What role can dermatologists play in diagnosing a cancer syndrome like BAP1?

By Kathryn Schwarzenberger, MD, March 1, 2018

In this month's Acta Eruditorum column, Physician Editor Kathryn Schwarzenberger, MD, talks with Hensin Tsao, MD, PhD, and Alexandra Haugh about their recent JAMA Dermatology article, "Genotypic and Phenotypic Features of BAP1 Cancer Syndrome: A Report of 8 New Families and Review of Cases in the Literature."  

Dr. Schwarzenberger: What is BAP1 and does it have any role in normal skin?

Dr. Tsao and Haugh: BAP1 is a nuclear deubiquitinating protein encoded by the BAP1 gene that functions as a tumor suppressor. As a deubiquitinase, the BAP1 enzyme removes ubiquitin molecules that can act as “tags” on other proteins, marking them for degradation or controlling their cellular function. The exact mechanisms by which BAP1 acts as a tumor suppressor are still under investigation but the protein has been shown to be involved with several cell processes, including DNA repair, cell cycle control, cell growth, and cell death.

Germline mutations in BAP1 are associated with an increased risk of melanocytic BAP1-mutated atypical intradermal tumors (MBAITs), uveal and cutaneous melanoma, mesothelioma, renal cell carcinoma, and basal cell carcinoma, in addition to several other tumors.

BAP1 likely plays several important roles in normal skin, evidenced by the prevalence of MBAITs and cutaneous melanoma in patients with germline inactivating mutations of the BAP1 gene. The exact mechanism through which an absence of BAP1 leads to tumorigenesis in the skin is still unclear.

Sporadic forms of several of the most common tumors associated with BAP1 deficiency, however, are strongly associated with environmental carcinogens that result in DNA damage, suggesting that the loss of BAP1’s function in the DNA damage response system may play an important role in the syndrome.

Dr. Schwarzenberger: Tell us more about MBAITs. Will we know one when we see it? Will our dermatopathologist recognize it?

Dr. Tsao and Haugh: Individuals with germline mutations in BAP1 often develop several flesh-colored or reddish-brown well-circumscribed papules with a characteristic histomorphology. These tumors were called melanocytic BAP1-mutated atypical intradermal tumors (MBAITs) when first described in the literature but have also been referred to as BAPomas and BAP1-deficient tumors (BDTs).

Individual MBAITs are admittedly often not particularly noticeable on clinical examination. They are most similar in appearance to dermal nevi and can range significantly in size (often between 2-10 mm). MBAITs are thought to arise primarily from BRAF-mutated conventional nevi that undergo subsequent biallelic loss of BAP1. A peripheral area of pigment globules representing the BRAF-mutated progenitor nevus can therefore sometimes be seen on dermoscopic examination. Biallelic inactivation of BAP1 leads to a central population of large, epithelioid melanocytes with more spitzoid cytomorphology. These cells typically lack pigment and result in a central flesh-colored, often structureless, area on dermoscopic examination.

Immunohistochemistry demonstrating loss of the BAP1 protein in the large epithelioid melanocytes is a very useful tool in evaluating these lesions and makes them much more identifiable histologically than they often are clinically. Lesions that contain both conventional nevomelanocytes and a population of larger, epithelioid melanocytes that resemble Spitz tumors may warrant immunohistochemical staining. Despite the concerning histologic features that MBAITs share with Atypical Spitz Tumors and melanoma, these lesions are considered slow growing and benign.

As MBAITs may be somewhat innocuous on clinical examination, an important feature to suggest an underlying germline predisposition is the presence of multiple lesions. The number of MBAITs in individuals with germline mutations in BAP1 is thought to increase with age and can number anywhere between 5 to over 50. MBAITs are also generally the first tumors to appear in patients with germline mutations in BAP1, highlighting the important role that dermatologists can play by recognizing the syndrome before the onset of its associated malignancies.

Dr. Schwarzenberger: Most of us are familiar with BRCA1 and BRCA2 gene mutations and the increased risk of cancer our patients with these may have. Are these genes related to BAP1?

Dr. Tsao and Haugh: BAP1 actually stands for BRCA1 Associated Protein-1. The protein was given this name because it was found to bind to one of the domains of the BRCA1 protein. Despite BAP1’s association with BRCA1, studies evaluating the specific interaction between the two proteins have been inconclusive. Germline BAP1 mutations have not been conclusively associated with an increased risk of malignancies seen in BRCA1 carriers such as breast, ovarian, or pancreatic cancer.

Most autosomal dominant cancer susceptibility genes, such as BRCA1 and BRCA2, cause tumors in specific tissues or organs. The BAP1 syndrome, however, continues to be associated with new malignancies in a variety of different tissue types, suggesting that it may be more similar to syndromes such as Li-Fraumeni that result in an overall increased risk of cancer.

If this is the case, however, it is unclear why germline mutations in BAP1 are associated with such a high frequency of mesothelioma, uveal and cutaneous melanoma, and MBAITs specifically. Further studies that prospectively evaluate the incidence of different tumors in this syndrome as well as further elucidate the mechanisms by which loss of BAP1 leads to tumorigenesis are necessary to better define the syndrome.

Dr. Schwarzenberger: If we suspect a patient might have a BAP1 mutation, what initial workup is appropriate?

Dr. Tsao and Haugh: If there is a high degree of suspicion for a germline mutation in BAP1, the first step would involve discussing genetic testing with the patient. If the patient is interested, testing can be facilitated either through referral to a genetic counselor or through several commercially available assays that can potentially be performed in clinic. This is dependent on available resources and the individual physician’s level of comfort and familiarity performing genetic testing and counseling patients about results.

As the syndrome was only very recently identified, there are no official guidelines for screening in this population. However, most authors suggest that individuals with germline mutations in BAP1 undergo total body skin examinations at least every six months and are referred to ophthalmology for routine yearly uveal melanoma screening. No concrete screening guidelines have been developed for the associated internal malignancies, yet this is an area of active investigation and discussion. Given the multiple organ systems that are often involved with this syndrome, multi-disciplinary collaboration amongst physicians with knowledge of the BAP1 syndrome is a crucial component to provide optimal care for this population.

Dr. Schwarzenberger: Skin findings are helpful in diagnosing many familial cancer syndromes, such as Birt Hogg Dub, Cowden’s syndrome, Muir-Torre syndrome, and now BAP1 syndrome. What role do you think dermatology should play in helping to identify and define these syndromes?

Dr. Tsao and Haugh: One of the most exciting aspects of the BAP1 syndrome for dermatologists specifically is that the only benign tumors yet to be associated with the syndrome are also the first to appear in many patients and may actually be the most prevalent of all of the associated tumors. As these benign tumors arise in the skin, dermatologists play a very crucial role in identifying the syndrome and prompting genetic testing before any of the malignant tumors arise. Dermatologists can also carefully screen these patients for melanoma and counsel them about the importance of avoiding UV exposure and other carcinogens such as tobacco given their underlying predisposition to cancer. As screening guidelines for the internal malignancies are developed, identifying these individuals early in their lives may represent a life-saving intervention.

Like the BAP1 syndrome, the skin tumors involved in Birt Hogg Dub and the hamartomas that characterize Cowden’s syndrome are benign and generally appear before any associated internal malignancies. Dermatologists therefore arguably play the most important role in caring for these patients because early identification can prompt screening and counseling for the associated malignant tumors. Whereas most other specialists who identify a germline cancer predisposition do so only after their patient presents with one or several malignant tumors, dermatologists have a unique opportunity to identify these patients either before the onset of any malignancies or before their internal tumors have become large enough to result in clinical symptoms.

Additionally, if there is any debate as to whether genetic testing is warranted in a specific patient based on a personal or family history of malignancy, a careful dermatologic examination can provide further evidence to prompt genetic testing. In syndromes where skin findings are known to be ubiquitous, dermatologists can also play an important role in providing evidence against a genetic predisposition if the patient lacks any of the characteristic skin lesions.

In thinking about cancer syndromes, I usually take a full spectrum cancer history (i.e. ask about all cancers beyond skin cancers) and look for a couple of features — early onset of cancer (usually <45 years), multiple primary tumors (e.g. multiple melanomas), cancers on one side of family and aggregation of rare tumors. It is not unusual, for instance, to have melanoma and breast cancer in the family since breast cancer is pretty common. However, to have mesothelioma, kidney cancer, uveal melanoma, and cutaneous melanoma on one side of the family would be highly unusual. I recommend genetic counseling to get a more detailed pedigree and to coordinate education and return-of-results if genetic testing is appropriate.

Additional DermWorld Resources