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Tidman ASM. Be vigilant for skin manifestations of inherited cancer syndromes. Practitioner 2017;260(1800):23-27

Be vigilant for skin manifestations of inherited cancer syndromes

23 Jan 2017

AUTHORS

Dr Alice SM Tidman BSc MBChB MRCP(UK) PGDipClinDerm
Core Medical Trainee Year 2, London, UK

Article

Abstract

More than 200 hereditary cancer susceptibility syndromes have been described, and it is thought that they account for 5-10% of all cancers. Many have dermatological manifestations (usually lesions, occasionally rashes) which frequently precede other systemic pathology. Dermatological signs are usually non-specific and often trivial in appearance, making their significance easy to overlook and a clinical diagnosis challenging. Histological examination is often required to differentiate lesions. They are usually benign and pathologically unrelated to the primary tumours, with the exception of the atypical moles of the dysplastic naevus syndrome, and may present simply as a cosmetic problem for the patient. However, a number of cancer syndromes exhibit an increased risk of developing malignant skin lesions. For instance, Gorlin syndrome (nevoid basal cell carcinoma syndrome) which typically results in the development of multiple basal cell carcinomas, within the first few decades of life. The majority of cancer syndromes with skin signs are inherited in an autosomal dominant pattern demonstrating complete penetrance before the age of 70. Once a cancer syndrome has been diagnosed, the cornerstone of management is frequent surveillance for the early detection and treatment of malignancy. Genetic testing and counselling should be offered to family members.

Article

A cancer syndrome is a genetic disorder that predisposes the affected individual to the development of primary malignant tumours, often involving multiple organ systems, including the skin, and occurring at an earlier age than their sporadic equivalents.

More than 200 hereditary cancer susceptibility syndromes have been described and it is thought that they account for 5-10% of all cancers.1

Many familial cancer syndromes have dermatological manifestations (usually lesions, occasionally rashes), and frequently the cutaneous signs precede other systemic pathology. They demonstrate considerable variety, from the lentigines of Peutz-Jeghers syndrome, and the innocuous looking fibrofolliculomas of Birt-Hogg-Dubé syndrome, to the epidermoid cysts of Gardner syndrome.

They may be relatively easy to diagnose, such as the soft neurofibromas of neurofibromatosis and the painful leiomyomas of Reed’s syndrome, but they are usually non-specific and often trivial in appearance, making their significance easy to overlook and clinical diagnosis challenging. As a result, histological examination is often required to differentiate lesions. They are usually benign and pathologically unrelated to the primary tumours, with the exception of the atypical moles of the dysplastic naevus syndrome, and may present simply as a cosmetic problem for the patient.

Pathogenesis of cancer syndromes

Recent advances in molecular genetics have led to a greater understanding of the pathogenesis of cancer syndromes. Most are inherited in an autosomal dominant pattern, demonstrating complete penetrance (all carriers of the gene will develop the condition) before the age of 70. The mutated genes are often involved in aspects of cell cycle regulation, and include tumour suppressor genes, DNA repair genes and oncogenes.

For example, the colorectal tumours associated with Muir-Torre (Lynch) syndrome are characterised by their microsatellite instability (nucleotide repeats with high mutation rates) through the inheritance of a germline mutation in DNA mismatch repair mechanisms that are important for the correction of concordance errors in newly replicated DNA.2

This biomolecular instability has also been observed in the sebaceous tumours associated with the syndrome, demonstrating a common pathogenesis.

Since mutations in the FLCN gene were identified as the genetic basis of Birt-Hogg-Dubé syndrome in 2002, the functions of the encoded protein folliculin, which is subsequently inactivated, are still being studied.3 However, it is considered to be a tumour suppressor protein.

Cutaneous manifestations of cancer syndromes

The list of inherited cancer syndromes continues to grow and the spectrum of associated cutaneous manifestations is broad, see table 1.

The majority of cancer syndromes with skin signs are autosomal dominant. Autosomal recessive cancer syndromes with dermatological features include ataxia telangiectasia, Bloom syndrome, Werner syndrome, xeroderma pigmentosum, and Rothmund-Thomson syndrome.

Some examples of cancer syndromes serve to illustrate the variety of skin involvement. For instance, Birt-Hogg-Dubé syndrome is characterised by multiple fibrofolliculomas (benign tumours of the hair follicle). These are dome-shaped, flesh coloured, smooth papules on the face and neck that can be easily mistaken for comedones, see figure 1. Renal tumours develop in 12-34% of patients, and there is an increased risk of pulmonary cysts (84% of affected individuals), predisposing to spontaneous pneumothorax, which is often a diagnostic clue in a patient’s family history, see box 1.3

Neurofibromatosis type I (von Recklinghausen’s disease) is a relatively common condition, which usually presents with café au lait patches and axillary freckling (Crowe’s sign), see figure 2.

The cutaneous neurofibromas that subsequently appear are soft and flesh coloured, and can be confused with simple melanocytic naevi especially when present in small numbers, see figure 3. Individuals affected with neurofibromatosis are at risk of malignant peripheral nerve sheath tumours and juvenile myelomonocytic leukaemia, as well as optic glioma and phaeochromocytoma.

Muir-Torre syndrome is the association of a sebaceous gland tumour (an adenoma, sebaceoma or carcinoma) with internal malignancy. These tumours are usually smallnondescript papules on the face, scalp and eyelids, often misdiagnosed on the basis of the clinical features as basal cell carcinomas, see figure 4. Sebaceous tumours are rare and if discovered should raise the suspicion of Muir-Torre syndrome. The syndrome shares the same genetic pathogenesis as Lynch syndrome (hereditary non-polyposis colorectal cancer syndrome), and is associated with colorectal, endometrial and ovarian cancer.2

Another cancer syndrome with significant morbidity and mortality is Gardner syndrome, a subset of familial adenomatous polyposis (multiple colonic polyps which have a very high risk of malignant transformation). In addition to colorectal cancer, Gardner syndrome is associated with malignancies occurring in other organs, albeit much less frequently, including the small intestine, stomach, pancreas, liver, thyroid and central nervous system. More than 50% of individuals with Gardner syndrome develop epidermoid cysts, and it is their number, distribution (often on the face, scalp and extremities rather than the trunk), and their presentationat a young age (during puberty) that indicates that they might be a marker for internal malignancy.4

A number of cancer syndromes exhibit an increased risk of developing malignant skin lesions. For instance, Gorlin syndrome (nevoid basal cell carcinoma syndrome) typically results in the development of multiple basal cell carcinomas, usually within the first few decades of life. Close inspection usually reveals palmar and plantar pits, caused by defects in the stratum corneum, in about 85% of patients over the age of 20. A characteristic phenotype, with macrocephaly, frontal bossing and skeletal abnormalities, including odontogenic keratocysts (benign but often aggressive developmental cysts arising in the mandible or maxilla), is evident in 60% of patients with Gorlin syndrome, and there is a high risk of affected individuals developing multiple neoplasms, such as childhood medulloblastomas, meningiomas, and ovarian and cardiac fibromas.5

Management of cancer syndromes

Once a cancer syndrome has been successfully diagnosed, the cornerstone of management is frequent surveillance for the early detection and treatment of malignancy, under specialist guidance. Genetic counselling and subsequent genetic testing should be offered to family members, and is now available for many of the mutations described.

With advances in the identification of the specific gene mutations involved in individual cancer syndromes, the opportunity for novel, tailored, gene specific treatment widens.

Currently the therapeutic options are limited but with promising results from BRAF inhibitors (for example vemurafenib and dabrafenib) and MEK inhibitors (for example trametinib and cobimetinib) in metastatic malignant melanoma,6 the potential for targeted therapies is growing. Already in Gorlin syndrome, vismodegib (an inhibitor of hedgehog signalling pathway) has been used to reduce basal cell carcinoma burden.7

The demonstration of overactivation of mTOR signalling in animal models of Birt-Hogg-Dubé syndrome has lead to trials of rapamycin (an mTOR inhibitor), already used as an effective treatment for angiofibromas in tuberous sclerosis,3 see figure 5. However, targeted therapies are currently not available for the prevention of malignancies.

With regard to the treatment of the skin lesions themselves, this depends on the diagnosis and patient preference. In patients with Gorlin syndrome and dysplastic naevus syndrome, where the skin lesions are potentially malignant, treatment is the same as for sporadic skin cancers; surgical excision and emphasis on sun protection. For the benign skin lesions associated with internal malignancies, patients may request removal of asymptomatic lesions for cosmetic reasons. Potential treatments include electrocautery of fibrofolliculomas, laser treatment of facial angiofibromas, and oral retinoids (acitretin) for the cutaneous manifestations of Cowden syndrome. 

Patients with cutaneous manifestations of cancer syndromes not only suffer from the potential implications but also from a psychosocial burden. For some of the cancer syndromes, the skin lesions can be extensive and unsightly often leading to low self-confidence, social stigma and risk of isolation.

Furthermore, the psychological implications of positive genetic (predisposition) tests include coping with the unpredictability of developing a malignancy, and concern about the future effect on offspring.

Conclusion

There is a maxim that the skin acts as a window into the inner workings of the body, and the inherited cancer syndromes are a group of conditions that may provide an opportunity for the astute clinician to diagnose, from cutaneous signs alone, an underlying genetically based tendency to malignancy. The significance of such signs may not be obvious given their often non-specific and apparently trivial nature, see box 1.

It is prudent to undertake a skin biopsy for histological evaluation before considering cosmetic surgery with destructive techniques on lesions that lack a diagnosis.

The inherited cancer syndromes are an example of how clinicians can learn from the characteristics of Sherlock Holmes: to observe keenly, to pay particular attention to detail, and to keep an open mind to seemingly irrelevant and inconsequential complaints, enshrined in the concept of ‘Sherlockian dermatology’.8 

REFERENCES

1 Nagy R, Sweet K, Eng C. Highly penetrant hereditary cancer syndromes. Oncogene 2004;23:6445-70

2 Lazar AJ, Lyle S, Calonje E. Sebaceous neoplasia and Torre-Muir syndrome. Curr Diagn Pathol 2007;13(4):301-19

3 Schmidt LS, Linehan WM. Clinical features, genetics and potential therapeutic approaches for Birt-Hogg-Dubé syndrome. Expert Opin Orphan Drugs 2015;3(1):15-29

4 Juhn E, Khachemoune A. Gardner syndrome: skin manifestations, differential diagnosis and management. Am J Clin Dermatol 2010;11(2):117-22

5 Evans DG, Farndon PA. Nevoid basal cell carcinoma syndrome. 2002 Jun 20 [Updated 2015 Oct 1]. In: Pagon RA, Adam MP, Ardinger HH et al. Eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1151/

6 Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364(26):2507-16

7 Tang JY, Mackay-Wiggan JM, Aszterbaum M et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med 2012;366(23): 2180-88

8 Klauder JV. Sherlock Holmes as a dermatologist, with remarks on the life of Dr Joseph Bell and the Sherlockian Method of Teaching. AMA Arch Derm Syphilol 1953;68(4):363-77

RELATED FILES

The following files will open in their associated programs.

Table 1 Autosomal dominant cancer syndromesBox 1 Case report