Two rare but life-threatening oncologic emergencies are tumor lysis syndrome (TLS) and hemophagocytic lymphohistiocytosis (HLH), both of which have been reported in solid tumors at increasing numbers. Tumor lysis syndrome (TLS) presents with hyperuricemia and electrolyte disturbances including hyperkalemia, hyperphosphatemia, hypocalcemia in the setting of massive tumor lysis, as its name implies. Frequently, TLS occurs after initiation of cytotoxic therapy in patients with high-grade or bulky lymphomas and acute lymphoblastic leukemia but can also rarely occur spontaneously in hematologic and solid tumors with high burden of disease [1]. With the development of new therapies including targeted treatments and immunotherapy, the incidence of solid tumor-associated TLS is rising [1]. Mortality rate in solid-tumor TLS is considerably higher (35%) than in liquid tumors (1.9%), which may be related to lower recognition of TLS in solid tumors given that it is contrary to classic teaching [2]. In light of the high rates of mortality associated with TLS in solid tumors, timely recognition and treatment is crucial.

In addition to TLS, HLH is another cancer-associated complication with a high morbidity and mortality rate. This disease process is characterized by uncontrolled dysregulation and hyperactivation of macrophages and lymphocytes [3]. It is comprised of two main subtypes, primary familial genetic HLH (FHL), which is considered largely a pediatric condition, and secondary HLH, which can occur in both children and adults. Secondary HLH can be precipitated by infection, rheumatologic conditions, transplant, malignancy (M-HLH), or be idiopathic without identified inciting cause. M-HLH occurs in up to 1% of patients, whether that is at diagnosis, during treatment, or after remission of the underlying malignancy [4]. It has been reported with various solid tumors including melanoma, squamous non-small cell lung cancer, testicular cancer, squamous cell carcinoma of the neck and metastatic prostate cancer [4],[5]. Although rare, HLH carries a high mortality rate of up to >80% and a median survival time of two months in M-HLH [5]. This high mortality rate is possibly related to lack of recognition of the disease. Indeed, Tamamyan et al. estimated that 50% of M-HLH cases are not recognized promptly resulting in delay of treatment or no treatment at all [5]. Historically, M-HLH has been treated with disease-specific therapy with addition of etoposide and dexamethasone [6]. Given the dismal mortality rate even with treatment, early diagnosis and treatment is essential.

In this case series, we present two cases of metastatic melanoma complicated by spontaneous TLS (sTLS), with possible concomitant M-HLH in the second case. We then review other cases of metastatic melanoma complicated by TLS and/or HLH and discuss factors that contribute to delay of diagnosis and treatment ambiguity.

Case 1

A 73-year-old man with a past medical history of obesity, hypertension, hyperlipidemia, obstructive sleep apnea, benign prostatic hypertrophy, and nephrolithiasis presented with several weeks of worsening abdominal pain, dark urine, and fatigue. He was evaluated in an urgent care clinic and found to have elevated liver enzymes prompting a computed tomography (CT) scan which revealed innumerable hepatic, pulmonary and osseous lesions along with diffuse lymphadenopathy (Figure 1A). Shortly after, biopsy results confirmed a new diagnosis of metastatic melanoma. The patient developed progressive, severe fatigue and nausea, and 10 days after initial presentation was admitted for acute kidney injury with creatinine of 3.17 mg/dL, up from 1.1 mg/dL ten days prior. Vitals were significant for tachycardia, and initial exam confirmed lymphadenopathy above and below the diaphragm, abdominal tenderness, and hepatosplenomegaly. Inpatient labs revealed a markedly elevated uric acid (16.2 mg/dL), lactic acidosis (6.2 mmol/L), acute liver injury [aspartate transaminase (AST) 890 U/L, alanine transaminase (ALT) 361 U/L, alkaline phosphatase 269 U/L, total bilirubin 2.6 mg/dL], and lactate dehydrogenase >4200 U/L all consistent with TLS. He was started on allopurinol and rasburicase with improvement in his hyperuricemia. Unfortunately, his kidney injury continued to worsen, and he developed progressive hyperkalemia and hyperphosphatemia. His liver dysfunction also progressed leading to acute liver failure with encephalopathy and coagulopathy. His renal injury was thought multifactorial due to hyperuricemia and contrast-induced nephropathy from multiple CT scans, and his liver injury was believed due to the extent of disease burden alone. The patient was lucid enough on day 4 of his hospitalization for a goals of care discussion at which point he declined initiation of dialysis and elected to transition to comfort-directed care. He was discharged to inpatient hospice on day 6 of his hospitalization and passed the following day secondary to kidney and liver failure.

Case 2

An 81-year-old woman with a past medical history of hyperlipidemia and reflux disease was diagnosed with stage I melanoma in 2010. Her primary lesion was localized to the right calf and pathology following excisional biopsy showed clear margins. The patient had no evidence of disease relapse until two weeks prior to admission when she presented to her primary care physician for progressive malaise, weakness, and abdominal pain. A CT scan of her chest, abdomen and pelvis, and magnetic resonance imaging (MRI) of her brain showed numerous lesions involving the brain, liver, retroperitoneal lymph nodes, bilateral adrenal glands, and iliac lymph nodes (Figure 1B). A liver biopsy confirmed a diagnosis of metastatic melanoma. On admission, the patient was afebrile, tachycardic, tachypneic, and normotensive with a 3-liter oxygen requirement. On physical exam she was ill-appearing with diffuse abdominal distension and tenderness, most prominent in the right upper quadrant. Shortly thereafter she progressed into undifferentiated shock and acute hypoxic respiratory failure with laboratory findings concerning for acute liver and renal injury. Initial laboratory findings included an elevated serum creatinine (1.77 mg/dL), hyperkalemia (6.1 mmol/L), leukocytosis (14.5 × 109/L), anemia (hemoglobin 12.4 g/dL), normal platelets (259 × 109/L), acute liver injury (AST 1751 U/L, ALT 5,470 U/L, alkaline phosphatase 423 U/L, total bilirubin of 3.4 mg/dL), and lactic acidosis (8 mmol/L). Computed tomography abdomen/pelvis confirmed widely metastatic disease (Figure 1B) and a CT pulmonary angiogram noted numerous enlarged mediastinal lymph nodes without evidence of a pulmonary embolism. The patient was admitted to the intensive care unit (ICU), aggressively rehydrated, and started on pressors and empiric antibiotics. Despite initial stabilization, the patient rapidly developed hyperuricemia (10.9 mg/dL), hyperphosphatemia (6.4 mg/dL), hypocalcemia (ionized calcium 1.14 mmol/L), and markedly elevated LDH (>6000 U/L) concerning for the development of spontaneous TLS. She was started on allopurinol and rasburicase with mild improvement of hyperuricemia. She rapidly developed progressive anemia (hemoglobin of 8.3 g/dL), thrombocytopenia (100 × 109/L), coagulopathy [international normalized ratio (INR) 5.3)], hypoalbuminemia (2.5 g/dL), and hypofibrinogenemia (125 g/dL). She also had a markedly elevated ferritin (>37,500 ng/mL) with an H-score of 156, concerning for HLH. Notably, she became hypothermic to 35°C without hypertriglyceridemia, and did not have splenomegaly on either exam or imaging. Initiating treatment for HLH was strongly debated and ultimately 80 mg methylprednisolone alone was administered; other agents including etoposide were held given concern for the patient’s overall clinical status, liver injury, and general ambiguity surrounding this diagnosis of HLH. Despite aggressive measures, the patient progressed to anuric renal failure with plans to pursue continuous renal replacement therapy (CRRT). However, before CRRT was started, the patient became acutely altered, short of breath, and developed hemoptysis that quickly led to acute respiratory distress requiring intubation. The patient’s status continued to decline, and her daughter opted to transition to comfort care. The patient passed away within ~24 hours of admission. Several days after her death, a soluble IL-2 receptor level came back elevated at 9477.6 pg/mL (reference range 175.3–858.2 pg/mL).

These two cases highlight the potential for severe complications secondary to widely metastatic melanoma in the absence of cancer-specific treatment. Both cases demonstrate spontaneous TLS (sTLS) in melanoma and in the second case possible concurrent HLH. They highlight the complexity of diagnosing these oncologic complications in the critically ill patient with confounding factors such as acute liver and renal failure and illustrate the challenges behind initiating appropriate treatment. While both entities are well-known complications of malignancy, they are classically associated with hematologic malignancies following cytotoxic treatment. Here we review the literature regarding other cases of TLS and HLH in association with metastatic melanoma and discuss issues regarding their diagnosis and management.

To the best of our knowledge, there are only 17 reported cases of TLS in malignant melanoma (Table 1) [7],[8],[9],[10],[11],[12],[13],[14],[15],[16]. A manuscript by Cordel et al. reported three additional cases of sTLS, two of which were following initiation of chemotherapy and one spontaneous; however, the details of this publication are not available online and we therefore did not include these within Table 1 [17]. Of the available cases, only 4 occurred spontaneously [7],[8],[9],[16]. Notably, all reported cases of sTLS in melanoma had liver metastases and died shortly after their diagnosis of TLS [7],[18]. This suggests that identification of sTLS is a particularly poor prognostic sign for patients with metastatic melanoma. Diagnosis generally requires one clinical criteria (acute kidney injury, seizure, cardiac arrhythmia, or sudden death) and two laboratory criteria (25% increase in uric acid, potassium, or phosphorus from baseline or 25% decrease in calcium from baseline) based on the Cairo-Bishop criteria [19]. These criteria were developed in 2004 to define TLS in the setting of cytotoxic treatment. Subsequently, numerous cases have now reported clinical and laboratory findings consistent with TLS in the absence of treatment, suggesting that spontaneous TLS (sTLS) can occur [17]. Furthermore, the current diagnostic criterion for TLS requires that this process occurs between 3 days before and 7 days after the initiation of cytotoxic chemotherapy. With increasing recognition of TLS syndromes independent from cytotoxic therapy, we propose these criteria should be revised to exclude any temporal relationship with treatment and include a caveat for bulky solid disease. In circumstances where melanoma has significant visceral metastatic involvement, particularly liver disease and concurrent renal injury, we suggest more routine testing of TLS labs in order to facilitate earlier detection and thereby possible improvement of outcomes. As with hematologic malignancies, prophylactic allopurinol treatment should be considered.

The concern for HLH in our second patient led to much more complex diagnostic and management considerations. Her initial laboratory findings of severe liver injury, coagulopathy, hyperferritinemia, and dramatic clinical decline prompted concern for this process. To our knowledge there are 16 cases of metastatic melanoma associated HLH (Table 2) [20],[21],[22]. Only one of these prior cases of HLH occurred spontaneously before treatment initiation [21]. In contrast to our case, this 47-year-old was able to receive BRAF/MEK inhibitor therapy and one dose of etoposide after recognition of HLH, leading to stabilization of her acute illness. The remaining cases occurred following treatment of their malignancy with either BRAF/MEK inhibitors, anti-PD-1 therapy followed by BRAF/MEK inhibitor therapy, or immune checkpoint blockade alone (Table 2) [22]. Nine of these 12 cases were treated with steroids alone, one was treated with steroids and mycophenolate, two were treated with steroids and etoposide, one was treated with steroids and tocilizumab, and one was treated with supportive care alone. Remarkably, only one died from HLH complicated by cerebral hemorrhage, and another passed away six weeks after diagnosis from fungal pneumonia.

Taken together, these historical cases statistically represent a mortality of 7.7% (1/13), a much lower rate than the reported mortality associated with HLH in solid malignancies in general. Many HLH cases were associated with anti-cancer immunotherapy, a treatment modality which itself can induce a cytokine release syndrome that highly resembles HLH in its immunologic signature [3]. Given these observations, it is possible that the HLH-like syndrome in metastatic melanoma with or without immunotherapy is pathophysiologically distinct from similar syndromes observed in other clinical contexts. This consideration warrants a discussion of how M-HLH is defined and if there is a reliable strategy to differentiate it from other proinflammatory states or various degrees of organ failure often associated with malignancy.

The diagnostic criteria for HLH have been revised several times (see Table 3 for comparison). Most recent general HLH guidelines were defined in 2004 [23] and led to the development of the H-score, which calculates a sum score of nine weighted variables (known underlying immunosuppression, temperature, organomegaly, hemoglobin levels, leukocyte count, platelet count, ferritin level, triglyceride level, fibrinogen level, AST level, hemophagocytosis features on bone marrow aspirate) to aid in the diagnosis of HLH [24]. To further clarify specific diagnosis of HLH in the context of malignancy, Daver et al. proposed a new set of criteria that included 18 variables derived from review of the current literature and expert opinion [3]. Some studies have examined the sensitivity and specificity of individual lab parameters in making a diagnosis of HLH. For instance, a study by Hayden et al. suggested that a sIL-2R level of >2515 U/mL (22,256 pg/mL) was 100% sensitive in detecting HLH, but only 73% specific [25]. With ferritin levels exceeding 10,000 U/mL the specificity of this elevated sIL-2R increased to 93%. When applying the HLH diagnostic criteria to the patient presented in our second case, our patient meets the Daver criteria but not either HLH-94 or HLH-2004 criteria, and had an H-score of 156, which is below the proposed cut off of 168. While the elevated level of sIL-2R seen in our patient (9477 pg/mL) is highly suggestive of HLH, particularly in combination with significant hyperferritinemia, these results are by no means definitive and unfortunately pathological evaluation of tissue to look for hemophagocytosis or lymphohistiocytosis was not possible given her rapid clinical decline. Her constellation of lab abnormalities could have been due to liver and renal failure alone, a cytokine release syndrome (CRS) driven by TLS, or the cancer itself.

Given the overall diagnostic complexity of this case, there was significant debate as to whether initiation of treatment for HLH was indicated or not. Treatment of HLH traditionally focuses on suppressing the overactive immune system to prevent further organ damage. According to the HLH-2004 guidelines, induction therapy should include dexamethasone, etoposide, and intrathecal methotrexate if there is CNS tumor involvement [3]. However, several more targeted approaches have also been used that focus on suppressing macrophages and CD8+ T cells using antithymocyte globulin (ATG) [3]. For adults with HLH, particularly M-HLH, treatment is often more complex. These patients frequently present with concurrent multiorgan failure, making initiation of cytotoxic therapy risky. Therefore, one may postulate that M-HLH treatment should target the underlying malignancy. However, studies suggest that treatment of the cancer alone is insufficient to limit the often rapid progression of M-HLH [3].

Of note, as mentioned above, the patient’s clinical presentation also raised the question of whether concurrent cytokine release syndrome (CRS) contributed to her clinical decline, a distinction which could impact treatment. While classically CRS is associated with immunotherapy [26], CRS has also been described in the setting of severe viral illnesses such as influenza and COVID-19 [26],[27]. To our knowledge, there are no reports of spontaneous CRS in metastatic melanoma. Clinically CRS can present with a wide array of symptoms ranging from mild fatigue, myalgias, and rash, to profound hypotension, disseminated intravascular coagulopathy and multiorgan failure [26]. While many cytokines contribute to this syndrome, IL-6 plays the predominant role [26]. Interestingly, IL-6 secretion as a result of CRS can lead to the development of hemophagocytic lymphohistocytosis (HLH) in the context of severe COVID-19 cases and CAR-T cell therapies [26],[27]. Therefore, it is possible that a similar mechanism is at play in the context of M-HLH and may explain why in one reported case, M-HLH improved with treatment of tocilizumab (an anti-IL-6 agent) [28],[29]. However, given that patients with clinical presentations concerning for overlapping CRS and HLH (as in the case of our second patient) often have severe hepatic injury, initiation of tocilizumab harbors significant risk. In addition, the unique steroid-responsiveness of the HLH-like syndrome observed in metastatic melanoma patients suggests that M-HLH may represent a distinct disease entity from other HLH contexts and needs further investigation. Collectively, these findings suggest that clarification of diagnostic criteria for M-HLH to distinguish this physiologic process from other hyperinflammatory states is necessary to guide appropriate management.

These cases illustrate the importance of checking both TLS- and HLH-associated labs when a clinical decline is observed in patients with metastatic melanoma, particularly if the patient has widespread hepatic involvement. Identification of TLS carries a very poor prognosis, thus should prompt immediate goals of care conversations with patients and family and aggressive early management. HLH-like syndromes can be seen but carry a better prognosis and appear to be more steroid responsive than cases of primary HLH or HLH due to other secondary causes. Individual context must be considered and discussion amongst a multidisciplinary team as well as the patient and/or their family members is necessary to guide appropriate management.