Giant lung metastasis of NRAS-mutant melanoma in a 24 ......CASE REPORT Open Access Giant lung metastasis of NRAS-mutant melanoma in a 24-year-old patient with a history of BRAF-mutant

CASE REPORT Open Access

Giant lung metastasis of NRAS-mutantmelanoma in a 24-year-old patient with ahistory of BRAF-mutant conventionalmelanoma harboring Spitzoid morphology:a case reportJiri Vachtenheim Jr1* , Roman Kodet2, Ondrej Fischer3, Vitezslav Kolek3, Zuzana Strizova4, Andrej Ozaniak1,Jan Simonek1, Alan Stolz1, Jiri Pozniak1, Jan Kolarik1, Monika Svorcova1, Jiri Vachtenheim5 and Robert Lischke1

Abstract

Background: Spitzoid melanocytic lesions represent a heterogeneous group of proliferations with ambiguous andoverlapping terminology. The exact distinction of a Spitz nevus from a Spitzoid melanoma can be very difficult or, insome cases, impossible. Among the Spitzoid lesions, there is a lesion termed an atypical Spitz tumour (AST) that hasintermediate histopathologic features between those of a Spitz nevus and a Spitzoid melanoma and thus uncertainmalignant potential. There are several rare cases of patients with a Spitzoid melanoma initially misdiagnosed as a Spitznevus or an AST with fatal consequences. It is, therefore, advised to perform a molecular characterization in caseswhere uncertain skin lesions are presented, as it may provide extended set of information with a possible impact onthe treatment options. Furthermore, preventive measures, such as regular physical and skin examinations, as well asthorough scheduling of individual follow-up visits, are essential in patients with potentially malignant skin nevi.

Case report: We report a case of a young adult female with a history of AST excision with a negative sentinel lymphnode biopsy (SLNB) and insufficient follow-up. Four years after the primary dermatological diagnosis, she presented with agiant tumour in the right hemithorax. Radical en bloc resection of the tumour with right pneumonectomy and resectionof the pericardium with reconstruction of the pericardium using mesh was performed. A definitive histopathologicalexamination revealed a metastatic melanoma. The association of the previously diagnosed AST and subsequentappearance of melanoma metastases led to a retrospective re-evaluation of the initial lesion. The suspected diagnosis ofSpitzoid melanoma, however, was not confirmed. Moreover, the molecular examination revealed a major discordancebetween the initial lesion and the lung tumour, which most likely excluded the possible association of the lungmetastasis with the initial skin lesion. The initial skin lesion was a BRAF-mutant melanoma with Spitzoid features andtermed as AST, while the giant lung metastasis was NRAS-mutant melanoma. The subsequent postoperative course wascomplicated by the appearance of brain metastases that were stereotactically irradiated. Nevertheless, despite complex(Continued on next page)

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* Correspondence: [email protected] Department of Surgery, First Faculty of Medicine, Charles Universityand University Hospital Motol, Prague, Czech RepublicFull list of author information is available at the end of the article

Vachtenheim et al. Diagnostic Pathology (2020) 15:132 https://doi.org/10.1186/s13000-020-01046-3

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specialised medical care, the patient’s clinical condition rapidly deteriorated. By this time, no active oncological treatmentwas possible. The patient was delegated to local hospice for palliative care six months after the surgery and died threeweeks later.

Conclusions: Our patient was surgically treated at the age of 20 for AST and died four years later of metastatic NRAS-mutant melanoma most likely of different occult origin. Molecular characterization, as well as the close clinical follow-upshould be always precisely performed in patients with uncertain skin lesions, such as AST.

Keywords: Spitz nevus, Atypical spitz tumour, Spitzoid melanoma, Conventional melanoma, Metastasis, Molecularanalysis, Case report

BackgroundA Spitz nevus was originally described by Sophie Spitzin 1948 [1]. This uncommon melanocytic proliferation ischaracterised by spindled and/or epitheloid nevomelano-cytes [2]. More than 70 years after its first description, aSpitz nevus is now classified within a number of Spitzoidlesions and represents a heterogeneous group of prolifer-ations with ambiguous and overlapping terminology.The spectrum of Spitzoid proliferations ranges from a

Spitz nevus, with completely benign biological behav-iour, to a Spitzoid (Spitz-like) melanoma, which bearsoverlapping features of a Spitz nevus and conventionalmelanoma, carrying a malignant nature.Among the Spitzoid lesions, there is a lesion termed

an atypical Spitz tumour (AST) that has intermediatehistopathologic features between those of a Spitz nevusand a Spitzoid melanoma and thus uncertain malignantpotential [3].The proper understanding of the potential risk associ-

ated with Spitzoid lesions is of particular importance, es-pecially in tumours displaying features similar to those ofa malignant melanoma. However, due to histopathologicalcontroversies, the clinical management of Spitzoid lesionsremains extremely challenging, and to date, standardizedhistopathological classification criteria are lacking.The exact distinction of a Spitz nevus from a Spitzoid

melanoma can be very difficult or, in some cases, impos-sible [4]. Barnhill et al. conducted a blind study in which30 Spitz-type lesions (including ASTs and Spitzoid mela-nomas) were reviewed by 10 independent pathologists,and they failed to reach a consensus on the diagnosis,discrimination from a melanoma, and prediction of out-come [5]. Thus, Spitzoid neoplasms are among the mostdifficult lesions to diagnose in dermatopathology, and amisdiagnosis of a melanoma for a Spitz nevus or an ASTis one of the most frequent causes of malpractice law-suits in surgical pathology and dermatopathology [6, 7].There have been reported several cases of patients witha Spitzoid melanoma initially misdiagnosed as a Spitznevus or an AST with fatal consequences [8].Here, we report a case of a young adult female with a

history of AST excision with a negative sentinel lymph

node biopsy (SLNB) and insufficient follow-up. Fouryears after the primary diagnosis, she presented with agiant tumour in the right hemithorax. Radical surgerywas performed, and a definitive histopathological exam-ination revealed a metastatic melanoma. The associationof the previously diagnosed AST and subsequent appear-ance of melanoma metastases led to a retrospectivefurther re-evaluation of the initial skin lesion with mo-lecular analysis. However, the suspected diagnosis ofmetastatic Spitzoid melanoma was not conclusivelyconfirmed. The specific mutation of the BRAF gene wasdetected in the initial skin lesion. Nevertheless, thismutational pattern was not observed in the giant lungtumour. Moreover, the lung metastasis exhibited theNRAS gene mutation, while the initial skin lesion wasNRAS negative. This discordance between the initial le-sion and the giant lung tumour most likely excluded thepossible association of the lung metastasis with the ini-tial skin lesion originally termed as AST.

Case presentationA 24-year-old female patient with a two-month historyof cough resistant to antibiotic treatment was further ex-amined at the Department of Pneumology at anothermedical facility after the appearance of haemoptysis.Computed tomography (CT) revealed a giant tumour inthe right hemithorax. Based on the presence of spindlecells and immunohistochemical positivity for S-100 andSOX 10 with negativity for MelanA and HMB-45, a sus-picion on diagnosis of malignant peripheral nerve sheathtumour was made at another medical facility. The differ-ential diagnoses comprised synovial sarcoma and malig-nant solitary fibrous tumour.Her past medical history included excision of AST local-

ised under right breast at another medical facility fouryears prior. The tissue sample was described as melanocy-tic affection displaying patterns of intradermal prolifera-tion of large melanocytes with abundant amphophiliccytoplasm, epitheloid and vesicular nuclei, focally contain-ing prominent nucleoli. A certain proportion of cells wasarranged in small nests and isolated mitoses, together withthe maturation disorders were seen. A dense lymphoid

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infiltrate was observed in the stroma. The expression ofp21 and p16 was demonstrated, as well as positive stainingfor Melan A and S-100 protein. By fluorescence in situhybridization (FISH) method, the evaluation of numericalaberrations in the region of CCND1 (11q13), RREB1(6p25), MYB (6q23) and centromeric CEP 6 genes wasperformed and stated negative for all of the above-mentioned regions. According to the evaluating depart-ment of pathology, the initial lesion was classified as AST.Therefore, reexcision with margin of 1 cm was performedand involvement of the sentinel lymphatic node was ruledout by an SLNB executed at the same facility. However,the patient did not obtain any information regarding thepossible overlap of an AST with another malignant skinlesions at that time, and no follow-up was scheduled.At the Department of Pneumology, distant metastases

were excluded by brain CT with intravenous contrastagent and positron emission tomography/computedtomography (PET/CT) of the trunk. Bronchoscopy dis-played extramural compression of airways distal to thetracheal carina. Significant elevation of neuron-specificenolase (NSE) and CA 125 was present.Because of the airway compression and a rapid wors-

ening of clinical symptoms, the patient was immediatelytransferred to our surgical department with a request forradical surgery. During the examination, the patient ex-hibited a very low physical performance, dyspnoea atrest, cough, mild haemoptysis with secondary anaemia,borderline respiratory sufficiency, fever, sinus tachycar-dia, lack of appetite and a history of 10 kg weight lossduring the past two months. Operability was promptlyevaluated by cardiovascular magnetic resonance (CMR),which verified intimate contact of the tumour to theright atrium and superior vena cava and excluded infil-tration of the heart and great vessels (Fig. 1a-b).Radical en bloc resection of the tumour with right

pneumonectomy and resection of the pericardium withreconstruction of the pericardium using mesh was per-formed (Fig. 2a-b). The postoperative course was un-eventful, and the patient was discharged eleven daysafter the surgery in a very good clinical condition.Macroscopic examination of the resected specimen

showed tumour localised between upper and middlelobe measuring 190 × 120 × 110 mm. The lesion was sur-rounded by a thin fibrous capsule and was yellowish incolour, lobulated, with pseudocystic transformation, ne-crosis and hemorrhage on cut surface.Definitive histology revealed that the lesion was com-

posed of elongated spindle cells that were arranged in a fas-cicular or storiform pattern. Also, frequent necroses andhaemorrhages were observed. In a minor portion of the le-sion, a round cell component was found. The lesional cellshad round to oval nuclei of various sizes with clear chroma-tin, visible nucleoli and a clear to eosinophilic cytoplasm

(Fig. 3a-b). Angioinvasion was also present, nevertheless,the visceral pleura and pericardium were not affected.Immunohistochemistry showed that the tumour cells

were positive for Vimentin, CD99, S100, SOX10, MITF,MelanA, INI-1 and Ki-67 (Fig. 3c-d). The tumour cellswere negative for desmin, myogenin, myoD1, CK-AE1/3,HMB45, CD57 and GFAP.Molecular characterization revealed the tumour as nega-

tive for the fusion of EWSR1 (22q12) and testing for BRAFexon 15 was negative for the V600E mutation. The DNAisolated from the formalin-fixed/paraffin-embedded (FFPE)sample was analysed by next-generation sequencing (NGS)and an NRAS p.(Q61K) mutation was detected. Mutationsin KRAS, HRAS, SMARCA4 and SMARCB1 were notfound (Roche NimbleGen Inc., Madison, WI, USA). Fu-sions involving BRAF, ALK, NTRK1, RET or ROS1 wereassessed as negative (ArcherDX, Boulder, CO, USA).Based on the morphological, immunohistochemical

(mainly MelanA and MITF positivity) and molecularfeatures, the diagnosis of metastatic NRAS-mutant melan-oma was established. Based on the medical history of apreviously excised AST, an original biopsy of the primarycutaneous lesion was requested and reviewed at our De-partment of Pathology. The second-look histopathologicalexamination verified spindle and epitheloid nevomelano-cytes arranged in junctional and intradermal nests. Cyto-logic atypia and numerous mitotic activities were present(Fig. 4 a-b). The lesion was pervaded with lymphoid infil-trate, and pagetoid spread was not demonstrated. TheBreslow thickness was approximately 2.7 mm. Immuno-histochemistry showed positivity for HMB45, p16, p21,and S100, and the MIB1 proliferation index was 20%.Based on the patient’s clinical course and the appearanceof melanoma metastasis, the initial cutaneous lesion wasthought to require reclassification as a Spitzoid melanomawith subsequent lung metastasis. However, the molecularexamination of the initial lesion revealed a BRAF mutationwithout the mutation of NRAS gene.After the establishment of a definitive diagnosis of a

metastatic NRAS-mutant melanoma of occult primarysite, the patient was planned to be referred to theDepartment of Oncology. However, the further postop-erative course became complicated, and right-sidedtonsillitis with methicillin-resistant Staphylococcus aur-eus appeared. Moreover, eight weeks after the surgery,a follow-up PET/CT was performed and revealed mul-tiple new metastases located in the right-sided pleura,left suprarenal gland, thoracic and retroperitoneallymph nodes, sternal bone and eighth rib on the right.PET/CT also highlighted right palatal tonsillitis, whichwas presumed to be of staphylococcal origin. The sus-pected brain metastases were confirmed by immediatebrain magnetic resonance, which also showed two smalllesions with cerebral oedema.

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Corticosteroid antioedematous treatment was givenimmediately, and the brain metastases were stereotactic-ally irradiated. However, the patient´s condition at thatmoment did not allow immunotherapy or chemother-apy. Furthermore, dysphagia occurred, and a tumour inthe area of the right palatal tonsil was identified.An otorhinolaryngological examination and biopsy

proved a malignant melanoma. The patient underwenttonsillectomy; however, the postoperative course wascomplicated by left-sided hemiparesis, and further brainCT showed multiple new metastases. Palliative irradiationof brain metastases was performed. Nevertheless, despite

complex specialised medical care, the patient’s clinicalcondition rapidly deteriorated. By that time, no activeoncological treatment was possible. The patient was dele-gated to local hospice for palliative care six months afterpneumonectomy and died three weeks later.

DiscussionSpitzoid lesions are uncommon but extremely diagnos-tically challenging. The most difficult steps in the man-agement of such a heterogeneous group of cutaneousproliferations are the establishment of histopathologicalfeatures, prediction of the biologic behaviour and

Fig. 1 Preoperative cardiovascular magnetic resonance of thorax shows a giant tumour in the right hemithorax. a Frontal position withmediastinal shift to the left side. b Transverse position

Fig. 2 Intraoperative findings – clamshell thoracotomy. a Giant tumour of the right hemithorax originating from the right lung. b After en blocresection of the tumour with right pneumonectomy and resection of the pericardium with reconstruction of the pericardium using mesh

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decision whether to apply systemic therapy or minimizeaggressive treatment.AST displays similar histopathological features to Spitz

nevus, such as enlarged epithelioid and/or spindled me-lanocytes with abundant opaque or glass cytoplasm, andalso to melanoma, such as asymmetry, lack of matur-ation deep in the dermis, atypical and frequent mitosisin the dermal component, and a brisk lymphocytic

infiltrate [9]. Even though most Spitzoid lesions behavein an indolent manner, both ASTs and Spitzoid melano-mas can metastasize.SLNB positivity in patients with ATS (which is re-

ported in approximately 30–50% of cases) does not pre-dict a poor outcome, and thus, the sentinel lymph nodestatus is of questionable diagnostic and prognostic valuein these particular neoplasms [10, 11]. Although the

Fig. 3 Lung metastatic melanoma – predominantly spindle cell component (a H&E stain 200x); epitheloid cell component; no melanin pigmentpresent (b H&E staining, 200x). The neoplastic cells are melan A positive, admixt lymphocytes are negative (c IHC 100x) and MITF positive (d IHC200x). S100 protein and S0X10 were also strongly positive, whereas HMB45 was negative (not shown)

Fig. 4 Initial skin lesion, the epidermis uninvolved (a H&E stain 100x), epitheloid cell component with atypical cells infiltrating the dermis andpartly the epidermis in a different part of the investigated specimen, admixt there are numerous lymphocytes (b H&E stain 100x)

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SNLB procedure and complete lymphadenectomy do notprovide a clinical benefit, they should be considered in in-dividual patients with challenging Spitzoid lesions [12].Ancillary diagnostic techniques such as comparative

genomic hybridization (CGH), FISH or NGS offer newopportunities for the precise diagnosis. Spitz tumoursare defined in the 2018 WHO classification of skin tu-mours by the presence of specific genetic alterations,such as HRAS mutations or kinase fusions (BRAF,MAP3K8, ROS1, ALK, NTRK1, NTRK3, RET, MET andMERTK) [13]. Activating HRAS mutations are found inapproximately 20% of Spitzoid neoplasms, while BRAFand NRAS mutations are mostly found in conventionalmelanomas. However, further studies reported the pres-ence of BRAF mutations in up to 20% and NRAS muta-tions in up to 5% of Spitzoid neoplasms. ALK, ROS1,NTRK1 and RET gene fusions were found in 10%, 17%,16% and 5% of the cases respectively [14].In our case report, a young woman with a giant metas-

tasis of NRAS-mutant melanoma in the right hemi-thorax was immediately operated, however, died fewmonths later due to the development of brain and otherdistant metastases. Chemotherapy, nor checkpoint im-munotherapy, were not indicated.The patient’s medical history of previous AST excision

caused a discussion about the AST being origin of lungmetastasis and should be therefore reclassified as Spitzoidmelanoma as rare cases of patients with a melanoma thatwas initially misdiagnosed for a Spitz nevus or an ASTwith fatal consequences have already been reported.The available data have prompted us to request for the

initial skin lesion and re-evaluate the tissue sample, ori-ginally termed at another medical facility as AST. IHCshowed positivity for HMB45 in the AST, while thismarker was negative in the lung metastasis. However, itis known that 25% melanoma metastasis are negative forHMB45 [14]. Further molecular characterisation re-vealed discordance in BRAF and NRAS mutation in ini-tial AST and lung metastasis, as AST was positive forBRAF mutation and negative for NRAS mutation. Inter-estingly, intra-patient heterogeneity of BRAF and NRASmolecular alterations between paired primary melanomaand metastasis has been described with observed dis-cordance rate 13,3% [15]. Moreover, a distinct subset ofAST with BRAF mutation and loss of BAP1 expressionhas also been reported [16].Molecular analysis demonstrated that the lung metas-

tasis most likely did not originate from the initial ASTand the patient presented with two different melanocyticlesions in a four-year time period: AST of the trunk andlung metastasis from presumably occult cutaneous mel-anoma of unknown primary site. Considering molecularcharacterisation of both lesions, it is rather improbablethat there was an association between the initial AST

and the giant lung metastasis. However, discordance inBRAF and NRAS mutation between primary lesion andmetastasis or AST with BRAF mutation is conceivable.Possibility of primary pulmonary melanoma with no as-sociation with the initial AST is highly controversial[17]. However, primary pulmonary melanoma withNRAS mutation has been recently reported [18].Finally, despite the previously mentioned controver-

sies, presence of BRAF mutation in the skin lesion previ-ously diagnosed at another medical facility most likelyrules out a Spitzoid melanocytic neoplasms and assignsthe atypical lesion to the group of conventional melano-cytic neoplasms. Thus, the most correct diagnosis of theinitial skin lesion would be a “conventional” melanomaharboring a Spitzoid morphology [14].

ConclusionOur patient was surgically treated at the age of 20 forAST and died four years later of metastatic NRAS-mutant melanoma most likely of different occult origin.However, we aim to highlight that due to the histopath-ologic controversies regarding Spitzoid lesions, a previ-ous clinical presence of an AST should be a reason for asystematic follow-up. Moreover, precise molecularcharacterization should be always performed in patientswith uncertain skin lesions, such as AST. However, thereis not clearly defined distinct set of biomarkers currentlyused that can with high sensitivity and specificity dis-criminate Spitz lesions from melanoma or distinguishwhether an ambiguous Spitzoid lesion will behave be-nign or malignant in the future [14].

AbbreviationsAST: Atypical Spitz tumour; SLNB: Sentinel lymph node biopsy;CT: Computed tomography; FISH: Fluorescence in situ hybridization; PET/CT: Positron emission tomography/computed tomography; NSE: Neuron-specific enolase; CMR: Cardiovascular magnetic resonance; FFPE: Formalin-fixed/paraffin-embedded; NGS: Next-generation sequencing;CGH: Comparative genomic hybridization; H&E: Hematoxylin–eosin;IHC: Immunohistochemical staining

AcknowledgementsThe authors thank prof. Skálová, MD, PhD (Bioptická laboratoř s.r.o., Pilsen,Czech Republic) for kindly provided pictures shown in Fig. 4.

Authors‘ contributionsJV Jr designed the report, analyzed the data, and wrote major part of themanuscript. OF, VK, ZS, AO, RK, JV, RL, JS, AS, JP, JK, MS contributed to thewriting of the manuscript. RL performed the operation; JS and JV Jr were thesurgery assistants. RK performed the pathological diagnosis,immunohistochemistry, molecular analysis and prepared histopathologicalfigures. All authors edited the final manuscript. All authors read and approvedthe final manuscript.

FundingThis work was supported by the institutional project PROGRESQ25 from theCharles University Prague and from the internal grant of the UniversityHospital Motol (no. 6028).

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Availability of data and materialsAll data generated or analyzed in the current article are available from thecorresponding author on reasonable request.

Ethics approval and consent to participateThe present study was approved by the ethics committee of the UniversityHospital Motol (reference no. EK—36/20) and adhered to the tenets of theDeclaration of Helsinki.

Consent for publicationNot applicable.

Competing interestsThe authors declare that they have no competing interests.

Author details1Third Department of Surgery, First Faculty of Medicine, Charles Universityand University Hospital Motol, Prague, Czech Republic. 2Department ofPathology and Molecular Medicine, Second Faculty of Medicine, CharlesUniversity and University Hospital Motol, Prague, Czech Republic.3Department of Respiratory Medicine, Palacký University Medical School andTeaching Hospital, Olomouc, Czech Republic. 4Department of Immunology,Second Faculty of Medicine, Charles University and University Hospital Motol,Prague, Czech Republic. 5Department of Transcription and Cell Signaling,Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty ofMedicine, Charles University, Prague, Czech Republic.

Received: 18 February 2020 Accepted: 15 October 2020

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