard doses are typically difficult to tolerate for patients aged > 80 years.

table.png

Patients with immunosuppression are at higher risk for developing LPDs, including aggressive B-cell non-Hodgkin lymphomas such as diffuse large B-cell lymphoma. These patients are frequently classified into 2 groups: those with underlying autoimmune conditions (RA-associated LPDs), or those who have undergone solid-organ or allogeneic hematopoietic stem-cell transplants, which drives the development of posttransplant LPDs (Table).^8-11 Both types of LPDs are often EBER positive, indicating some association with Epstein-Barr virus infection driven by ongoing immunosuppression, with knowledge that this finding is not absolute and is less frequent among patients with autoimmune conditions than those with posttransplant LPD.^8,12

For indolent and early-stage aggressive LPDs, reduction of immunosuppression is a reasonable frontline treatment. In fact, Tokuyama and colleagues reported a previous case in which an methotrexate-associated EBER-positive early-stage diffuse large B-cell lymphoma responded well to methotrexate withdrawal.¹³ For advanced, aggressive LPDs associated with immunosuppression, a combination strategy of reducing immunosuppression and initiating a standard multiagent systemic therapy such as with R-CHOP is more common. Reducing immunosuppression without adding systemic anticancer therapy can certainly be considered in patients with EBER-negative LPDs; however, there is less evidence supporting this approach in the literature.

A case series of patients with EBER-positive double-hit HGBCL has been described previously, and response rates were low despite aggressive treatment.¹⁴ The current case differs from that case series in 2 ways. First, our patient did not have EBER-positive disease despite having an HGBCL associated with RA and methotrexate use. Second, our patient had a very rapid and excellent partial response simply with methotrexate discontinuation. Aggressive treatment was considered initially; however, given the patient’s age and performance status, reduction of immunosuppression alone was considered the frontline approach.

This case indicates that methotrexate withdrawal may lead to remission in patients with double-hit lymphoma, even without clear signs of Epstein-Barr virus infection being present. We are not sure why our patient with EBER-negative HGBCL responded differently to methotrexate withdrawal than the patients in the aforementioned case series with EBER-positive disease; nevertheless, a short trial of methotrexate withdrawal with repeat imaging 4 to 8 weeks after discontinuation seems reasonable for patients who are older, frail, and seemingly not fit for more aggressive treatment.

CONCLUSIONS

For our older patient with RA and biopsy-proven, stage IV EBER-negative HGBCL bearing MYC and BCL6 rearrangements (double hit), discontinuation of methotrexate led to a rapid and sustained marked response. Reducing immunosuppression should be considered for patients with LPDs associated with autoimmune conditions or immunosuppressive medications, regardless of additional multiagent systemic therapy administration. In older patients who are frail with aggressive B-cell lymphomas, a short trial of methotrexate withdrawal with quick interval imaging is a reasonable frontline option, regardless of EBER status.

High-grade B-cell lymphomas (HGBCLs) are aggressive lymphoproliferative disorders (LPDs) that require fluorescence in-situ hybridization to identify gene rearrangements within MYC and BCL2 and/or BCL6 oncogenes. Traditionally referred to as double-hit or triple-hit lymphomas, HGBCL is a newer entity in the 2016 updated World Health Organization classification of lymphoid neoplasms.¹ More than 90% of patients with HGBCL present with advanced clinical features, such as central nervous system involvement, leukocytosis, or lactose dehydrogenase (LDH) greater than 3 times the upper limit of normal. Treatment outcomes with aggressive multiagent chemotherapy combined with anti-CD20–targeted therapy are generally worse for patients with double-hit disease, especially among frail patients with advanced age. Patients with underlying autoimmune and rheumatologic conditions, such as rheumatoid arthritis (RA), are at higher risk for developing LPDs. These include highly aggressive subtypes of non-Hodgkin lymphoma, such as HGBCL, likely due to cascading events secondary to chronic inflammation and/or immunosuppressive medications. These immunodeficiency-associated LPDs often express positivity for Epstein-Barr virus-encoded small RNA (EBER).

We present a case of double-hit HGBCL that was EBER negative with MYC and BCL6 rearrangements in an older veteran with RA managed with methotrexate. An excellent sustained response was observed for the patient’s stage IV double-hit HGBCL disease within 4 weeks of methotrexate discontinuation. To our knowledge, this is the first reported response to methotrexate discontinuation for a patient with HGBCL.

CASE PRESENTATION

A male veteran aged 81 years presented to the Raymond G. Murphy Veterans Affairs Medical Center (RGMVAMC) in Albuquerque, New Mexico, with an unintentional 25-pound weight loss over 18 months. Pertinent history included RA managed with methotrexate 15 mg weekly for 6 years and a previous remote seizure. The patients prior prostate cancer was treated with radiation at the time of diagnosis and ongoing androgen deprivation therapy. Initial workup with chest X-ray and chest computed tomography (CT) indicated loculated left pleural fluid collection with a suspected splenic tumor.

figure_1.png

A positron-emission tomography (PET)/CT was ordered given his history of prostate cancer, which showed potential splenic and sternal metastases with corresponding fludeoxyglucose F18 uptake (Figure 1A). Biopsy was not pursued due to the potential for splenic hemorrhage. Based on the patient’s RA and methotrexate use, the collection of findings was initially thought to represent a non-Hodgkin lymphoma, with knowledge that metastatic prostate cancer refractory to androgen deprivation therapy was possible. Because he was unable to undergo a splenic biopsy, an observation strategy involving repeat PET/CT every 6 months was started.

The surveillance PET/CT 6 months later conveyed worsened disease burden with increased avidity in the manubrium (Figure 1B). The patient’s case was discussed at the RGMVAMC tumor board, and the recommendation was to continue with surveillance follow-up imaging because image-guided biopsy might not definitively yield a diagnosis. Repeat PET/CT3 months later indicated continued worsening of disease (Figure 1C) with a rapidly enlarging hypermetabolic mass in the manubrium that extended anteriorly into the subcutaneous tissues and encased the bilateral anterior jugular veins. On physical examination, this sternal mass had become painful and was clearly evident. Additionally, increased avidity in multiple upper abdominal and retroperitoneal lymph nodes was observed.

figure_2.png

Interventional radiology was consulted to assist with a percutaneous fine-needle aspiration of the manubrial mass, which revealed a dense aggregate of large, atypical lymphocytes confirmed to be of B-cell origin (CD20 and PAX5 positive) (Figure 2). The atypical B cells demonstrated co-expression of BCL6, BCL2, MUM1, and MYC but were negative for CD30 and EBER by in situ hybridization. The overall morphologic and immunophenotypic findings were consistent with a large B-cell lymphoma. Fluorescent in-situ hybridization identified the presence of MYC and BCL6 gene rearrangements, and the mass was consequently best classified as a double-hit HGBCL.

Given the patient’s history of long-term methotrexate use, we thought the HGBCL may have reflected an immunodeficiency-associated LPD, although the immunophenotype was not classic because of the CD30 and EBER negativity. With the known toxicity and poor treatment outcomes of aggressive multiagent chemotherapy for patients with double-hit HGBCL—particularly in the older adult population—methotrexate was discontinued on a trial basis.

A PET/CT was completed 4 weeks after methotrexate was discontinued due to concerns about managing an HGBCL without chemotherapy or anti-CD20–directed therapy. The updated PET/CT showed significant improvement with marked reduction in avidity of his manubrial lesion (Figure 1D). Three months after methotrexate discontinuation, the patient remained in partial remission for his double-hit HGBCL, as evidenced by no findings of sternal mass on repeat examinations with continued decrease in hypermetabolic findings on PET/CT. The patient's RA symptoms rebounded, and rheumatology colleagues prescribed sulfasalazine and periodic steroid tapers to help control his inflammatory arthritis. Fourteen months after discontinuation of methotrexate, the patient died after developing pneumonia, which led to multisystemic organ failure.

DISCUSSION

HGBCL with MYC and BCL2 and/or BCL6 rearrangements is an aggressive LPD.¹ A definitive diagnosis requires collection of morphologic and immunophenotypic evaluations of suspicious tissue. Approximately 60% of patients with HGBCL have translocations in MYC and BCL2, 20% have MYC and BCL6 translocations, and the remaining 20% have MYC, BCL2 and BCL6 translocations (triple-hit disease).¹

The MYC and BCL gene rearrangements are thought to synergistically drive tumorigenesis, leading to accelerated lymphoma progression and a lesser response to standard multiagent chemotherapy than seen in diffuse large B-cell lymphoma.^1-3 Consequently, there have been several attempts to increase treatment efficacy with intense chemotherapy regimens, namely DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab), or by adding targeted agents, such as ibrutinib and venetoclax to a standard R-CHOP (rituximab with reduced cyclophosphamide, doxorubicin, vincristine, and prednisone) backbone.^4-7 Though the standard choice of therapy for fit patients harboring HGBCL remains controversial, these aggressive regimens at standard doses are typically difficult to tolerate for patients aged > 80 years.

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Patients with immunosuppression are at higher risk for developing LPDs, including aggressive B-cell non-Hodgkin lymphomas such as diffuse large B-cell lymphoma. These patients are frequently classified into 2 groups: those with underlying autoimmune conditions (RA-associated LPDs), or those who have undergone solid-organ or allogeneic hematopoietic stem-cell transplants, which drives the development of posttransplant LPDs (Table).^8-11 Both types of LPDs are often EBER positive, indicating some association with Epstein-Barr virus infection driven by ongoing immunosuppression, with knowledge that this finding is not absolute and is less frequent among patients with autoimmune conditions than those with posttransplant LPD.^8,12

For indolent and early-stage aggressive LPDs, reduction of immunosuppression is a reasonable frontline treatment. In fact, Tokuyama and colleagues reported a previous case in which an methotrexate-associated EBER-positive early-stage diffuse large B-cell lymphoma responded well to methotrexate withdrawal.¹³ For advanced, aggressive LPDs associated with immunosuppression, a combination strategy of reducing immunosuppression and initiating a standard multiagent systemic therapy such as with R-CHOP is more common. Reducing immunosuppression without adding systemic anticancer therapy can certainly be considered in patients with EBER-negative LPDs; however, there is less evidence supporting this approach in the literature.

A case series of patients with EBER-positive double-hit HGBCL has been described previously, and response rates were low despite aggressive treatment.¹⁴ The current case differs from that case series in 2 ways. First, our patient did not have EBER-positive disease despite having an HGBCL associated with RA and methotrexate use. Second, our patient had a very rapid and excellent partial response simply with methotrexate discontinuation. Aggressive treatment was considered initially; however, given the patient’s age and performance status, reduction of immunosuppression alone was considered the frontline approach.

This case indicates that methotrexate withdrawal may lead to remission in patients with double-hit lymphoma, even without clear signs of Epstein-Barr virus infection being present. We are not sure why our patient with EBER-negative HGBCL responded differently to methotrexate withdrawal than the patients in the aforementioned case series with EBER-positive disease; nevertheless, a short trial of methotrexate withdrawal with repeat imaging 4 to 8 weeks after discontinuation seems reasonable for patients who are older, frail, and seemingly not fit for more aggressive treatment.

CONCLUSIONS

For our older patient with RA and biopsy-proven, stage IV EBER-negative HGBCL bearing MYC and BCL6 rearrangements (double hit), discontinuation of methotrexate led to a rapid and sustained marked response. Reducing immunosuppression should be considered for patients with LPDs associated with autoimmune conditions or immunosuppressive medications, regardless of additional multiagent systemic therapy administration. In older patients who are frail with aggressive B-cell lymphomas, a short trial of methotrexate withdrawal with quick interval imaging is a reasonable frontline option, regardless of EBER status.

Finding new liver lesions on imaging during a febrile illness may indicate hepatic abscesses or malignancy. These can be difficult to diagnose with imaging alone. Differentiating between infectious and neoplastic etiologies may require additional images and/or tissue samples.

Hepatic abscesses are more commonly seen with other abdominal or biliary infections while metastatic disease usually presents in patients with active cancer or on surveillance imaging. While renal cell carcinoma (RCC) is the most common malignant neoplasm of the kidney, chromophobe renal cell carcinoma (chRCC) is a rare subtype that comprises only 5% of RCC cases.¹ We present a case of a patient with numerous new liver lesions and fever, initially thought to be hepatic abscesses, who was found to have metastatic chRCC.

CASE PRESENTATION

A 53 year-old male with a history of stage 2 chRCC and right radical nephrectomy 2 years prior presented to the emergency department following 1 week of drenching night sweats, fatigue, and subjective fevers. In addition, the patient reported gradually progressive, dull, right upper-quadrant abdominal pain. He noted no other acute medical complaints at the time of presentation. His history was notable for hyperlipidemia. His only surgery was the nephrectomy 2 years earlier. The patient reported no alcohol, tobacco, or drug use, any recent travel, or pet or animal exposure. On admission, he was afebrile with normal heart rate and was normotensive. His physical examination was remarkable for hepatomegaly with right upper-quadrant abdominal tenderness to palpation with a negative Murphy sign. There were otherwise no abnormal cardiovascular, respiratory, or skin findings.

Laboratory tests during initial evaluation were notable for hemoglobin of 10.0 g/dL, white blood cell count of 16.7×10³ μL, alkaline phosphatase of 213 U/L, aspartate aminotransferase of 185 U/L, and alanine aminotransferase of 36 U/L. Screening tests for viral hepatitis A, B, and C were negative. Additional tests for HIV, rapid plasma reagin, Epstein-Barr virus, cytomegalovirus, and toxoplasma were negative. Tests for antimitochondrial, antismooth muscle, and serum antinuclear antibodies were negative.

figure_1.png

Chest X-ray did not reveal any acute cardiopulmonary process. Computed tomography with contrast of the abdomen and pelvis demonstrated numerous hypodensities within the right hepatic lobe. Right upper-quadrant ultrasound demonstrated multiple hyperechoic foci throughout the liver. confluent decreased T1 signal lesions with peripheral gadolinium hyperenhancement were evident on Gadolinium-enhanced T1-weighted magnetic resonance imaging (MRI) with fat saturation demonstrated numerous (Figure 1).

Liver biopsy and tissue cultures demonstrated normal hepatic tissue and no organism growth. Blood cultures demonstrated no growth. The patient was empirically treated with IV ceftriaxone 1 g daily and metronidazole 500 mg every 8 hours for suspected hepatic abscesses after he was admitted to the hospital.

figure_2.png

The patient’s symptoms initially improved following antibiotic treatment; however, he reported recurrence of the initial symptoms2 months later at a follow-up appointment with gastroenterology. Liver-associated enzymes also remained elevated despite 4 weeks of antibiotic treatment. Repeat gadolinium-enhanced T1 fat-saturated MRI demonstrated an interval increase in size and number of confluent hepatic lesions throughout the liver (Figure 2).

figure_4.png

figure_3.png

A repeat liver biopsy revealed metastatic chRCC (Figures 3 and 4) that was both morphologically and immunohistochemically similar to the first pathologic diagnosis made following nephrectomy. The first liver biopsy likely did not sample the metastatic lesions that were present but instead sampled the surrounding normal liver. The patient was initiated on lenvatinib and everolimus therapy with oncology, a recommended regimen per the National Comprehensive Cancer Network for patients with nonclear cell RCC.¹

DISCUSSION

Chromophobe RCC is a rare form of RCC that has a recurrence-free survival of > 80% when treated in early stages.² These neoplasms represent only 3000 to 6000 new cases of RCC annually, with an even lower incidence (6% to 7%) resulting in metastatic disease. The liver is the most common site of metastases (39%).² Previously reported metastatic chRCC hepatic lesions have been incidentally noted on imaging with asymptomatic clinical presentations. In contrast to our patient, most documented cases report metastatic chRCC as a solitary hepatic lesion.^3-7

A noteworthy genetic association with ChRCC is the Birt-Hogg-Dubé syndrome, which is an autosomal-dominant genetic disorder that results from germline mutations in the tumor suppressor folliculin gene located on chromosome 17.⁸ This syndrome is characterized by the development of various benign and malignant tumors, particularly chRCC. Our patient appeared to have a sporadic chRCC with the absence of other tumors and negative family history for malignancies. On his initial staging imaging, in accordance with National Comprehensive Cancer Network guidelines, our patient was identified only as having a 10-cm right renal mass and 1 benign regional lymph node with an otherwise unremarkable computed tomography of the chest, abdomen and pelvis, corresponding to stage 2 cancer.

Common causes of hepatic abscesses, the other potential diagnosis of concern for the patient, were biliary infections, portal vein ascension from abdominal sources, arterial translocation due to bacteremia, and local invasion due to suppuration of adjacent tissue.⁹ Incidence for hepatic abscesses increases with comorbidities such as diabetes, cirrhosis, malignancy, immunosuppression, and malnutrition.¹⁰Candida is also a common culprit when there are multiple, small abscesses, often in immunocompromised patients.¹¹ Given the high mortality rates associated with hepatic abscesses, prompt treatment is imperative.^10,12 Since the clinical signs and symptoms for hepatic abscesses are nonspecific (abdominal pain, fever, and malaise) and liver function tests can vary, the diagnosis primarily relies on imaging or tissue sampling.⁹

It can be difficult to distinguish abscesses from metastatic lesions based on imaging alone without microbiologic and pathologic confirmation.^11,13,14 There are certain radiologic characteristics that have been found to favor abscesses over metastasis, including parenchymal enhancement, arterial rim enhancement, and perilesional hyperemia.¹⁵ However, previously described hallmark characteristics of hepatic abscesses, such as the “cluster sign” demonstrating early stages of abscess coalescence, have also been seen in some hepatic metastases.¹⁶

CONCLUSIONS

This patient highlights the presentation of a rare case of metastatic chRCC with multiple hepatic lesions. While often differentiated clinically, radiographically, or histologically, malignancy and abscess can be difficult to differentiate in a patient with fevers and leukocytosis with hepatic lesions.¹⁷ Early diagnosis of hepatic abscesses and initiation of antibiotic therapy are essential. In cases when it is challenging to characterize the hepatic lesions, repeated tissue sampling and imaging can help direct therapy. Attention should be paid to a previous history of malignancy and should raise suspicion for metastatic disease, particularly with misleading imaging studies and tissue samples.

Acknowledgments

This case was presented as a poster presentation at the Tri-Service American College of Physicians Meeting, September 7-10, 2022, San Antonio, Texas.

Finding new liver lesions on imaging during a febrile illness may indicate hepatic abscesses or malignancy. These can be difficult to diagnose with imaging alone. Differentiating between infectious and neoplastic etiologies may require additional images and/or tissue samples.

Hepatic abscesses are more commonly seen with other abdominal or biliary infections while metastatic disease usually presents in patients with active cancer or on surveillance imaging. While renal cell carcinoma (RCC) is the most common malignant neoplasm of the kidney, chromophobe renal cell carcinoma (chRCC) is a rare subtype that comprises only 5% of RCC cases.¹ We present a case of a patient with numerous new liver lesions and fever, initially thought to be hepatic abscesses, who was found to have metastatic chRCC.

CASE PRESENTATION

A 53 year-old male with a history of stage 2 chRCC and right radical nephrectomy 2 years prior presented to the emergency department following 1 week of drenching night sweats, fatigue, and subjective fevers. In addition, the patient reported gradually progressive, dull, right upper-quadrant abdominal pain. He noted no other acute medical complaints at the time of presentation. His history was notable for hyperlipidemia. His only surgery was the nephrectomy 2 years earlier. The patient reported no alcohol, tobacco, or drug use, any recent travel, or pet or animal exposure. On admission, he was afebrile with normal heart rate and was normotensive. His physical examination was remarkable for hepatomegaly with right upper-quadrant abdominal tenderness to palpation with a negative Murphy sign. There were otherwise no abnormal cardiovascular, respiratory, or skin findings.

Laboratory tests during initial evaluation were notable for hemoglobin of 10.0 g/dL, white blood cell count of 16.7×10³ μL, alkaline phosphatase of 213 U/L, aspartate aminotransferase of 185 U/L, and alanine aminotransferase of 36 U/L. Screening tests for viral hepatitis A, B, and C were negative. Additional tests for HIV, rapid plasma reagin, Epstein-Barr virus, cytomegalovirus, and toxoplasma were negative. Tests for antimitochondrial, antismooth muscle, and serum antinuclear antibodies were negative.

figure_1.png

Chest X-ray did not reveal any acute cardiopulmonary process. Computed tomography with contrast of the abdomen and pelvis demonstrated numerous hypodensities within the right hepatic lobe. Right upper-quadrant ultrasound demonstrated multiple hyperechoic foci throughout the liver. confluent decreased T1 signal lesions with peripheral gadolinium hyperenhancement were evident on Gadolinium-enhanced T1-weighted magnetic resonance imaging (MRI) with fat saturation demonstrated numerous (Figure 1).

Liver biopsy and tissue cultures demonstrated normal hepatic tissue and no organism growth. Blood cultures demonstrated no growth. The patient was empirically treated with IV ceftriaxone 1 g daily and metronidazole 500 mg every 8 hours for suspected hepatic abscesses after he was admitted to the hospital.

figure_2.png

The patient’s symptoms initially improved following antibiotic treatment; however, he reported recurrence of the initial symptoms2 months later at a follow-up appointment with gastroenterology. Liver-associated enzymes also remained elevated despite 4 weeks of antibiotic treatment. Repeat gadolinium-enhanced T1 fat-saturated MRI demonstrated an interval increase in size and number of confluent hepatic lesions throughout the liver (Figure 2).

figure_4.png

figure_3.png

A repeat liver biopsy revealed metastatic chRCC (Figures 3 and 4) that was both morphologically and immunohistochemically similar to the first pathologic diagnosis made following nephrectomy. The first liver biopsy likely did not sample the metastatic lesions that were present but instead sampled the surrounding normal liver. The patient was initiated on lenvatinib and everolimus therapy with oncology, a recommended regimen per the National Comprehensive Cancer Network for patients with nonclear cell RCC.¹

DISCUSSION

Chromophobe RCC is a rare form of RCC that has a recurrence-free survival of > 80% when treated in early stages.² These neoplasms represent only 3000 to 6000 new cases of RCC annually, with an even lower incidence (6% to 7%) resulting in metastatic disease. The liver is the most common site of metastases (39%).² Previously reported metastatic chRCC hepatic lesions have been incidentally noted on imaging with asymptomatic clinical presentations. In contrast to our patient, most documented cases report metastatic chRCC as a solitary hepatic lesion.^3-7

A noteworthy genetic association with ChRCC is the Birt-Hogg-Dubé syndrome, which is an autosomal-dominant genetic disorder that results from germline mutations in the tumor suppressor folliculin gene located on chromosome 17.⁸ This syndrome is characterized by the development of various benign and malignant tumors, particularly chRCC. Our patient appeared to have a sporadic chRCC with the absence of other tumors and negative family history for malignancies. On his initial staging imaging, in accordance with National Comprehensive Cancer Network guidelines, our patient was identified only as having a 10-cm right renal mass and 1 benign regional lymph node with an otherwise unremarkable computed tomography of the chest, abdomen and pelvis, corresponding to stage 2 cancer.

Common causes of hepatic abscesses, the other potential diagnosis of concern for the patient, were biliary infections, portal vein ascension from abdominal sources, arterial translocation due to bacteremia, and local invasion due to suppuration of adjacent tissue.⁹ Incidence for hepatic abscesses increases with comorbidities such as diabetes, cirrhosis, malignancy, immunosuppression, and malnutrition.¹⁰Candida is also a common culprit when there are multiple, small abscesses, often in immunocompromised patients.¹¹ Given the high mortality rates associated with hepatic abscesses, prompt treatment is imperative.^10,12 Since the clinical signs and symptoms for hepatic abscesses are nonspecific (abdominal pain, fever, and malaise) and liver function tests can vary, the diagnosis primarily relies on imaging or tissue sampling.⁹

It can be difficult to distinguish abscesses from metastatic lesions based on imaging alone without microbiologic and pathologic confirmation.^11,13,14 There are certain radiologic characteristics that have been found to favor abscesses over metastasis, including parenchymal enhancement, arterial rim enhancement, and perilesional hyperemia.¹⁵ However, previously described hallmark characteristics of hepatic abscesses, such as the “cluster sign” demonstrating early stages of abscess coalescence, have also been seen in some hepatic metastases.¹⁶

CONCLUSIONS

This patient highlights the presentation of a rare case of metastatic chRCC with multiple hepatic lesions. While often differentiated clinically, radiographically, or histologically, malignancy and abscess can be difficult to differentiate in a patient with fevers and leukocytosis with hepatic lesions.¹⁷ Early diagnosis of hepatic abscesses and initiation of antibiotic therapy are essential. In cases when it is challenging to characterize the hepatic lesions, repeated tissue sampling and imaging can help direct therapy. Attention should be paid to a previous history of malignancy and should raise suspicion for metastatic disease, particularly with misleading imaging studies and tissue samples.

Acknowledgments

This case was presented as a poster presentation at the Tri-Service American College of Physicians Meeting, September 7-10, 2022, San Antonio, Texas.

Finding new liver lesions on imaging during a febrile illness may indicate hepatic abscesses or malignancy. These can be difficult to diagnose with imaging alone. Differentiating between infectious and neoplastic etiologies may require additional images and/or tissue samples.

Hepatic abscesses are more commonly seen with other abdominal or biliary infections while metastatic disease usually presents in patients with active cancer or on surveillance imaging. While renal cell carcinoma (RCC) is the most common malignant neoplasm of the kidney, chromophobe renal cell carcinoma (chRCC) is a rare subtype that comprises only 5% of RCC cases.¹ We present a case of a patient with numerous new liver lesions and fever, initially thought to be hepatic abscesses, who was found to have metastatic chRCC.

CASE PRESENTATION

A 53 year-old male with a history of stage 2 chRCC and right radical nephrectomy 2 years prior presented to the emergency department following 1 week of drenching night sweats, fatigue, and subjective fevers. In addition, the patient reported gradually progressive, dull, right upper-quadrant abdominal pain. He noted no other acute medical complaints at the time of presentation. His history was notable for hyperlipidemia. His only surgery was the nephrectomy 2 years earlier. The patient reported no alcohol, tobacco, or drug use, any recent travel, or pet or animal exposure. On admission, he was afebrile with normal heart rate and was normotensive. His physical examination was remarkable for hepatomegaly with right upper-quadrant abdominal tenderness to palpation with a negative Murphy sign. There were otherwise no abnormal cardiovascular, respiratory, or skin findings.

Laboratory tests during initial evaluation were notable for hemoglobin of 10.0 g/dL, white blood cell count of 16.7×10³ μL, alkaline phosphatase of 213 U/L, aspartate aminotransferase of 185 U/L, and alanine aminotransferase of 36 U/L. Screening tests for viral hepatitis A, B, and C were negative. Additional tests for HIV, rapid plasma reagin, Epstein-Barr virus, cytomegalovirus, and toxoplasma were negative. Tests for antimitochondrial, antismooth muscle, and serum antinuclear antibodies were negative.

figure_1.png

Chest X-ray did not reveal any acute cardiopulmonary process. Computed tomography with contrast of the abdomen and pelvis demonstrated numerous hypodensities within the right hepatic lobe. Right upper-quadrant ultrasound demonstrated multiple hyperechoic foci throughout the liver. confluent decreased T1 signal lesions with peripheral gadolinium hyperenhancement were evident on Gadolinium-enhanced T1-weighted magnetic resonance imaging (MRI) with fat saturation demonstrated numerous (Figure 1).

Liver biopsy and tissue cultures demonstrated normal hepatic tissue and no organism growth. Blood cultures demonstrated no growth. The patient was empirically treated with IV ceftriaxone 1 g daily and metronidazole 500 mg every 8 hours for suspected hepatic abscesses after he was admitted to the hospital.

figure_2.png

The patient’s symptoms initially improved following antibiotic treatment; however, he reported recurrence of the initial symptoms2 months later at a follow-up appointment with gastroenterology. Liver-associated enzymes also remained elevated despite 4 weeks of antibiotic treatment. Repeat gadolinium-enhanced T1 fat-saturated MRI demonstrated an interval increase in size and number of confluent hepatic lesions throughout the liver (Figure 2).

figure_4.png

figure_3.png

A repeat liver biopsy revealed metastatic chRCC (Figures 3 and 4) that was both morphologically and immunohistochemically similar to the first pathologic diagnosis made following nephrectomy. The first liver biopsy likely did not sample the metastatic lesions that were present but instead sampled the surrounding normal liver. The patient was initiated on lenvatinib and everolimus therapy with oncology, a recommended regimen per the National Comprehensive Cancer Network for patients with nonclear cell RCC.¹

DISCUSSION

Chromophobe RCC is a rare form of RCC that has a recurrence-free survival of > 80% when treated in early stages.² These neoplasms represent only 3000 to 6000 new cases of RCC annually, with an even lower incidence (6% to 7%) resulting in metastatic disease. The liver is the most common site of metastases (39%).² Previously reported metastatic chRCC hepatic lesions have been incidentally noted on imaging with asymptomatic clinical presentations. In contrast to our patient, most documented cases report metastatic chRCC as a solitary hepatic lesion.^3-7

A noteworthy genetic association with ChRCC is the Birt-Hogg-Dubé syndrome, which is an autosomal-dominant genetic disorder that results from germline mutations in the tumor suppressor folliculin gene located on chromosome 17.⁸ This syndrome is characterized by the development of various benign and malignant tumors, particularly chRCC. Our patient appeared to have a sporadic chRCC with the absence of other tumors and negative family history for malignancies. On his initial staging imaging, in accordance with National Comprehensive Cancer Network guidelines, our patient was identified only as having a 10-cm right renal mass and 1 benign regional lymph node with an otherwise unremarkable computed tomography of the chest, abdomen and pelvis, corresponding to stage 2 cancer.

Common causes of hepatic abscesses, the other potential diagnosis of concern for the patient, were biliary infections, portal vein ascension from abdominal sources, arterial translocation due to bacteremia, and local invasion due to suppuration of adjacent tissue.⁹ Incidence for hepatic abscesses increases with comorbidities such as diabetes, cirrhosis, malignancy, immunosuppression, and malnutrition.¹⁰Candida is also a common culprit when there are multiple, small abscesses, often in immunocompromised patients.¹¹ Given the high mortality rates associated with hepatic abscesses, prompt treatment is imperative.^10,12 Since the clinical signs and symptoms for hepatic abscesses are nonspecific (abdominal pain, fever, and malaise) and liver function tests can vary, the diagnosis primarily relies on imaging or tissue sampling.⁹

It can be difficult to distinguish abscesses from metastatic lesions based on imaging alone without microbiologic and pathologic confirmation.^11,13,14 There are certain radiologic characteristics that have been found to favor abscesses over metastasis, including parenchymal enhancement, arterial rim enhancement, and perilesional hyperemia.¹⁵ However, previously described hallmark characteristics of hepatic abscesses, such as the “cluster sign” demonstrating early stages of abscess coalescence, have also been seen in some hepatic metastases.¹⁶

CONCLUSIONS

This patient highlights the presentation of a rare case of metastatic chRCC with multiple hepatic lesions. While often differentiated clinically, radiographically, or histologically, malignancy and abscess can be difficult to differentiate in a patient with fevers and leukocytosis with hepatic lesions.¹⁷ Early diagnosis of hepatic abscesses and initiation of antibiotic therapy are essential. In cases when it is challenging to characterize the hepatic lesions, repeated tissue sampling and imaging can help direct therapy. Attention should be paid to a previous history of malignancy and should raise suspicion for metastatic disease, particularly with misleading imaging studies and tissue samples.

Acknowledgments

This case was presented as a poster presentation at the Tri-Service American College of Physicians Meeting, September 7-10, 2022, San Antonio, Texas.

Nonadherence to medications is an issue across health care. In endocrinology, hypothyroidism, a deficiency of thyroid hormones, is most often treated with levothyroxine and if left untreated can lead to myxedema coma, which can lead to death due to multiorgan dysfunction.¹ Therefore, adherence to levothyroxine is very important in preventing fatal complications.

We present the case of a patient with persistent primary hypothyroidism who was suspected to be nonadherent to levothyroxine, although the patient consistently claimed adherence. The patient’s plasma thyrotropin (TSH) level improved to reference range after 6 weeks of weekly primary care clinic visits. After stopping the visits, his plasma TSH level increased again, so 9 more weeks of visits resumed, which again helped bring down his plasma TSH levels.

Case Presentation

A male patient aged 67 years presented to the Dayton Veterans Affairs Medical Center (VAMC) endocrinology clinic for evaluation of thyroid nodules. The patient reported no history of neck irradiation and a physical examination was unremarkable. At that time, laboratory results showed a slightly elevated plasma TSH level of 4.35 uIU/mL (reference range, 0.35-4.00 uIU/mL) and normal free thyroxine (T4) of 1.00 ng/dL (reference range, 0.74-1.46 ng/dL). Later that year, the patient underwent a total thyroidectomy at the Cincinnati VAMC for Hurthle cell variant papillary thyroid carcinoma that was noted on biopsy at the Dayton VAMC. After surgical pathology results were available, the patient started levothyroxine 200 mcg daily, although 224 mcg would have been more appropriate based on his 142 kg weight. Due to a history of arrhythmia, the goal plasma TSH level was 0.10 to 0.50 uIU/mL. The patient subsequently underwent radioactive iodine ablation. After levothyroxine dose adjustments, the patient’s plasma TSH level was noted to be within his target range at 0.28 uIU/mL 3 months postablation.

Over the next 5 years the patient had regular laboratory tests during which his plasma TSH level rose and were typically high despite adjusting levothyroxine doses between 200 mcg and 325 mcg. The patient received counseling on taking the medication in the morning on an empty stomach and waiting at least 1 hour before consuming anything, and he went to many follow-up visits at the Dayton VAMC endocrinology clinic. He reported no vomiting or diarrhea but endorsed weight gain once. The patient also had high free T4 at times and did not take extra levothyroxine before undergoing laboratory tests.

Nonadherence to levothyroxine was suspected, but the patient insisted he was adherent. He received the medication in the mail regularly, generally had 90-day refills unless a dose change was made, used a pill box, and had social support from his son, but he did not use a phone alarm to remind him to take it. A home care nurse made weekly visits to make sure the remaining levothyroxine pill counts were correct; however, the patient continued to have difficulty maintaining daily adherence at home as indicated by the nurse’s pill counts not aligning with the number of pills which should have been left if the patient was talking the pills daily.

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The patient was asked to visit a local community-based outpatient clinic (CBOC) weekly (to avoid patient travel time to Dayton VAMC > 1 hour) to check pill counts and assess adherence. The patient went to the CBOC clinic for these visits, during which pill counts indicated much better but not 100% adherence. After 6 weeks of clinic visits, his plasma TSH decreased to 1.01 uIU/mL, which was within the reference range, and the patient stopped coming to the weekly clinic visits (Table). Four months later, the patient's plasma TSH levels increased to 80.72 uIU/mL. Nonadherence to levothyroxine was suspected again. He was asked to resume weekly clinic visits, and the life-threatening effects of hypothyroidism and not taking levothyroxine were discussed with the patient and his son. The patient made CBOC clinic visits for 9 weeks, after which his plasma TSH level was low at 0.23 uIU/mL.

There are multiple important causes to consider in patients with persistent hypothyroidism. One is medication nonadherence, which was most likely seen in the patient in this case. Missing even 1 day of levothyroxine can affect TSH and thyroid hormone levels for several days due to the long half-life of the medication.² Hepp and colleagues found that patients with hypothyroidism were significantly more likely to be nonadherent to levothyroxine if they had comorbid conditions such as type 2 diabetes or were obese.³ Another study of levothyroxine adherence found that the most common reason for missing doses was forgetfulness.⁴ However, memory and cognition impairments can also be symptoms of hypothyroidism itself; Haskard-Zolnierek and colleagues found a significant association between nonadherence to levothyroxine and self-reported brain fog in patients with hypothyroidism.⁵

Another cause of persistent hypothyroidism is malabsorption. Absorption of levothyroxine can be affected by intestinal malabsorption due to inflammatory bowel disease, lactose intolerance, or gastrointestinal infection, as well as several foods, drinks (eg, coffee), medications, vitamins, and supplements (eg, proton-pump inhibitors and calcium).^2,6 Levothyroxine is absorbed mainly at the jejunum and upper ileum, so any pathologies or ingested items that would directly or indirectly affect absorption at those sites can affect levothyroxine absorption.²

A liquid levothyroxine formulation can help with malabsorption.² Alternatively, weight gain may lead to a need for increasing the dosage of levothyroxine.^2,6 Other factors that can affect TSH levels include Addison disease, dysregulation of the hypothalamic-pituitary-thyroid axis, and TSH heterophile antibodies.²

Research describes methods that have effectively treated hypothyroidism in patients struggling with levothyroxine adherence. Two case reports describe weekly visits for levothyroxine administration successfully treating uncontrolled hypothyroidism.^7,8 A meta-analysis found that while weekly levothyroxine tablets led to a higher mean TSH level than daily use, weekly use still led to reference-range TSH levels, suggesting that weekly levothyroxine may be a helpful alternative for nonadherent patients.⁹ Alternatively, patients taking levothyroxine tablets have been shown to forget to take their medication more frequently compared to those taking the liquid formulation.^10,11 Additionally, a study by El Helou and colleagues found that adherence to levothyroxine was significantly improved when patients had endocrinology visits once a month and when the endocrinologist provided information about hypothyroidism.¹²

Another method that may improve adherence to levothyroxine is telehealth visits. This would be especially helpful for patients who live far from the clinic or do not have the time, transportation, or financial means to visit the clinic for weekly visits to assess medication adherence. Additionally, patients may be afraid of admitting to a health care professional that they are nonadherent. Clinicians must be tactful when asking about adherence to make the patient feel comfortable with admitting to nonadherence if their cognition is not impaired. Then, a patient-led conversation can occur regarding realistic ways the patient feels they can work toward adherence.

To our knowledge, the patient in this case report had no symptoms of intestinal malabsorption, and weight gain was not thought to be the issue, as levothyroxine dosage was adjusted multiple times. His plasma TSH levels returned to reference range after weekly pill count visits for 6 weeks and after weekly pill count visits for 9 weeks. Therefore, nonadherence to levothyroxine was suspected to be the cause of frequently elevated plasma TSH levels despite the patient’s insistence on adherence. While the patient did not report memory issues, cognitive impairments due to hypothyroidism may have been contributing to his probable nonadherence. Additionally, he had comorbidities, such as type 2 diabetes mellitus and obesity, which may have made adherence more difficult.

Levothyroxine was also only prescribed in daily tablet form, so the frequency and formulation may have also contributed to nonadherence. While the home nurse was originally sent to assess the patient’s adherence, the care team could have had the nurse start giving the patient weekly levothyroxine once nonadherence was determined to be a likely issue. The patient’s adherence only improved when he went to the clinic for pill counts but not when the home nurse came to his house weekly; this could be because the patient knew he had to invest the time to physically go to clinic visits for pill checks, motivating him to increase adherence.

Conclusions

This case reports a patient with frequently high plasma TSH levels achieving normalization of plasma TSH levels after weekly medication adherence checks at a primary care clinic. Weekly visits to a clinic seem impractical compared to weekly dosing with a visiting nurse; however, after review of the literature, this may be an approach to consider in the future. This strategy may especially help in cases of persistent abnormal plasma TSH levels in which no etiology can be found other than suspected medication nonadherence. Knowing their medication use will be checked at weekly clinic visits may motivate patients to be adherent.

Nonadherence to medications is an issue across health care. In endocrinology, hypothyroidism, a deficiency of thyroid hormones, is most often treated with levothyroxine and if left untreated can lead to myxedema coma, which can lead to death due to multiorgan dysfunction.¹ Therefore, adherence to levothyroxine is very important in preventing fatal complications.

We present the case of a patient with persistent primary hypothyroidism who was suspected to be nonadherent to levothyroxine, although the patient consistently claimed adherence. The patient’s plasma thyrotropin (TSH) level improved to reference range after 6 weeks of weekly primary care clinic visits. After stopping the visits, his plasma TSH level increased again, so 9 more weeks of visits resumed, which again helped bring down his plasma TSH levels.

Case Presentation

A male patient aged 67 years presented to the Dayton Veterans Affairs Medical Center (VAMC) endocrinology clinic for evaluation of thyroid nodules. The patient reported no history of neck irradiation and a physical examination was unremarkable. At that time, laboratory results showed a slightly elevated plasma TSH level of 4.35 uIU/mL (reference range, 0.35-4.00 uIU/mL) and normal free thyroxine (T4) of 1.00 ng/dL (reference range, 0.74-1.46 ng/dL). Later that year, the patient underwent a total thyroidectomy at the Cincinnati VAMC for Hurthle cell variant papillary thyroid carcinoma that was noted on biopsy at the Dayton VAMC. After surgical pathology results were available, the patient started levothyroxine 200 mcg daily, although 224 mcg would have been more appropriate based on his 142 kg weight. Due to a history of arrhythmia, the goal plasma TSH level was 0.10 to 0.50 uIU/mL. The patient subsequently underwent radioactive iodine ablation. After levothyroxine dose adjustments, the patient’s plasma TSH level was noted to be within his target range at 0.28 uIU/mL 3 months postablation.

Over the next 5 years the patient had regular laboratory tests during which his plasma TSH level rose and were typically high despite adjusting levothyroxine doses between 200 mcg and 325 mcg. The patient received counseling on taking the medication in the morning on an empty stomach and waiting at least 1 hour before consuming anything, and he went to many follow-up visits at the Dayton VAMC endocrinology clinic. He reported no vomiting or diarrhea but endorsed weight gain once. The patient also had high free T4 at times and did not take extra levothyroxine before undergoing laboratory tests.

Nonadherence to levothyroxine was suspected, but the patient insisted he was adherent. He received the medication in the mail regularly, generally had 90-day refills unless a dose change was made, used a pill box, and had social support from his son, but he did not use a phone alarm to remind him to take it. A home care nurse made weekly visits to make sure the remaining levothyroxine pill counts were correct; however, the patient continued to have difficulty maintaining daily adherence at home as indicated by the nurse’s pill counts not aligning with the number of pills which should have been left if the patient was talking the pills daily.

table.png

The patient was asked to visit a local community-based outpatient clinic (CBOC) weekly (to avoid patient travel time to Dayton VAMC > 1 hour) to check pill counts and assess adherence. The patient went to the CBOC clinic for these visits, during which pill counts indicated much better but not 100% adherence. After 6 weeks of clinic visits, his plasma TSH decreased to 1.01 uIU/mL, which was within the reference range, and the patient stopped coming to the weekly clinic visits (Table). Four months later, the patient's plasma TSH levels increased to 80.72 uIU/mL. Nonadherence to levothyroxine was suspected again. He was asked to resume weekly clinic visits, and the life-threatening effects of hypothyroidism and not taking levothyroxine were discussed with the patient and his son. The patient made CBOC clinic visits for 9 weeks, after which his plasma TSH level was low at 0.23 uIU/mL.

There are multiple important causes to consider in patients with persistent hypothyroidism. One is medication nonadherence, which was most likely seen in the patient in this case. Missing even 1 day of levothyroxine can affect TSH and thyroid hormone levels for several days due to the long half-life of the medication.² Hepp and colleagues found that patients with hypothyroidism were significantly more likely to be nonadherent to levothyroxine if they had comorbid conditions such as type 2 diabetes or were obese.³ Another study of levothyroxine adherence found that the most common reason for missing doses was forgetfulness.⁴ However, memory and cognition impairments can also be symptoms of hypothyroidism itself; Haskard-Zolnierek and colleagues found a significant association between nonadherence to levothyroxine and self-reported brain fog in patients with hypothyroidism.⁵

Another cause of persistent hypothyroidism is malabsorption. Absorption of levothyroxine can be affected by intestinal malabsorption due to inflammatory bowel disease, lactose intolerance, or gastrointestinal infection, as well as several foods, drinks (eg, coffee), medications, vitamins, and supplements (eg, proton-pump inhibitors and calcium).^2,6 Levothyroxine is absorbed mainly at the jejunum and upper ileum, so any pathologies or ingested items that would directly or indirectly affect absorption at those sites can affect levothyroxine absorption.²

A liquid levothyroxine formulation can help with malabsorption.² Alternatively, weight gain may lead to a need for increasing the dosage of levothyroxine.^2,6 Other factors that can affect TSH levels include Addison disease, dysregulation of the hypothalamic-pituitary-thyroid axis, and TSH heterophile antibodies.²

Research describes methods that have effectively treated hypothyroidism in patients struggling with levothyroxine adherence. Two case reports describe weekly visits for levothyroxine administration successfully treating uncontrolled hypothyroidism.^7,8 A meta-analysis found that while weekly levothyroxine tablets led to a higher mean TSH level than daily use, weekly use still led to reference-range TSH levels, suggesting that weekly levothyroxine may be a helpful alternative for nonadherent patients.⁹ Alternatively, patients taking levothyroxine tablets have been shown to forget to take their medication more frequently compared to those taking the liquid formulation.^10,11 Additionally, a study by El Helou and colleagues found that adherence to levothyroxine was significantly improved when patients had endocrinology visits once a month and when the endocrinologist provided information about hypothyroidism.¹²

Another method that may improve adherence to levothyroxine is telehealth visits. This would be especially helpful for patients who live far from the clinic or do not have the time, transportation, or financial means to visit the clinic for weekly visits to assess medication adherence. Additionally, patients may be afraid of admitting to a health care professional that they are nonadherent. Clinicians must be tactful when asking about adherence to make the patient feel comfortable with admitting to nonadherence if their cognition is not impaired. Then, a patient-led conversation can occur regarding realistic ways the patient feels they can work toward adherence.

To our knowledge, the patient in this case report had no symptoms of intestinal malabsorption, and weight gain was not thought to be the issue, as levothyroxine dosage was adjusted multiple times. His plasma TSH levels returned to reference range after weekly pill count visits for 6 weeks and after weekly pill count visits for 9 weeks. Therefore, nonadherence to levothyroxine was suspected to be the cause of frequently elevated plasma TSH levels despite the patient’s insistence on adherence. While the patient did not report memory issues, cognitive impairments due to hypothyroidism may have been contributing to his probable nonadherence. Additionally, he had comorbidities, such as type 2 diabetes mellitus and obesity, which may have made adherence more difficult.

Levothyroxine was also only prescribed in daily tablet form, so the frequency and formulation may have also contributed to nonadherence. While the home nurse was originally sent to assess the patient’s adherence, the care team could have had the nurse start giving the patient weekly levothyroxine once nonadherence was determined to be a likely issue. The patient’s adherence only improved when he went to the clinic for pill counts but not when the home nurse came to his house weekly; this could be because the patient knew he had to invest the time to physically go to clinic visits for pill checks, motivating him to increase adherence.

Conclusions

This case reports a patient with frequently high plasma TSH levels achieving normalization of plasma TSH levels after weekly medication adherence checks at a primary care clinic. Weekly visits to a clinic seem impractical compared to weekly dosing with a visiting nurse; however, after review of the literature, this may be an approach to consider in the future. This strategy may especially help in cases of persistent abnormal plasma TSH levels in which no etiology can be found other than suspected medication nonadherence. Knowing their medication use will be checked at weekly clinic visits may motivate patients to be adherent.

Nonadherence to medications is an issue across health care. In endocrinology, hypothyroidism, a deficiency of thyroid hormones, is most often treated with levothyroxine and if left untreated can lead to myxedema coma, which can lead to death due to multiorgan dysfunction.¹ Therefore, adherence to levothyroxine is very important in preventing fatal complications.

We present the case of a patient with persistent primary hypothyroidism who was suspected to be nonadherent to levothyroxine, although the patient consistently claimed adherence. The patient’s plasma thyrotropin (TSH) level improved to reference range after 6 weeks of weekly primary care clinic visits. After stopping the visits, his plasma TSH level increased again, so 9 more weeks of visits resumed, which again helped bring down his plasma TSH levels.

Case Presentation

A male patient aged 67 years presented to the Dayton Veterans Affairs Medical Center (VAMC) endocrinology clinic for evaluation of thyroid nodules. The patient reported no history of neck irradiation and a physical examination was unremarkable. At that time, laboratory results showed a slightly elevated plasma TSH level of 4.35 uIU/mL (reference range, 0.35-4.00 uIU/mL) and normal free thyroxine (T4) of 1.00 ng/dL (reference range, 0.74-1.46 ng/dL). Later that year, the patient underwent a total thyroidectomy at the Cincinnati VAMC for Hurthle cell variant papillary thyroid carcinoma that was noted on biopsy at the Dayton VAMC. After surgical pathology results were available, the patient started levothyroxine 200 mcg daily, although 224 mcg would have been more appropriate based on his 142 kg weight. Due to a history of arrhythmia, the goal plasma TSH level was 0.10 to 0.50 uIU/mL. The patient subsequently underwent radioactive iodine ablation. After levothyroxine dose adjustments, the patient’s plasma TSH level was noted to be within his target range at 0.28 uIU/mL 3 months postablation.

Over the next 5 years the patient had regular laboratory tests during which his plasma TSH level rose and were typically high despite adjusting levothyroxine doses between 200 mcg and 325 mcg. The patient received counseling on taking the medication in the morning on an empty stomach and waiting at least 1 hour before consuming anything, and he went to many follow-up visits at the Dayton VAMC endocrinology clinic. He reported no vomiting or diarrhea but endorsed weight gain once. The patient also had high free T4 at times and did not take extra levothyroxine before undergoing laboratory tests.

Nonadherence to levothyroxine was suspected, but the patient insisted he was adherent. He received the medication in the mail regularly, generally had 90-day refills unless a dose change was made, used a pill box, and had social support from his son, but he did not use a phone alarm to remind him to take it. A home care nurse made weekly visits to make sure the remaining levothyroxine pill counts were correct; however, the patient continued to have difficulty maintaining daily adherence at home as indicated by the nurse’s pill counts not aligning with the number of pills which should have been left if the patient was talking the pills daily.

table.png

The patient was asked to visit a local community-based outpatient clinic (CBOC) weekly (to avoid patient travel time to Dayton VAMC > 1 hour) to check pill counts and assess adherence. The patient went to the CBOC clinic for these visits, during which pill counts indicated much better but not 100% adherence. After 6 weeks of clinic visits, his plasma TSH decreased to 1.01 uIU/mL, which was within the reference range, and the patient stopped coming to the weekly clinic visits (Table). Four months later, the patient's plasma TSH levels increased to 80.72 uIU/mL. Nonadherence to levothyroxine was suspected again. He was asked to resume weekly clinic visits, and the life-threatening effects of hypothyroidism and not taking levothyroxine were discussed with the patient and his son. The patient made CBOC clinic visits for 9 weeks, after which his plasma TSH level was low at 0.23 uIU/mL.

There are multiple important causes to consider in patients with persistent hypothyroidism. One is medication nonadherence, which was most likely seen in the patient in this case. Missing even 1 day of levothyroxine can affect TSH and thyroid hormone levels for several days due to the long half-life of the medication.² Hepp and colleagues found that patients with hypothyroidism were significantly more likely to be nonadherent to levothyroxine if they had comorbid conditions such as type 2 diabetes or were obese.³ Another study of levothyroxine adherence found that the most common reason for missing doses was forgetfulness.⁴ However, memory and cognition impairments can also be symptoms of hypothyroidism itself; Haskard-Zolnierek and colleagues found a significant association between nonadherence to levothyroxine and self-reported brain fog in patients with hypothyroidism.⁵

Another cause of persistent hypothyroidism is malabsorption. Absorption of levothyroxine can be affected by intestinal malabsorption due to inflammatory bowel disease, lactose intolerance, or gastrointestinal infection, as well as several foods, drinks (eg, coffee), medications, vitamins, and supplements (eg, proton-pump inhibitors and calcium).^2,6 Levothyroxine is absorbed mainly at the jejunum and upper ileum, so any pathologies or ingested items that would directly or indirectly affect absorption at those sites can affect levothyroxine absorption.²

A liquid levothyroxine formulation can help with malabsorption.² Alternatively, weight gain may lead to a need for increasing the dosage of levothyroxine.^2,6 Other factors that can affect TSH levels include Addison disease, dysregulation of the hypothalamic-pituitary-thyroid axis, and TSH heterophile antibodies.²

Research describes methods that have effectively treated hypothyroidism in patients struggling with levothyroxine adherence. Two case reports describe weekly visits for levothyroxine administration successfully treating uncontrolled hypothyroidism.^7,8 A meta-analysis found that while weekly levothyroxine tablets led to a higher mean TSH level than daily use, weekly use still led to reference-range TSH levels, suggesting that weekly levothyroxine may be a helpful alternative for nonadherent patients.⁹ Alternatively, patients taking levothyroxine tablets have been shown to forget to take their medication more frequently compared to those taking the liquid formulation.^10,11 Additionally, a study by El Helou and colleagues found that adherence to levothyroxine was significantly improved when patients had endocrinology visits once a month and when the endocrinologist provided information about hypothyroidism.¹²

Another method that may improve adherence to levothyroxine is telehealth visits. This would be especially helpful for patients who live far from the clinic or do not have the time, transportation, or financial means to visit the clinic for weekly visits to assess medication adherence. Additionally, patients may be afraid of admitting to a health care professional that they are nonadherent. Clinicians must be tactful when asking about adherence to make the patient feel comfortable with admitting to nonadherence if their cognition is not impaired. Then, a patient-led conversation can occur regarding realistic ways the patient feels they can work toward adherence.

To our knowledge, the patient in this case report had no symptoms of intestinal malabsorption, and weight gain was not thought to be the issue, as levothyroxine dosage was adjusted multiple times. His plasma TSH levels returned to reference range after weekly pill count visits for 6 weeks and after weekly pill count visits for 9 weeks. Therefore, nonadherence to levothyroxine was suspected to be the cause of frequently elevated plasma TSH levels despite the patient’s insistence on adherence. While the patient did not report memory issues, cognitive impairments due to hypothyroidism may have been contributing to his probable nonadherence. Additionally, he had comorbidities, such as type 2 diabetes mellitus and obesity, which may have made adherence more difficult.

Levothyroxine was also only prescribed in daily tablet form, so the frequency and formulation may have also contributed to nonadherence. While the home nurse was originally sent to assess the patient’s adherence, the care team could have had the nurse start giving the patient weekly levothyroxine once nonadherence was determined to be a likely issue. The patient’s adherence only improved when he went to the clinic for pill counts but not when the home nurse came to his house weekly; this could be because the patient knew he had to invest the time to physically go to clinic visits for pill checks, motivating him to increase adherence.

Conclusions

This case reports a patient with frequently high plasma TSH levels achieving normalization of plasma TSH levels after weekly medication adherence checks at a primary care clinic. Weekly visits to a clinic seem impractical compared to weekly dosing with a visiting nurse; however, after review of the literature, this may be an approach to consider in the future. This strategy may especially help in cases of persistent abnormal plasma TSH levels in which no etiology can be found other than suspected medication nonadherence. Knowing their medication use will be checked at weekly clinic visits may motivate patients to be adherent.