Dermatologic Findings

Benign or malignant skin findings are a common feature of several cancer predisposition syndromes, and evaluation by a dermatologist may be helpful in characterizing these findings and facilitating the diagnosis. Café-au-lait macules and axillary and inguinal freckling are a well-known example and are crucial in establishing a clinical diagnosis of neurofibromatosis type 1 (NF1) ( Fig. 42-1 ). Café-au-lait macules are often the earliest clinical manifestation of NF1, as they are present in 99% of affected children by 1 year of age. Café-au-lait macules are also a cardinal feature of CMMR-D. Skin pigmentation differences may also provide a clue to the diagnosis of PTEN hamartoma tumor syndrome (PHTS). For example, boys with PHTS may exhibit pigmented macules of the glans penis, which should raise the suspicion of the diagnosis, especially if features such as macrocephaly, developmental delay, or autism are present. Other skin findings are also found in PHTS, including trichilemmomas and papillomatous papules; however, these may not be diagnosed until later in life. Individuals with Peutz-Jeghers syndrome (PJS) commonly exhibit mucocutaneous pigmentation resembling “freckling” around the mouth, eyes, or nostrils, or on the buccal mucosa or perianal area. Skin cancers in children may also indicate the presence of a syndrome predisposing to cancer. NBCCS predisposes individuals to basal cell carcinomas, which generally appear in the late teens or early adult years, but can occasionally develop in young children. Benign skin findings such as palmar and plantar pits and facial milia may be present in individuals with NBCCS.

Café-au-lait spots in neurofibromatosis type 1 (NF1). ( A to D ). Photographs depicting the appearance of typical café-au-lait spots, as seen in NF1. Café-au-lait spots exhibit distinct edges and are slightly darker than the surrounding skin. Café-au-lait spots can increase in size, number, and darkness throughout childhood. Multiple café-au-lait spots alone are not a definitive indication for NF1; they must be present with other established criteria in order to make the diagnosis. In ( C ), there is also evidence of bilateral axillary freckling.

Developmental or Cognitive Abnormalities

Developmental or cognitive disabilities, including delays in achieving motor milestones, intellectual disabilities, and autism-spectrum disorders are commonly seen in cancer predisposition syndromes, including PHTS; WT, aniridia, genitourinary malformations, and retardation (WAGR) syndrome; tuberous sclerosis; 13q deletion syndrome (which predisposes to RB); and NF1. Seizures may also be a feature, where they are often seen in NF1 and tuberous sclerosis, and may indicate the presence of an underlying tumor. Any child with cancer who has a history of developmental or intellectual disabilities, autism-spectrum disorders, seizures, and/or other neurologic features should be considered a candidate for referral for a possible cancer genetics evaluation.

Overgrowth

Generalized or focal overgrowth of specific parts of the body can be a feature of a condition predisposing to cancer, such as Beckwith-Wiedemann syndrome (BWS), PHTS, and Simpson Golabi Behmel syndrome. In BWS overgrowth may manifest with generalized macrosomia at birth, and some patients may also exhibit macroglossia and/or asymmetric overgrowth of one side of the body (hemihypertrophy). Hemihypertrophy may involve the extremities or external physical features (face, labia, buttocks), as well as internal organs (where, for example, one kidney may be larger than the other). Macrosomia is also a feature of Simpson Golabi Behmel syndrome and Proteus syndrome (PS), while macrocephaly can be a manifestation of PHTS and NBCCS.

Specific Congenital Anomalies

In some cases, the presence of specific congenital anomalies can serve as an early indicator of a condition predisposing to cancer. For example, an omphalocele or umbilical hernia, especially in a child with macrosomia, macroglossia, ear pits or creases, or neonatal hypoglycemia, can point to the diagnosis of BWS. Another good example is WAGR syndrome, where affected children have aniridia, often in combination with genitourinary abnormalities such as hypospadias or cryptorchidism.

Other Physical Features

Other physical manifestations may also suggest an underlying hereditary cancer syndrome. Examples include individuals with multiple endocrine neoplasia type 2B (MEN2B), who often present with mucosal neuromas of the lips and tongue, ganglioneuromas, and marfanoid habitus, and those with FAP, who may present with dental abnormalities (missing or extra teeth), epidermal cysts or pilomatrixomas, Gardner fibromas (also known as desmoid tumors), osteomas (usually involving the jaws), and congenital hypertrophy of the retinal pigmented epithelium. Generally these manifestations present prior to the development of colon polyps.

Complexities of Childhood Cancer Genetic Testing

Genetic testing for cancer predisposition is a complex process that should be explored with the patient and family, preferably by a genetic counselor or trained genetics professional, prior to performing the testing. Counseling should include information about the natural history of the condition under consideration, methods of testing and its possible outcomes, as well as the potential risks, benefits, and limitations of testing. Patients may have concerns about privacy, confidentiality, insurance coverage, and genetic discrimination, all of which must be addressed. For the oncologist, it is important to recognize that genetic test results have implications not only for the individual being tested but also for his or her family members. This factor necessitates counseling of the whole family and discussion of how the results will be communicated between various members. When the individual under consideration is a minor (defined here as a person <18 years), the importance of these issues is further magnified by the fact that children generally do not have the capacity to fully understand the risks, benefits, and limitations of genetic testing. Therefore, they are not able to make their own informed decisions about whether or not to be tested. Instead, this decision falls to the child’s parent(s) or guardian(s), and strips the child of the opportunity to make an autonomous decision about genetic testing later in life. Testing in childhood and disclosure of results to parents, guardians, and/or other family members may violate the child’s privacy, confidentiality, and right not to know. Many also fear that performing genetic testing on a child may have adverse psychological consequences, such as depression, anxiety, fear of the future, altered self-image, limited horizons (i.e., impact on thoughts about future education and career choices), and altered family relationships. However, others have argued for the possible benefits of genetic testing in childhood, such as relief if test results are negative, providing certainty about genetic risk, and allowing the child to integrate genetic information into the self-concept at a younger age, when it is less disruptive to the sense of self. Until recently, the concerns about testing children have more or less superseded the possible benefits of such testing.

Despite much debate, available evidence suggests that the negative consequences of cancer genetic testing may be fewer and less severe than anticipated. Studies of the psychosocial consequences of genetic testing in adults have generally shown minimal or no negative consequences and suggested that emotional outcomes may be more dependent on factors such as pretest emotional state and social support than on the actual genetic test result itself. Several studies report that adults undergoing genetic testing for LFS consider obtaining certainty about cancer risk a psychological benefit of testing, even if adults are found to be affected. Data on the outcomes of presymptomatic cancer genetic testing of children are more limited. Much of the data comes from testing for FAP, where affected individuals are prone to develop multiple gastrointestinal polyps, which if left untreated invariably lead to early-onset colorectal cancer. In FAP, polyps generally begin to form during adolescence. Consequently, it is recommended that children begin surveillance with colonoscopy around the age of 10 to 12 years. Based on these factors, it is deemed appropriate to offer FAP genetic testing to minors. Published reports describing the psychosocial consequences of pediatric FAP genetic testing reveal that children by and large do not experience significant distress related to this testing. One report describing the psychological outcomes of genetic testing of minors for LFS did not note any significant negative outcomes after up to 12 years of follow-up. However, in this study, the participation rate in testing for minors was low, with only 4 of 26 parents who were offered testing for their children actually following through with the test. Therefore, it remains to be determined whether and how genetic testing for these or other conditions predisposing to cancer impacts the well-being of children and their families.

Guidelines for Testing Children for a Heritable Predisposition to Cancer

The controversies surrounding genetic testing of children have prompted several groups to issue guidelines and recommendations. Most recommendations indicate that the primary justification for presymptomatic (i.e., pre­dictive) genetic testing is medical benefit for the child. Therefore, testing should be offered to minors only if the condition is known to manifest in childhood and there are effective preventive or therapeutic interventions available. Conversely, if cancer risk is not increased in childhood or if there are not effective surveillance or intervention measures, it is recommended that testing be delayed until adulthood, when a child can then independently decide whether or not to pursue the testing. Families must be counseled about the benefits, risks, and limitations of genetic testing in order to give informed consent for genetic testing on behalf of their child. As with other medical interventions, it is the role of the health care provider to advocate for the best interests of the child when discussing the option of genetic testing. If possible, minors should be encouraged to participate in decision making about genetic testing; however, the capacity of children to understand genetic information is variable and depends upon their age, maturity, education, and cognitive abilities. Disclosure of results to tested minors is also encouraged once the minor reaches the legal age of majority, or possibly sooner if it is felt that the minor is capable of understanding and coping with the results.

Principles of Tumor Surveillance

Cancer surveillance guidelines exist or are being developed for several conditions predisposing to childhood cancer. The primary goal of surveillance is to detect cancers at the earliest and most curable stage. For this reason, cancer surveillance protocols are best suited for solid tumors, where survival is often linked to the size and extent of spread of the tumor at diagnosis. Tumors identified in individuals undergoing regular monitoring may be smaller. As a result, surveillance allows for less invasive surgical procedures and can also reduce or eliminate the need for additional chemotherapy and/or irradiation. However, surveillance can also be complicated by the possibility of false-positive results, which often lead to worry about cancer, excess rates of follow-up imaging and/or biopsy, and possibly increased costs of care.

Several factors must be taken into account in the development and implementation of a cancer surveillance protocol. First, there must be a benefit for early cancer detection in an individual undergoing monitoring (i.e., there should be an effective treatment available and preferably also demonstration that early detection improves outcome). Second, the age-specific tumor risks for syndromes predisposing to cancer must be known and deemed high enough to warrant surveillance (generally, a tumor incidence of ≥5% is considered sufficiently high to initiate monitoring). This information helps to identify candidates for surveillance, when it should be initiated, and how long it should be continued. The surveillance method(s) and interval between specific tests must also be carefully considered in light of the specific tumor risks and growth rate associated with a given syndrome. Ideally, surveillance methods should be readily available, safe, and have high sensitivity and specificity. Whenever possible, screening tools that involve no or minimal irradiation should be used, as patients with hereditary cancer syndromes may be at increased risk to develop irradiation-induced cancers (as is the case for hereditary RB, LFS, ataxia telangiectasia, and other genetic syndromes associated with defects in DNA repair).

Cancer Prevention Strategies

For some syndromes, early identification of at-risk children allows for the elimination or dramatic reduction of cancer risk through prophylactic surgery. MEN2 and FAP are excellent examples, where removal of the at-risk organ may be considered early in a patient’s lifetime to prevent the development of thyroid or colorectal cancer, respectively. In MEN2, there is a nearly 100% lifetime risk for MTC, an aggressive type of thyroid cancer with a high metastatic potential. As a result, it is recommended that individuals with MEN2 undergo prophylactic thyroidectomy, a procedure that has greatly reduced the likelihood of developing MTC. It should be noted that while all individuals with MEN2 are at increased risk for MTC, there are significant genotype-phenotype correlations that predict the age of thyroid cancer onset, and this information can dictate the appropriate timing for prophylactic removal of the thyroid. In FAP, individuals have a similarly high risk of early-onset colon cancer that nears 100% if colonic polyps are not removed. To prevent colon cancer, affected individuals should undergo colectomy when polyps become too numerous to clinically follow or remove, generally in the late teens to early 20s. Studies of the efficacy of colectomy reveal a significant reduction in colon cancer risk. Due to the morbidities associated with colectomy, alternatives to surgery are being sought. Nonsteroidal antiinflammatory medications such as sulindac and Cox-2 inhibitors reduce polyp formation in adults with FAP ; however, these medications are currently under examination for use in children with the condition.

Incidence

Hereditary RB is an example of a classic syndrome predisposing to cancer and the first for which the underlying genetic mechanism was recognized. RB is a malignant tumor of the embryonic neural retina that has an incidence of two to five cases per million children per year and accounts for 3% to 4% of all pediatric cancers. Nonhereditary RB accounts for 60% of cases and is associated with development of unilateral eye tumors at a median age of 22 months. The remaining 40% of patients have hereditary RB, which involves both eyes in more than 80% of cases and presents at a median age of 11 months. Heritable RB is highly penetrant, with more than 90% of patients developing RB and 0.5% to 15% also developing intracranial tumors of the pineal gland. Over the course of their lives, survivors of hereditary RB remain at increased risk to develop second malignant neoplasms, including bone and soft tissue sarcomas, which commonly occur in previously irradiated sites, as well as melanomas and cancer of the lungs, gastrointestinal tract, and bladder.

Genetics

RB is caused by mutations in RB1 , which resides at chromosomal locus 13q14. RB1 encodes the RB protein (pRB), a potent tumor suppressor that regulates cell growth by inhibiting the function of the E2F family of transcription factors and preventing inappropriate S-phase entry. pRB also regulates cellular glucose tolerance, mitogenesis, glutathione synthesis, and the expression of genes involved in carbon metabolism. When both RB1 alleles are mutated within a developing retinal cell, pRB expression and/or function are diminished, cell division proceeds in a dysregulated manner, and, ultimately, RB tumors form.

In patients with nonhereditary RB, both RB1 gene copies are mutated within a single postzygotic retinal cell. In contrast, patients with hereditary RB harbor one mutated RB1 allele within the germline. This mutation is inherited from a similarly affected parent in 10% to 20% of cases. In the remaining cases, the RB1 mutation arises de novo within one of the parent’s gametes or a cell of the developing embryo. Mutation of the remaining RB1 allele occurs somatically. Genetic testing for germline RB1 gene mutations can identify mutations in more than 90% of individuals with hereditary disease. While most patients can be identified clinically due to the presence of multifocal or bilateral eye tumors and/or a positive family history, 10% to 15% of patients have single eye tumors and no family history of RB. These latter factors make them indistinguishable from those with the sporadic form of disease. The identification of RB1 mutations in unilateral patients enables appropriate primary eye tumor treatment as well as initiation of surveillance for involvement of the pineal gland and later second cancers. Identification of a germline RB1 mutation in any child with RB also allows for presymptomatic testing of other family members, including siblings who may not yet have developed RB but carry a mutated RB1 gene copy, as well as children of RB survivors.

Tumor Risks and Surveillance

Individuals harboring germline RB1 mutations are at greatly increased risk to develop bilateral RB tumors, generally during the first 5 years of life ( Fig. 42-2 ). During this time period patients are also at increased risk to develop tumors involving the pineal gland (so-called trilateral RB). Later in life, individuals with hereditary RB can develop second malignant neoplasms. While the risk for these cancers is greatest in those treated with external-beam radiation therapy, nonirradiated long-term survivors of hereditary RB have an approximately 10% to 15% risk of developing one or more second malignant neoplasms

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