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Melanoma Institute Australia, The University of Sydney, Sydney, NSW, AustraliaCharles Perkins Centre, The University of Sydney, Sydney, NSW, AustraliaRoyal North Shore and Mater Hospitals, Sydney, New South Wales, AustraliaFaculty of Medicine and Health, The University of Sydney, NSW, Australia
Melanoma Institute Australia, The University of Sydney, Sydney, NSW, AustraliaRoyal North Shore and Mater Hospitals, Sydney, New South Wales, AustraliaFaculty of Medicine and Health, The University of Sydney, NSW, Australia
Melanoma Institute Australia, The University of Sydney, Sydney, NSW, AustraliaCharles Perkins Centre, The University of Sydney, Sydney, NSW, AustraliaFaculty of Medicine and Health, The University of Sydney, NSW, Australia
Melanoma Institute Australia, The University of Sydney, Sydney, NSW, AustraliaNSW Health Pathology, Sydney, NSW, AustraliaRoyal Prince Alfred Hospital, Sydney, NSW, AustraliaCharles Perkins Centre, The University of Sydney, Sydney, NSW, AustraliaFaculty of Medicine and Health, The University of Sydney, NSW, Australia
Differentiating between metastatic melanoma and malignant perivascular epithelioid cell tumour (malignant PEComa; also known as malignant epithelioid angiomyolipoma) may present a difficult diagnostic challenge due to the presence of overlapping histological and immunohistochemical features, particularly when occurring in patients with a history of melanoma. Given the marked differences in their natural history, prognosis and management (including systemic therapy options), distinguishing between them is critical for optimal patient care. Herein, we present a case of a high grade epithelioid malignancy associated with a conventional angiomyolipoma/PEComa of the kidney, in a patient with a history of melanoma, in which the ultimate diagnosis was established by analysing the primary melanoma and the two distinct areas of the kidney tumour using a next generation sequencing (NGS) panel. The case highlights the utility of DNA sequencing to establish the correct diagnosis when the results of routine clinical, morphological, immunohistochemical and molecular evaluation remain inconclusive.
A 58-year-old female presented with abdominal pain. An abdominal positron emission tomography-computed tomography (PET-CT) scan identified a biphasic, PET-avid left renal mass. No other suspicious lesions were apparent on clinical examination or imaging. She had a history of primary cutaneous melanoma of the thigh resected 3 years previously, which showed high risk features including a Breslow thickness of 10 mm and an elevated mitotic rate (5 mitoses/mm2), although no metastatic disease was identified in three sentinel lymph nodes from the right inguinal and iliac crest regions at that time. The melanoma was predominantly intradermal, with a growth pattern reminiscent of a deep penetrating naevus but with atypical spindled cytomorphology, prominent nuclear pleomorphism and frequent mitotic activity (Fig. 1A–D). It was positive with melanocyte markers (SOX10, S100, Melan-A and HMB45) and PRAME, while p16 expression was lost. It was negative for desmin, CD31, ERG, CD10, cytokeratin and p63.
The left renal mass was removed with a radical nephrectomy. No extrarenal disease was identified intraoperatively. On macroscopic pathological examination, the upper pole of the kidney contained an exophytic, 44×35×23 mm tumour with a mainly solid, lobulated, focally nodular appearance. The cut surface was heterogeneous, with cream, pale tan and brown areas, with focal necrosis and haemorrhage (Fig. 1E). Histologically, the tumour had a biphasic appearance, with one region showing features of a classical angiomyolipoma/PEComa, and the other showing overt features of malignancy. The two regions were discretely separated in some areas, and more intimately admixed elsewhere (Fig. 1H,I). The low grade region (Fig. 1F,G) contained bland spindle cells with myoid features, some with cytoplasmic clearing, arranged in short fascicles. Focal adipocytes and variably sized vessels were identified. No mitoses or necrosis were seen in this area. The second component consisted of large, epithelioid cells with eosinophilic cytoplasm and prominent nucleoli, showing solid and pseudopapillary growth, with some areas showing perivascular condensation, areas of necrosis, and up to 18 mitoses per 10 high power fields (Fig. 1J,K).
The immunohistochemical findings are summarised in Fig. 2. The low grade region of the kidney tumour showed diffuse positivity with SMA, patchy staining with desmin and HMB45, and focal weak positivity with Melan-A (Fig. 3). It was negative for S100, SOX10, PRAME and p16. There was focal, weak cytoplasmic positivity for WT1, patchy positivity for CD56, and occasional cells were positive for CCNB3. The high grade region showed patchy staining for S100 and moderate staining for PRAME and Cyclin D1, with focal HMB45 positivity and focal weak Melan-A positivity (Fig. 3). SOX10 was negative across multiple blocks of the high grade component. CD56 and CCNB3 were positive, WT1 showed cytoplasmic positivity, there was non-specific cytokeratin uptake in the necrotic areas, and p16 showed patchy positive staining. BRAFVE1, TFE3, GATA3, CD57, MyoD1 and Myogenin were negative in both components, and INI1 was retained. In both components MiTF was weakly positive.
Differential diagnoses based on the morphology and immunoprofile included an angiomyolipoma/PEComa with malignant transformation, or a benign angiomyolipoma involved by metastatic melanoma. Initially it was considered that, despite the negativity with SOX10, the malignant component was morphologically more in keeping with metastatic melanoma than a malignant PEComa. Routine molecular analysis for metastatic melanoma was performed on the primary melanoma and the kidney tumour at that time using a PCR-based DNA sequencing assay (Illumina technology), which showed no hotspot mutations in BRAF, NRAS or KIT in either tumour. The key pathological features are summarised in Fig. 2.
In light of the prognostic and treatment implications of the two differential diagnoses, additional DNA sequencing was performed on tissue from the patient's primary melanoma and separately on each component of the renal tumour using a customised next generation sequencing panel (ArcherDX), which incorporated a total of 54 recurrently mutated coding and non-coding melanoma-related genes discovered in our previous whole genome sequencing of a large cohort of melanomas.
This revealed abnormalities in the primary melanoma that were absent in both zones of the kidney lesion, including a CDKN2A mutation and a TERT promoter mutation. In contrast, the two components of the kidney tumour harboured an identical TP53 mutation, which was absent from the melanoma (Fig. 2). These findings indicated that the malignant renal tumour was molecularly more similar to the adjacent angiomyolipoma/PEComa than to the melanoma. Consequently, the kidney tumour was diagnosed as a malignant PEComa arising in association with an angiomyolipoma/PEComa. Within 12 months of diagnosis the patient developed metastatic PEComa in retroperitoneal lymph nodes, as well as a cerebellar dysfunction syndrome that was considered to be paraneoplastic in nature.
Angiomyolipoma, a member of the family of perivascular epithelioid cell neoplasms (PEComa), represents a rare mesenchymal neoplasm with an unusual immunoprofile, expressing both smooth muscle markers (SMA, desmin and caldesmon) and melanocytic markers (usually Melan-A and HMB45 and sometimes S100).
‘Classical’ angiomyolipoma is considered benign, and has characteristic histological features that allow diagnosis on routine histology. However, the epithelioid variant has malignant potential and can occasionally demonstrate histological features similar to melanoma including large polygonal or spindled cells with atypical nuclei, prominent nucleoli, intranuclear inclusions, multinucleated giant cells, mitoses and necrosis.
While it is not often that malignant PEComa of the kidney occurs in a patient with a history of melanoma, distinguishing between these entities is of significant clinical importance due to the implications for both prognosis and ongoing management. A diagnosis of resected American Joint Committee on Cancer (AJCC) stage IV metastatic melanoma would result in consideration of adjuvant immune checkpoint inhibitor therapy, and possible enrolment into a clinical trial. Malignant PEComa often shows resistance to chemotherapy and radiotherapy, and thus the mainstay of treatment is radical resection and close observation, with long-term follow-up due to the risk of late recurrence.
Immunohistochemistry does not necessarily help differentiate these entities. Melan-A and HMB45, markers that are otherwise considered relatively specific for melanocyte differentiation, are positive in angiomyolipoma/PEComa. While SOX10 and S100 positivity would favour a diagnosis of melanoma, absence of staining does not exclude this entity: the capacity of melanoma to dedifferentiate and lose expression of one or more melanocyte markers is well known.
In addition, while expression of smooth muscle markers may be more suggestive of a PEComa, melanoma may also show divergent differentiation, aberrantly expressing other markers (including muscle markers).
Routine melanoma-related molecular testing may be useful if a common melanoma-associated driver mutation (such as a BRAF or NRAS mutation) is identified, however almost 50% of melanomas are negative for these mutations, thus, if absent/wild-type, melanoma still remains a possibility.
which can be identified using immunohistochemistry and with fluorescent in situ hybridisation (FISH). If positive, this may assist in recognising a PEComa, however it was negative in our case and thus did not assist in the diagnosis.
The most common molecular event in angiomyolipoma/PEComa is deletion and/or loss of heterozygosity in TSC2 or TSC1; genes which were not included in our customised melanoma NGS panel.
The NGS results thus provided the evidence needed to demonstrate the molecular similarity between the malignant renal component and the classical angiomyolipoma, and exclude metastatic melanoma.
This case highlights the utility of deep sequencing molecular analysis to establish a correct diagnosis in cases where results of clinical, morphological, immunohistochemical and standard molecular evaluation remain inconclusive, particularly where the findings will have an immediate impact on patient management.
Conflicts of interest and sources of funding
RAS has received fees for professional services from F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc., Bristol-Myers Squibb, Myriad Genetics, GlaxoSmithKline. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Merck Sharpe & Dohme, Merck Sharpe & Dohme, Novartis, OncoSec, Pierre Fabre, Provectus, Qbiotics, Regeneron.
This work was supported by a National Health and Medical Research Council of Australia (NHMRC) Program Grant ( APP1093017 ) (to RAS and GVL). RAS is supported by an NHMRC Practitioner Fellowship ( APP1141295 ). GVL is supported by an NHMRC Investigator Grant and the University of Sydney Medical Foundation. Support from the BB and A Miller Foundation (the Jani Haenke Melanoma Pathology Fellowship to ECP), The Ainsworth Foundation, and the CLEARbridge Foundation, as well as from colleagues at Melanoma Institute Australia, Royal Prince Alfred Hospital, and NSW Health Pathology, is also gratefully acknowledged. The authors state that there are no other conflicts of interest to disclose.
Whole-genome landscapes of major melanoma subtypes.