Nevoid Basal Cell Carcinoma Syndrome 

Updated: Mar 29, 2017
Author: Daniel Berg, MD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Nevoid basal cell carcinoma syndrome (NBCCS) represents a series of multiorgan abnormalities known to be the consequence of abnormalities in the PTCH gene. The syndrome has been documented for 50 years, but more recent developments in molecular genetics have dramatically increased understanding of its pathophysiology and opened up molecular avenues for treatment in the future.

Go to Basal Cell Carcinoma for more complete information on this topic.

Pathophysiology

Multiple organ systems may be impacted in nevoid basal cell carcinoma syndrome (NBCCS). Abnormalities of the skin, the skeletal system, the genitourinary system, and the central nervous system (CNS) are the most common. Other less common neoplasms and abnormalities are also associated with the disease and are well documented.[1]

Etiology

NBCCS, also known as basal cell nevus syndrome (BCNS), is an autosomal dominant syndrome caused by mutations in the PTCH (patched) gene found on chromosome arm 9q. The disease has complete penetrance and variable expressivity. Although clinical features vary more among families than within families, no clear-cut link exists between specific mutations and phenotype. Approximately one third of cases are new mutations.

Genetics

First elucidated in fruit flies, the protein product of the PTCH gene is important in determining segment polarity of wings and limbs (anterior-posterior relationships in developing embryos). In mammals, PTCH is an important inhibitor in the so-called hedgehog (HH) signaling pathway, whose downstream proteins can lead to cell growth. PTCH is frequently mutated on 1 allele in sporadic basal cell carcinomas (BCCs), and according to Epstein, "upregulation of HH signaling is the pivotal abnormality in all BCCs."[2] . Its wide-reaching activity accounts for the myriad findings in patients with NBCCS.[3, 4, 5, 6, 7]

Ultraviolet exposure

Ultraviolet (UV) light exposure appears to be an important cofactor. BCCs are much more common in sun-exposed areas and are much more common in white individuals with the syndrome. Nevertheless, molecular genetic studies looking for UV-related mutations in BCCs obtained from patients with NBCCS leave the possibility that agents other than UV-B may cause alterations to the gene.[8]

Radiation

Patients are particularly sensitive to ionizing radiation (radiation therapy; XRT), and reports have described multiple BCCs in the radiation portal developing in patients treated with XRT for medulloblastoma. Reports of more aggressive BCCs occurring in sites of previous XRT for BCC also exist. Radiobiologic studies on fibroblasts suggest an abnormal response to radiation in fibroblasts obtained from patients with NBCCS.

Epidemiology

The approximate prevalence of NBCCS is reported to be 1 case per 56,000-164,000 population. The prevalence is likely to be considerably higher in individuals younger than 20 years who present with BCCs.

The syndrome is found in all races, and men and women are affected about equally (1:1.3). However, a definite but smaller percentage of black individuals present with skin cancer and have fewer skin cancers than affected white individuals. This decreased number of skin cancers, a diagnostic hallmark, may account for the comparatively fewer patients with darker skin ascertained in reviews of the syndrome. The lone study evaluating an African cohort found that only 20% with NBCCS had basal cell carcinoma.[9] Recent Japanese data also showed a lower rate of skin cancer with a later age of onset compared with whites.[10] Full expression of the non–skin cancer features of the syndrome is found in patients of all skin types.

Prognosis

Morbidity and premature mortality in nevoid basal cell carcinoma syndrome (NBCCS) are primarily related to the development of skin cancers and other tumors associated with the syndrome. Actual mortality rates are unavailable; morbidity from multiple skin cancers and their treatment may be severe.

Patient Education

Patients with nevoid basal cell carcinoma syndrome (NBCCS) need information about the syndrome. Coping with the multiple BCCs and the required multiple treatments is often difficult, and patient counseling and support may be critical. Web sites exist with resources for patients with NBCCS (see BCCNS Life Support Network).

Patients should be educated about the hereditary nature of NBCCS, and they should have genetic counseling. In addition, with regard to skin cancer, patients should be advised to reduce UV light exposure, as well as advised about the relative risk and possible deleterious effects of receiving radiation therapy for their skin cancers or for other tumors as well.

With respect to other findings, patients should be counseled to look for symptoms referable to the CNS, the genitourinary system, the cardiovascular system, and dentition, as well as other potentially involved systems.

For patient education information, see the Cancer and Tumors Center, as well as Skin Cancer and Skin Biopsy.

 

Presentation

History

Many of the features of nevoid basal cell carcinoma syndrome (NBCCS) present as signs rather than symptoms. The presence of symptoms is most likely related to the major findings. For example, local invasion of an aggressive BCC may lead to pain or symptoms (eg, neurologic) related to local invasion. Metastasis is extremely rare.

Head/face symptoms

Odontogenic keratocysts (also called keratocystic odontogenic tumors) may be asymptomatic, or they may manifest as jaw pain or abnormal dentition.

Neurologic symptoms

Medulloblastoma, a cerebellar tumor of young childhood, may manifest as neurologic symptoms in an affected child.

Genitourinary symptoms

Ovarian fibromas are usually asymptomatic, but they may present as pain secondary to torsion.

Physical Examination

Several studies have documented the incidence of the various features found in nevoid basal cell carcinoma syndrome (NBCCS).[11, 12, 13, 14, 15] The syndrome is present (inherited) at birth and most commonly manifests itself with either BCCs (usually multiple) occurring at a young age (third decade or earlier) or odontogenic keratocysts presenting in the second or third decade.

Other incidental findings, such as cleft lip, or asymptomatic findings, such as hypertelorism, may be noticed earlier, but these features may not lead to the diagnosis until the development of more specific findings. Findings usually seen in the syndrome, such as jaw cysts, BCCs, calcification of the falx, and ovarian fibromas, develop more commonly with increasing age in the individual who is affected. Some findings are present earlier in childhood—for example, palmar/plantar pits; craniofacial features like macrocephaly, frontal bossing, and palate abnormalities; and radiologic findings that are distinct from adults with NBCCS (see Radiography).[16]

Medulloblastoma, though a relatively less common manifestation of NBCCS, is a tumor of early childhood. Radiologic abnormalities, such as bifid ribs, or asymptomatic findings, such as palmar pits, may be present at a higher frequency in childhood; these findings may be helpful in making an early diagnosis.[17]

Head and face

Characteristic facies may occur due to increased calvarial size. Other contributing features include increased head circumference; a broadened nasal root; frontal and biparietal bossing, mild hypertelorism; and an exaggerated length of the mandible. Cleft lip or palate may occur in 3-5% of patients.

Odontogenic keratocysts are seen in 74-80% of patients. These lesions usually begin to develop in the first decade (after age 7 y), with the peak incidence in the second and third decades, which is younger than that which is seen with isolated odontogenic cysts. Odontogenic keratocysts are more common in the mandible than in the maxilla. Although these lesions are usually asymptomatic, they may cause pathologic fracture, swelling, loose teeth, or displacement of developing permanent teeth. Jaw cysts appear to occur only rarely after age 30 years.

Ophthalmologic findings

Ocular findings include congenital blindness due to corneal opacity and cataract or glaucoma, occurring in as many as 10-15% of patients. Up to 40% of patients may have milialike lesions on the palpebral conjunctiva. Strabismus (exotropia) may be seen, as may other rare ocular findings.[1]

Cutaneous and connective tissue findings

BCCs are the most common finding in NBCCS. In a study of white persons older than 40 years, 97% had BCCs. The tumors are usually multiple, and they are most common on the face, neck, and upper part of the trunk—that is, in sun-exposed areas—but they are also increased in relatively sun-protected areas. As is true for sporadic BCCs, some lesions may become aggressive, although many are not. (See the images below.)

Multiple basal cell carcinomas on the back of a pa Multiple basal cell carcinomas on the back of a patient with nevoid basal cell carcinoma syndrome.
Multiple small papules on the neck and upper trunk Multiple small papules on the neck and upper trunk in a 10-year-old patient. Biopsy confirmed basal cell carcinoma.

The tumors largely begin to appear between puberty and age 35 years, but they may appear at a younger age. Kimonis et al found that 50% of white individuals had their first BCC by age 21.5 years and 90% had it by age 35 years.[15] Lesions may present as any kind of clinical or histologic BCC; however, some lesions may be small and resemble milia, small nevi, tags, or hemangiomas. Milia may be seen in as many as 30% of patients with NBCCS.

Asymmetric palmar and/or plantar pits are seen in 65-87% of all people with NBCCS (see the following image). When these lesions do develop, they often do so early in life, being found in as many as 80% of patients younger than 10 years. Thus, palmar and/or plantar pits may be a helpful early criterion for the diagnosis of NBCCS. More than 3 pits should be noted, because the relevance of 1 or 2 pits may not be diagnostic.

Palmar pits in an adult. Palmar pits in an adult.

Other tumors, including fibrosarcoma, rhabdomyosarcoma, may also be increased in frequency in persons with NBCCS.

Neurologic findings

Medulloblastoma (malignant tumors of the cerebellum) occurs in 1-4% of patients. These tumors present in early childhood, with the greatest risk from birth to age 3 years, although cases have been reported as late as 7 years. Meningiomas may also be increased in frequency in persons with NBCCS.

Genitourinary findings

Genitourinary findings include bilateral calcified ovarian fibromas, which are found in 14-24% of women; these are often asymptomatic and rarely become malignant. Men may have associated cryptorchidism or gynecomastia and reduced body hair.

Skeletal findings

Skeletal abnormalities include polydactyly of the hands or the feet, hallux valgus, pectus excavatum or pectus carinatum, and syndactyly of the second and third fingers (see the image below).

Syndactyly is noted in some affected persons such Syndactyly is noted in some affected persons such as this 8-year-old boy.

Kyphoscoliosis may also be more common or more severe in NBCCS. Sprengel deformity of the shoulder occurs in 5-10% of patients. A short fourth metacarpal may be seen with increased frequency, although as many as 10% of healthy persons also have this sign.

Cardiovascular findings

Cardiac findings are less common, but an increased risk of cardiac fibroma may be present in approximately 2% of cases, although none was found in the large study by Kimonis et al.[15] These may be asymptomatic or cause arrhythmia or cardiac flow obstruction. Cardiac fibroma, if present, usually develops in children.

Major and Minor Criteria

Despite the understanding of the underlying genetic basis of nevoid basal cell carcinoma syndrome (NBCCS), the diagnosis remains clinical. Although not absolute, the following diagnostic criteria were suggested by Kimonis et al to help guide the clinician in choosing laboratory evaluation for both diagnostic purposes and ongoing surveillance.[15] Clinicians must remember that some of the findings listed may present at different ages; therefore, ongoing surveillance with respect to diagnosis may be needed. The diagnosis of NBCCS is made in the presence of 2 major criteria or 1 major and 2 minor criteria.

Major criteria are as follows:

  • Major criteria include the following:

  • More than 2 BCCs or 1 BCC in patients younger than 20 years

  • Odontogenic keratocysts of the jaw (proven by histologic analysis)

  • Three or more palmar or plantar pits

  • Bilamellar calcification of the falx cerebri

  • Bifid, fused, or markedly splayed ribs

  • First-degree relative with NBCCS

Minor criteria are as follows:

  • Macrocephaly

  • Congenital malformations, such as cleft lip or palate, frontal bossing, coarse facies, and moderate or severe hypertelorism

  • Other skeletal abnormalities, such as Sprengel deformity, marked pectus deformity, and marked syndactyly of the digits

  • Radiologic abnormalities such as bridging of the sella turcica, vertebral anomalies such as hemivertebrae, fusion or elongation of the vertebral bodies, modeling defects of the hands and feet, or flame-shaped lucencies of the hands and the feet

  • Ovarian fibroma or medulloblastoma

 

DDx

Diagnostic Considerations

The diagnosis of nevoid basal cell carcinoma syndrome (NBCCS) remains a clinical one, despite advances in genetic understanding of this disease.

Radiologic abnormalities, such as rib abnormalities, or asymptomatic findings, such as palmar pits, may be present at a higher frequency in childhood; these findings may be helpful in making an early diagnosis.[17]

Other problems to be considered in the diagnosis of NBCCS include the following:

  • Bazex syndrome (X-linked dominant syndrome with BCCs, follicular atrophoderma, hypertrichosis, and hypohidrosis of the face and the head)

  • Pseudohypoparathyroidism

  • Rombo syndrome

  • Unilateral nevoid BCC with comedones

Differential Diagnoses

 

Workup

Approach Considerations

Although no routine laboratory studies are helpful for nevoid basal cell carcinoma syndrome (NBCCS), some studies may potentially aid in the diagnosis.

Molecular Genetic Testing

Molecular testing is available to confirm the diagnosis in patients with atypical findings or possibly for prenatal diagnosis. This study may be useful for infants of an affected patient who is too young to have developed diagnostic clinical findings. Because of imperfect sensitivity and specificity, genetic testing should be performed in conjunction with a genetic counselor. Availability and methodology of testing may change with time; this is another reason genetic counseling is recommended. Current and updated information on available genetic testing is available through GeneTests.

Radiography

Radiologic abnormalities, such as bifid ribs, or asymptomatic findings, such as palmar pits, may be present at a higher frequency in childhood; these findings may be helpful in making an early diagnosis.[17, 18]

Skull radiography

Calcification of the falx cerebri is the most common radiologic finding in NBCCS, occurring in 65-92% of individuals and seen on anteroposterior skull radiographs. This finding is age-related; in one study, calcification of the falx cerebri was observed in 37% of patients younger than 20 years and in 77-79% of patients older than 20 years. However, this finding may also be seen in approximately 5% of unaffected individuals.

Calcification of the tentorium cerebelli is observed in 20-40% of patients with NBCCS. This is more typically seen on lateral skull radiographs. Calcification of the petroclinoid ligament, pia, and choroid plexus may also be observed. Calcification of the diaphragma sellae may be observed in 60-80% of patients with NBCCS, as compared with 4% of the healthy population; however, some studies have suggested both a lower prevalence in the persons affected and a higher prevalence in unaffected relatives, making this finding less specific.

Therefore, consider anteroposterior and lateral radiographs of the skull or MRI if indicated to aid in diagnosis.

Skeletal radiography

Bifid, hypoplastic, fused, partially missing, or splayed ribs are observed in 38-60% of patients with NBCCS. These features may be helpful diagnostic criteria, because they are present in children before other features may show up and because they are uncommon in the general population. A recent study found that 29% of children with NBCSS had bifid ribs (the most common radiographic abnormality seen in children) and 7% had fused/splayed ribs.[16] The most commonly affected ribs are the third, fourth and fifth ribs, although others may be involved. It is important that the radiologist specifically look for these features.

Malformations at the occipitovertebral junction and cervical or upper thoracic vertebral fusion may also be observed. In one study, calcification of the nuchal ligament occurred in 18% of affected people. Small, pseudocystic, lytic bone lesions known as "flame-shaped lucencies" are found on radiographs of the hands (30%) and feet (17%) of affected people.

Therefore, consider chest, cervical and thoracic spine (anteroposterior and lateral), and hand or foot radiographs if indicated to aid in the diagnosis. It is important to ask the radiologist to specifically look for findings of NBCCS because he or she may not otherwise comment on these.

Dental panoramic radiography

This screening is useful for the finding of odontogenic keratocysts, which are relatively common in NBCCS. When monitoring a child with NBCCS, consider regular dental visits plus panoramic radiography to detect these cysts.

Echocardiography

Cardiac fibromas have an incidence as high as 3% in some studies (rarer in other studies). In patients with NBCCS, one might consider a baseline echocardiogram at birth or within the first year of life and then subsequently, primarily if clinical suspicion arises for a cardiac fibroma.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) may be more sensitive than plain radiography for calcification, and it may be indicated if medulloblastoma is suspected in a child with NBCCS. Because of the concern about exposure to radiation in patients with the syndrome, MRI is the preferred imaging modality over computed tomography (CT) scanning. Consider an annual MRI up to age 7 years, to coincide with the main age of risk of medulloblastoma.

Ultrasonography

To diagnose ovarian fibromas, consider performing pelvic ultrasonography around puberty, as a baseline, and later in life if symptoms are present.

Biopsy

Because the histologic features of the individual skin cancers are indistinguishable from ordinary BCC and include the full spectrum of histologic subtypes, biopsy of the skin lesions is recommended. Biopsy of jaw cysts are also recommended, as odontogenic keratocysts have a characteristic pathologic finding that shows the lining with keratinizing epithelium.

 

Treatment

Approach Considerations

Treatment of patients with nevoid basal cell carcinoma syndrome (NBCCS) involves surveillance for and treatment of the associated findings. Because most of the findings involve tumors (benign and malignant), treatment is often surgical.

Go to Basal Cell Carcinoma for more complete information on this topic.

Pharmacologic Therapy

Topical agents such as imiquimod[19] and 5-fluorouracil are available and have been approved for treatment of basal cell carcinoma (BCC) in the United States. These medications have a lower cure rate than surgical therapy but may be a useful adjunct in patients with multiple lesions and may help play a chemopreventative role in the development of new BCCs.[20] Despite the lower cure rate (which may reach up to 80% for superficial BCCs with imiquimod), these agents may play a useful role in allowing patients to treat their own selected smaller lesions, especially superficial BCCs on the trunk and extremities. In general, such medications should be considered best for use in smaller or more superficial lesions, away from critical anatomic sites.

Investigations and clinical trials are evaluating topical photodynamic therapy, which is approved in the United States only for the treatment of actinic keratosis. Topical photodynamic therapy may be a useful treatment for multiple BCCs in patients with nevoid basal cell carcinoma syndrome (NBCCS). This therapy consists of an application of a commercially available topical agent (either aminolevulinic acid [ALA] or methyl-ALA), followed by treatment with an appropriate visible light (typically blue or red light), which causes tumor destruction by a photo-induced reaction.[21, 22]

Other novel agents, such as the relatively newly developed hedgehog (HH) inhibitors, are oral medications.[2] In 2012, vismodegib, a small-molecule inhibitor of the HH pathway, was approved by the US Food and Drug Administration (FDA) for the treatment of locally advanced or metastatic BCC, and sonidegib was approved in the summer of 2015.[23] There is not yet a specific FDA approval for the use of either drug in NBCSS, although a randomized, placebo-controlled, phase 2 trial of 42 NBCSS patients from 2012 treated with vismodegib showed a 70% reduction in the number of new surgically eligible tumors and a decrease in the size of many existing tumors, sometimes dramatically.[24] This and other studies show that tumors tend to recur following cessation of treatment,[24, 25] and a significant number of patients have treatment-limiting adverse effects.[24, 26, 27]

Similar findings were reported in 2016 in a study of vismodegib in patients with NBCSS.[28] In this study, further information was gleaned, including that hair regrowth may be incomplete after longer treatment. This study also did not find resistance to vismodegib (seen more commonly in patients treated for advanced BCC) in NBCSS patients, who appear to remain sensitive to vismodegib with intermittent treatment.

A 2017 study of patients with multiple BCCs, including patients with NBCSS, used intermittent therapy with vismodegib.[29] These trials suggest that intermittent therapy with planned breaks may be useful at reducing the size of existing BCCs and the number of new BCCs in these patients, with fewer adverse effects than with continuous therapy. This suggests that intermittent therapy may be an alternative dosing strategy for patients with NBCSS.

Excision of Tumors

Oral surgery involving cyst enucleation followed by mechanical curettage or use of peripheral ostectomy may be required for odontogenic keratocysts. The incidence of recurrence following treatment is high.

For BCCs, early detection and treatment are critical to prevent any individual lesion from becoming invasive. Avoidance of radiation is an important principle based on several reports of BCCs developing in radiated fields. Surgical methods include electrodesiccation and curettage (ED&C), simple excision, and Mohs micrographic surgery.

Because of the large number of tumors expected over a lifetime, surgical methods should be chosen with attention given to cure rate and scarring potential. Less invasive approaches should be considered for small tumors, and these include topical therapies as well as curettage rather than excision. Similarly, reconstruction after tumor removal should take into account the likelihood of further BCCs in the vicinity and should be kept simple whenever possible (eg, second intention healing or primary closure vs use of flaps).

Of note, the small acrochordonlike, flesh-colored papules commonly seen on the upper trunk and neck seen more commonly in children and teens are usually slowly growing and can often be treated conservatively (eg, with light electrosurgery) rather than with potentially more disfiguring excision.

Surgery for ovarian tumors or cardiac tumors may be required for either treatment or prevention of symptoms.

Consultations

A dermatologist should maintain ongoing surveillance and treatment of skin cancer. Frequent visits (sometimes as often as every 2-3 mo) are recommended to identify and to treat lesions when they are as small as possible.

A genetic counselor is a very important component of the ongoing care of the patient, particularly regarding issues of having children, but also to help determine if other family members are at risk of having the syndrome. As new research is performed, the availability, sensitivity, and specificity of molecular testing may change.

Other specialists may be needed to (1) assess a newly diagnosed individual and (2) help manage associated abnormalities if they develop, including a neurologist, neurosurgeon, pediatrician, cardiologist, cardiac surgeon, gynecologist, dentist, oral surgeon, plastic surgeon, and ophthalmologist.

Long-Term Monitoring

Ongoing surveillance and treatment for sequelae of nevoid basal cell carcinoma syndrome (NBCCS) is required. In addition, in family members of patients with NBCCS in whom the diagnosis is possible but not confirmed, ongoing follow-up to help detect diagnostic criteria may be important.

BCCs require frequent follow-up care, 3-4 times a year (or more), to achieve early diagnosis and treatment. Odontogenic keratocysts require dental follow-up visits, including periodic radiographic evaluation, especially in childhood and early adolescence.

Screening for cardiac fibromas with echocardiography should be considered in infants with the syndrome and then if symptoms suggest their presence. Ovarian fibromas can be visualized on a peripubertal ultrasound as a baseline and then can be considered if symptoms develop.

In young children at risk, medulloblastomas necessitate a neurologic examination every 6 months; annual MRIs should be considered in children younger than 7 years.

 

Medication

Medication Summary

Topical agents such as imiquimod and 5-fluorouracil are available and have been approved for treatment of basal cell carcinoma (BCC) in the United States. These medications have a lower cure rate than surgical therapy but may be useful adjuncts in patients with multiple lesions.

Investigations and clinical trials are evaluating the use of these and other novel agents such as ALA and methyl-ALA in topical photodynamic therapy, tazarotene (Tazorac), and newly developed HH pathway inhibitors, both topical and systemic.[2] Tazarotene and photodynamic therapy are available (off-label), and vismodegib (hedgehog inhibitor) and more recently sonidegib are now FDA approved for the treatment of metastatic or locally advanaced BCC—as such, their use solely in NBCSS, while clearly effective,[24] also remains off-label at present.

Topical Skin Product

Class Summary

Agents such as imiquimod and 5-fluorouracil are approved in the United States for use topically for BCC. Despite the lower cure rate (than with surgery), imiquimod and 5-fluorouracil may play a useful role in allowing patients to treat their own selected smaller lesions, especially superficial BCCs on the trunk and extremities. In general, such medications should be considered best for use in smaller or more superficial lesions, away from critical anatomic sites.

Imiquimod (Aldara)

The precise mechanism of imiquimod on superficial BCC is unknown. It may increase tumor infiltration of lymphocytes, dendritic cells, and macrophages. It is indicated for biopsy-confirmed, primary superficial BCC in adults with normal immune systems. Additionally, tumors generally should not exceed 2 cm in diameter on certain areas of the body. It is indicated primarily when surgical methods are not appropriate, including in situations in which, because of multiple lesions, scarring from surgical methods may be a consideration.

5-Fluorouracil (Efudex, Carac, Fluoroplex)

5-Fluorouracil is a cycle-specific agent that has activity as single agent and, for many years, has been combined with the biochemical modulator leucovorin. It is shown to be effective in an adjuvant setting. 5-Fluorouracil inhibits tumor cell growth through at least 3 different mechanisms that ultimately disrupt DNA synthesis or cellular viability. It is used topically for the management of superficial BCC.