Peritoneal melanosis associated with metastatic melanoma previously treated with targeted and immune checkpoint inhibitor therapy
- 1 Department of General Surgery, Fiona Stanley Hospital, Murdoch, Western Australia, Australia
- 2 Anatomical Pathology, Western Diagnostic Pathology, Myaree, Western Australia, Australia
- 3 Department of General Surgery, Hepatopancreaticobiliary Surgery, Fiona Stanley Hospital, Murdoch, Western Australia, Australia
- 4 School of Medicine, Curtin University, Bentley, Western Australia, Australia
- Correspondence to Dr Kwang Kiat Sim; kwang.sim@health.wa.gov.au
Abstract
Peritoneal melanosis is an uncommon benign condition, the pathophysiology of which is unclear. Macroscopically, it appears as diffuse dark brown or black pigmentation within the peritoneum, mimicking more sinister conditions such as metastatic melanoma. It has been described in a variety of contexts, but only exceedingly rarely in association with metastatic melanoma, with only two previous published case reports. We present a case of peritoneal melanosis associated with metastatic melanoma involving the spleen, previously treated with targeted and immune checkpoint inhibitor therapy. With increasing reports of melanoma regression manifesting as cutaneous tumorous melanosis in patients treated with immune checkpoint inhibitors, we postulate that, similarly, immunotherapy and tumour regression might have a role to play in the pathogenesis of the peritoneal pigmentation in this case.
Background
Peritoneal melanosis is an uncommon benign condition that is usually found incidentally during surgery.1–6 It is described as focal or diffused pigmentation of mesothelial surfaces in the abdominal cavity. Its pathophysiology remains unclear.1–6 Only two previous cases have been described associated with metastatic melanoma; however, prior targeted or immune checkpoint inhibitor therapy was not described in either case.2 7 In patients treated with BRAF/MEK inhibitors,8–10 as well as immune checkpoint inhibitors, there have been reports of regression of disease presenting as cutaneous tumorous melanosis, but there have been no peritoneal cases reported to our knowledge.11–14 We present a case of peritoneal melanosis associated with BRAF/MEK inhibitor and immune checkpoint inhibitor treated metastatic melanoma involving the spleen.
Case presentation
A 49-year-old man underwent excision of a right shoulder melanoma and wide local excision sentinel node biopsy in October 2016. This revealed a BRAF V600E mutated melanoma with metastasis to a solitary right axillary node. He subsequently underwent a right axillary dissection in December 2016 that showed no residual disease and was diagnosed with stage IIIA melanoma with plans for active surveillance via 3 monthly positron emission tomography (PET) scans.
In April 2017, surveillance PET scan found a right supraclavicular nodal relapse confirmed on fine needle aspiration biopsy. Systemic therapy was started with vemurafenib 960 mg twice daily and cobimetinib 40 mg once daily, plus enrolment into the Trilogy phase III atezolizumab/placebo study. Due to grade 2 serous retinopathy, the cobimetinib dose was reduced to 40 mg OD. Continued close surveillance showed stable low volume disease localised to the right supraclavicular region.
Unfortunately, in November 2018, localised progression of his right supraclavicular disease was found. He was unblinded, having been allocated to the placebo arm and removed from the trial. Systemic therapy was withheld temporarily as the patient underwent a right supraclavicular node and neck dissection for a solitary right supraclavicular nodal metastasis, followed by postoperative adjuvant radiotherapy, which was completed in March 2019.
Surveillance PET in October 2019 revealed progression with a new splenic lesion and right axillary lesion. His targeted therapy was changed to combination immunotherapy with ipilimumab plus nivolumab. After two cycles, the patient developed lung toxicity pneumonitis treated with a week of steroids and was continued on single agent nivolumab for a further four cycles.
The patient underwent a laparoscopic splenectomy and hookwire excision of axillary lesions. Intraoperatively, diffuse black speckling was found on the perisplenic omental surface, as well as the anterior abdominal wall and diaphragmatic surface of the left upper region (figure 1A). Biopsies sent for frozen section ruled out further melanoma deposits, and splenectomy proceed uneventfully (figure 1B).
(A) Intraoperative findings of diffuse dark pigment lesions on the diaphragm, anterior abdominal wall and perisplenic omentum. (B) Macroscopic findings showing speckling of the omental surface.
Omental histopathology revealed subserosal nodular aggregates of histiocytes containing dark brown pigment (figure 2A,B). The pigment stained black with Fontana-Masson (figure 2C) and was removed with the melanin bleach procedure (figure 2D), confirming it to be melanin, consistent with peritoneal melanosis. There was no evidence of metastatic melanoma in the omental tissue.
(A) H&E stain showing pigmented omental deposits. (B) High power view showing subserosal aggregates of histiocytes containing dark brown pigment. (C) Fontana-Masson stain highlighting the pigment consistent with melanin. (D) Melanin bleach preparation, with the negative staining confirming melanin.
Histological examination of the spleen confirmed three nodules of pigmented metastatic melanoma, the largest measuring 90 mm, abutting but not breaching the splenic capsular surface. Recurrent melanoma was also confirmed in the right axillary tissue.
Outcome and follow-up
Given the findings of metastasis to the spleen, as well as local recurrence, the patient was restarted on low dose ipilimumab, with plans for a repeat surveillance PET after four cycles.
Discussion
Peritoneal melanosis is a rare condition of uncertain pathophysiology.1–7 There have been approximately 15 cases reported in the English literature, and they were mostly associated with ovarian epithelial and teratomatous tumours.1 3–5 15–18 Other reported associated conditions include one case with peritoneal cysts, two with enteric duplication cysts,6 19 one with gastric triplications cysts,20 one with rectal adenocarcinoma4 and two metastatic melanomas involving the spleen and omentum.2 7
Macroscopically, peritoneal melanosis can mimic endometriosis, peritoneal lipofuscinosis and metastatic melanoma; these are readily distinguished histologically.4 5
When found with ovarian lesions, it has been postulated that melanin spilled from melanogenic ovarian tumours has been phagocytosed by histiocytes and deposited in the peritoneum.4 5 In non-ovarian cases of peritoneal melanosis, the source of melanin has been attributed to abnormal development of the neural crest cells during early embryological development, resulting in excessive migration or ectopic deposition of neural crest cells or defective regression of the neuroenteric canal.6 19 20
In the two reported cases of melanosis peritonei associated with metastatic melanoma, both had previous resected disease, but a history of targeted or immune checkpoint inhibitor therapy was not described in either case. They presented with advanced intraperitoneal disease, and it was suggested the liberated free melanin from these tumour cells as a likely source of the peritoneal pigmentation.2 Distinctively, in our case, the patient had previously been treated with targeted inhibitor therapy and subsequently immune checkpoint inhibitors. Vemurafenib and cobimetinib is a combination BRAF/MEK targeted inhibitor, while ipilimumab and nivolumab are immune checkpoint inhibitors that target cytotoxic T-lymphocyte associated protein 4 and programmed cell death 1 receptor.8 12 Cases of cutaneous and nodal tumorous melanosis have recently been attributed to such treatments, with approximately 20 cases reported attributing to immune checkpoint inhibitors10–14 and two cases with targeted therapy.8 9
Tumorous melanosis can be a rare manifestation of completely regressed primary or metastatic melanoma. Extensive regression in more than 75% of the lesion has been associated with increased aggression and possible metastatic disease.14 21 In the setting of immunotherapy, tumorous melanosis is considered to be completely regressed melanoma secondary to treatment response although its significance is unclear. It commonly manifests as dark pigmented lesions in various skin locations, with only two other cases presenting as a palpable mass10 and one found in a sentinel node.22 Macroscopically, tumorous melanosis can mimic malignant melanoma or other pigmented neoplasms. Histologically, tumorous melanosis is similar to peritoneal melanosis, appearing as aggregates of melanophages in the absence of malignant melanocytes.8 10 21
In the current case, the subserosal distribution of the melanin pigment suggests absorption of free melanin pigment from within the peritoneal cavity. This could have derived from direct spread from the melanoma deposits across the splenic capsule. In a manner analogous to cutaneous tumorous melanosis, however, we also suggest that it could have derived from subclinical melanoma deposits within the abdominal cavity that had regressed as a result of targeted and immune checkpoint inhibitor therapy. This phenomenon may become more common as a result of increased availability of these modern therapies.
Learning points
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Peritoneal melanosis is a rare benign condition manifesting as dark speckling of the peritoneal surface, generally detected incidentally during abdominal surgery.
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It should not be mistaken for metastatic melanoma, which can be reliably excluded by frozen section histological examination.
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When treated with immune checkpoint inhibitors or targeted therapy, regression of peritoneal melanoma metastasis could be considered as a possible contributor to peritoneal pigmentation.
Footnotes
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Contributors Supervised by MB and DP. Patient was under care of MB. Report was written and edited by KKS, DP and MB. Photos prepared by KC.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Patient consent for publication Obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.
References
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