Tumor lysis syndrome in an adolescent with recurrence of abdominal rhabdomyosarcoma: A case report and literature review

Introduction

Tumor lysis syndrome (TLS) is a life-threatening oncologic emergency that results when massive cell breakdown occurs either spontaneously or in response to cytotoxic chemotherapy. TLS is characterized by metabolic derangements, including hyperkalemia and hyperphosphatemia, secondary to the release of intracellular components into the systemic circulatory system. In addition, purine degradation can lead to hyperuricemia, and precipitation of calcium phosphate can result in hypocalcemia. Lactate dehydrogenase (LDH) levels are often elevated, especially in higher risk patients; however, this finding is not a specific marker for TLS.

TLS more commonly occurs in patients with rapidly proliferating hematological malignancies, such as acute leukemias with a high white blood cell count and Burkitt’s lymphoma, and is a relatively rare event in patients with solid malignancies.^1-3 It is even more rare in patients with tumor recurrence.

There are few reported cases of TLS in children with solid malignancies. To our knowledge, only one case of TLS has previously been reported in a pediatric patient with abdominal rhabdomyosarcoma. We report the second such case, and what we believe to be the only reported case of TLS occurring in a pediatric patient with recurrence of a solid tumor.

Case Description

A 15-year-old male from Saudi Arabia presented to our hospital with confirmed stage IV abdominal rhabdomyosarcoma and lung metastases diagnosed in 2012. His initial treatment consisted of complete surgical resection, lung irradiation, and chemotherapy with intercalating cycles of ifosfamide/etoposide and vincristine/doxorubicin/cyclophosphamide, as per the COG-ARST0431 high-risk sarcoma protocol (NCT00354744). He completed treatment without any reported TLS in Saudi Arabia in June 2014. He had no residual tumor at the end of therapy, but six months later he was found to have an abdominal recurrence and started treatment with single-agent topotecan chemotherapy. He experienced worsening abdominal distention, pain, and difficulty voiding, prompting his family to seek further treatment options abroad.

The patient was admitted to our hospital in March 2015. Despite being severely malnourished, he was in stable condition. He was noted to have a markedly enlarged, firm, distended abdomen with dilated veins, abdominal and lower back pain, lower extremity pitting edema, and difficulty urinating.

Initial laboratory findings were unremarkable except for elevated levels of BUN (29 mg/dL), creatinine (1.69 mg/dL), and phosphorus (5.6 mg/dL). MRI revealed a large pelvic mass measuring 15.3 x 15.2 x 21.3 centimeters in transverse, anterior-posterior, and craniocaudal dimensions, respectively; with concomitant severe bilateral hydroureternephrosis (FIGURE 1).

FIGURE 1. Sagittal (A) and Axial (B) T2-weighted MR images of the pelvis (prior to initiating therapy) demonstrating a large heterogeneous mass occupying the entire pelvis. There is evidence of edema involving the soft tissues of the perineum (long arrow) and a large associated hydrocele (short arrow).

Three days following admission, the patient’s urine output decreased and his creatinine level rose rapidly. His worsening abdominal distention was attributed to growing tumor bulk and obstructive nephropathy. He required emergency placement of bilateral nephrostomy tubes. Urine output subsequently improved; although, serum creatinine remained persistently elevated.

Given his worsening condition, chemotherapy was begun three days after nephrostomy tube placement with vinorelbine, cyclophosphamide, and temsirolimus, as per COG-ARST0921 (NCT01222715), at renal-adjusted doses. Laboratory studies approximately 24 hours after chemotherapy initiation demonstrated the presence of TLS (TABLE 1). Potassium level was at the upper end of normal at 4.9 mmol/L, calcium level was decreased to 7.1 mg/dL, phosphorus level elevated to 12 mg/dL, uric acid level was markedly elevated to 19.5 mg/dL, and LDH elevated to 662 unit/L. A dose of 0.15 mg/kg of rasburicase was immediately given with a second dose repeated 14 hours later, after which the uric acid level decreased to less than 0.5 mg/dL. Sevelamer, sodium polystyrene, calcium carbonate, and magnesium gluconate were also administered to treat other electrolyte imbalances. The patient remained at clinical baseline throughout, and the TLS laboratory derangements normalized by three days after the TLS diagnosis; LDH level normalized after one week. The patient continued with chemotherapy, per protocol, with no further TLS-related complications. Over subsequent weeks, his tumor continued to shrink dramatically. Pain related to intra-abdominal compression, lower extremity edema, and difficulty voiding resolved.

Discussion

A literature search was performed using Pubmed/Medline and Scopus from 1950 to July 2016 using key words “TLS,” “tumor lysis syndrome,” “pediatric tumor lysis syndrome,” “tumor lysis syndrome in solid malignancies,” “recurrence,” “solid tumor,” “sarcoma,” “rhabdomyosarcoma,” and their combinations. The references of relevant articles were reviewed. Baeksgaard and Sorensen,³ and Vodopivec, et al⁴ provide an organized review of reported cases of TLS in solid tumors until 2002 and 2011 respectively; their articles are supported by the 2014 literature review by Mirrakhimov, et al.¹ Excluding our case, 13 cases of TLS have been described in pediatric patients with solid tumors, with only one occurring in patient with abdominal rhabdomyosarcoma⁵. Patients’ ages ranged from 2 days to 23 years; the cases are summarized in the following table (TABLE 2). To our knowledge, ours is the first case of TLS reported in association with a pediatric solid tumor recurrence.

It is important to note that the three reported cases of disseminated rhabdomyosarcoma^6,7 were initially believed to be hematologic malignancies because of their presentation with lymphadenopathy, metastases to the bone marrow, and spontaneous onset of TLS. Rhabdomyosarcoma with bone marrow involvement without an obvious primary tumor is easily confused with acute leukemia, particularly of the lymphoblastic type.¹² However, this disseminated-hematologic presentation of rhabdomyosarcoma differs from the solid abdominal-pelvic tumor, which we describe.

Cairo and Bishop¹³ categorize patients as either laboratory TLS, depicted by metabolic abnormalities alone, or clinical TLS, occurring when laboratory imbalances lead to significant, life-threatening clinical manifestations. Hyperkalemia may lead to cardiac arrhythmias such as torsades de pointes and cardiac arrest. Obstructive nephropathy can occur from the precipitation of calcium phosphate or uric acid crystals in the renal tubules. Hypocalcemia may cause neuromuscular irritability including tetany, convulsions, and altered mental status.^{13, 14}The 2015 “Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology”⁴ state there are well-recognized risk factors for the development of TLS including, but not limited to, high tumor burden, tumors with rapid cell turnover, and pre-existing renal impairment. Cairo and Bishop, on behalf of the TLS expert panel consensus of 2010², classify patients as having low-risk disease (LRD), intermediate-risk disease (IRD), or high-risk disease (HRD) based on the risk factors and type of malignancy. All patients with solid tumors are classified into LRD, unless the tumors are bulky or sensitive to chemotherapy, mentioning specifically that neuroblastomas, germ-cell tumors and small cell lung cancers are classified as IRD. Cairo and Bishop take into account the risk factor of renal dysfunction/ involvement, which if present, increases the risk by one level. For example, if the patient has IRD and has renal dysfunction, risk increases to HRD². However, these guidelines do not mention or address the significance of recurrence in any kind of malignancy with regards to assessing risk for TLS.

The British Committee’s 2015 Guidelines for management of TLS in hematologic malignancies¹⁴ provide recommendations for treatment based on the patient’s risk classification (TABLE 3). Children with HRD are recommended to be treated prophylactically with a single dose of 0.2 mg/kg of rasburicase. Patients with IRD are recommended to be offered up to 7 days of allopurinol prophylaxis with increased hydration post initiation of treatment or until risk of TLS has resolved. Patients with LRD are recommended to be managed essentially with close observation. Patients with established TLS should receive rasburicase 0.2 mg/kg/day - duration to depend on clinical response. If the patient is receiving rasburicase, the addition of allopurinol is not recommended, as it has the potential to reduce the effectiveness of rasburicase. Further, rasburicase is to be avoided in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency¹⁴.

Our patient likely developed TLS because of a fast growing tumor that caused significant tumor burden and renal involvement, indicated by an elevated phosphorus level. Despite these risk factors, TLS was not anticipated in the case presented; therefore, a uric acid level was not collected at the time of admission. Review of the literature indicates that the incidence of TLS in a solid tumor recurrence is either unheard of, or is likely under-reported and truly unknown. Further, the TLS expert panel consensus of 2010², which provides guidelines on risk assessment for TLS, does not address the risk of TLS in a malignancy recurrence. The British Committee’s 2015 guidelines¹⁴ also do not address hyperuricemia prophylaxis in a solid tumor recurrence.

Our case presents a question regarding the degree of risk for the development of TLS in a solid tumor recurrence. If the guidelines had existed at the time of the case presentation and had been applied, our patient would likely be classified as having IRD because of his renal involvement. This classification would have lead to a different course of management when initiating chemotherapy, likely prevented laboratory TLS, and provided more cost effective treatment, as rasburicase is known to be expensive.

On the other hand, it can also be argued that our patient classifies as LRD, considering the rarity of TLS in a solid tumor recurrence, that the patient had no TLS complication with his initial course of therapy, and also had a normal LDH on admission. LDH is sometimes used to assess risk in hematological malignancies, although it is not used to make the diagnosis of TLS². However, with such an argument, it is assumed that the risk of TLS in a solid tumor malignancy recurrence, with no previous TLS complication, is less than the risk associated with a new-onset solid tumor malignancy when, truly, the actual risk is not known. Again, the question is raised of the degree of risk for the development of TLS in a case of a malignancy recurrence, and also in a pediatric patient with risk factors.

In our patient’s case, close observation allowed for prompt diagnosis, appropriate treatment of laboratory TLS, and prevented clinical symptoms from developing. However, a screening or baseline uric acid level may have lead to a more conservative approach towards hyperuricemia prophylaxis, similar to treating the patient as IRD. Therefore, we recommend that a screening or baseline uric acid level and LDH level be obtained when initiating chemotherapy, even in patients with LRD.

Our patient was never hyperkalemic, likely because of concomitant administration of furosemide in an attempt to improve his decreased urine output. Hyperuricemia dropped from 19.5 mg/dL to less than 0.5 mg/dL within 24 hours, following two doses of 0.15 mg/kg of rasburicase, confirming the efficacy of this therapy in cases of established TLS, as is recommended by the British Committee’s 2015 guidelines.¹⁴

Conclusion

TLS is a relatively rare event in patients with solid malignancies and even more rare in a tumor recurrence. While there is only one previously reported case of TLS occurring in a pediatric patient with abdominal rhabdomyosarcoma, there are not any reported cases to date of TLS occurring in pediatric solid tumor recurrence. This may be because the incidence is truly rare or because cases may be under-reported. Thus, a question is raised regarding the risk for TLS in a solid tumor recurrence, and moreover in a pediatric patient with pre-existing risk factors, such as renal involvement.

TLS remains a life-threatening emergency that can be prevented and reversed if a high index of suspicion is maintained. We recommend all patients with malignancies receiving chemotherapy, especially those with risk factors, have a baseline or screening uric acid and LDH level drawn, as part of the assessment and risk-stratification for TLS which should always be performed. TSJ

Correspondence

References

1. Mirrakhimov AE, Ali AM, Khan M, et al. Tumor lysis syndrome in solid tumors: an up to date review of the literature. Rare Tumors. 2014;6:68-74.

2. Cairo MS, Bertrand C, Reiter A, et al. Recommendation for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol. 2010;149:578-586.

3. Baeksgaard L, Sorensen JB. Acute tumor lysis syndrome in solid tumors – a case report and review of the literature. Cancer Chemother Pharmacol. 2003;51:187-192.

4. Vodopivec D, Rubio J, Fornoni A, et al. An unusual presentation of tumor lysis syndrome in a patient with advanced gastric adenocarcinoma: case report and literature review. Case Rep Med. 2012;2012:1-12.

5. Khan J, Broadbent VA. Tumor lysis syndrome complicating treatment of widespread metastatic abdominal rhabdomyosarcoma. Pediatr Hematol Oncol. 1993;10:151-155.

6. Bien E, Maciejka-Kapuscinka L, Niedzwiecki M, et al. Childhood rhabdomyosarcoma metastatic to bone marrow presenting with disseminated intravascular coagulation and acute tumour lysis syndrome: review of the literature apropos of two cases. Clin Exp Metastasis. 2010;27:399-407.

7. Patiroglu T, Isik B, Unal E, et al. Cranial metastatic alveolar rhabdomyosarcoma mimicking hematological malignancy in an adolescent boy. Childs Nerv Syst. 2014;30:1737-1741.

8. Hain RD, Rayner L, Weitzman S, et al. Acute tumour lysis syndrome complicating treatment of stage IVS neuroblastoma in infants under six months old. Med Pediatr Oncol. 1994;23:136-139.

9. Kushner BH, LaQuaglia MP, Modak S, et al. Tumor lysis syndrome, neuroblastoma, and correlation between serum lactate dehydrogenase levels and MYCN-amplification. Med Pediatr Oncol. 2003;41:80-82.

10. Bercovitz RS, Greffe BS, Hunger SP. Acute tumor lysis syndrome in a 7-month-old with hepatoblastoma. Curr Opin Pediatr. 2010;22:113-116.

11. Lobe TE, Karkera MS, Custer MD, et al. Fatal refractory hyperkalemia due to tumor lysis during primary resection for hepatoblastoma. J Pediatr Surg. 1990;25:249-250.

12. Sandberg A, Stone J, Czarnecki L, et al. Hematologic Masquerade of Rhabdomyosarcoma. Am J Hematol. 2001;68:51-57

13. Cairo M, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol. 2004;127:3-11.

14. Jones G, Will A, Jackson GH, et al. Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology. Br J Haematol. 2015;169:661-671.

Introduction

Tumor lysis syndrome (TLS) is a life-threatening oncologic emergency that results when massive cell breakdown occurs either spontaneously or in response to cytotoxic chemotherapy. TLS is characterized by metabolic derangements, including hyperkalemia and hyperphosphatemia, secondary to the release of intracellular components into the systemic circulatory system. In addition, purine degradation can lead to hyperuricemia, and precipitation of calcium phosphate can result in hypocalcemia. Lactate dehydrogenase (LDH) levels are often elevated, especially in higher risk patients; however, this finding is not a specific marker for TLS.

TLS more commonly occurs in patients with rapidly proliferating hematological malignancies, such as acute leukemias with a high white blood cell count and Burkitt’s lymphoma, and is a relatively rare event in patients with solid malignancies.^1-3 It is even more rare in patients with tumor recurrence.

There are few reported cases of TLS in children with solid malignancies. To our knowledge, only one case of TLS has previously been reported in a pediatric patient with abdominal rhabdomyosarcoma. We report the second such case, and what we believe to be the only reported case of TLS occurring in a pediatric patient with recurrence of a solid tumor.

Case Description

A 15-year-old male from Saudi Arabia presented to our hospital with confirmed stage IV abdominal rhabdomyosarcoma and lung metastases diagnosed in 2012. His initial treatment consisted of complete surgical resection, lung irradiation, and chemotherapy with intercalating cycles of ifosfamide/etoposide and vincristine/doxorubicin/cyclophosphamide, as per the COG-ARST0431 high-risk sarcoma protocol (NCT00354744). He completed treatment without any reported TLS in Saudi Arabia in June 2014. He had no residual tumor at the end of therapy, but six months later he was found to have an abdominal recurrence and started treatment with single-agent topotecan chemotherapy. He experienced worsening abdominal distention, pain, and difficulty voiding, prompting his family to seek further treatment options abroad.

The patient was admitted to our hospital in March 2015. Despite being severely malnourished, he was in stable condition. He was noted to have a markedly enlarged, firm, distended abdomen with dilated veins, abdominal and lower back pain, lower extremity pitting edema, and difficulty urinating.

Initial laboratory findings were unremarkable except for elevated levels of BUN (29 mg/dL), creatinine (1.69 mg/dL), and phosphorus (5.6 mg/dL). MRI revealed a large pelvic mass measuring 15.3 x 15.2 x 21.3 centimeters in transverse, anterior-posterior, and craniocaudal dimensions, respectively; with concomitant severe bilateral hydroureternephrosis (FIGURE 1).

FIGURE 1. Sagittal (A) and Axial (B) T2-weighted MR images of the pelvis (prior to initiating therapy) demonstrating a large heterogeneous mass occupying the entire pelvis. There is evidence of edema involving the soft tissues of the perineum (long arrow) and a large associated hydrocele (short arrow).

Three days following admission, the patient’s urine output decreased and his creatinine level rose rapidly. His worsening abdominal distention was attributed to growing tumor bulk and obstructive nephropathy. He required emergency placement of bilateral nephrostomy tubes. Urine output subsequently improved; although, serum creatinine remained persistently elevated.

Given his worsening condition, chemotherapy was begun three days after nephrostomy tube placement with vinorelbine, cyclophosphamide, and temsirolimus, as per COG-ARST0921 (NCT01222715), at renal-adjusted doses. Laboratory studies approximately 24 hours after chemotherapy initiation demonstrated the presence of TLS (TABLE 1). Potassium level was at the upper end of normal at 4.9 mmol/L, calcium level was decreased to 7.1 mg/dL, phosphorus level elevated to 12 mg/dL, uric acid level was markedly elevated to 19.5 mg/dL, and LDH elevated to 662 unit/L. A dose of 0.15 mg/kg of rasburicase was immediately given with a second dose repeated 14 hours later, after which the uric acid level decreased to less than 0.5 mg/dL. Sevelamer, sodium polystyrene, calcium carbonate, and magnesium gluconate were also administered to treat other electrolyte imbalances. The patient remained at clinical baseline throughout, and the TLS laboratory derangements normalized by three days after the TLS diagnosis; LDH level normalized after one week. The patient continued with chemotherapy, per protocol, with no further TLS-related complications. Over subsequent weeks, his tumor continued to shrink dramatically. Pain related to intra-abdominal compression, lower extremity edema, and difficulty voiding resolved.

Discussion

A literature search was performed using Pubmed/Medline and Scopus from 1950 to July 2016 using key words “TLS,” “tumor lysis syndrome,” “pediatric tumor lysis syndrome,” “tumor lysis syndrome in solid malignancies,” “recurrence,” “solid tumor,” “sarcoma,” “rhabdomyosarcoma,” and their combinations. The references of relevant articles were reviewed. Baeksgaard and Sorensen,³ and Vodopivec, et al⁴ provide an organized review of reported cases of TLS in solid tumors until 2002 and 2011 respectively; their articles are supported by the 2014 literature review by Mirrakhimov, et al.¹ Excluding our case, 13 cases of TLS have been described in pediatric patients with solid tumors, with only one occurring in patient with abdominal rhabdomyosarcoma⁵. Patients’ ages ranged from 2 days to 23 years; the cases are summarized in the following table (TABLE 2). To our knowledge, ours is the first case of TLS reported in association with a pediatric solid tumor recurrence.

It is important to note that the three reported cases of disseminated rhabdomyosarcoma^6,7 were initially believed to be hematologic malignancies because of their presentation with lymphadenopathy, metastases to the bone marrow, and spontaneous onset of TLS. Rhabdomyosarcoma with bone marrow involvement without an obvious primary tumor is easily confused with acute leukemia, particularly of the lymphoblastic type.¹² However, this disseminated-hematologic presentation of rhabdomyosarcoma differs from the solid abdominal-pelvic tumor, which we describe.

Cairo and Bishop¹³ categorize patients as either laboratory TLS, depicted by metabolic abnormalities alone, or clinical TLS, occurring when laboratory imbalances lead to significant, life-threatening clinical manifestations. Hyperkalemia may lead to cardiac arrhythmias such as torsades de pointes and cardiac arrest. Obstructive nephropathy can occur from the precipitation of calcium phosphate or uric acid crystals in the renal tubules. Hypocalcemia may cause neuromuscular irritability including tetany, convulsions, and altered mental status.^{13, 14}The 2015 “Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology”⁴ state there are well-recognized risk factors for the development of TLS including, but not limited to, high tumor burden, tumors with rapid cell turnover, and pre-existing renal impairment. Cairo and Bishop, on behalf of the TLS expert panel consensus of 2010², classify patients as having low-risk disease (LRD), intermediate-risk disease (IRD), or high-risk disease (HRD) based on the risk factors and type of malignancy. All patients with solid tumors are classified into LRD, unless the tumors are bulky or sensitive to chemotherapy, mentioning specifically that neuroblastomas, germ-cell tumors and small cell lung cancers are classified as IRD. Cairo and Bishop take into account the risk factor of renal dysfunction/ involvement, which if present, increases the risk by one level. For example, if the patient has IRD and has renal dysfunction, risk increases to HRD². However, these guidelines do not mention or address the significance of recurrence in any kind of malignancy with regards to assessing risk for TLS.

The British Committee’s 2015 Guidelines for management of TLS in hematologic malignancies¹⁴ provide recommendations for treatment based on the patient’s risk classification (TABLE 3). Children with HRD are recommended to be treated prophylactically with a single dose of 0.2 mg/kg of rasburicase. Patients with IRD are recommended to be offered up to 7 days of allopurinol prophylaxis with increased hydration post initiation of treatment or until risk of TLS has resolved. Patients with LRD are recommended to be managed essentially with close observation. Patients with established TLS should receive rasburicase 0.2 mg/kg/day - duration to depend on clinical response. If the patient is receiving rasburicase, the addition of allopurinol is not recommended, as it has the potential to reduce the effectiveness of rasburicase. Further, rasburicase is to be avoided in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency¹⁴.

Our patient likely developed TLS because of a fast growing tumor that caused significant tumor burden and renal involvement, indicated by an elevated phosphorus level. Despite these risk factors, TLS was not anticipated in the case presented; therefore, a uric acid level was not collected at the time of admission. Review of the literature indicates that the incidence of TLS in a solid tumor recurrence is either unheard of, or is likely under-reported and truly unknown. Further, the TLS expert panel consensus of 2010², which provides guidelines on risk assessment for TLS, does not address the risk of TLS in a malignancy recurrence. The British Committee’s 2015 guidelines¹⁴ also do not address hyperuricemia prophylaxis in a solid tumor recurrence.

Our case presents a question regarding the degree of risk for the development of TLS in a solid tumor recurrence. If the guidelines had existed at the time of the case presentation and had been applied, our patient would likely be classified as having IRD because of his renal involvement. This classification would have lead to a different course of management when initiating chemotherapy, likely prevented laboratory TLS, and provided more cost effective treatment, as rasburicase is known to be expensive.

On the other hand, it can also be argued that our patient classifies as LRD, considering the rarity of TLS in a solid tumor recurrence, that the patient had no TLS complication with his initial course of therapy, and also had a normal LDH on admission. LDH is sometimes used to assess risk in hematological malignancies, although it is not used to make the diagnosis of TLS². However, with such an argument, it is assumed that the risk of TLS in a solid tumor malignancy recurrence, with no previous TLS complication, is less than the risk associated with a new-onset solid tumor malignancy when, truly, the actual risk is not known. Again, the question is raised of the degree of risk for the development of TLS in a case of a malignancy recurrence, and also in a pediatric patient with risk factors.

In our patient’s case, close observation allowed for prompt diagnosis, appropriate treatment of laboratory TLS, and prevented clinical symptoms from developing. However, a screening or baseline uric acid level may have lead to a more conservative approach towards hyperuricemia prophylaxis, similar to treating the patient as IRD. Therefore, we recommend that a screening or baseline uric acid level and LDH level be obtained when initiating chemotherapy, even in patients with LRD.

Our patient was never hyperkalemic, likely because of concomitant administration of furosemide in an attempt to improve his decreased urine output. Hyperuricemia dropped from 19.5 mg/dL to less than 0.5 mg/dL within 24 hours, following two doses of 0.15 mg/kg of rasburicase, confirming the efficacy of this therapy in cases of established TLS, as is recommended by the British Committee’s 2015 guidelines.¹⁴

Conclusion

TLS is a relatively rare event in patients with solid malignancies and even more rare in a tumor recurrence. While there is only one previously reported case of TLS occurring in a pediatric patient with abdominal rhabdomyosarcoma, there are not any reported cases to date of TLS occurring in pediatric solid tumor recurrence. This may be because the incidence is truly rare or because cases may be under-reported. Thus, a question is raised regarding the risk for TLS in a solid tumor recurrence, and moreover in a pediatric patient with pre-existing risk factors, such as renal involvement.

TLS remains a life-threatening emergency that can be prevented and reversed if a high index of suspicion is maintained. We recommend all patients with malignancies receiving chemotherapy, especially those with risk factors, have a baseline or screening uric acid and LDH level drawn, as part of the assessment and risk-stratification for TLS which should always be performed. TSJ

Correspondence

References

1. Mirrakhimov AE, Ali AM, Khan M, et al. Tumor lysis syndrome in solid tumors: an up to date review of the literature. Rare Tumors. 2014;6:68-74.

2. Cairo MS, Bertrand C, Reiter A, et al. Recommendation for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol. 2010;149:578-586.

3. Baeksgaard L, Sorensen JB. Acute tumor lysis syndrome in solid tumors – a case report and review of the literature. Cancer Chemother Pharmacol. 2003;51:187-192.

4. Vodopivec D, Rubio J, Fornoni A, et al. An unusual presentation of tumor lysis syndrome in a patient with advanced gastric adenocarcinoma: case report and literature review. Case Rep Med. 2012;2012:1-12.

5. Khan J, Broadbent VA. Tumor lysis syndrome complicating treatment of widespread metastatic abdominal rhabdomyosarcoma. Pediatr Hematol Oncol. 1993;10:151-155.

6. Bien E, Maciejka-Kapuscinka L, Niedzwiecki M, et al. Childhood rhabdomyosarcoma metastatic to bone marrow presenting with disseminated intravascular coagulation and acute tumour lysis syndrome: review of the literature apropos of two cases. Clin Exp Metastasis. 2010;27:399-407.

7. Patiroglu T, Isik B, Unal E, et al. Cranial metastatic alveolar rhabdomyosarcoma mimicking hematological malignancy in an adolescent boy. Childs Nerv Syst. 2014;30:1737-1741.

8. Hain RD, Rayner L, Weitzman S, et al. Acute tumour lysis syndrome complicating treatment of stage IVS neuroblastoma in infants under six months old. Med Pediatr Oncol. 1994;23:136-139.

9. Kushner BH, LaQuaglia MP, Modak S, et al. Tumor lysis syndrome, neuroblastoma, and correlation between serum lactate dehydrogenase levels and MYCN-amplification. Med Pediatr Oncol. 2003;41:80-82.

10. Bercovitz RS, Greffe BS, Hunger SP. Acute tumor lysis syndrome in a 7-month-old with hepatoblastoma. Curr Opin Pediatr. 2010;22:113-116.

11. Lobe TE, Karkera MS, Custer MD, et al. Fatal refractory hyperkalemia due to tumor lysis during primary resection for hepatoblastoma. J Pediatr Surg. 1990;25:249-250.

12. Sandberg A, Stone J, Czarnecki L, et al. Hematologic Masquerade of Rhabdomyosarcoma. Am J Hematol. 2001;68:51-57

13. Cairo M, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol. 2004;127:3-11.

14. Jones G, Will A, Jackson GH, et al. Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology. Br J Haematol. 2015;169:661-671.

Introduction

Tumor lysis syndrome (TLS) is a life-threatening oncologic emergency that results when massive cell breakdown occurs either spontaneously or in response to cytotoxic chemotherapy. TLS is characterized by metabolic derangements, including hyperkalemia and hyperphosphatemia, secondary to the release of intracellular components into the systemic circulatory system. In addition, purine degradation can lead to hyperuricemia, and precipitation of calcium phosphate can result in hypocalcemia. Lactate dehydrogenase (LDH) levels are often elevated, especially in higher risk patients; however, this finding is not a specific marker for TLS.

TLS more commonly occurs in patients with rapidly proliferating hematological malignancies, such as acute leukemias with a high white blood cell count and Burkitt’s lymphoma, and is a relatively rare event in patients with solid malignancies.^1-3 It is even more rare in patients with tumor recurrence.

There are few reported cases of TLS in children with solid malignancies. To our knowledge, only one case of TLS has previously been reported in a pediatric patient with abdominal rhabdomyosarcoma. We report the second such case, and what we believe to be the only reported case of TLS occurring in a pediatric patient with recurrence of a solid tumor.

Case Description

A 15-year-old male from Saudi Arabia presented to our hospital with confirmed stage IV abdominal rhabdomyosarcoma and lung metastases diagnosed in 2012. His initial treatment consisted of complete surgical resection, lung irradiation, and chemotherapy with intercalating cycles of ifosfamide/etoposide and vincristine/doxorubicin/cyclophosphamide, as per the COG-ARST0431 high-risk sarcoma protocol (NCT00354744). He completed treatment without any reported TLS in Saudi Arabia in June 2014. He had no residual tumor at the end of therapy, but six months later he was found to have an abdominal recurrence and started treatment with single-agent topotecan chemotherapy. He experienced worsening abdominal distention, pain, and difficulty voiding, prompting his family to seek further treatment options abroad.

The patient was admitted to our hospital in March 2015. Despite being severely malnourished, he was in stable condition. He was noted to have a markedly enlarged, firm, distended abdomen with dilated veins, abdominal and lower back pain, lower extremity pitting edema, and difficulty urinating.

Initial laboratory findings were unremarkable except for elevated levels of BUN (29 mg/dL), creatinine (1.69 mg/dL), and phosphorus (5.6 mg/dL). MRI revealed a large pelvic mass measuring 15.3 x 15.2 x 21.3 centimeters in transverse, anterior-posterior, and craniocaudal dimensions, respectively; with concomitant severe bilateral hydroureternephrosis (FIGURE 1).

FIGURE 1. Sagittal (A) and Axial (B) T2-weighted MR images of the pelvis (prior to initiating therapy) demonstrating a large heterogeneous mass occupying the entire pelvis. There is evidence of edema involving the soft tissues of the perineum (long arrow) and a large associated hydrocele (short arrow).

Three days following admission, the patient’s urine output decreased and his creatinine level rose rapidly. His worsening abdominal distention was attributed to growing tumor bulk and obstructive nephropathy. He required emergency placement of bilateral nephrostomy tubes. Urine output subsequently improved; although, serum creatinine remained persistently elevated.

Given his worsening condition, chemotherapy was begun three days after nephrostomy tube placement with vinorelbine, cyclophosphamide, and temsirolimus, as per COG-ARST0921 (NCT01222715), at renal-adjusted doses. Laboratory studies approximately 24 hours after chemotherapy initiation demonstrated the presence of TLS (TABLE 1). Potassium level was at the upper end of normal at 4.9 mmol/L, calcium level was decreased to 7.1 mg/dL, phosphorus level elevated to 12 mg/dL, uric acid level was markedly elevated to 19.5 mg/dL, and LDH elevated to 662 unit/L. A dose of 0.15 mg/kg of rasburicase was immediately given with a second dose repeated 14 hours later, after which the uric acid level decreased to less than 0.5 mg/dL. Sevelamer, sodium polystyrene, calcium carbonate, and magnesium gluconate were also administered to treat other electrolyte imbalances. The patient remained at clinical baseline throughout, and the TLS laboratory derangements normalized by three days after the TLS diagnosis; LDH level normalized after one week. The patient continued with chemotherapy, per protocol, with no further TLS-related complications. Over subsequent weeks, his tumor continued to shrink dramatically. Pain related to intra-abdominal compression, lower extremity edema, and difficulty voiding resolved.

Discussion

A literature search was performed using Pubmed/Medline and Scopus from 1950 to July 2016 using key words “TLS,” “tumor lysis syndrome,” “pediatric tumor lysis syndrome,” “tumor lysis syndrome in solid malignancies,” “recurrence,” “solid tumor,” “sarcoma,” “rhabdomyosarcoma,” and their combinations. The references of relevant articles were reviewed. Baeksgaard and Sorensen,³ and Vodopivec, et al⁴ provide an organized review of reported cases of TLS in solid tumors until 2002 and 2011 respectively; their articles are supported by the 2014 literature review by Mirrakhimov, et al.¹ Excluding our case, 13 cases of TLS have been described in pediatric patients with solid tumors, with only one occurring in patient with abdominal rhabdomyosarcoma⁵. Patients’ ages ranged from 2 days to 23 years; the cases are summarized in the following table (TABLE 2). To our knowledge, ours is the first case of TLS reported in association with a pediatric solid tumor recurrence.

It is important to note that the three reported cases of disseminated rhabdomyosarcoma^6,7 were initially believed to be hematologic malignancies because of their presentation with lymphadenopathy, metastases to the bone marrow, and spontaneous onset of TLS. Rhabdomyosarcoma with bone marrow involvement without an obvious primary tumor is easily confused with acute leukemia, particularly of the lymphoblastic type.¹² However, this disseminated-hematologic presentation of rhabdomyosarcoma differs from the solid abdominal-pelvic tumor, which we describe.

Cairo and Bishop¹³ categorize patients as either laboratory TLS, depicted by metabolic abnormalities alone, or clinical TLS, occurring when laboratory imbalances lead to significant, life-threatening clinical manifestations. Hyperkalemia may lead to cardiac arrhythmias such as torsades de pointes and cardiac arrest. Obstructive nephropathy can occur from the precipitation of calcium phosphate or uric acid crystals in the renal tubules. Hypocalcemia may cause neuromuscular irritability including tetany, convulsions, and altered mental status.^{13, 14}The 2015 “Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology”⁴ state there are well-recognized risk factors for the development of TLS including, but not limited to, high tumor burden, tumors with rapid cell turnover, and pre-existing renal impairment. Cairo and Bishop, on behalf of the TLS expert panel consensus of 2010², classify patients as having low-risk disease (LRD), intermediate-risk disease (IRD), or high-risk disease (HRD) based on the risk factors and type of malignancy. All patients with solid tumors are classified into LRD, unless the tumors are bulky or sensitive to chemotherapy, mentioning specifically that neuroblastomas, germ-cell tumors and small cell lung cancers are classified as IRD. Cairo and Bishop take into account the risk factor of renal dysfunction/ involvement, which if present, increases the risk by one level. For example, if the patient has IRD and has renal dysfunction, risk increases to HRD². However, these guidelines do not mention or address the significance of recurrence in any kind of malignancy with regards to assessing risk for TLS.

The British Committee’s 2015 Guidelines for management of TLS in hematologic malignancies¹⁴ provide recommendations for treatment based on the patient’s risk classification (TABLE 3). Children with HRD are recommended to be treated prophylactically with a single dose of 0.2 mg/kg of rasburicase. Patients with IRD are recommended to be offered up to 7 days of allopurinol prophylaxis with increased hydration post initiation of treatment or until risk of TLS has resolved. Patients with LRD are recommended to be managed essentially with close observation. Patients with established TLS should receive rasburicase 0.2 mg/kg/day - duration to depend on clinical response. If the patient is receiving rasburicase, the addition of allopurinol is not recommended, as it has the potential to reduce the effectiveness of rasburicase. Further, rasburicase is to be avoided in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency¹⁴.

Our patient likely developed TLS because of a fast growing tumor that caused significant tumor burden and renal involvement, indicated by an elevated phosphorus level. Despite these risk factors, TLS was not anticipated in the case presented; therefore, a uric acid level was not collected at the time of admission. Review of the literature indicates that the incidence of TLS in a solid tumor recurrence is either unheard of, or is likely under-reported and truly unknown. Further, the TLS expert panel consensus of 2010², which provides guidelines on risk assessment for TLS, does not address the risk of TLS in a malignancy recurrence. The British Committee’s 2015 guidelines¹⁴ also do not address hyperuricemia prophylaxis in a solid tumor recurrence.

Our case presents a question regarding the degree of risk for the development of TLS in a solid tumor recurrence. If the guidelines had existed at the time of the case presentation and had been applied, our patient would likely be classified as having IRD because of his renal involvement. This classification would have lead to a different course of management when initiating chemotherapy, likely prevented laboratory TLS, and provided more cost effective treatment, as rasburicase is known to be expensive.

On the other hand, it can also be argued that our patient classifies as LRD, considering the rarity of TLS in a solid tumor recurrence, that the patient had no TLS complication with his initial course of therapy, and also had a normal LDH on admission. LDH is sometimes used to assess risk in hematological malignancies, although it is not used to make the diagnosis of TLS². However, with such an argument, it is assumed that the risk of TLS in a solid tumor malignancy recurrence, with no previous TLS complication, is less than the risk associated with a new-onset solid tumor malignancy when, truly, the actual risk is not known. Again, the question is raised of the degree of risk for the development of TLS in a case of a malignancy recurrence, and also in a pediatric patient with risk factors.

In our patient’s case, close observation allowed for prompt diagnosis, appropriate treatment of laboratory TLS, and prevented clinical symptoms from developing. However, a screening or baseline uric acid level may have lead to a more conservative approach towards hyperuricemia prophylaxis, similar to treating the patient as IRD. Therefore, we recommend that a screening or baseline uric acid level and LDH level be obtained when initiating chemotherapy, even in patients with LRD.

Our patient was never hyperkalemic, likely because of concomitant administration of furosemide in an attempt to improve his decreased urine output. Hyperuricemia dropped from 19.5 mg/dL to less than 0.5 mg/dL within 24 hours, following two doses of 0.15 mg/kg of rasburicase, confirming the efficacy of this therapy in cases of established TLS, as is recommended by the British Committee’s 2015 guidelines.¹⁴

Conclusion

TLS is a relatively rare event in patients with solid malignancies and even more rare in a tumor recurrence. While there is only one previously reported case of TLS occurring in a pediatric patient with abdominal rhabdomyosarcoma, there are not any reported cases to date of TLS occurring in pediatric solid tumor recurrence. This may be because the incidence is truly rare or because cases may be under-reported. Thus, a question is raised regarding the risk for TLS in a solid tumor recurrence, and moreover in a pediatric patient with pre-existing risk factors, such as renal involvement.

TLS remains a life-threatening emergency that can be prevented and reversed if a high index of suspicion is maintained. We recommend all patients with malignancies receiving chemotherapy, especially those with risk factors, have a baseline or screening uric acid and LDH level drawn, as part of the assessment and risk-stratification for TLS which should always be performed. TSJ

Correspondence

References

1. Mirrakhimov AE, Ali AM, Khan M, et al. Tumor lysis syndrome in solid tumors: an up to date review of the literature. Rare Tumors. 2014;6:68-74.

2. Cairo MS, Bertrand C, Reiter A, et al. Recommendation for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol. 2010;149:578-586.

3. Baeksgaard L, Sorensen JB. Acute tumor lysis syndrome in solid tumors – a case report and review of the literature. Cancer Chemother Pharmacol. 2003;51:187-192.

4. Vodopivec D, Rubio J, Fornoni A, et al. An unusual presentation of tumor lysis syndrome in a patient with advanced gastric adenocarcinoma: case report and literature review. Case Rep Med. 2012;2012:1-12.

5. Khan J, Broadbent VA. Tumor lysis syndrome complicating treatment of widespread metastatic abdominal rhabdomyosarcoma. Pediatr Hematol Oncol. 1993;10:151-155.

6. Bien E, Maciejka-Kapuscinka L, Niedzwiecki M, et al. Childhood rhabdomyosarcoma metastatic to bone marrow presenting with disseminated intravascular coagulation and acute tumour lysis syndrome: review of the literature apropos of two cases. Clin Exp Metastasis. 2010;27:399-407.

7. Patiroglu T, Isik B, Unal E, et al. Cranial metastatic alveolar rhabdomyosarcoma mimicking hematological malignancy in an adolescent boy. Childs Nerv Syst. 2014;30:1737-1741.

8. Hain RD, Rayner L, Weitzman S, et al. Acute tumour lysis syndrome complicating treatment of stage IVS neuroblastoma in infants under six months old. Med Pediatr Oncol. 1994;23:136-139.

9. Kushner BH, LaQuaglia MP, Modak S, et al. Tumor lysis syndrome, neuroblastoma, and correlation between serum lactate dehydrogenase levels and MYCN-amplification. Med Pediatr Oncol. 2003;41:80-82.

10. Bercovitz RS, Greffe BS, Hunger SP. Acute tumor lysis syndrome in a 7-month-old with hepatoblastoma. Curr Opin Pediatr. 2010;22:113-116.

11. Lobe TE, Karkera MS, Custer MD, et al. Fatal refractory hyperkalemia due to tumor lysis during primary resection for hepatoblastoma. J Pediatr Surg. 1990;25:249-250.

12. Sandberg A, Stone J, Czarnecki L, et al. Hematologic Masquerade of Rhabdomyosarcoma. Am J Hematol. 2001;68:51-57

13. Cairo M, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol. 2004;127:3-11.

14. Jones G, Will A, Jackson GH, et al. Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology. Br J Haematol. 2015;169:661-671.