BAP1-inactivated melanocytoma

INTRODUCTION — BAP1-inactivated melanocytomas (BIMs) are rare melanocytic tumors characterized by the loss of nuclear expression of the BRCA1-associated protein-1 (BAP1), a nuclear protein encoded by the BAP1 tumor suppressor gene. BIMs, which clinically resemble intradermal nevi or dermatofibromas and were initially considered atypical Spitz tumors, can occur sporadically or in the setting of BAP1 tumor predisposition syndrome. First described in 2011, BAP1 tumor predisposition syndrome (MIM #614327) is a rare autosomal dominant tumor predisposition syndrome caused by germline variants in the BAP1 tumor suppressor gene [1,2].

Carriers of BAP1 variants have an increased risk of developing a variety of tumors, including uveal melanoma, malignant mesotheliomas, cutaneous melanoma, renal cell carcinoma, basal cell carcinoma, hepatocellular carcinoma, and cholangiocarcinoma [1,3-10]. Most affected individuals also develop multiple cutaneous BIMs, which were previously considered atypical Spitz tumors [11,12].

This topic will discuss the pathogenesis, diagnosis, and management of BIMs. Spitz tumors are discussed separately. (See "Spitz nevus and atypical Spitz tumors".)

TERMINOLOGY AND CLASSIFICATION — BIMs were previously referred to as Wiesner nevi, BAPomas, BAP1 mutant Spitz nevi, melanocytic BAP1-mutated atypical intradermal tumors (MBAITs), or BAP1-inactivated melanocytic tumors (BIMTs) [11]. In this topic, we will use the term "BAP1-inactivated melanocytoma" (BIM).

The fifth edition of the World Health Organization (WHO) Classification of Skin Tumours Online includes two entities classified as intermediate/low-grade dysplasias and intermediate/high-grade dysplasias, respectively called "BAP1-inactivated melanocytoma" and "BAP1-inactivated melanocytoma/melanocytic tumor of uncertain malignant potential" (table 1) [13]. In the revised Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx version 2.0) schema, BIM is categorized as class II [14].

Although severely atypical variants of BIMs with uncertain malignant potential are recognized, such tumors and malignant variants are extremely rare. BIMs represent a spectrum of neoplasia in which true malignancy is difficult to conclusively substantiate except by proof of distant metastasis or death. This is because convincing clinical, histopathologic, and genetic data are not available for a sufficient cohort of patients with sufficiently long follow-up to draw definitive conclusions.

EPIDEMIOLOGY — The incidence and prevalence of BIMs are not known. BIMs can appear at any age, most often in the second or third decade of life, without sex predilection [11]. They can occur sporadically or be a manifestation of BAP1 tumor predisposition syndrome, associated with autosomal dominant BAP1 germline variants.

The true prevalence of germline BAP1 variants in the general population is not precisely known. According to the Genome Aggregation (gnomAD) database, the prevalence of germline loss-of-function variants in BAP1 ranges between 0.007 to 0.613 percent, depending on the variant [15]. The most common variant is a p.Tyr401Ter variant (dbSNP [rs200156887]). An Australian population-based study detected BAP1 germline variants in <1 percent of patients with cutaneous melanoma from high-density melanoma families [16].

MOLECULAR PATHOGENESIS — The BAP1 tumor suppressor gene located on chromosome 3 (3p21.1) encodes the BRCA1-associated protein-1 (BAP1), a nuclear protein that functions as a deubiquitinating enzyme. It regulates the degradation of proteins and is involved in numerous cellular functions, including chromatin remodeling, transcriptional regulation, deoxyribonucleic acid (DNA) repair, and cell cycle regulation [17]. Germline BAP1 variants are inherited in an autosomal dominant pattern with high penetrance.

In individuals with germline BAP1 variants, most BIMs show biallelic loss of BAP1. One allele is inactivated through the germline mutation, and the other is somatically inactivated by several genetic alterations, such as chromosomal deletion involving the wild-type BAP1 locus at 3p21, uniparental disomy of chromosome 3 with the mutated BAP1, or additional inactivating mutations. Biallelic loss of BAP1 results in the loss of nuclear expression of BAP1 on immunohistochemistry in the large epithelioid melanocytes. (See 'Immunohistochemistry' below.)

Somatic inactivating mutations in BAP1 were first identified in cases of sporadic metastasizing uveal melanoma [6] and, subsequently, in cutaneous tumors with features of atypical Spitz tumors in individuals from two unrelated families with autosomal dominantly inherited germline variants of BAP1 [12]. Subsequently, inactivating BAP1 somatic mutations were identified in morphologically similar tumors arising sporadically [18].

In addition to biallelic inactivation of BAP1, most BIMs also harbor driver mutations, most commonly BRAF V600E mutations or, less commonly, NRAS mutations, BRAF fusions, and RAF1 fusions [19-21]. In a series of 30 melanocytic lesions from three patients with BAP1 germline variants and a family history of uveal melanoma, concurrent BAP1 loss and BRAF V600E expression was seen in 67 percent of the tumors [22]. In a case report, a 35-year-old female patient with BAP1 tumor predisposition syndrome presented with a melanocytic lesion harboring three histologically distinct melanocytic populations, indicating a progression from nevus to melanoma through a melanocytoma stage [23]. This progression was further supported by the finding of BRAF V600E, BAP1, and, interestingly, TERT-promoter (TERT-p) hotspot mutations.

Compared with conventional nevi, BIMs show loss of primary cilia and amplification of centrosomes. Primary cilium is an organelle involved in signal transduction and cell cycle progression. Studies have also shown a role for BAP1 in centrosome and mitotic spindle formation [24]. Primary cilia have also been demonstrated to be absent in melanoma but retained in melanocytic nevi [25]. Therefore, centrosome and cilia formation are likely important in the pathogenesis of other BAP1-inactivated tumors.

CLINICAL FEATURES — BIMs present as 2 to 10 mm skin-colored to red-brown, dome-shaped or pedunculated papules, resembling intradermal nevi or cutaneous fibromas (picture 1A-B) [11]. Occasionally, they may present as brown, pigmented papules or tan macules [26].

Lesions are most frequently located on the head and neck, followed by trunk, upper limbs, and lower limbs [26]. BIMs can occur at any age but are predominantly seen in children and young adults [21].

Most BIMs are sporadic, occurring in individuals who do not carry germline variants in BAP1, and usually present as solitary lesions [18]. In contrast, in individuals carrying germline variants in BAP1, these tumors are generally multiple, first appear in the second or third decade of life, and increase in number with age [1,9,27]. The number of lesions typically ranges from 5 to 50 [18].

ASSOCIATION WITH BAP1 TUMOR PREDISPOSITION SYNDROME — BAP1 tumor predisposition syndrome (MIM #614327), first described in 2011, is a rare autosomal dominant tumor predisposition syndrome caused by germline variants in the BAP1 tumor suppressor gene [2,8]. Individuals with multiple BIMs have a high likelihood of carrying germline variants in BAP1, and approximately 70 percent of germline BAP1 variant carriers have BIMs.

Individuals with germline BAP1 variants have a high risk of developing malignancies at an early age, most frequently uveal melanoma, malignant mesothelioma, cutaneous melanoma, and renal cell carcinoma [1,3-10]. Other associated tumors include nonmelanoma skin cancer (predominantly basal cell carcinoma), meningioma, and cholangiocarcinoma [28].

In a worldwide study of 181 families with 804 individuals carrying BAP1 variants, 88 percent of proband and 83 percent of nonproband variant carriers were found to have at least one tumor, suggesting that the risk of developing at least one tumor type may approach 100 percent over a lifetime [28].

DIAGNOSIS — BIM is often clinically misdiagnosed as an atypical Spitz tumor. The definitive diagnosis is based on histopathologic evaluation of the excised lesion and immunohistochemical demonstration of nuclear BAP1 loss. (See 'Histopathology' below.)

Genetic testing for germline BAP1 variants should be performed in patients with multiple BIMs and/or a personal or family history of cancer to confirm or exclude BAP1 tumor predisposition syndrome. Individuals with a single isolated BIM in the absence of a significant family history for malignancies associated with the BAP1 tumor predisposition syndrome probably do not need to be routinely tested. (See 'Association with BAP1 tumor predisposition syndrome' above and 'Genetic testing' below.)

Clinical findings and history — The diagnosis of syndromic BIMs is suspected in a patient presenting with multiple skin-colored to red-brown, dome-shaped or pedunculated papules (picture 1A), predominantly located on the head and neck or trunk, and a personal or family history of cancer [8,28]. In these patients, it is reasonable to biopsy one or two lesions to confirm the diagnosis with histopathologic and immunohistochemical evaluation.

Sporadic, solitary lesions may be easily overlooked, as they resemble banal intradermal nevi or cutaneous fibromas in most cases. These lesions may come to attention if they have unusual features suspicious of skin cancer or because of the patient's concern.

Dermoscopy — Dermoscopy is of limited value in the clinical diagnosis of BIM. In a retrospective study of 48 histopathologically confirmed BIMs from 31 patients, the most prevalent dermoscopic pattern was a pink to tan, structureless area with irregular, eccentric dots and globules [26]. Other dermoscopic features include serpentine vessels, dotted vessels, and atypical network. Additionally, a structureless, pink background with central, bluish hue or light brown globules has been described [29].

Biopsy — Excisional biopsy for routine histopathologic evaluation and immunohistochemical demonstration of nuclear BAP1 loss is necessary for the diagnosis of BIM. Some experts suggest that in patients with multiple lesions demonstrating concerning clinical and/or dermoscopic findings, one or two lesions should be biopsied to confirm the diagnosis histopathologically and immunophenotypically.

Histopathology — A histopathologic spectrum of cytologic atypia exists for BIMs. The World Health Organization (WHO) classifies all lesions with both benign-appearing nevoid cells and minimal atypia and those with marked pleomorphism and large epithelioid cells as "BAP1 melanocytomas" [13].

Morphologic features — Both sporadic and syndromic BIMs show similar clinical and histopathologic features in most cases. In one study, the presence of an extensive junctional component of epithelioid cells was the only morphologic feature showing a statistically significant association with germline BAP1 mutations [30].

●At scanning magnification, BIMs appear as symmetric, dermal, melanocytic proliferations, with occasional involvement of the dermoepidermal junction [18,26,31,32].

●At higher magnification, lesions may show two different histologic patterns. One is characterized by uniformly large epithelioid cells with abundant eosinophilic cytoplasm, and the other is characterized by a biphasic proliferation of small nevoid cells and large epithelioid cells [11,18,30].

•The epithelioid pattern displays uniformly large epithelioid "spitzoid" cells with well-defined cytoplasmic borders and sheet-like growth. This pattern was prominent in the cases initially described as atypical Spitz tumors or nevoid melanoma found to harbor an acquired BAP1 mutation [18].

•The biphasic pattern shows conventional, dermal-based clusters and nests of nevus cells, often located at the periphery of the tumor, and atypical epithelioid cells with abundant, eosinophilic, glassy cytoplasm, sometimes with a spitzoid appearance, often lacking melanin (picture 2).

In both patterns, the epithelioid cells show variable cytologic atypia, with pleomorphic, hyperchromatic nuclei, and haphazard maturation. Mitotic activity is usually low. There is often an inflammatory infiltrate.

In a series of 102 BIMs (17 from eight patients with confirmed germline BAP1 variants), the histopathologic features were broad and included [30]:

●Spitzoid cytomorphology (69 percent)

●Smaller epithelioid cells without spitzoid features (31 percent)

●Rhabdoid cytologic features (58 percent)

The spitzoid features noted in the majority of BIMs included [30]:

●Large epithelioid cells with abundant, pale cytoplasms

●Marked variation in nuclear sizes

●Nuclear pleomorphism with dispersed chromatin patterns and prominent nucleoli

However, several histopathologic features typical of Spitz nevi were remarkably absent in BIMs [30]:

●Kamino bodies

●Spindled melanocytes

●Epidermal hyperplasia and hypergranulosis

●Vertical ("raining down") orientation of junctional and dermal fascicles of melanocytes

●"V" or "wedge-shaped" dermal architectural configuration

Additional nuclear features that have been described include nuclear blebbing, nuclear budding, micronuclei, shadow nuclei, tetraploidy, peculiar cytoplasmic projections ("ant-bear cells") often containing micronuclei, and cell-in-cell structures (entosis) [21]. In addition, mixed nests of conventional nevus cells and BAP1-inactivated melanocytes with squeezed remnants of the original nevus have been observed [21].

Immunohistochemistry — Immunohistochemical staining using an antibody specific to the C-terminal end of the BAP1 protein demonstrates the following [30,33]:

●The large epithelioid cells of both sporadic and syndromic BIMs showed nuclear loss of BAP1 expression but retained cytoplasmic staining in a clumped perinuclear or fine granular pattern or combination of the two (picture 2). The nuclear loss of BAP1 staining is often coupled with diffuse, cytoplasmic staining for the BRAF V600E protein.

●In contrast, the background nevus cells show nuclear staining for BAP1 but are BRAF V600E negative.

Immunohistochemistry for BAP1 is sensitive and specific; however, false negatives occur [34]. Possible explanations include:

●BIM with inactivation of only one allele (eg, due to germline variant) may demonstrate retention of nuclear staining, as one wild-type copy of BAP1 is functional.

●Function-altering somatic or germline BAP1 variants may affect either the nuclear localization sequence at the N-terminus, resulting in cytoplasmic retention, or the ubiquitin carboxy-terminal hydrolase catalytic domain at the C-terminus, altering the deubiquitinating activity [9,27]. However, milder mutations affecting the N-terminus may not compromise protein folding or stability and, thus, its transfer to the nucleus with an intact C-terminus, resulting in positive nuclear staining [35].

What is the malignant potential of BAP1-inactivated melanocytomas? — The vast majority of BIMs are indolent. However, those with an accumulation of atypical features, such as ulceration, large diameter (>1 cm), nodule formation, high mitotic rate ≥6 mitoses per mm², and high-grade atypia, should be considered tumors with uncertain malignant potential and suspicious for melanoma.

Immunohistochemical expression of the preferentially expressed antigen in melanoma (PRAME) has been demonstrated to assist in the diagnosis of primary cutaneous melanoma, which typically demonstrates diffuse and strong, positive nuclear staining [36]. In one study, five BIMs were analyzed with regard to PRAME, and none had an immunoreactivity score greater than +1 (1 to 25 percent of tumor cells positive) [37]. These results further support the notion that BIMs lack the typical immunophenotypic features of melanoma.

However, there are reports of progression of BIM into melanoma, likely as a result of additional genetic or epigenetic alterations [12,23,38].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of BIMs is broad and includes melanocytic and nonmelanocytic skin lesions that can mimic BIMs clinically. In many cases, histopathologic examination is necessary for the correct diagnosis.

●Spitz nevus – Histologically, Spitz nevus (picture 3A-B) shows epidermal hyperplasia, Kamino bodies, vertical orientation of melanocytes, "V" or "wedge-shaped" configuration, large epithelioid cells with opaque cytoplasm, and large vesicular nuclei. Immunohistochemistry demonstrates nuclear BAP1 staining. (See "Spitz nevus and atypical Spitz tumors".)

●Intradermal nevus – Intradermal nevus (picture 4) is a benign proliferation of nevus cells residing in the dermis that often lose their capacity to produce melanin. (See "Acquired melanocytic nevi (moles)".)

●Amelanotic/hypomelanotic melanoma – Amelanotic melanoma may exhibit a population of large epithelioid melanocytes with cytologic atypia devoid of melanin pigment or with minimal melanin pigment. (See "Pathologic characteristics of melanoma".)

●Cutaneous neurofibroma – Neurofibromas (picture 5) consist of a bland spindle cell proliferation with coarse collagen. (See "Overview of benign lesions of the skin", section on 'Cutaneous neurofibroma'.)

●Skin tag (acrochordon) – Skin tags lack epithelioid melanocytes within the dermis. (See "Overview of benign lesions of the skin", section on 'Acrochordon (skin tag)'.)

●Dermatofibroma – Dermatofibromas (picture 6) consist of spindled cells with collagen trapping and overlying epidermal induction that are negative for melanocytic markers. (See "Overview of benign lesions of the skin", section on 'Dermatofibroma'.)

●Xanthogranuloma – Xanthogranuloma (picture 7) is a histiocytic tumor with Touton giant cells that are S100 negative. (See "Juvenile xanthogranuloma (JXG)".)

●Nodular basal cell carcinoma – Basal cell carcinoma (picture 8) consists of nodules and/or strands of atypical basaloid cells that show nuclear palisading cellular apoptosis and scattered mitotic activity in the dermis. (See "Basal cell carcinoma: Epidemiology, pathogenesis, clinical features, and diagnosis".)

MANAGEMENT

Lesion management — There are no specific evidence-based guidelines for the management of BIMs. Our approach is as follows [14,39,40]:

●A lesion suspicious for BIM is initially excised with 2 mm margins.

●If the lesion is low grade and the histologic margins are clear, no further treatment is required. If the lesion has positive margins, re-excision with 2 to 3 mm margins is recommended.

●Lesions that are high grade with either negative or positive margins should be re-excised to achieve 5 to 10 mm margins.

●The management of lesions with undetermined malignant potential may be discussed in multidisciplinary consensus conferences.

●In patients with multiple BIMs, lesions that are not excised should be closely monitored clinically. Digital dermoscopic imaging may be considered to follow these patients [26].

Genetic testing — DNA obtained from blood, saliva, or directly from tumors is subjected to Sanger sequencing or other sequencing for germline mutations in BAP1. Genetic testing for germline BAP1 variants is indicated in the following circumstances [34,41]:

●Patients with a confirmed diagnosis of BIM or melanocytic tumor of uncertain malignant potential and a personal or family history of at least one BAP1 tumor predisposition syndrome-related cancer (eg, mesothelioma, uveal melanoma, cutaneous melanoma, renal cell carcinoma) should be referred to a cancer genetic service for counseling and possible genetic testing [1].

●Young adults with multiple BIMs may benefit from genetic testing, even in the absence of a personal or family history of cancer, to exclude BAP1 tumor predisposition syndrome. Genetic counseling referral should be undertaken prior to decision making for genetic testing.

●It is unclear whether there is a benefit for genetic testing in individuals with a solitary BIM and no personal/family history of cancer. These patients may undergo clinical surveillance for additional melanocytic tumors or cancer, including basal cell carcinoma [5].

SURVEILLANCE FOR PATIENTS WITH BAP1 GERMLINE VARIANTS — There are no formal guidelines for cancer surveillance protocols for patients diagnosed with germline BAP1 variants. A simulation model indicated that active surveillance for the main cancers associated with BAP1 tumor predisposition syndrome could reduce mortality, improve survival, and be cost effective for the health care system [42].

Proposed recommendations include [1,2,17,27,41,43]:

●Patients with germline BAP1 mutations should receive routine skin and ophthalmologic examinations for cutaneous and uveal melanoma. (See "Inherited susceptibility to melanoma", section on 'Surveillance and management'.)

●Some experts recommend total skin examination every six months and annual ophthalmologic examinations starting at age 11 to 16 years [1,8,41,43].

●Sun protection should be recommended. (See "Selection of sunscreen and sun-protective measures".)

●Because of the increased risk of mesothelioma and kidney cancer, a multidisciplinary team is often necessary to screen for BAP1-related visceral malignancies, although there are no formal evidence-based guidelines on how that should be done.

•For renal cell carcinoma, the surveillance recommendations are those for hereditary kidney cancer syndromes. (See "Hereditary leiomyomatosis and renal cell cancer (HLRCC)", section on 'Surveillance for renal cancer' and "Clinical features, diagnosis, and management of von Hippel-Lindau disease", section on 'Surveillance protocols' and "Birt-Hogg-Dubé syndrome", section on 'Surveillance'.)

•For mesothelioma, some experts suggest annual abdominal and respiratory clinical examination from the age of 30 years, with asymptomatic surveillance with ultrasound or magnetic resonance imaging (MRI) every two years [1].

PROGNOSIS — BIMs are usually clinically stable and have an indolent course. Patients with BAP1 tumor predisposition syndrome have an increased cancer risk. Cutaneous melanoma has been reported in 18 to 23 percent of probands with germline BAP1 variants, at a median age of approximately 45 years [3,41,42]. Risk may be higher for uveal melanoma (36 percent) and mesothelioma (25 percent) [42].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Melanoma screening, prevention, diagnosis, and management".)

SUMMARY AND RECOMMENDATIONS

●Definition and molecular pathogenesis – BAP1-inactivated melanocytomas (BIMs) are rare melanocytic tumors characterized by the loss of nuclear expression of the BRCA1-associated protein-1 (BAP1), a nuclear protein encoded by the BAP1 tumor suppressor gene. Germline variants in BAP1 cause BAP1 tumor predisposition syndrome, a rare autosomal dominant cancer predisposition syndrome. Carriers of BAP1 variants often develop multiple BIMs and have an increased risk of developing uveal melanoma, malignant mesotheliomas, cutaneous melanoma, renal cell carcinoma, and other internal cancers. (See 'Introduction' above and 'Molecular pathogenesis' above.)

●Clinical features – BIMs present as skin-colored to red-brown, dome-shaped or pedunculated papules, ranging in diameter from 2 to 10 mm (picture 1A-B). In individuals carrying germline variants in BAP1, these tumors are generally multiple, appear in the second or third decade of life, and increase in number with age. (See 'Clinical features' above.)

●Diagnostic evaluation – The definitive diagnosis of BIM is based on histopathologic evaluation of the excised lesion and immunohistochemical demonstration of nuclear BAP1 loss. Genetic testing for germline BAP1 variants should be performed in patients with BIMs and a personal or family history of at least one BAP1 tumor predisposition syndrome-related cancer (ie, mesothelioma, uveal melanoma, cutaneous melanoma, renal cell carcinoma) and for young adults with multiple BIMs in the absence of a family or personal history of cancer to confirm or exclude BAP1 tumor predisposition syndrome. (See 'Diagnosis' above and 'Histopathology' above and 'Genetic testing' above.)

●Differential diagnosis – The differential is broad and includes melanocytic and nonmelanocytic skin lesions (Spitz nevus, amelanotic/hypomelanotic melanoma, neurofibroma, dermatofibroma, xanthogranuloma, nodular basal cell carcinoma). (See 'Differential diagnosis' above and "Spitz nevus and atypical Spitz tumors".)

●Treatment – There are no specific evidence-based guidelines for the management of BIMs. Lesions are typically diagnosed as BIMs via excision, as discussed above (see 'Diagnosis' above). Our approach to lesion management is as follows (see 'Lesion management' above):

•For lesions with low-grade histologic atypia excised with clear margins, no further intervention is needed.

•For lesions with low-grade histologic atypia and positive margins, we suggest re-excision with 2 to 3 mm margins (Grade 2C).

•For lesions showing high-grade histologic atypia with or without positive margins, we suggest re-excision to achieve 5 to 10 mm margins (Grade 2C).

•For patients with a prior diagnosis of BIM who present with multiple lesions suspicious for BIM, we advise genetic testing for germline variants in BAP1 to exclude BAP1 tumor predisposition syndrome (see 'Genetic testing' above). Irrespective of the results of genetic testing:

-For lesions that exhibit clinical changes, we suggest excision rather than observation (Grade 2C).

-Lesions without clinical changes can be monitored clinically and dermoscopically.

●Prognosis – BIMs are usually clinically stable and have an indolent course. Patients with BAP1 tumor predisposition syndrome have an increased risk of uveal melanoma, mesothelioma, renal cell carcinoma, and cutaneous melanoma. (See 'Prognosis' above.)