INTRODUCTION — The BAP1 tumor predisposition syndrome (MIM #614327), first described in 2011, is a rare, autosomal dominant tumor predisposition syndrome caused by germline variants in BAP1 tumor suppressor gene. 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 [1-9].
Most affected individuals also develop multiple cutaneous, melanocytic neoplasms called "BAP1-inactivated melanocytic tumors" (BIMTs; melanocytomas) [10,11]. These tumors, which clinically resemble intradermal nevi or cutaneous fibromas and were initially considered atypical Spitz tumors (picture 1A-B), are often the earliest sign of the BAP1 tumor predisposition syndrome. BIMTs may occur sporadically in individuals who do not carry germline variants in BAP1 [12]. Both sporadic and syndromic BIMTs show the same clinical and histopathologic features.
This topic will discuss the pathogenesis, diagnosis, and management of BIMTs. Spitz tumors are discussed separately. (See "Spitz nevus and atypical Spitz tumors".)
TERMINOLOGY — BAP1-inactivated melanocytic tumors (BIMTs) were previously referred to as Wiesner nevi, BAPomas, BAP1 mutant Spitz nevi, or melanocytic BAP1-mutated atypical intradermal tumors [10]. The fourth edition of the World Health Organization (WHO) Classification of Skin Tumors includes two entities classified as intermediate/low-grade dysplasias and intermediate/high-grade dysplasias, called "BAP1-inactivated nevus" and "BAP1-inactivated melanocytoma," respectively (table 1) [13].
In this topic, we will use the term "BAP1-inactivated melanocytic tumors."
EPIDEMIOLOGY — The incidence and prevalence of BAP1-inactivated melanocytic tumors (BIMTs) are not known. BIMTs can appear at any age, most often in the second or third decade of life, and equally affect males and females [10]. They can occur sporadically or be a manifestation of the BAP1 tumor predisposition syndrome, associated with autosomal dominant BAP1 germline variants.
The true prevalence of germline BAP1 variants in the general population is also unknown. An Australian, population-based study detected BAP1 germline variants in <1 percent of patients with cutaneous melanoma from high-density melanoma families [14].
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 [1-9]. 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 [15].
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, DNA repair, and cell cycle regulation [16]. Germline BAP1 variants are inherited in an autosomal dominant pattern with high penetrance.
The majority of BAP1-inactivated melanocytic tumors (BIMTs) occurring in individuals with germline BAP1 variants 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 an additional inactivating mutation in the second wild-type BAP1 allele. Biallelic loss of BAP1 results in the loss of nuclear expression of BAP1 on immunohistochemistry. (See 'Immunohistochemistry' below.)
Somatic inactivating mutations in BAP1 were first identified in cases of sporadic, metastasizing uveal melanoma [4] 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 [11]. Subsequently, inactivating BAP1 somatic mutations were identified in morphologically similar tumors arising sporadically [12].
Most BIMTs also harbor BRAF V600E mutations. In a series of 30 melanocytic lesions from three patients with BAP1 germline variant and family history of uveal melanoma, concurrent BAP1 loss and BRAF V600E expression was seen in 67 percent of the tumors [17].
CLINICAL FEATURES — BAP1-inactivated melanocytic tumors (BIMTs) present as skin-colored to red-brown, dome-shaped or pedunculated papules, ranging in diameter from 2 to 10 mm (picture 1A-B) [10]. Occasionally, they may present as brown, pigmented papules or tan macules [18]. Lesions are most frequently located on the head and neck, followed by trunk, upper limbs, and lower limbs [18].
Most BIMTs are sporadic, with only approximately 12 percent of cases being associated with germline BAP1 variants [19]. Sporadic BIMTs are usually solitary.
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 [7,8,20]. The number of lesions typically ranges from 5 to 50 [12].
ASSOCIATION WITH BAP1 TUMOR PREDISPOSITION SYNDROME — Individuals with multiple BAP1-inactivated melanocytic tumors (BIMTs) have a high likelihood of carrying germline variants in BAP1. Approximately 70 percent of germline BAP1 variant carriers have BIMTs. These individuals are prone to developing a variety of cancers, most frequently uveal melanoma, mesothelioma, cutaneous melanoma, and renal cell carcinoma [8,9,15]. Other associated tumors include nonmelanoma skin cancer (predominantly basal cell carcinoma), meningioma, and cholangiocarcinoma [15].
DIAGNOSIS — The definitive diagnosis of BAP1-inactivated melanocytic tumor (BIMT) 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 BIMTs and a personal or family history of cancer to confirm or exclude BAP1 tumor predisposition syndrome. (See 'Association with BAP1 tumor predisposition syndrome' above and 'Genetic testing' below.)
Clinical findings and history — The diagnosis of syndromic BIMTs 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 [6,15]. 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 is of limited value in the clinical diagnosis. In a retrospective study of 48 histopathologically confirmed BIMTs from 31 patients, the most prevalent dermoscopic pattern was a pink to tan, structureless area with irregular, eccentric dots and globules [18]. Other dermoscopic features include serpentine vessels, dotted vessels, and atypical network.
Biopsy — Excisional biopsy is necessary for the diagnosis of BIMT. 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
Morphologic features — At scanning magnification, BIMTs appear as symmetric, dermal, melanocytic proliferations, with occasional involvement of the dermoepidermal junction [12,18,21,22]. 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 [10,12,19]:
●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 [12].
●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 BAP1-inactivated melanocytic lesions (17 from eight patients with confirmed germline BAP1 variants), the histopathologic features were broad and included [19]:
●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 BIMTs included [19]:
●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 BIMTs [19]:
●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
The authors reported that the presence of an extensive junctional component of epithelioid cells was the only statistically significant feature associated with germline BAP1 mutations [19].
A spectrum exists for BAP1-inactivated melanocytic proliferations. The World Health Organization (WHO) classifies lesions with benign-appearing nevoid cells and minimal atypia as "BAP1-inactivated nevi" and those with marked pleomorphism and large epithelioid cells as "BAP1 melanocytomas" [13].
Immunohistochemistry — On immunohistochemical staining using an antibody specific to the C-terminal end of the BAP1 protein, the large epithelioid cells of both sporadic and syndromic BIMTs 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) [19,23]. The nuclear loss of BAP1 staining is often coupled with diffuse, cytoplasmic staining for BRAF V600E. 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 [24]. Possible explanations include:
●BIMT with inactivation of only one allele (germline mutation) may demonstrate retention of nuclear staining, as one wild-type copy of BAP1 is functional.
●Significant BAP1 mutations 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 [8,20]. 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 [25].
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of BAP1-inactivated melanocytic tumors (BIMTs) is broad and includes melanocytic and nonmelanocytic skin lesions that can mimic BIMTs clinically. In many cases, histopathologic examination is necessary for the correct diagnosis:
●Spitz nevus – Histologically, Spitz nevus 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 nevi – Intradermal nevi are benign proliferations of nevus cells residing in the dermis that often lose their capacity to produce melanin. (See "Acquired melanocytic nevi (moles)".)
●Amelanotic 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".)
●Neurofibroma – Neurofibromas 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 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 is a histiocytic tumor with Touton giant cells that are S100 negative. (See "Juvenile xanthogranuloma (JXG)".)
●Basal cell carcinoma – Basal cell carcinoma consists of nodules and/or strands of atypical basaloid cells that show nuclear palisading, cellular apoptosis, and scattered mitotic activity in the dermis. (See "Epidemiology, pathogenesis, clinical features, and diagnosis of basal cell carcinoma".)
MANAGEMENT
Lesion management — There are no specific, evidence-based guidelines for the management of BAP1-inactivated melanocytic tumors (BIMTs). The malignant potential of BIMTs is uncertain, but transformation of BIMTs into melanoma occurs, likely resulting from additional genetic or epigenetic alterations [11,26].
Our approach to the management of patients with BIMTs is as follows:
●Excision with clear histologic margins is appropriate in cases with clinical change or atypia. In cases with intermediate/high-grade dysplasia, re-excision is recommended.
●Management of intermediate lesions or those with undetermined malignant potential may be discussed in multidisciplinary consensus conferences.
●In patients with multiple BIMTs, lesions that are not excised should be closely monitored clinically. Digital dermoscopic imaging may be considered to follow these patients [18].
Genetic testing — Indications for genetic testing for patients diagnosed with BIMT include [24,27]:
●Patients with a confirmed diagnosis of BIMT or melanocytoma and 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 [7].
●Young adults with multiple BIMTs who may be at risk for development of multiple cancers may benefit from genetic testing, even in the absence of personal or family history of cancer. 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 BIMT and no personal/family history of cancer. These patients may undergo clinical surveillance for additional melanocytic tumors or cancer, including basal cell carcinoma [3].
DNA obtained from blood, saliva, or directly from tumors is subjected to Sanger sequencing or other sequencing for germline mutations in BAP1.
SURVEILLANCE FOR PATIENTS WITH BAP1 GERMLINE VARIANTS — There are no formal guidelines for cancer surveillance protocols for patients with diagnosed 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 is cost effective for the health care system [28].
Proposed recommendations include [7,16,20,27,29,30]:
●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 [6,7,27,30].
●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 every two years [7].
PROGNOSIS — BAP1-inactivated melanocytic tumors (BIMTs) 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 [1,27,28]. Risk may be higher for uveal melanoma (36 percent) and mesothelioma (25 percent) [28].
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
●The BAP1 tumor predisposition syndrome (MIM #614327) is a rare, autosomal dominant tumor predisposition syndrome caused by germline variants in BAP1 tumor suppressor gene. Carriers of BAP1 variants often develop multiple cutaneous, melanocytic neoplasms called BAP1-inactivated melanocytic tumors (BIMTs) and have an increased risk of developing uveal melanoma, malignant mesotheliomas, cutaneous melanoma, renal cell carcinoma, and other internal cancers. (See 'Introduction' above.)
●BIMTs 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.)
●The definitive diagnosis of BIMT 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 BIMTs and a personal or family history of cancer to confirm or exclude BAP1 tumor predisposition syndrome. (See 'Diagnosis' above and 'Histopathology' above.)
●There are no specific, evidence-based guidelines for the management of BIMTs. Excision with clear histologic margins is appropriate for lesions exhibiting clinical changes or histologic atypia. (See 'Lesion management' above.)
●Genetic testing for germline BAP1 variants is indicated for patients with a confirmed diagnosis of BIMT and 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 BIMTs in the absence of family or personal history of cancer. (See 'Genetic testing' above.)
