|Ahead of print
Rhabdoid melanoma: A diagnostic ordeal
Anurag Mehta1, Abhimanyu Sharma2, Garima Gupta3
1 Molecular Diagnostic Services and Research, Rajiv Gandhi Cancer Institute and Research Centre, Sector-V, Rohini, Delhi, India
2 Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre, Sector-V, Rohini, Delhi, India
3 Department of Research, Rajiv Gandhi Cancer Institute and Research Centre, Sector-V, Rohini, Delhi, India
|Date of Submission||12-Jun-2019|
|Date of Decision||30-Aug-2019|
|Date of Acceptance||06-Sep-2019|
|Date of Web Publication||05-Aug-2020|
Molecular Diagnostic Services and Research, Rajiv Gandhi Cancer Institute and Research Centre, Sector-V, Rohini, Delhi
Source of Support: None, Conflict of Interest: None
A 64-year-old man presented with multiple, bilateral pulmonary nodules, considered clinically to be intrapulmonary metastasis from lung carcinoma. On histopathologic examination, a tumor with a solid growth pattern and rhabdoid neoplastic morphology was seen. Initially, a diagnosis of nonsmall cell carcinoma of lung was considered but the immunophenotype was not supportive. Further, extensive immunohistochemistry revealed SOX10, Melan-A, and HMB45 expression in the absence of S-100. Strong globular cytoplasmic staining for vimentin, SMA, Desmin, and WT1 were observed. A final diagnosis of rhabdoid melanoma was made. The immunoprofile of our case was unique from previously described rhabdoid melanoma in English literature. The globular staining for intermediate filaments such as desmin and SMA is a novel finding. The strong WT1 intracytoplasmic staining reported previously was also observed in this case, with intense globular characteristics.
Keywords: C-KIT, rhabdoid melanoma, S-100
| » Introduction|| |
Rhabdoid tumors typically demonstrate spheroidal cells with abundant eosinophilic cytoplasm, each containing a globular hyaline inclusion in the cytoplasm, an eccentric vesicular nucleus with a prominent pink nucleolus. Rhabdoid phenotype is observed in a diverse set of tumors. Some of these tumors have a distinctive genotypic alteration in switch1/sucrose non fermenter (SW1/SNF) pathway especially the loss of function mutation in SMARCB1 (INI-1) while others produce rhabdoid morphology without such genetic alteration. Biallelic loss of SMARCB1 in cancer was first reported in malignant rhabdoid tumors (MRT) and later noted in a range of cancers such as extrarenal malignant rhabdoid tumor, epithelioid sarcoma, renal medullary carcinoma, myoepithelial carcinoma, extraskeletal myxoid chondrosarcoma, INI-1 deficient nasopharyngeal carcinoma, and primary pulmonary myxoid sarcoma. Identifying the histogenesis of a rhabdoid tumor is a challenge. We faced this situation in a man who presented with multiple, bilateral pulmonary nodules, considered clinically to be intrapulmonary metastasis from lung carcinoma.
Report of the case
A 64-year-old, hypertensive man presented with complaints of cough of 6-month duration besides pain on the right side of the chest and intermittent fever for a week. A chest X-ray (PA view) revealed a well-defined rounded shadow in the right lower zone and a small lesion in the right upper zone. computed tomography (CT) scan of chest exhibited multiple heterogeneously enhancing lung masses in both upper and lower lobes of the right lung with scattered patchy ground-glass opacities. In addition, the left lung showed a lesion measuring 5.8 × 6.5 cm in the lower lobe. A right adrenal mass measuring 3.6 × 1.8 cm was also observed. Further, imaging with Positron Emission Tomography (PET) showed metabolically active bilateral lung lesions, mediastinal lymph nodes, and solitary bony lesion [Figure 1]. The right lung mass located in lower lobe abutting oblique fissure and diaphragmatic pleura measured 6.7 × 6 × 6.4 cm, was partly necrotic, well marginated with a maximum SUV of 13.1 [Figure 1]. A focal increase of tracer uptake appeared in the left iliac bone. The adrenal lesion was metabolically inactive and measured 3.9 × 1.8 cm.
|Figure 1: (a). PET-CT appearance- Right lung shows a large partly necrotic well marginated soft tissue mass lesion (6.7 × 6 × 6.4 cm, SUV max 13.1) in lower lobe abutting oblique fissure and diaphragmatic pleura. (b). Metabolically active variable-sized subpleural and parenchymal nodules right lung. (c). A metabolically active nodular lesion in left suprahilar region abutting left upper lobe bronchus|
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A diagnosis of carcinoma of the lung was entertained and a bronchoscopy was performed that revealed obstruction of the right bronchus segment eight and endobronchial mass in the left bronchus at level three from which a biopsy was taken.
The biopsy was processed following 18 hours of fixation in neutral buffered formalin in the usual way and 4 μM sections stained with H and E were examined.
The microscopic examination revealed an exophytic and endophytic bronchial growth with no discernible growth pattern. Neoplastic cells were large and rhabdoid in appearance. Typical and atypical mitoses were readily observed. A diagnosis of nonsmall cell lung carcinoma was made. TTF1 and P40 immunohistochemistry (IHC) was applied and were found to be negative. In view of the rhabdoid morphology, SMARCA4 deficient nonsmall cell carcinoma was considered but CK, EMA, and CK7 were not expressed by the tumor cells thereby excluding epithelial histogenesis. At this juncture, metastasis from other nonepithelial INI-1 deficient tumors formed the differential diagnosis (D/D). The tumor was, however, found to be INI-1 proficient. D/D was shifted to mesenchymal tumors with rhabdoid morphology and intact INI-1 phenotype. Epithelioid leiomyosarcoma, metastasis from epithelioid gastrointestinal stromal tumor (GIST), rhabdomyosarcoma and rhabdoid melanoma were considered as D/D. Further, IHC examination revealed SOX10, Melan-A, and HMB45 expression. S-100 was nonreactive. Curious but strong globular cytoplasmic staining for WT1 was observed. Similar globular staining was noted for Vimentin, SMA, and Desmin though Myo-D1 and Myogenin were not expressed. A final diagnosis of rhabdoid melanoma was made [Figure 2].
|Figure 2: (a): low magnification view showing tumor along with adjacent bronchial lining (H and E; magnification 40×). (b): high magnification view showing tumor with no discernible pattern. Tumor cells show marked atypia with atypical mitosis (H and E; magnification 400×). (c): high magnification view showing tumor cells with a large eccentric nucleus and dense eosinophilic cytoplasm-rhabdoid appearance (H and E; magnification 400×). (d): immunohistochemistry showing intense cytoplasmic staining for vimentin (magnification 400×). (e): immunohistochemistry showing absent staining for S-100 (magnification 400×). (f): immunohistochemistry showing intense globoid cytoplasmic staining for SMA (magnification 400×). (g): immunohistochemistry showing globoid cytoplasmic staining for desmin (magnification 400×). (h): immunohistochemistry showing intense membranous staining for CD99 (magnification 200×). (i): immunohistochemistry showing retained INI-1 in tumor cells (magnification 400×). (j): immunohistochemistry showing strong positivity for SOX-10 (magnification 400×). (k): immunohistochemistry showing focal staining for Melan-A (magnification 200×). (l): immunohistochemistry showing strong positivity for HMB45(magnification 400×). (m): immunohistochemistry showing intense cytoplasmic staining for WT1 (magnification 200×)|
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PET-CT images were re-examined to identify the primary site that might have been overlooked at the first examination. Cutaneous, orificial, and ocular examinations were noncontributory. History was sought of any nevus or skin lesion being removed in the recent past. The patient offered a history of removal of a small filiform pigmented lesion next to the right angle of mouth, a year and a half ago at a peripheral center, but had no histopathological report to share. Given this history, the lung lesions were redefined as metastatic rhabdoid melanoma.
Molecular subtyping was done for BRAFV600E and C-KIT mutations with an intent to find a predictive biomarker. The neoplasm was negative for BRAFV600E but showed a well-described exon 11 mutation NM_000222.2 (KIT): c.1727T>C (p. Leu576Pro) - rs121913513.
Though C-KIT: c.1727T>C has been reported several times in the database of curated mutations and has been annotated differently by databases as pathogenic and a variant of undetermined significance (VUS) as shown in the Lolliplot above [Figure 3]. Lolliplot were extracted from VarSome to highlight conflicting interpretation with a red dot indicating pathogenicity and black dot at the same location showing VUS. In view of the conflicting pathogenicity of this mutation and the best overall response rate (BORR) of 29% to imatinib, the multidisciplinary team decided to administer immunotherapy. The patient is currently being treated by immunotherapy (Nivolumab).
|Figure 3: Lolliplot of the identified mutation in Exon 11of C-KIT. The mutation detected in C-KIT gene in this case (transparent blue box) has been varyingly identified as “pathogenic” (Black lollipop) and “variant of undetermined significance” (Red lollipop). Image generated through VarSome search engine|
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Discussion of the case
Melanoma is not a common malignancy in the Indian population., A melanoma with rhabdoid morphology is exceptionally rare. These two facts coupled with a large differential diagnosis of aggressive tumors with rhabdoid morphology makes the diagnosis of rhabdoid melanoma a diagnostic ordeal. In addition, the current case was S-100 negative, the tier 1 immunophenotype marker for melanoma. S-100 has been reported to have a sensitivity of 96-100%.,,,
The immunoprofile of our case was unlike the previously described cases of rhabdoid melanoma which were positive for S-100 protein but negative for other melanocytic markers, such as HMB45, Melan- A, Mart-1, tyrosinase, and microphthalmia transcription factor. In contrast, our case was negative for S-100 and diagnosis was first entertained only after SOX10 expression was identified. Of the second tier and specific markers of Melanoma, HMB45 was strongly expressed but Melan A was weak and focal. Chang and colleagues in their publication summarised that rhabdoid melanomas tend to lose their immunoreactivity to HMB45 and, to a lesser degree of S-100 protein. Our case instead, showed a completely opposite immunophenotype. We contend that rhabdoid melanoma's lack consistent immunophenotype. This statement is strengthened by the observation of Borek et al. who reported that all three of their cases were positive for S-100 protein but negative for HMB45. On the contrary, Laskin et al. described a possible case of malignant melanoma with rhabdoid features that did not stain with either S-100 protein or HMB45. The reason for this variability in immunostaining has been attributed to the “dedifferentiated” state of the rhabdoid phenotype.
More curiously, immunostaining was observed in the form of globular cytoplasmic staining with vimentin, SMA, Desmin, and WT1. While, the globular staining for vimentin is expected in line with rhabdoid morphology caused by intracytoplasmic accumulation of intermediate filaments, the globoid collection of SMA, and Desmin in rhabdoid melanoma has not been reported in any of the eight cases described till date in English literature. This additional finding supports the fact that rhabdoid morphology is a consequence of stuffing of cytoplasm by various intermediate filaments with or without abnormal SW1-SNF pathway.
WT1 is a nuclear immunostain seen in mesothelioma, ovarian epithelial malignancies, and several soft tissue sarcomas. The cytoplasmic staining is nonspecific and inconsequential. Till recently, it was ascribed to cross-reactivity of the diagnostic antibodies to an unknown cytoplasmic protein. Current literature, however, accedes to cytoplasmic existence of WT1 protein and speculates of its role in translation as well. This case revealed a strong and globoid accumulation of WT1 protein in cytoplasm. A literature search showed several reports of strong intracytoplasmic WT1 staining in malignant melanoma. We consider WT1 intracytoplasmic staining can add an additional layer of evidence in cases with uncertain immunophenotype. BRAF, NRAS, and NF1 mutations are the hallmark of malignant melanoma with C-KIT mutation closely following. Of these BRAF and C-KIT mutation have been treated with biomarker directed targeted therapies., In our case the C-KIT missense mutation was observed which has been varyingly considered as VUS and deleterious. This is the first observation of molecular drivers in case of rhabdoid melanoma.
| » Conclusion|| |
Rhabdoid melanoma is a curiosity with few anecdotal reports. We have presented here a case of rhabdoid melanoma with a unique immunophenotypic profile and a C-KIT mutation. The case reports highlight the necessity of broad tier 1 and tier 2 immune marker profiling with the necessity to use multiple antibodies because of inconsistent immunophenotype of rhabdoid melanoma.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Kalimuthu SN, Chetty R. Gene of the month: SMARCB1. J Clin Pathol 2016;69:484-9.
Nakayama RT, Pulice JL, Valencia AM, McBride MJ, McKenzie ZM, Gillespie MA, et al
. SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters. Nat Genet 2017;49:1613-23.
Suvarna S, Layton C, Bancroft J. Bancroft's Theory and Practice of Histological Techniques. 8th
ed. Elsevier. 2018.
Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Aguilera MA, Meyer R, et al
. VarSome: The human genomic variant search engine. Bioinformatics 2019;35:1978-80.
Hodi FS, Corless CL, Giobbie-Hurder A, Fletcher JA, Zhu M, Marino-Enriquez A, et al
. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol 2013;31:3182-90.
Nair MK, Varghese C, Mahadevan S, Cherian T, Joseph F. Cutaneous malignant melanoma--clinical epidemiology and survival. J Indian Med Assoc 1998;96:19-20.
Radhika K, Prayaga AK, Sundaram C. A clinicopathologic study of malignant melanoma based on cytomorphology. Indian J Cancer 2016;53:199-203.
] [Full text]
Chung BY, Ahn IS, Cho SI, Kim HO, Kim KH, Park CW, et al
. Primary malignant rhabdoid melanoma. Ann Dermatol 2011;23:S155-9.
de Vries TJ, Smeets M, de Graaf R, Hou-Jensen K, Bröcker EB. Expression of gp100, MART-1, tyrosinase, and S-100 in paraffin-embedded primary melanomas and locoregional, lymph node, and visceral metastases: Implications for diagnosis and immunotherapy. A study conducted by the EORTC Melanoma Cooperative Group. J Pathol 2001;193:13-20.
Karimipour DJ, Lowe L, Su L, Hamilton T, Sondak V, Johnson TM, et al
. Standard immunostains for melanoma in sentinel lymph node specimens: Which ones are most useful? J Am Acad Dermatol 2004;50:759-64.
Kaufmann O, Koch S, Burghardt J, Audring H, Dietel M. Tyrosinase, melan-A, and KBA62 as markers for the immunohistochemical identification of metastatic amelanotic melanomas on paraffin sections. Mod Pathol 1998;11:740-6.
Mangini J, Li N, Bhawan J. Immunohistochemical markers of melanocytic lesions: A review of their diagnostic usefulness. Am J Dermatopathol 2002;24:270-81.
Chang ES, Wick MR, Swanson PE, Dehner LP. Metastatic malignant melanoma with “rhabdoid” features. Am J Clin Pathol 1994;102:426-31.
Borek BT, McKee PH, Freeman JA, Maguire B, Brander WL, Calonje E. Primary malignant melanoma with rhabdoid features: A histologic and immunocytochemical study of three cases. Am J Dermatopathol 1998;20:123-7.
Laskin WB, Knittel DR, Frame JN. S-100 protein and HMB-45 negative “rhabdoid” malignant melanoma: A totally dedifferentiated malignant melanoma? Am J Clin Pathol 1995;103:772-3.
Kaneko T, Korekawa A, Akasaka E, Rokunohe D, Nakano H, Sawamura D. Primary amelanotic rhabdoid melanoma: A case report with review of the literature. Case Rep Dermatol 2015;7:292-7.
Hohenstein P, Hastie ND. The many facets of the Wilms' tumour gene, WT1. Hum Mol Genet 2006;15:R196-201.
Akbani R, Akdemir KC, Aksoy BA, Albert M, Ally A, Amin SB, et al
. Genomic classification of cutaneous melanoma. Cell 2015;161:1681-96.
[Figure 1], [Figure 2], [Figure 3]