Faciocutaneous Cancer Syndromes: Spot the Diagnosis

Abstract

This commentary highlights the potential for early diagnosis of certain cancers diagnoses for individuals with hereditary faciocutaneous disorders.

Hereditary cancer disorders due to germline mutations offer oncologists an opportunity for early diagnosis of individuals who carry deleterious gene mutations that cause an increased risk of cancer. There is potential for early detection or even prevention through screening and lifestyle management. Most of these conditions are due to mutations in tumor suppressor genes and generally follow autosomal dominant inheritance. For some of these genetic disorders, the risk of malignancy and variable physical signs pass from one generation to the next, often leaving a legacy of malignant tumors that are too often diagnosed at late stage. Some more common hereditary disorders, such as BRCA1- and BRCA2-related breast-ovarian cancer, may be missed for a number of reasons, including incomplete family history in earlier generations due to lack of diagnosis, poor communication within families, or alternatively the stigma of a diagnosis of cancer. Sometimes there is a lack of recognition by patients (or occasionally by their physicians). Many cases are inherited through the paternal side, and patients who have paternal aunts with breast and ovarian cancers may not believe those relatives are relevant enough to tell their physicians unless prompted.

In hereditary faciocutaneous disorders, however, the diagnosis is literally staring the oncologist in the face. These conditions provide recognizable stigmata such that careful (albeit brief) examinations of patients for specific abnormalities of skin, skin appendages, or features consistent with subcutaneous neoplasia can provide clues directing the observant physician to entertain a cancer predisposition syndrome.

In this issue of the journal, Shen et al. [1] highlight a collection of cutaneous physical signs discernible on physical examination that are associated with a variety of cutaneous disorders with heightened cancer risk. The associated changes in skin and skin appendages for a series of disorders are discussed along with their expected malignancies. Most notable is Peutz-Jeghers syndrome—a disorder of mucocutaneous pigmentation, gastrointestinal hamartomas, and a range of malignancies including breast and lung—which has characteristic pigmentation of the lips and neck [2]. Virtually all cases are due to mutations within the LKB1 (STK11) gene [3, 4]. The pigmentation fades with age and can be disguised with cosmetic products, so sometimes careful questioning is needed. Other disorders, such as multiple endocrine neoplasia syndromes, may be obvious from tongue neuromas (a risk of medullary thyroid cancer). Prominent telangiectasia or sun damage could be a clue to photosensitivity disorders due to a lack of DNA repair or to hereditary hemorrhagic telangiectasia or ataxia telangiectasia—as well as the constellation of cancers involved in these groups of disorders.

Some patients may present with “lumpy” skin, which is an indication of either subcutaneous lipomas or rare benign tumors, including the characteristic pearly raised fibrofolliculomas present in Birt-Hogg-Dubé syndrome (a disorder causing renal cancers associated with pneumothorax and an increased risk of colonic tumors). Oncologists specializing in renal cancer will increasingly recognize a range of renal-cutaneous disorders [5] and careful monitoring can allow early detection and prevention.

Oncologists may also be interested in reading another article in this issue by Hardy et al. [6] documenting a report of a patient with tuberous sclerosis complex (TSC)—a neurocutaneous disorder characterized by facial features that is associated with renal and brain tumors in approximately 3% of cases [7]. Although only 1 in 25,000 patients have TSC, early recognition is of clinical value because of the emerging role of mammalian target of rapamycin (mTOR) inhibitors in the management of both central nervous system and systemic tumors, specifically renal angiomyolipomas and subependymal giant cell astrocytomas [8]. Such drugs may be the first of a series of pharmacological therapies for this group of disorders as new reversible mTOR inhibitors that inhibit both TORC1 and TORC2 complexes move through clinical development.

Sometimes other unusual cancers appear within these disorders and the etiology cannot easily be explained by the gene in question. In another article in this issue, Malinowska et al. [9] examine a patient with TSC who had a germline mutation in the TSC2 gene and had bilateral testicular tumors—one malignant Leydig cell tumor (LCT) and one benign Leydig cell tumor. Although the authors found no direct evidence that the TSC genes or the mTOR pathway caused the neoplasia, the fact that two other cases of TSC have been reported in the literature in association with LCTs raises the distinct possibility of a biologic link. Curiously, the description of two cases of LCTs in association with fumarate hydratase mutations—an enzyme in intermediate metabolism that is found in hereditary leiomyomas and renal cell cancer syndromes—provides further circumstantial evidence that disruptions in metabolism that ultimately interact downstream with the mTOR pathway are at least one pathway towards LCT and cutaneous disorders of the skin. Clearly, more work needs to be done on the molecular causes of LCT to find what further factors are in play in the etiology.

In the meantime, it behooves oncologists to have a look at the excellent figures in these papers. Some patients coming through the door of your clinic in the next few weeks may then receive a “spot diagnosis ” that prompts further evaluation of family history, germline genetics, and potentially specific recommendations for prevention, screening, and (soon) an expanded role of targeted therapies in cancer prevention and management. An opportunity for early prevention of cancers in other family members following family mutation screening also exists, which is a laudable aim for all cancer specialists.

Editor's Note: This month, we are pleased to bring you a series of articles on diagnosing hereditary cancer disorders through faciocutaneous clues. See pages 925–926 of this issue for a report on tuberous sclerosis in a child with TSC2 1808A>G mutation; 927–929 for a case of Leydig cell tumor of the testis in tuberous sclerosis; and 930–936 for an overview of genetic syndromes that have dermatologic markers.