Novel Response to Neoadjuvant Anti-PD1 Therapy for a Patient with Retrocaval Melanotic Schwannoma

Abstract

Melanotic schwannoma is a rare nerve sheath tumor composed of melanin-producing Schwann cells with the potential for metastasis. These tumors can be associated with familial tumor syndromes and can cause significant symptoms related to nerve compression and mass effect. Due to the rarity of these lesions, they can be initially misidentified as melanocytomas, pigmented dermatofibrosarcoma protuberans, neurofibromas, or malignant melanomas. Surgical excision is the mainstay of treatment with limited benefit from adjuvant systemic chemotherapy or radiation. Modern treatments with immune checkpoint blockade have demonstrated significant improvements in progression free and overall survival for a variety of cancer histologies, however, anti-PD1 therapy has yet to be evaluated in patients with melanotic schwannoma. This report demonstrates a significant improvement in symptomatology and tumor stability with neoadjuvant anti-PD1 therapy for a retrocaval melanotic schwannoma initially masquerading as malignant melanoma. This report demonstrates the potential benefit of a novel therapeutic option for patients with melanotic schwannoma.

Introduction

Melanotic schwannoma (MS), also known as malignant melanotic schwannian tumor, is a rare nerve sheath tumor with malignant potential. It is composed of melanin-producing Schwann cells and was first described by Millar in 1932 [1]. Fewer than 250 cases have been described, with the tumor most frequently located in the paraspinal sympathetic chain (28%) or gastrointestinal tract (esophagus, stomach, or rectum; 28% of cases) [2-6]. Approximately one half of patients with MS have Carney complex, a familial tumor syndrome defined by pigmented skin lesions such as blue nevi and lentigines, myxomas of the heart, skin or breast, and endocrine tumors [4,7].

Symptoms of primary melanotic schwannomas are related to the location, size and local compressive effects although a substantial number of cases present asymptomatically (29%). These tumors can compress the spinal nerves and cause numbness, weakness or lower extremity pain (36% of cases), whereas tumors arising near organs can cause symptoms related to mass effect (13% of cases) [6,8]. The differential diagnosis for these lesions include pigmented dermatofibrosarcoma protuberans, melanocytoma, melanin-laden neurofibromas, and malignant melanomas and differentiation may be difficult due to the similarities in immunohistochemical staining.

The primary treatment for melanotic schwannomas is wide local excision with the goal of obtaining negative margins [6,9,10]. Due to the rarity of this tumor, there are no formal guidelines for the use of adjuvant therapies including radiation and chemotherapy and their use is controversial [6,9,10]. Therefore, management of these lesions is based upon outcomes from case reports and retrospective reviews.

Herein, we report a unique case of a patient with a retrocaval melanotic schwannoma presenting as flank pain, initially diagnosed as metastatic melanoma and demonstrating significant improvement in symptomatology and lack of progression in response to anti-PD1 targeted therapy, prior to definitive resection and final diagnosis.

Case Presentation

An otherwise healthy 28-year-old male presented to an urgent care clinic for severe crescendoing right flank pain radiating towards his abdomen, associated with nausea and vomiting. His history was notable for a giant congenital nevus located on his posterior occiput and neck that was resected as a child. On exam he was tender to palpation in the right upper quadrant without evidence of testicular mass. He subsequently underwent a computed tomography (CT) scan of the abdomen which demonstrated a 5.0cm x 3.4cm retrocaval soft tissue mass medial to the right adrenal and superior to the right renal hilum (Figure 1A-B). A CT-guided biopsy of the mass demonstrated a heavily pigmented neoplasm. Immunohistochemistry showed strong immunoreactivity for S100 and panmelonoma (HMB45/MART-1/tyrosinase), without staining for keratin (AE1/AE3) and an initial diagnosis of metastatic malignant melanoma was made. This diagnosis was made from a limited tissue sample given the technical challenge of the biopsy; the sample was insufficient for molecular testing. A completion full body skin exam did not demonstrate any concerning lesions. A staging fluorodeoxyglucose-positron emission tomography (FDG-PET) scan demonstrated a hypermetabolic retroperitoneal mass with a standardized uptake value (SUV) maximum of 8.2 without evidence of other sites of disease.

Figure 1.

Appearance and surgical outcome of retrocaval mass presenting with flank pain in an otherwise healthy 28 year old male. A-B. Contrast enhanced cross sectional imaging. The green arrow denotes the mass. A. Representative slice of the coronal images. B. Representative slice the axial images. C. Intraoperative image of the skeletonized inferior vena cava and resection bed with the liver mobilized and rotated medially.

Given the presumptive diagnosis of metastatic melanoma and due to the extreme symptomatic nature of the lesion, he was rapidly initiated on anti-PD1 therapy with pembrolizumab every three weeks. After the initial dose of pembrolizumab, the patient noted dramatic pain improvement and was able to discontinue the use of narcotics. After the patient completed four cycles of pembrolizumab, a repeat CT scan revealed stable disease, with the mass measuring 5.1cm x 3.5cm, with continued pain control.

A repeat FDG-PET redemonstrated the retroperitoneal mass with a decrease in the maximum SUV from 8.2 to 5.9. Additionally, there was a central photopenic area, consistent with central necrosis without evidence of other sites of disease. A repeat CT-guided biopsy of the lesion was performed in order to obtain BRAF molecular testing should subsequent lines of therapy have been warranted. This specimen contained numerous melanophages as confirmed by immunohistochemical staining for CD163 and lacked any significant population of neoplastic cells. Furthermore, the biopsy showed a background of peripheral nerves and peripheral ganglia in close proximity with the lesion. The anatomic relationship of the lesion to preexisting retroperitoneal peripheral nerve structures and the absence of any pre-existing lymph node tissue led to the consideration of melanotic schwannoma as an alternate diagnosis. A multidisciplinary sarcoma tumor board determined that surgical resection would provide definitive treatment. Due to the location of the mass, the patient was consented for radical resection of retroperitoneal mass, possible resection and reconstruction of the inferior vena cava (IVC).

On exploratory laparotomy, no evidence of metastatic disease was identified. A full Kocher maneuver was performed exposing the infrahepatic IVC and bilateral renal veins. The right colon and hepatic flexure were mobilized to improve visualization and exposure. The IVC was mobilized and vessel loops were passed to obtain proximal and distal control. The mass was adherent to the retroperitoneum and posterior wall of the IVC distal to the insertion of the left renal vein, and required sharp dissection with en bloc resection of a portion of the right adrenal gland (Figure 1C). The patient's postoperative course was unremarkable and the patient was discharged home after 4 days. On follow-up, the patient was offered a referral for genetic testing to rule out a pathogenic germline mutation

The gross specimen showed uniform dark pigmentation (Figure 2). Large areas of the lesion appeared amorphous and soft suggesting widespread tumor necrosis. This was also confirmed on the histologic sections that showed large areas of necrosis with melanophages. The tumor consisted of cells exhibiting variable histomorphology, with a predominant epithelioid pattern but also areas of more spindled appearance, as has been described in previous cases of melanotic schwannoma [2,8,11]. In addition, some tumor cells showed cytoplasmic vacuolation, atypical nuclei with distinct nucleoli, and rare mitotic figures. Histologic sections confirmed the intimate association with retroperitoneal nerves as well as peripheral ganglia suggested by the second biopsy. The capsular tissue surrounding the lesion contained EMA positive perineurial cells, suggesting that the tumor arose from a pre-existing neural structure (Figure 3). No remnants of a pre-existing lymph node were found but focal lymphocytic infiltrates were present within the tumor. The presence of lymphocytes associated with tumor nodules, but more importantly extensive necrosis scattered throughout the tumor, may be suggestive of treatment effect from the anti-PD1 agent, pembrolizumab.

Figure 2.

Gross examination and hematoxylin and eosin stain. A. Gross cross-section demonstrating heavily-pigmented, circumscribed, encapsulated, multinodular tumor within retroperitoneal adipose tissue. The central amorphous pigmented areas correspond histologically to sheets of degenerative melanophages. B-F. H&E stained tumor sections demonstrating nodular growth pattern (B) within peripheral nerve (C). The tumor contains densely pigmented melanophages (B-E) and relatively hypopigmented tumor cells (E-F) with predominantly epithelioid cytomorphology, nuclear atypia and prominent nucleoli (E-F). Associated with the tumor are scattered lymphoid clusters (B-C) and individual lymphocytes, but no lymph node parenchyma.

Figure 3.

Immunohistochemical stains and molecular sequencing. A-C. Immunohistochemical stains demonstrating expression of epithelial membrane antigen (EMA) by adjacent perineurial cells and expression of melanocytic markers, HMB45 (B) and melan-A (C) in tumor cells. Melan-A stain is combined with MIB-1, which shows increased proliferative activity. D. Manual inspection of next generation sequencing data revealed a 10 bp frameshift mutation in the PRKAR1A gene (chr. 17q24.2), which has been associated with Carney complex.

NGS-based studies using an in-house hybrid-capture panel targeting 1213 cancer-associated genes (UCM-OncoPlus) [12,13] identified a frameshift mutation in the PRKAR1A gene as well as additional pathogenic variants in TP53 (c.559+1G>T, p.?) and NF1 (c.2033dup, p.I679Dfs*21). Notable negative results were the absence of variants in BRAF, NRAS, CDKN2A, GNAQ, and GNAS. MLH1, MSH2, and MSH6 were also evaluated with no mutations. Tumor mutational burden (TMB) was relatively low at 1 mutation per megabase. The histopathology, molecular profile, anatomic location and clinical context are interpreted as supporting a classification as melanotic schwannoma (malignant melanotic schwannian tumor) [14,15].

Discussion

Herein, we report for the first time, a melanotic schwannoma demonstrating symptomatic relief and a decrease in SUV uptake on FDG-PET in response to anti-PD1 targeted therapy prior to radical resection. The treatment choice for the anti-PD1 antibody pembrolizumab was made due to the initial diagnosis of metastatic melanoma, which often presents with a similar immunohistochemical profile and is often initially treated with anti-PD-1 therapy in advanced cases [16]. Treatment with pembrolizumab led to a substantial improvement in the patient’s symptoms and tumor stability, allowing the discontinuation of narcotics. Following symptom control and a progression free interval, a repeat biopsy and subsequent resection revealed findings that support a diagnosis of melanotic schwannoma with extensive degenerative changes that could potentially be the result of prior anti-PD-1 therapy.

The preferred treatment for melanotic schwannoma is en bloc surgical excision [2,6,17,18], with outcomes dependent on the grade and location of malignancy as well as the completeness of removal [6,19,20]. Although melanotic schwannoma was considered to be a benign tumor in the majority of cases [21,22], recent literature increasingly suggests that it carries significant risk for recurrence as well as a distinct risk for metastatic spread and may therefore warrant classification as a malignant neoplasm: Local recurrence occurs in 15-35% of cases, and metastatic spread occurs within 5 years in 26-44% of cases [14,23,24].

Studies investigating the utility of chemotherapy in treating melanotic schwannoma are limited. The combination of ifosfamide and doxorubicin has been reported as the most effective chemotherapy for metastatic melanotic schwannoma [6,25]. In two cases refractory to ifosfamide/doxorubicin, carboplatin/etoposide led to partial remission [25]. One case also reported stable disease for 1 year with foremustine therapy [26]. However, chemotherapy has demonstrated low response rates and no benefit in mortality [5,26].

The use of adjuvant radiation for patients with melanotic schwannoma has been explored. In one case report, in which the resection margins were positive, 60-Gy of adjuvant radiotherapy was utilized with no evidence of recurrence after 2 years of follow-up. No significant data exists for the use of neoadjuvant radiation in patients with melanotic schwannoma however it may be beneficial for organ preservation or improving margin status in the setting of close proximity to vital structures [6,9,27].

Given the high rate of recurrence of melanotic schwannoma and ineffectiveness of chemotherapy, it is important to be aware of adjunctive treatment options. To our knowledge, this is the first report of treatment of melanotic schwannoma with anti-PD1 targeted therapy, which is thought to restore functional activity of tumor-infiltrating T lymphocytes [16]. A dramatic improvement in pain control was achieved two weeks after the first treatment. It is conceivable that the improvement in pain control was due to a transient decrease in the size of the tumor, suggesting that pembrolizumab has a partial therapeutic effect. Another theory is that the clinical response resulting in symptomatic relief without a change in the overall tumor size was achieved due to the response in the more malignant or aggressive component of the tumor. It will be important to assess the future applicability of pembrolizumab treatment to melanotic schwannoma, perhaps in combination with other immunotherapy or chemotherapy approaches.

The effectiveness of anti-PD1 targeted therapy, routinely used to treat melanoma, may be related to the shared lineage between Schwann cells and melanocytes. Both Schwann cells and melanocytes originate from neural crest-derived precursors, which are multipotent embryonic progenitors associated with developing peripheral nerves [28,29]. This shared lineage may also explain the capacity of these abnormal Schwann cells to produce melanin.

High TMB has been shown to be associated with response to anti-PD1 targeted therapy [30]. Our patient had a relatively low TMB at 1 mutation per megabase, so would not fit the usual paradigm. However, TMB is not a highly specific biomarker, and response to anti-PD1 targeted therapy has also been seen with low TMB.

Retroperitoneal melanotic schwannomas are exceedingly rare. At the time of publishing, only seven cases have been reported, two of which were of renal and pancreatic origin, respectively [19,31-36]. Of the seven cases, four were discovered incidentally, either during routine ultrasonography or ultrasonography for unrelated complaints such as urethrorrhagia. One of the seven cases was discovered in a patient presenting with urinary frequency and vague abdominal pain. The other two case reports did not specify the nature of the presentation. To our knowledge, our case is the first case of a retroperitoneal melanotic schwannoma presenting as severe, intractable flank pain radiating to the abdomen. The retrocaval location and intimate association with retroperitoneal nerves and peripheral ganglia likely contributed to the manifestation as flank pain.

Conclusion

In summary, we report a case of a retrocaval melanotic schwannoma masquerading as malignant melanoma, presenting as flank pain, with alleviation of symptoms and FDG-PET maximum SUV decrease after neoadjuvant anti-PD1 therapy, followed by definitive surgical resection. Treatment options for patients with melanotic schwannoma are limited and this demonstrated that anti-PD1 therapy may be beneficial as neoadjuvant or adjuvant therapy, however its application remains investigational. Further research is required to determine the optimal management of these rare tumors.