Austin C. Casillas, BS

The Diagnosis: Lymphoepithelioma-like Carcinoma

Lymphoepithelioma-like carcinoma (LELC) is a rare, poorly differentiated, primary cutaneous neoplasm that occurs on sun-exposed skin, particularly on the head and neck of elderly individuals. It often manifests as an asymptomatic, slow-growing, flesh-colored or erythematous dermal nodule, though ulceration and tenderness have been reported.¹ Histopathologically, these neoplasms often are poorly circumscribed and can infiltrate surrounding subcutaneous and soft tissue. As a biphasic tumor, LELC is characterized by islands, nests, or trabeculae of epithelioid cells within the mid dermis surrounded by a dense lymphocytic infiltrate with plasma cells (Figure 1).¹ The epithelial component rarely communicates with the overlying epidermis and is composed of atypical polygonal cells with eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli, and frequent mitosis.² These epithelial nests can be highlighted by pancytokeratin AE1/AE3 or other epithelial differentiation markers (eg, CAM 5.2, CK5/6, epithelial membrane antigen, high-molecular-weight cytokeratin), while the surrounding lymphocytic infiltrate consists of an admixture of T cells and B cells. Lymphoepithelioma-like carcinomas also can demonstrate sebaceous, eccrine, or follicular differentiations.³ The epithelial nests of LELC also are positive for p63 and epithelial membrane antigen.²

Chaiprasit_1.jpg

The usual treatment of LELC is wide local excision or Mohs micrographic surgery.¹ Despite the poorly differentiated morphology of the tumor, LELC has a generally good prognosis with low metastatic potential and few reports of local recurrence after incomplete excision.³ Patients who are not candidates for surgery as well as recalcitrant cases are managed with radiotherapy.¹

Cutaneous lymphadenoma (CL) is a benign adnexal neoplasm that manifests as a small, solitary, fleshcolored nodule usually in the head and neck region.⁴ Histologically, CL consists of well-circumscribed epithelial nests within the dermis that are peripherally outlined by palisading basaloid cells and filled with clear to eosinophilic epithelioid cells (Figure 2).5 The fibrotic tumor stroma often is infiltrated by numerous intralobular dendritic cells and lymphocytes that occasionally can be arranged in germinal center–like nodules.⁴ The lymphoepithelial nature of CL can be challenging to distinguish morphologically from LELC, and immunohistochemistry stains may be required. In CL, both the basaloid and epithelioid cells stain positive for pancytokeratin AE1/ AE3, but the peripheral palisaded basaloid cells also stain positive for BerEP4. Additionally, the fibrotic stroma can be highlighted by CD34 and the intralobular dendritic cells by S-100.⁴

Chaiprasit_2.jpg

Nasopharyngeal carcinoma (NPC), formerly known as lymphoepithelioma, refers to carcinoma arising within the epithelium of the nasopharynx.⁶ Endemic to China, NPC manifests as an enlarging nasopharyngeal mass, causing clinical symptoms such as nasal obstruction and epistaxis.⁷ Histologically, nonkeratinizing NPC exhibits a biphasic morphology consisting of epithelioid neoplastic cells and background lymphocytic infiltrates (Figure 3). The epithelial component consists of round to oval neoplastic cells with amphophilic to eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli.⁶ Nasopharyngeal carcinoma is associated strongly with the Epstein-Barr virus while LELC is not; thus, Epstein- Barr encoding region in situ hybridization can reliably distinguish these entities. Metastatic NPC is rare but has been reported; therefore, it is highly recommended to perform an otolaryngologic examination in addition to testing for Epstein-Barr virus reactivity as part of a complete evaluation.⁸

Chaiprasit_3.jpg

Cutaneous squamous cell carcinoma (SCC) is a common epidermal malignancy with multiple subtypes and variable morphology. The clinical presentation of SCC is similar to LELC—an enlarging hyperkeratotic papule or nodule on sun-exposed skin that often is ulcerated and tender.⁹ Histologically, poorly differentiated nonkeratinizing SCC can form nests and trabeculae of epithelioid cells that are stained by epithelial differentiation markers, resembling the epithelioid nests of LELC. Distinguishing between LELC and poorly differentiated SCC with robust inflammatory infiltrate can be challenging (Figure 4). In fact, some experts support LELC as an SCC variant rather than a separate entity.9 However, in contrast to LELC, the dermal nests of SCC usually maintain an epidermal connection and often are associated with an overlying area of SCC in situ or welldifferentiated SCC.³

Chaiprasit_4.jpg

Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma. It is the most common type of cutaneous lymphoma, accounting for almost 50% of all reported cases.¹⁰ Classic MF has an indolent course and progresses through several clinical stages. Patches and plaques characterize early stages; lymphadenopathy indicates progression to later stages in which erythroderma may develop with coalescence of patches, plaques, and tumors; and MF present in blood or lymph nodes characterizes the late stage. Each stage of MF is different histologically—from a superficial lichenoid infiltrate with exocytosis of malignant T cells in the patch stage, to more robust epidermotropism and dermal infiltrate in the plaque stage, and finally a dense dermal infiltrate in the late stage.¹¹ The rare syringotropic variant of MF clinically manifests as solitary or multiple erythematous lesions, often with overlying alopecia. Syringotropic MF uniquely exhibits folliculotropism and syringotropism along with syringometaplasia on histologic evaluation (Figure 5).¹² The syringometaplasia can be difficult to distinguish from the epithelial nests of LELC, particularly with the lymphocytic background. Immunohistochemical panels for T-cell markers can highlight aberrant T cells in syringotropic MF through their usual loss of CD5 and CD7, in comparison to normal T cells in LELC.¹¹ An elevated CD4:CD8 ratio of 4:1 and molecular analysis for T-cell receptor gene clonal rearrangements also can support the diagnosis of MF.¹²

Chaiprasit_5.jpg

The Diagnosis: Lymphoepithelioma-like Carcinoma

Lymphoepithelioma-like carcinoma (LELC) is a rare, poorly differentiated, primary cutaneous neoplasm that occurs on sun-exposed skin, particularly on the head and neck of elderly individuals. It often manifests as an asymptomatic, slow-growing, flesh-colored or erythematous dermal nodule, though ulceration and tenderness have been reported.¹ Histopathologically, these neoplasms often are poorly circumscribed and can infiltrate surrounding subcutaneous and soft tissue. As a biphasic tumor, LELC is characterized by islands, nests, or trabeculae of epithelioid cells within the mid dermis surrounded by a dense lymphocytic infiltrate with plasma cells (Figure 1).¹ The epithelial component rarely communicates with the overlying epidermis and is composed of atypical polygonal cells with eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli, and frequent mitosis.² These epithelial nests can be highlighted by pancytokeratin AE1/AE3 or other epithelial differentiation markers (eg, CAM 5.2, CK5/6, epithelial membrane antigen, high-molecular-weight cytokeratin), while the surrounding lymphocytic infiltrate consists of an admixture of T cells and B cells. Lymphoepithelioma-like carcinomas also can demonstrate sebaceous, eccrine, or follicular differentiations.³ The epithelial nests of LELC also are positive for p63 and epithelial membrane antigen.²

Chaiprasit_1.jpg

The usual treatment of LELC is wide local excision or Mohs micrographic surgery.¹ Despite the poorly differentiated morphology of the tumor, LELC has a generally good prognosis with low metastatic potential and few reports of local recurrence after incomplete excision.³ Patients who are not candidates for surgery as well as recalcitrant cases are managed with radiotherapy.¹

Cutaneous lymphadenoma (CL) is a benign adnexal neoplasm that manifests as a small, solitary, fleshcolored nodule usually in the head and neck region.⁴ Histologically, CL consists of well-circumscribed epithelial nests within the dermis that are peripherally outlined by palisading basaloid cells and filled with clear to eosinophilic epithelioid cells (Figure 2).5 The fibrotic tumor stroma often is infiltrated by numerous intralobular dendritic cells and lymphocytes that occasionally can be arranged in germinal center–like nodules.⁴ The lymphoepithelial nature of CL can be challenging to distinguish morphologically from LELC, and immunohistochemistry stains may be required. In CL, both the basaloid and epithelioid cells stain positive for pancytokeratin AE1/ AE3, but the peripheral palisaded basaloid cells also stain positive for BerEP4. Additionally, the fibrotic stroma can be highlighted by CD34 and the intralobular dendritic cells by S-100.⁴

Chaiprasit_2.jpg

Nasopharyngeal carcinoma (NPC), formerly known as lymphoepithelioma, refers to carcinoma arising within the epithelium of the nasopharynx.⁶ Endemic to China, NPC manifests as an enlarging nasopharyngeal mass, causing clinical symptoms such as nasal obstruction and epistaxis.⁷ Histologically, nonkeratinizing NPC exhibits a biphasic morphology consisting of epithelioid neoplastic cells and background lymphocytic infiltrates (Figure 3). The epithelial component consists of round to oval neoplastic cells with amphophilic to eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli.⁶ Nasopharyngeal carcinoma is associated strongly with the Epstein-Barr virus while LELC is not; thus, Epstein- Barr encoding region in situ hybridization can reliably distinguish these entities. Metastatic NPC is rare but has been reported; therefore, it is highly recommended to perform an otolaryngologic examination in addition to testing for Epstein-Barr virus reactivity as part of a complete evaluation.⁸

Chaiprasit_3.jpg

Cutaneous squamous cell carcinoma (SCC) is a common epidermal malignancy with multiple subtypes and variable morphology. The clinical presentation of SCC is similar to LELC—an enlarging hyperkeratotic papule or nodule on sun-exposed skin that often is ulcerated and tender.⁹ Histologically, poorly differentiated nonkeratinizing SCC can form nests and trabeculae of epithelioid cells that are stained by epithelial differentiation markers, resembling the epithelioid nests of LELC. Distinguishing between LELC and poorly differentiated SCC with robust inflammatory infiltrate can be challenging (Figure 4). In fact, some experts support LELC as an SCC variant rather than a separate entity.9 However, in contrast to LELC, the dermal nests of SCC usually maintain an epidermal connection and often are associated with an overlying area of SCC in situ or welldifferentiated SCC.³

Chaiprasit_4.jpg

Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma. It is the most common type of cutaneous lymphoma, accounting for almost 50% of all reported cases.¹⁰ Classic MF has an indolent course and progresses through several clinical stages. Patches and plaques characterize early stages; lymphadenopathy indicates progression to later stages in which erythroderma may develop with coalescence of patches, plaques, and tumors; and MF present in blood or lymph nodes characterizes the late stage. Each stage of MF is different histologically—from a superficial lichenoid infiltrate with exocytosis of malignant T cells in the patch stage, to more robust epidermotropism and dermal infiltrate in the plaque stage, and finally a dense dermal infiltrate in the late stage.¹¹ The rare syringotropic variant of MF clinically manifests as solitary or multiple erythematous lesions, often with overlying alopecia. Syringotropic MF uniquely exhibits folliculotropism and syringotropism along with syringometaplasia on histologic evaluation (Figure 5).¹² The syringometaplasia can be difficult to distinguish from the epithelial nests of LELC, particularly with the lymphocytic background. Immunohistochemical panels for T-cell markers can highlight aberrant T cells in syringotropic MF through their usual loss of CD5 and CD7, in comparison to normal T cells in LELC.¹¹ An elevated CD4:CD8 ratio of 4:1 and molecular analysis for T-cell receptor gene clonal rearrangements also can support the diagnosis of MF.¹²

Chaiprasit_5.jpg

The Diagnosis: Lymphoepithelioma-like Carcinoma

Lymphoepithelioma-like carcinoma (LELC) is a rare, poorly differentiated, primary cutaneous neoplasm that occurs on sun-exposed skin, particularly on the head and neck of elderly individuals. It often manifests as an asymptomatic, slow-growing, flesh-colored or erythematous dermal nodule, though ulceration and tenderness have been reported.¹ Histopathologically, these neoplasms often are poorly circumscribed and can infiltrate surrounding subcutaneous and soft tissue. As a biphasic tumor, LELC is characterized by islands, nests, or trabeculae of epithelioid cells within the mid dermis surrounded by a dense lymphocytic infiltrate with plasma cells (Figure 1).¹ The epithelial component rarely communicates with the overlying epidermis and is composed of atypical polygonal cells with eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli, and frequent mitosis.² These epithelial nests can be highlighted by pancytokeratin AE1/AE3 or other epithelial differentiation markers (eg, CAM 5.2, CK5/6, epithelial membrane antigen, high-molecular-weight cytokeratin), while the surrounding lymphocytic infiltrate consists of an admixture of T cells and B cells. Lymphoepithelioma-like carcinomas also can demonstrate sebaceous, eccrine, or follicular differentiations.³ The epithelial nests of LELC also are positive for p63 and epithelial membrane antigen.²

Chaiprasit_1.jpg

The usual treatment of LELC is wide local excision or Mohs micrographic surgery.¹ Despite the poorly differentiated morphology of the tumor, LELC has a generally good prognosis with low metastatic potential and few reports of local recurrence after incomplete excision.³ Patients who are not candidates for surgery as well as recalcitrant cases are managed with radiotherapy.¹

Cutaneous lymphadenoma (CL) is a benign adnexal neoplasm that manifests as a small, solitary, fleshcolored nodule usually in the head and neck region.⁴ Histologically, CL consists of well-circumscribed epithelial nests within the dermis that are peripherally outlined by palisading basaloid cells and filled with clear to eosinophilic epithelioid cells (Figure 2).5 The fibrotic tumor stroma often is infiltrated by numerous intralobular dendritic cells and lymphocytes that occasionally can be arranged in germinal center–like nodules.⁴ The lymphoepithelial nature of CL can be challenging to distinguish morphologically from LELC, and immunohistochemistry stains may be required. In CL, both the basaloid and epithelioid cells stain positive for pancytokeratin AE1/ AE3, but the peripheral palisaded basaloid cells also stain positive for BerEP4. Additionally, the fibrotic stroma can be highlighted by CD34 and the intralobular dendritic cells by S-100.⁴

Chaiprasit_2.jpg

Nasopharyngeal carcinoma (NPC), formerly known as lymphoepithelioma, refers to carcinoma arising within the epithelium of the nasopharynx.⁶ Endemic to China, NPC manifests as an enlarging nasopharyngeal mass, causing clinical symptoms such as nasal obstruction and epistaxis.⁷ Histologically, nonkeratinizing NPC exhibits a biphasic morphology consisting of epithelioid neoplastic cells and background lymphocytic infiltrates (Figure 3). The epithelial component consists of round to oval neoplastic cells with amphophilic to eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli.⁶ Nasopharyngeal carcinoma is associated strongly with the Epstein-Barr virus while LELC is not; thus, Epstein- Barr encoding region in situ hybridization can reliably distinguish these entities. Metastatic NPC is rare but has been reported; therefore, it is highly recommended to perform an otolaryngologic examination in addition to testing for Epstein-Barr virus reactivity as part of a complete evaluation.⁸

Chaiprasit_3.jpg

Cutaneous squamous cell carcinoma (SCC) is a common epidermal malignancy with multiple subtypes and variable morphology. The clinical presentation of SCC is similar to LELC—an enlarging hyperkeratotic papule or nodule on sun-exposed skin that often is ulcerated and tender.⁹ Histologically, poorly differentiated nonkeratinizing SCC can form nests and trabeculae of epithelioid cells that are stained by epithelial differentiation markers, resembling the epithelioid nests of LELC. Distinguishing between LELC and poorly differentiated SCC with robust inflammatory infiltrate can be challenging (Figure 4). In fact, some experts support LELC as an SCC variant rather than a separate entity.9 However, in contrast to LELC, the dermal nests of SCC usually maintain an epidermal connection and often are associated with an overlying area of SCC in situ or welldifferentiated SCC.³

Chaiprasit_4.jpg

Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma. It is the most common type of cutaneous lymphoma, accounting for almost 50% of all reported cases.¹⁰ Classic MF has an indolent course and progresses through several clinical stages. Patches and plaques characterize early stages; lymphadenopathy indicates progression to later stages in which erythroderma may develop with coalescence of patches, plaques, and tumors; and MF present in blood or lymph nodes characterizes the late stage. Each stage of MF is different histologically—from a superficial lichenoid infiltrate with exocytosis of malignant T cells in the patch stage, to more robust epidermotropism and dermal infiltrate in the plaque stage, and finally a dense dermal infiltrate in the late stage.¹¹ The rare syringotropic variant of MF clinically manifests as solitary or multiple erythematous lesions, often with overlying alopecia. Syringotropic MF uniquely exhibits folliculotropism and syringotropism along with syringometaplasia on histologic evaluation (Figure 5).¹² The syringometaplasia can be difficult to distinguish from the epithelial nests of LELC, particularly with the lymphocytic background. Immunohistochemical panels for T-cell markers can highlight aberrant T cells in syringotropic MF through their usual loss of CD5 and CD7, in comparison to normal T cells in LELC.¹¹ An elevated CD4:CD8 ratio of 4:1 and molecular analysis for T-cell receptor gene clonal rearrangements also can support the diagnosis of MF.¹²

Chaiprasit_5.jpg

Hidradenitis suppurativa (HS) has an unpredictable disease course and poses substantial therapeutic challenges. It carries an increased risk for adverse cardiovascular outcomes and all-cause mortality. It also is associated with comorbidities including mood disorders, tobacco smoking, obesity, diabetes mellitus, sleep disorders, sexual dysfunction, and autoimmune diseases, which can complicate its management and considerably affect patients’ quality of life (QOL).¹ Hidradenitis suppurativa also disproportionately affects minority groups and has far-reaching inequities; for example, the condition has a notable economic impact on patients, including higher unemployment and disability rates, lower-paying jobs, less paid time off, and other indirect costs.^2,3 Race can impact how pain itself is treated. In one study (N = 217), Black patients with extremity fractures presenting to anemergency department were significantly less likely to receive analgesia compared to White patients despite reporting similar pain (57% vs 74%, respectively; P = .01).⁴ In another study, Hispanic patients were 7-times less likely to be treated with opioids compared to non-Hispanic patients with long-bone fractures.⁵ Herein, we highlight pain management disparities in HS patients.

Treating HS Comorbidities Helps Improve Pain

Pain is reported by almost all HS patients and is the symptom most associated with QOL impairment.^6,7 Pain in HS is multifactorial, with other symptoms and comorbidities affecting its severity. Treatment of acute flares often is painful and procedural, including intralesional steroid injections or incision and drainage.⁸ Algorithms for addressing pain through the treatment of comorbidities also have been developed.⁶ Although there are few studies on the medications that treat related comorbidities in HS, there is evidence of their benefits in similar diseases; for example, treating depression in patients with irritable bowel disease (IBD) improved pain perception, cognitive function, and sexual dysfunction.⁹

Depression exacerbates pain, and higher levels of depression have been observed in severe HS.^10,11 Additionally, more than 80% of individuals with HS report tobacco smoking.¹ Nicotine not only increases pain sensitivity and decreases pain tolerance but also worsens neuropathic, nociceptive, and psychosocial pain, as well as mood disorders and sleep disturbances.¹² Given the higher prevalence of depression and smoking in HS patients and the impact on pain, addressing these comorbidities is crucial. Additionally, poor sleep amplifies pain sensitivity and affects neurologic pain modulation.¹³ Chronic pain also is associated with obesity and sleep dysfunction.¹⁴

Treatments Targeting Pain and Comorbidities

Treatments that target comorbidities and other symptoms of HS also may improve pain. Bupropion is a well-studied antidepressant and first-line option to aid in smoking cessation. It provides acute and chronic pain relief associated with IBD and may perform similarly in patients with HS.^15-18 Bupropion also demonstrated dose-dependent weight reduction in obese and overweight individuals.^19,20 Additionally, varenicline is a first-line option to aid in smoking cessation and can be combined with bupropion to increase long-term efficacy.^21,22

Other antidepressants may alleviate HS pain. The selective norepinephrine reuptake inhibitors duloxetine and venlafaxine are recommended for chronic pain in HS.⁶ Selective serotonin reuptake inhibitors such as citalopram, escitalopram, and paroxetine are inexpensive and widely available antidepressants. Citalopram is as efficacious as duloxetine for chronic pain with fewer side effects.²³ Paroxetine has been shown to improve pain and pruritus, QOL, and depression in patients with IBD.²⁴ Benefits such as improved weight and sexual dysfunction also have been reported.²⁵

Metformin is well studied in Black patients, and greater glycemic response supports its efficacy for diabetes as well as HS, which disproportionately affects individuals with skin of color.²⁶ Metformin also targets other comorbidities of HS, such as improving insulin resistance, polycystic ovary syndrome, acne vulgaris, weight loss, hyperlipidemia, cardiovascular risk, and neuropsychologic conditions.²⁷ Growing evidence supports the use of metformin as a new agent in chronic pain management, specifically for patients with HS.^28,29

Final Thoughts

Hidradenitis suppurativa is a complex medical condition seen disproportionately in minority groups. Understanding common comorbidities as well as the biases associated with pain management will allow providers to treat HS patients more effectively. Dermatologists who see many HS patients should become more familiar with treating these associated comorbidities to provide patient care that is more holistic and effective.

Hidradenitis suppurativa (HS) has an unpredictable disease course and poses substantial therapeutic challenges. It carries an increased risk for adverse cardiovascular outcomes and all-cause mortality. It also is associated with comorbidities including mood disorders, tobacco smoking, obesity, diabetes mellitus, sleep disorders, sexual dysfunction, and autoimmune diseases, which can complicate its management and considerably affect patients’ quality of life (QOL).¹ Hidradenitis suppurativa also disproportionately affects minority groups and has far-reaching inequities; for example, the condition has a notable economic impact on patients, including higher unemployment and disability rates, lower-paying jobs, less paid time off, and other indirect costs.^2,3 Race can impact how pain itself is treated. In one study (N = 217), Black patients with extremity fractures presenting to anemergency department were significantly less likely to receive analgesia compared to White patients despite reporting similar pain (57% vs 74%, respectively; P = .01).⁴ In another study, Hispanic patients were 7-times less likely to be treated with opioids compared to non-Hispanic patients with long-bone fractures.⁵ Herein, we highlight pain management disparities in HS patients.

Treating HS Comorbidities Helps Improve Pain

Pain is reported by almost all HS patients and is the symptom most associated with QOL impairment.^6,7 Pain in HS is multifactorial, with other symptoms and comorbidities affecting its severity. Treatment of acute flares often is painful and procedural, including intralesional steroid injections or incision and drainage.⁸ Algorithms for addressing pain through the treatment of comorbidities also have been developed.⁶ Although there are few studies on the medications that treat related comorbidities in HS, there is evidence of their benefits in similar diseases; for example, treating depression in patients with irritable bowel disease (IBD) improved pain perception, cognitive function, and sexual dysfunction.⁹

Depression exacerbates pain, and higher levels of depression have been observed in severe HS.^10,11 Additionally, more than 80% of individuals with HS report tobacco smoking.¹ Nicotine not only increases pain sensitivity and decreases pain tolerance but also worsens neuropathic, nociceptive, and psychosocial pain, as well as mood disorders and sleep disturbances.¹² Given the higher prevalence of depression and smoking in HS patients and the impact on pain, addressing these comorbidities is crucial. Additionally, poor sleep amplifies pain sensitivity and affects neurologic pain modulation.¹³ Chronic pain also is associated with obesity and sleep dysfunction.¹⁴

Treatments Targeting Pain and Comorbidities

Treatments that target comorbidities and other symptoms of HS also may improve pain. Bupropion is a well-studied antidepressant and first-line option to aid in smoking cessation. It provides acute and chronic pain relief associated with IBD and may perform similarly in patients with HS.^15-18 Bupropion also demonstrated dose-dependent weight reduction in obese and overweight individuals.^19,20 Additionally, varenicline is a first-line option to aid in smoking cessation and can be combined with bupropion to increase long-term efficacy.^21,22

Other antidepressants may alleviate HS pain. The selective norepinephrine reuptake inhibitors duloxetine and venlafaxine are recommended for chronic pain in HS.⁶ Selective serotonin reuptake inhibitors such as citalopram, escitalopram, and paroxetine are inexpensive and widely available antidepressants. Citalopram is as efficacious as duloxetine for chronic pain with fewer side effects.²³ Paroxetine has been shown to improve pain and pruritus, QOL, and depression in patients with IBD.²⁴ Benefits such as improved weight and sexual dysfunction also have been reported.²⁵

Metformin is well studied in Black patients, and greater glycemic response supports its efficacy for diabetes as well as HS, which disproportionately affects individuals with skin of color.²⁶ Metformin also targets other comorbidities of HS, such as improving insulin resistance, polycystic ovary syndrome, acne vulgaris, weight loss, hyperlipidemia, cardiovascular risk, and neuropsychologic conditions.²⁷ Growing evidence supports the use of metformin as a new agent in chronic pain management, specifically for patients with HS.^28,29

Final Thoughts

Hidradenitis suppurativa is a complex medical condition seen disproportionately in minority groups. Understanding common comorbidities as well as the biases associated with pain management will allow providers to treat HS patients more effectively. Dermatologists who see many HS patients should become more familiar with treating these associated comorbidities to provide patient care that is more holistic and effective.

Hidradenitis suppurativa (HS) has an unpredictable disease course and poses substantial therapeutic challenges. It carries an increased risk for adverse cardiovascular outcomes and all-cause mortality. It also is associated with comorbidities including mood disorders, tobacco smoking, obesity, diabetes mellitus, sleep disorders, sexual dysfunction, and autoimmune diseases, which can complicate its management and considerably affect patients’ quality of life (QOL).¹ Hidradenitis suppurativa also disproportionately affects minority groups and has far-reaching inequities; for example, the condition has a notable economic impact on patients, including higher unemployment and disability rates, lower-paying jobs, less paid time off, and other indirect costs.^2,3 Race can impact how pain itself is treated. In one study (N = 217), Black patients with extremity fractures presenting to anemergency department were significantly less likely to receive analgesia compared to White patients despite reporting similar pain (57% vs 74%, respectively; P = .01).⁴ In another study, Hispanic patients were 7-times less likely to be treated with opioids compared to non-Hispanic patients with long-bone fractures.⁵ Herein, we highlight pain management disparities in HS patients.

Treating HS Comorbidities Helps Improve Pain

Pain is reported by almost all HS patients and is the symptom most associated with QOL impairment.^6,7 Pain in HS is multifactorial, with other symptoms and comorbidities affecting its severity. Treatment of acute flares often is painful and procedural, including intralesional steroid injections or incision and drainage.⁸ Algorithms for addressing pain through the treatment of comorbidities also have been developed.⁶ Although there are few studies on the medications that treat related comorbidities in HS, there is evidence of their benefits in similar diseases; for example, treating depression in patients with irritable bowel disease (IBD) improved pain perception, cognitive function, and sexual dysfunction.⁹

Depression exacerbates pain, and higher levels of depression have been observed in severe HS.^10,11 Additionally, more than 80% of individuals with HS report tobacco smoking.¹ Nicotine not only increases pain sensitivity and decreases pain tolerance but also worsens neuropathic, nociceptive, and psychosocial pain, as well as mood disorders and sleep disturbances.¹² Given the higher prevalence of depression and smoking in HS patients and the impact on pain, addressing these comorbidities is crucial. Additionally, poor sleep amplifies pain sensitivity and affects neurologic pain modulation.¹³ Chronic pain also is associated with obesity and sleep dysfunction.¹⁴

Treatments Targeting Pain and Comorbidities

Treatments that target comorbidities and other symptoms of HS also may improve pain. Bupropion is a well-studied antidepressant and first-line option to aid in smoking cessation. It provides acute and chronic pain relief associated with IBD and may perform similarly in patients with HS.^15-18 Bupropion also demonstrated dose-dependent weight reduction in obese and overweight individuals.^19,20 Additionally, varenicline is a first-line option to aid in smoking cessation and can be combined with bupropion to increase long-term efficacy.^21,22

Other antidepressants may alleviate HS pain. The selective norepinephrine reuptake inhibitors duloxetine and venlafaxine are recommended for chronic pain in HS.⁶ Selective serotonin reuptake inhibitors such as citalopram, escitalopram, and paroxetine are inexpensive and widely available antidepressants. Citalopram is as efficacious as duloxetine for chronic pain with fewer side effects.²³ Paroxetine has been shown to improve pain and pruritus, QOL, and depression in patients with IBD.²⁴ Benefits such as improved weight and sexual dysfunction also have been reported.²⁵

Metformin is well studied in Black patients, and greater glycemic response supports its efficacy for diabetes as well as HS, which disproportionately affects individuals with skin of color.²⁶ Metformin also targets other comorbidities of HS, such as improving insulin resistance, polycystic ovary syndrome, acne vulgaris, weight loss, hyperlipidemia, cardiovascular risk, and neuropsychologic conditions.²⁷ Growing evidence supports the use of metformin as a new agent in chronic pain management, specifically for patients with HS.^28,29

Final Thoughts

Hidradenitis suppurativa is a complex medical condition seen disproportionately in minority groups. Understanding common comorbidities as well as the biases associated with pain management will allow providers to treat HS patients more effectively. Dermatologists who see many HS patients should become more familiar with treating these associated comorbidities to provide patient care that is more holistic and effective.