Immunotherapy in a rare case of primary pelvic retroperitoneal melanoma

Abstract

Recent advances in novel immunotherapeutic and targeted therapeutic agents have increased treatment options in patients with advanced metastatic melanoma. However, evidence in the literature on whether or not extracutaneous melanoma will acquire an equivalent advantage from these therapies is very scarce. In general, extracutaneous melanomas are rare and aggressive melanomas, which are clinically and biologically unique, with higher incidence of metastatic disease and poor prognosis. In this case report, we present a very rare case of a 54-year-old woman with primary pelvic retroperitoneal melanoma treated with an anti-PD-1 antibody, pembrolizumab. Furthermore, we explore the role of novel immunotherapies in the treatment of advanced melanoma.

Background

Extracutaneous melanoma comprises only 5% of all melanomas. Owing to its rarity and its aggressive nature, it remains a diagnostic and treatment challenge in oncology. Its ability to microscopically invade the bloodstream and lymph nodes is thought to contribute to its aggressive nature.¹ The prognosis of this disease is also known to be very poor. However, it is not clear whether this is because it is biologically aggressive in nature, or because the diagnosis and treatment is often delayed. Unlike cutaneous melanoma, extracutaneous melanoma is generally not identified on physical examination and symptoms typically do not develop until the presence of local advancement or metastatic disease. Additionally, the Clark level and Breslow index have no utility in extracutaneous melanoma as there are no corresponding structures that are similar to the layers of the skin.²

In recent years, the approval of novel immunotherapy and targeted therapy as first-line treatments has broadened the therapeutic options for advanced melanoma. Immunotherapies targeting immune checkpoints include cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors. In addition, therapies that target genetic mutations found in a subset of melanoma patients include BRAF inhibitors, mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) Kinase (MEK) inhibitors and KIT inhibitors. However, even with these recent therapeutic advancements and significant improvements on outcome in cutaneous melanoma, it is not clear whether this can be generalised to extracutaneous melanoma. Owing to the rarity of extracutaneous melanoma, the therapeutic approach is largely based on the experience of systemic treatment of metastatic cutaneous melanoma. Currently, assessing the role of immunotherapy in extracutaneous melanoma through prospective clinical trials is deemed impractical. However, in order to estimate the benefit of therapeutic intervention, clinicians can use data from retrospective analyses and case reports. We sought to report this case due to its rarity and the impact of novel anti-PD-1 antibody in this distinct group of melanoma.

Case presentation

A 54-year-old Caucasian woman, with no significant medical history except for well-controlled hypertension and hypothyroidism, presented with postmenopausal vaginal bleeding and left lower quadrant pain. Gynaecological examination and endometrial biopsy were unremarkable. Transvaginal ultrasound revealed a 4.3×3.4×3.0 cm left adnexal lesion, with a differential diagnosis of either complex cystic or solid adnexal mass. Based on the ultrasound results, the patient was then referred to gynaecology oncology for further assessment and discussion of treatment options. The patient agreed to undergo a robotic-assisted total laparoscopic hysterectomy with bilateral salpingo-oophorectomy (TLH-BSO). While performing the TLH-BSO, a black, solid, right-sided retroperitoneal mass was identified. The mass was in close proximity to the right round ligament extending to the right paravesical and obturator space, displacing the bladder medially. Right retroperitoneal pelvic mass, bilateral pelvic lymph node dissection and omentectomy samples were sent for pathological investigation. Unexpectedly, the histomorphological features and immunohistochemical staining pattern (figure 1A–E) were most consistent with a malignant melanoma (positive for HMB45, Melan-A and S100, and negative for cytokeratin and inhibin). The uterine, ovarian, lymphatic and omental samples were unremarkable.

Figure 1.

(A–E) Immunohistochemistry of the pelvic mass shows cells staining positive for (A) Melan A (magnification, ×400), (B) HMB45 (magnification, ×400), (C) S100 (magnification, ×400) and negative for (D) cytokeratin (magnification, ×400). Image of mesenteric tumour (E) shows mitosis (M). Images are courtesy of Dr Teresa I Limjoco, Department of Anatomy and Pathology, Joan C Edwards School of Medicine.

Investigations

Given the pelvic retroperitoneal location of the mass, this was suspected to be a metastatic deposit. An extensive workup was therefore performed, which included a thorough skin and nail examination, colonoscopy, and esophagogastroduodenoscopy. Moreover, positron emission tomography (PET)/computed tomography (CT) scan and brain magnetic resonance imaging (MRI) were also performed. No significant abnormalities were identified. Further pathological studies did not reveal BRAF or KIT mutations. The negative results of the diagnostic workup suggested the differential diagnoses of primary pelvic retroperitoneal melanoma or metastatic melanoma of occult primary. After discussing management and treatment options, the patient opted to remain under observation for disease progression.

During a follow-up visit, a review of the patient's previous PET/CT scan exhibited a focal area of hypermetabolic activity posterior to the bladder. A cystogram ruled out a bladder diverticulum and a repeat transvaginal ultrasound revealed nothing additional. Abdominal/pelvic CT scan with intravenous contrast revealed a 2.5×1.8×2.0 cm hypodense mass adjacent to the right lateral aspect of the vaginal apex. CT-guided biopsy of the mass was undertaken and pathology was consistent with metastatic melanoma.

Differential diagnosis

Primary pelvic retroperitoneal melanoma or metastatic melanoma of occult primary.

Treatment

Given the patient's presentation, a systemic approach to treatment was considered most likely to benefit the patient. At the time of presentation, Food and Drug Administration (FDA)-approved novel immunotherapy options included monotherapy with pembrolizumab or nivolumab. Extrapolating from recent therapy guidelines for metastatic cutaneous melanoma, anti-PD-1 monotherapy with pembrolizumab (10 mg/kg every 3 weeks) was initiated. The patient did not qualify for any local or national clinical trials.

The patient tolerated the treatment well except for grade 1 side effects (ie, rash and hip pain). During a 6-month follow-up visit, PET/CT scan revealed nothing to suggest additional metastatic disease and repeat transvaginal ultrasound showed a well-circumscribed 2.4×2.6 cm mass distinct from the rectum, confirming stable disease. On discussion, immunotherapy was held and surgical removal of the mass was undertaken. Intraoperatively, multiple small deposits were found on the peritoneum adjacent to the mass, which prompted the discontinuation of the surgical resection. Biopsies of the peritoneum and mesenteric implants were taken for frozen section and revealed malignant cells, which were consistent with the patient's known malignant melanoma.

Although imaging studies revealed no evidence of disease progression (figure 2A–D) regional spread of the tumour was only evident during the attempt to surgically resect the mass (figure 3). Treatment with pembrolizumab was discontinued. After discussing the extent of the disease with the patient, she opted for a more aggressive approach and combination immunotherapy of nivolumab and ipilimumab was started in accordance with the CheckMate 067 trial,³ which the FDA had approved by that time.

Figure 2.

(A–D). Radiological findings exhibited no changes in tumour size (M=mass). CT image of the pelvic retroperitoneal mass on (A) initial presentation and (B) 1 year later. Positron emission tomography/CT image of the pelvic retroperitoneal mass on (C) initial presentation and (D) 1 year later. Images are courtesy of Dr Peter Chirico, Department of Diagnostic Radiology, Joan C Edwards School of Medicine.

Figure 3.

Intraoperative image of malignant melanoma implantation on the adjacent mesentery. Image is courtesy of Dr James Jensen, Department of Urology, Joan C Edwards School of Medicine.

Outcome and follow-up

After receiving 11 cycles of pembrolizumab over the course of 6 months, radiological imaging studies revealed neither disease progression nor a decrease in tumour size. As aforementioned, regional spread of the tumour was only evident during the attempt to surgically resect the mass. Owing to the size of the mesenteric foci, they were not detected on the most immediate radiological imaging taken prior to the surgery, which included CT, PET/CT and transvaginal ultrasound scans. On recognition of the extent of metastatic disease, treatment with pembrolizumab was discontinued and combination immunotherapy of nivolumab and ipilimumab was started in accordance with the CheckMate 067 trial.³ After two cycles of the combination therapy, she developed grade 4 side effects (ie, liver toxicity) requiring discontinuation of immunotherapy. This was resolved by treatment with steroids and mycophenolate. The patient continues to have stable disease and remains on observation. Thus, she has been progression-free for 12 months since initially starting immunotherapy.

Discussion

The mainstay of treatment for extracutaneous melanoma is surgical resection. However, if the patient cannot tolerate surgery or the mass is unresectable, a systemic approach is more appropriate.

Immunotherapy has been studied in patients with malignant melanoma since the mid-80s. A study that included metastatic melanoma, colon cancer, renal cell cancer and primary unresectable lung adenocarcinoma piloted interleukin-2 as the initial treatment used in patients with advanced cancer that did not respond to standard treatment.⁴ Results showed objective tumour regression, which included complete tumour regression in one patient with metastatic melanoma and partial tumour response in patients with hepatic and pulmonary metastatic disease from melanoma. Interleukin-2 became the standard treatment and the results of these studies paved the way for immunotherapy development. Although the results were encouraging, further studies using high-dose interleukin-2 treatment demonstrated significant adverse effects such as severe hypotension, oliguria, pulmonary congestion, arrhythmias and neurological toxicities. However, these adverse effects rapidly reversed when treatment was completed.^{5 6}

Major advances in immunotherapy that have emerged in recent years include adjuvant immunotherapy with interferon-α. Recently, the FDA approved four immunotherapies and four targeted therapies for the treatment of advanced melanomas. Immunotherapies that inhibit immune checkpoints include a CTLA-4 inhibitor (ipilimumab) and PD-1 inhibitors (pembrolizumab and nivolumab). Another immunotherapy is talimogene laherparepvec, which is an oncolytic virus therapy. Targeted therapies include BRAF kinase inhibitors (vemurafenib and dabrafenib) and MEK inhibitors (trametinib and cobimetinib). Although not new to the market, imatinib, a tyrosine kinase inhibitor, is known to target the BCR-ABL fusion gene in chronic myelogenous leukaemia, as well as KIT mutations in patients with gastrointestinal stromal tumour and melanoma. Despite the fact that these therapies were successful in clinical trials, documented cases using novel therapies with curative outcomes in advanced or extracutaneous melanoma were scarce during the writing of this report.

Genetic analysis was performed in our patient to determine if she had a BRAF V600E mutation. BRAF is a serine/thereonine protein kinase that activates the MAP/ERK kinase-signalling pathway. Mutations in the BRAF gene are present in 50% of cutaneous melanoma cases.⁷ Vemurafenib and dabrafenib are BRAF kinase inhibitors and are first-line options for BRAF mutation positive melanoma. In a case of BRAF-positive perianal melanoma, the patient was unresponsive to dacarbazine and was treated with vemurafenib.⁸ This case was deemed a rarity because the location of the disease was protected from the sun and ultraviolet exposure, similar to extracutaneous melanomas. Despite initial response to therapy, disease progression manifested after 5 months of treatment with vemurafenib. The patient was subsequently started on ipilimumab. However, he developed metastatic brain disease and died shortly after starting his new regimen. Our patient was negative for a BRAF mutation and would not have benefited from therapy with BRAF kinase inhibitors.

In addition to BRAF status, our patient was also investigated for KIT mutations. The KIT gene encodes for several proteins, which include the receptor tyrosine kinase KIT. Intracellular signalling pathways have a role in the development of melanocytes. Mutations in the KIT gene can lead to loss of allele function, affecting the migration, survival, proliferation and differentiation of melanocytes. In a case series report of mucosal melanomas, clinical response was demonstrated in patients with KIT mutations using tyrosine kinase inhibitors, imatinib or sorafenib.⁹ However, varying KIT mutations may have different responses to treatment. Therefore, identifying specific KIT mutations would be beneficial to ensure clinical response to treatment. The cases in the series showed partial response or stable systemic disease. However, three of the four patients developed central nervous system disease progression. As with the BRAF mutation, our patient was negative for KIT mutation and therefore would have been unlikely to benefit from treatment with imatinib.

Following diagnostic investigations and assessment of treatment options, our patient started immunotherapy with pembrolizumab. Like nivolumab, pembrolizumab is an immunotherapeutic agent that inhibits the PD-1 immune checkpoint. In a randomised, controlled, phase 3 trial, its progression-free survival (PFS) rates, overall survival rates and toxicity profile was compared with ipilimumab, an immunotherapy agent that inhibits the CTLA-4 immune checkpoint also used to treat advanced melanoma.¹⁰ Pembrolizumab exhibited greater PFS of 46.4% in pembrolizumab given every 2 weeks and 47.3% in pembrolizumab given every 3 weeks compared with ipilumumab with a PFS of 26.5%. The 12-month survival rates were also superior in the 2-week and 3-week regimens of pembrolizumab with 74.1% and 68.4%, respectively, compared with ipilimumab with 58.2%. Furthermore, a meta-analysis supports that PD-L1 expression is associated with decreased mortality in patients with malignant melanoma treated with anti-PD1/PD-L1 antibodies.¹¹ These studies showed a significant decrease in tumour size. However, there are individual studies that report a period of tumour ‘pseudo-progression’, which means an interim progression of the tumour before achieving a significant response.^{12 13} Although recent studies using pembrolizumab to treat cutaneous melanoma have shown meaningful responses in clinical trials, reports on successful treatment in extracutaneous melanoma remain scarce.

The decision to use pembrolizumab therapy in this case was made based on the following reasons:

• First, on the initial radiological images, the mass was regarded as unresectable owing to its retroperitoneal location. It was thought that attempting to resect the tumour would risk extensive damage to local structures (eg, bladder, ureters) or require pelvic exenteration. Therefore, a systemic approach to treatment seemed more beneficial.

• Second, despite an exhaustive workup, the primary source of the melanoma was not located and tissue analysis and immunohistochemistry were consistent with metastatic disease. Therefore, the disease was considered to be in an advanced state.

• Since the patient's genetic analysis was negative for BRAF V600 mutations, BRAF inhibitors or MEK inhibitors would be of little benefit to the patient. Moreover, results also showed that the patient was negative for KIT mutation and would therefore not benefit from targeted therapy using tyrosine kinase inhibitors.

• Finally, as aforementioned, pembrolizumab had greater progression-free survival rates and overall survival rates compared with ipilimumab.¹⁰

Patient's perspective.

• I've had a wonderful medical team. My lesson has been to always use sunscreen. I hope I will survive this.

Learning points.

• Extracutaneous melanoma comprises only 5% of all melanomas. Primary pelvic retroperitoneal melanoma has an even lower incidence.

• Owing to its rarity, there is no substantial evidence base for treatment of extracutaneous melanoma. Treatments are often based on knowledge derived from treatment of cutaneous melanoma.

• Pembrolizumab and nivolumab are PD-1 inhibitors recently approved by the Food and Drug Administration (FDA) to treat advanced melanoma. They demonstrate greater progression-free survival rates, overall survival rates and toxicity profile compared with ipilimumab. The combination of nivolumab with ipilimumab results in greater progression-free survival compared with ipilimumab alone.

• Multimodality imaging is essential in assessing the extent of extracutaneous melanoma disease. However, even comprehensive imaging may not reveal the true extent of disease spread and this may only become apparent following surgical exploration.