Unusual Clinical Presentation of Clear Cell Sarcoma in a Young Woman

ABSTRACT

BACKGROUND

Clear cell sarcoma (CCS) is a rare but aggressive malignancy that typically occurs in young adults and is characterized by soft tissue tumors of the extremities. CCS can be difficult to distinguish from metastatic melanoma based solely on histology and immunohistochemistry (IHC) because of the significant overlap between them. However, it is imperative to get an accurate clinical diagnosis, as it informs disease staging and treatment options for patient care. Present in approximately 75% of CCS cases, the EWSR1 gene rearrangement detected by fluorescence in situ hybridization (FISH) can help with establishing a diagnosis; the underlying reciprocal translocation has never been reported in cutaneous melanoma.

CASE DESCRIPTION

We reviewed a case of a young woman who presented with a confusing picture of widespread lymphadenopathy, cutaneous metastases, and electrolyte derangements and was subsequently diagnosed with metastatic CCS.

CONCLUSIONS

This case suggests possible value in performing molecular testing when a clinical picture does not correspond with what is expected for melanoma. It also raises the question of whether CCS cases may be underreported. This case highlights an uncommon presentation that may not be recognized as a manifestation of CCS by an oncologist who is not a sarcoma specialist. It is unclear how COVID-19 vaccination contributed to her clinical presentation, and it is also unclear whether an early diagnosis would have changed her clinical outcome.

Introduction

Clear cell sarcoma (CCS) is commonly seen in adolescents and young adults, with most patients aged 20 to 40 years at the time of diagnosis.¹ It commonly develops in the deep soft tissue of the extremities, usually in proximity to tendons and aponeuroses.²

CCS can be difficult to differentiate from malignant melanoma due to their histological and clinical similarities. In fact, CCS has historically been referred to in literature as “malignant melanoma of soft parts.”³ Like malignant melanoma, CCS demonstrates melanocytic differentiation, and they share similar immunohistochemical markers such as S100, HMB-45, and melanin.^4-6 CCS also has a propensity for repeated local recurrences, regional nodal metastases, in-transit metastases, and distant disease.⁷ However, in CCS, as with other soft tissue sarcomas, pulmonary metastases are the most commonly reported distant metastases.⁷

CCS typically presents as a slow-growing mass that may be painful. In a study by Kuiper et al, they reported an 18-month interval between a swelling first being noticed by a patient and a physician consultation.² In advanced stages, patients may also exhibit systemic symptoms such as weight loss, anorexia, and malaise.⁸

Here, we present a case of an unusual clinical presentation of CCS in a young patient with predominant cutaneous and lymph node involvement and rapid clinical deterioration.

Case Presentation

A 26-year-old woman with no pertinent medical history presented in July 2021 to the emergency department (ED) with painless lumps in her left groin 5 days after receiving a second monovalent Moderna COVID-19 vaccine. On physical examination, left inguinal lymphadenopathy without overlying skin changes was noted. This was suspected to be reactive adenopathy from her recent immunization, and follow-up with her primary care provider was advised.

She was reevaluated in the ED 6 weeks later for persistent left inguinal lymphadenopathy, now associated with left lateral hip pain. Tenderness to palpation overthe left lateral hip was noted during the examination. A bilateral pelvis plain radiograph showed no acute or healing fracture. She was discharged home with a diagnosis of left trochanteric bursitis. Subsequently, an outpatient ultrasound of the left inguinal region was performed due to persistent lymphadenopathy. It demonstrated multiple abnormal inguinal lymph nodes, suggestive of a malignant process. A CT scan of the chest, abdomen, and pelvis was planned, but she presented to the ED again with worsening symptoms.

She now reported bilateral hip and lower abdominal pain, persistent left inguinal lymphadenopathy, constipation, nausea and vomiting, fatigue, abdominal skin discoloration, and a 15-lb weight loss. A physical examination revealed hard ecchymosis over the pubis and erythema over the left flank (Figure 1) with nontender, firm lymphadenopathy in the left inguinal area. Initial laboratory test results were remarkable for an elevated lactate dehydrogenase level of 1097 U/L (normal range, 98-192 U/L), a uric acid level of 9.1 mg/dL (normal range, 3.0-6.8 mg/dL), an elevated serum creatinine level of 1.18 mg/dL (normal range, 0.44-1.03 mg/dL), and hypercalcemia with a serum calcium level of 1.7 mg/dL (normal range, 8.6-10.4 mg/dL).

Figure 1. Clear Cell Sarcoma Skin Involvement

A CT scan of the abdomen and pelvis with intravenous contrast demonstrated conglomerates of cardiophrenic, retroperitoneal, bilateral iliac chain, and bilateral inguinal lymph nodes, with the largest node being in the left iliac chain and measuring 7.4 cm. Additional findings included moderate left hydronephrosis, diffuse lytic osseous lesions, a left adnexal 5.1-cm soft tissue lesion suspected to be of ovarian etiology, a large indeterminate lesion measuring 9.3×4.3 cm in the left flank that infiltrated the abdominal muscles, and external compression of the left iliac veins. She was subsequently admitted for obstructive uropathy and hematologic consultation due to concerns about a possible lymphoproliferative disorder.

A fluorodeoxyglucose F 18 (FDG)–PET/CT scan revealed multifocal FDG-avid lymphadenopathy, lytic osseous lesions, and a left lower quadrant abdominal wall mass; overall radiographic findings were most suspicious for lymphoma (Figure 2). Hydronephrosis and left ovarian enlargement with mild FDG uptake were also noted, suggestive of a possible complex cyst rather than malignant involvement. An MRI of the brain revealed a right frontal bone lesion suspicious for metastasis but no intraparenchymal lesions.

Figure 2. FDG-PET/CT Imaging

A core biopsy of the left inguinal lymph node was obtained. On histopathology, numerous cohesive clusters of large and monotonous tumor cells were noted. Singly scattered tumor cells were also detected. These tumor cells had a high nucleus-to-cytoplasmic ratio, round nuclei with fine chromatin, 1 to 3 nucleoli, and clear to eosinophilic cytoplasm. Ki-67 expression was 40%. On immunostaining, tumor cells were positive for HMB-45, Melan-A, SOX10, and CD99 and negative for S100, AE1/AE3, desmin, SALL4, and Oct3/4. On flow cytometry, a lymphoma cell population was not identified, and both T cells and natural killer cells appeared normal via antigen profiling. Based on this biopsy, the diagnosis was reported as malignant melanoma (Figure 3).

Figure 3. Core Biopsy Results of the Left Inguinal Lymph Node

A bone marrow aspiration and biopsy of the left iliac crest had been obtained simultaneously with the lymph node biopsy due to high suspicion of a lymphoproliferative disorder and to expedite treatment initiation. This revealed normocellular marrow (70%) with focal involvement by a nonhematopoietic metastatic tumor (20%).

The patient was treated for hypercalcemia and hyperuricemia with intravenous hydration, pamidronate disodium, rasburicase, and allopurinol. Hypercalcemia was attributed to diffuse osteolytic metastases, and hyperuricemia and acute kidney injury were suspected to be from obstructive uropathy rather than tumor lysis syndrome. The urology team placed a left ureteral stent.

She was discharged to outpatient follow-up with a diagnosis of metastatic melanoma. Additional immunostains for melanoma were requested on her bone marrow aspiration/biopsy sample because of the atypical disease course and the lack of previous history of superficial melanoma; these tumor cells were strongly positive for HMB-45 and SOX10 and weakly positive for S100. Samples were also sent for additional analysis using cytogenetics, including fluorescence in situ hybridization (FISH), and next-generation sequencing. A melanoma-specific molecular analysis on the lymph node biopsy sample was negative for variants in BRAF, GNA11, GNAQ, HRAS, KIT, and NRAS. Initiation of treatment was planned with the combination immunotherapy ipilimumab and nivolumab.

Prior to her scheduled first dose of immunotherapy, the patient was brought to the ED with altered mental status and increased somnolence. Laboratory work-up demonstrated recurrent hyperuricemia and hypercalcemia with renal impairment, hyponatremia, and lactic acidosis. A CT scan of the head with contrast revealed no intraparenchymal metastases. Pamidronate and rasburicase were administered again. She was also given broad-spectrum antibiotics and fluid resuscitation. A percutaneous nephrostomy tube was placed because of the acute kidney injury. An extensive work-up for infectious etiologies was performed and was essentially negative.

Because of the rapid decline in her clinical condition, the first cycle of treatment with ipilimumab and nivolumab was administered while she was an inpatient. Approximately a week later, she developed fever and hypotension, requiring transfer to the intensive care unit and, eventually, mechanical ventilation and inotropic support. Broad-spectrum antibiotics were initiated again, and a repeat infectious work-up remained unrevealing. An increased confluence of her abdominal rash was also noted, prompting a biopsy of the skin rash. The possibility of cytokine release syndrome in the setting of dual immunotherapy was considered. Her IL-6 level was checked and elevated at 11.5 pg/mL (normal range,≤2 pg/mL). However, she subsequently improved with supportive care alone without steroid initiation or anti–IL-6 therapy and was extubated and weaned off vasopressor support.

At this time, results from the additional testing performed on the prior biopsy specimens became available. Cytogenetics revealed an abnormal karyotype with an EWSR1-ATF1 gene fusion identified by FISH and copy number losses in CDKN2A, CDKN2B, and MTAP. Although this tumor was previously reported as melanoma, due to the presence of the EWSR1-ATF1 gene fusion, the diagnosis was updated per pathology to CCS. Additionally, a skin punch biopsy revealed anastomosing cords and fascicles of pleomorphic cells throughout the mid- and deep dermis, diffusely positive for SOX-10 and also consistent with CCS.

After the oncology team consulted with a sarcoma expert at our institute, the University of Nebraska Medical Center, the decision was madeto continue with combination immunotherapy after optimization of her acute medical issues. However, she developed acute renal failure accompanied by worsening encephalopathy. Our nephrology service recommended urgent hemodialysis initiation. After multidisciplinary family meetings, the patient and her family elected to proceed with comfort measures, and the patient died later the same day.

Discussion

CCS is an uncommon malignancy, comprising approximately 1% of all soft tissue sarcomas.⁹ It is commonly seen in young adults with no specific gender predilection. The most common site of involvement is the lower extremities, especially the foot and ankle.¹⁰ Although primary cutaneous CCS has been reported, cutaneous metastasis from a deep-seated CCS is an uncommon phenomenon.5 In reported cutaneous cases of CCS, superficial dermis is involved and epidermal involvement by CCS is a rare occurrence.¹¹ Hypercalcemia is seen frequently among patients with malignancies, but it is rarely reported in patients with soft tissue sarcoma.¹² Only 1 prior case of CCS with hypercalcemia has been reported in which hypercalcemia was attributed to the presence of osteolytic metastases.¹³

The majority of patients with CCS are diagnosed with early-stage disease. In a Surveillance, Epidemiology, and End Results Program database study by Li et al, 57.7% and 33.7% of patients had localized and regional CCS, respectively, whereas only 8.6% of patients had distant or metastatic disease. Of these cases, 74.3% involved lower extremities. Based on this study, 5-year disease-specific survival was 62.9%. As expected, patients with localized stage had better 5-year disease-specific survival than those with regional stage (82.4% vs 44%, respectively). None of the patients with distant disease survived at 5 years; in fact, survival at 2 years was only 6.7%.⁹

In a small retrospective review of patients with CCS by Finley et al, patients with large primary tumors (> 5 cm) were noted to have an increased risk of disease recurrence and progression to metastatic disease despite optimal surgical management. The median survival for these patients was 3 months after progression to metastatic disease.¹⁴

Due to its rare nature and histological similarities, CCS can easily be mistaken for malignant melanoma. However, the need to distinguish between the 2 entities remains crucial due to the differences in their clinical course and management options. As witnessed in our case, differentiating between them based on histology alone can be a diagnostic challenge. Cutaneous CCS in particular may be confused with cutaneous spindle cell melanoma or metastatic melanoma based solely on histology and immunohistochemistry.⁶

Despite the histological commonalities of these 2 cancers, their molecular landscapes vary substantially. In as many as 75% of CCS cases, the cytogenetic analysis revealed the reciprocal translocation t(12;22)(q13;q12) involving the EWSR1 gene and the ATF1 gene.^15,16 Four types of EWSR1/ATF1 chimeric transcripts have been noted in CCS.^1,17 This translocation has not been described in malignant melanoma and, therefore, can help distinguish between the 2 diagnoses. A t(2:22)(q34;q12) translocation resulting from the fusion of the EWSR1 and CREB1 genes has been reported in CCS that arises in the gastrointestinal tract.18 Notably, CCS is marked by the absence of mutations in BRAF that are commonly noted in malignant melanoma.¹⁷

Other chromosomal abnormalities that may be observed in CCS include additional copies of chromosomes 2, 7, and 8.¹⁹ Luzar et al presented a series of 4 cases (3 primary cutaneous CCS, 1 CCS with metastases to skin).⁵ Three cases demonstrated a rearrangement of EWSR1 and 1 showed ESWR1-ATF1 translocation. Hence, FISH analysis is crucial to distinguish cases of CCS in which cutaneous involvement mimics that of malignant melanoma.

The rarity of this disease also limits the availability of information regarding its optimal management. Management of CCS should involve a multidisciplinary team.⁸ For patients with localized disease, wide local excision is the treatment of choice. The utility of sentinel lymph node biopsy or elective lymph node dissection in the management of localized CCS is unclear.^8,10 A reexcision can be considered to achieve tumor-free
margins, whereas adjuvant radiation therapy is recommended for close resection margins. For local recurrences or oligometastatic recurrences, surgery resection is usually recommended.⁸

Management of locally advanced or metastatic disease remains challenging. There is no clear effective or preferred treatment regimen due to the limited data from studies reviewing outcomes for a small number of patients with CCS.

Conventional chemotherapy has limited efficacy in CCS. Jones et al evaluated the role of palliative chemotherapy in patients with CCS, most of whom received anthracycline-based chemotherapy either as a single agent or in combination with ifosfamide and/or a platinum agent.²⁰ Other regimens included cisplatin; cisplatin in combination with vinblastine, dacarbazine, and interferon alfa 2B; vincristine as a single agent; or temozolomide with thalidomide, sorafenib, sirolimus, and IGF1R antibody.²⁰ Findings from this study showed only a 4% response rate to palliative chemotherapy.²⁰ The median progression-free survival with first-line chemotherapy was 11 weeks, and the median overall survival after initiation of chemotherapy was 39 weeks.²⁰ Similarly, in a study by Kawai et al of 75 patients with CCS receiving cisplatin-based chemotherapy regimens, the objective tumor response was low (23%).²¹

Because CCS responds poorly to chemotherapy and is histologically and clinically similar to malignant melanoma, the use of immune checkpoint inhibitors (ICIs) to treat CCS is of ongoing interest. In a case reported by Marcrom et al, a young woman with a bulky chest wall recurrence of mediastinal CCS had a complete clinical response after she was treated with pembrolizumab in combination with standard fractionated radiation.²² Additionally, Tawbi et al noted some clinical responses to ICIs in patients with soft tissue sarcomas, with response varying based on tumor type.²³ Additional studies with larger sample sizes and randomized settings are needed to further evaluate the role of immunotherapy in treatment of CCS.

Although targeted therapies have revolutionized care for melanoma and other cancers, the role of targeted therapies in CCS has yet to be determined. In an observational study by investigators at The University of Texas MD Anderson Cancer Center comparing outcomes of ICIs and targeted therapy with standard chemotherapy, Jones et al reported finding no significant difference in overall survival between those receiving an ICI (15.9 months) or a targeted therapy (16.9 months) and those receiving chemotherapy (17.1 months).²⁴ Moreover, in CCS with a MET alteration, crizotinib has shown similar efficacy as doxorubicin-based chemotherapy.²⁵ The VEGFR inhibitor pazopanib is also being investigated in patients with advanced or metastatic CCS.²⁶ Again, further investigations are needed to determine optimal targeted therapies for advanced CCS.

Conclusion

Because of the difficulty in differentiating CCS from malignant melanoma based solely on histology and immunohistochemistry, our case suggests that there may be value in performing molecular testing if a clinical picture does not correspond with what is clinically expected for melanoma. It also raises the question about whether CCS cases may be underreported due to the difficulty in differentiating them histologicallyfrom melanoma. This case particularly highlights an uncommon presentation with hypercalcemia and cutaneous metastases that may not be recognized as a manifestation of CCS by an oncologist who does not specialize in sarcomas.

It is unclear how COVID-19 vaccination contributed to this patient’s clinical presentation; these vaccines have been noted to cause transient lymphadenopathy, which was the “red herring” that led to the delayed diagnosis of cancer. It is also unclear whether an early diagnosis would have changed her clinical outcome, given the aggressive nature of the disease. The optimal systemic treatment for CCS has yet to be determined, and the rarity of CCS limits the information available via randomized control trials. The role of ICIs in the management of CCS remains an exciting avenue for future research, and participation in clinical trials under the care of sarcoma specialists should be encouraged.

References

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Author Contributions:

SA drafted the discussion section, and BH drafted the case presentation sections of the manuscript; both reviewed and edited the manuscript. SH reviewed the manuscript. SL contributed pathology images and reviewed the manuscript. BS provided supervision and final review and editing of the manuscript. All the authors have read and approved the final version of this manuscript.

Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Author Affiliations:

¹Department of Internal Medicine, Division of Hematology/Oncology, University of Nebraska Medical Center, 986840 Nebraska Medical Center, Omaha, NE 68198-6840, USA

²Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198-6840

³Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-5900

Corresponding Author
Samia Asif, MBBS

Department of Internal Medicine, Division of Hematology/Oncology, University of Nebraska Medical Center, 986840 Nebraska Medical Center, Omaha, NE 68198-6840, USA

Samia.asif@unmc.edu