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    Unusual Cancers of Childhood Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Other Rare Childhood Cancers

    Table 6. Clinical Features of MEN 2 Syndromes continued...

    In a randomized phase III trial for adult patients with unresectable locally advanced or metastatic hereditary or sporadic medullary thyroid carcinoma treated with vandetanib, a selective inhibitor of RET, VEGFR, and EGFR, versus placebo, vandetanib administration was associated with significant improvements in progression-free survival, response rate, disease control rates, and biochemical response.[34]

    Carney complex

    The Carney complex is an autosomal dominant syndrome caused by mutations in the PPKAR1A gene, located in chromosome 17.[35] The syndrome is characterized by cardiac and cutaneous myxomas, pale brown to brown lentigines, blue nevi, primary pigmented nodular adrenocortical disease causing Cushing syndrome, and a variety of endocrine and nonendocrine tumors, including pituitary adenomas, thyroid tumors, and large cell calcifying Sertoli cell tumor of the testis.[35,36,37] There are guidelines that may be followed for screening patients with Carney complex.

    For patients with the Carney complex, prognosis depends on the frequency of recurrences of cardiac and skin myxomas and other tumors.

    Pheochromocytoma and Paraganglioma

    Pheochromocytoma and paraganglioma are rare catecholamine-producing tumors with a combined annual incidence of three cases per 1 million individuals. Tumors arising within the adrenal gland are known as pheochromocytomas, whereas morphologically identical tumors arising elsewhere are termed paragangliomas. Paragangliomas are further divided into: (1) sympathetic paragangliomas that predominantly arise from the intra-abdominal sympathetic trunk and usually produce catecholamines, and (2) parasympathetic paragangliomas that are distributed along the parasympathetic nerves of the head, neck, and mediastinum and are rarely functional.[38,39]

    Genetic predisposition

    It is now estimated that up to 30% of all pheochromocytomas and paragangliomas are familial; several susceptibility genes have been described (see Table 7). The median age at presentation in most familial syndromes is 30 to 35 years, and up to 50% of subjects have disease by age 26 years.[40,41,42,43]

    Table 7. Characteristics of Paraganglioma (PGL) and Pheochromocytoma (PCC) Associated with Susceptibility Genesa

    Germline Mutation Syndrome Proportion of all PGL/PCC (%) Mean Age at Presentation (y) Penetrance of PGL/PCC (%)
    MEN1 = multiple endocrine neoplasia type 1; MEN2 = multiple endocrine neoplasia type 2; NF1 = neurofibromatosis type 1; VHL = von Hippel-Lindau.
    a Adapted from Welander et al.[40]
    RET MEN2 5.3 35.6 50
    VHL VHL 9.0 28.6 10-26
    NF1 NF1 2.9 41.6 0.1-5.7
    SDHD PGL1 7.1 35.0 86
    SDHFA2 PGL2 <1 32.2 100
    SDHC PGL3 <1 42.7 Unknown
    SDHB PGL4 5.5 32.7 77
    SDHA - <3 40.0 Unknown
    KIF1B-beta - <1 46.0 Unknown
    EGLN1 - <1 43.0 Unknown
    TMEM127 - <2 42.8 Unknown
    MAX[43] - <2 34 Unknown
    Unknown Carney triad <1 27.5 -
    SDHB, C, D Carney-Stratakis <1 33 Unknown
    MEN1 MEN1 <1 30.5 Unknown
    No mutation Sporadic disease 70 48.3 -
    1. Von Hippel-Lindau (VHL) syndrome-Pheochromocytoma and paraganglioma occur in 10% to 20% of patients with VHL.
    2. Multiple Endocrine Neoplasia (MEN) Syndrome Type 2-Codon-specific mutations of the RET gene are associated with a 50% risk of development of pheochromocytoma in MEN 2A and MEN 2B. Somatic RET mutations are also found in sporadic pheochromocytoma and paraganglioma.
    3. Neurofibromatosis type 1 (NF1)-Pheochromocytoma and paraganglioma are a rare occurrence in patients with NF1, and typically have characteristics similar to those of sporadic tumors, with a relatively late mean age of onset and rarity in pediatrics.
    4. Familial pheochromocytoma/paraganglioma syndromes, associated with germline mutations of mitochondrial succinate dehydrogenase (SDH) complex genes (see Table 7). They are all inherited in an autosomal dominant manner but with varying penetrance.
      • PGL1-Associated with SDHD mutations, manifests more commonly with head and neck paragangliomas, and has a very high penetrance, with more than 80% of carriers developing disease by age 50 years.
      • PGL2-Associated with SDHAF2 mutations, is very rare, and generally manifests as parasympathetic paraganglioma.
      • PGL3-Associated with SDHC mutations, is very rare, and usually presents with parasympathetic paraganglioma, often unifocal, benign, and in the head and neck location.
      • PGL4-Associated with SDHB mutations and usually manifests with intra-abdominal sympathetic paraganglioma. The neoplasms associated with this mutation have a much higher risk of malignant behavior, with more than 50% of patients developing metastatic disease. There is also an increased risk of renal cell carcinoma and gastrointestinal stromal tumor (GIST).
    5. Other susceptibility genes recently discovered include KIF1B-beta, EGLN1/PHD2, TMEM127, SDHA, and MAX.[43]
    6. Other syndromes:
      • Carney triad syndrome is a condition that includes three tumors: paraganglioma, GIST, and pulmonary chondromas. Pheochromocytomas and other lesions such as esophageal leiomyomas and adrenocortical adenomas have also been described. The syndrome primarily affects young women, with a mean age of 21 years at time of presentation. Approximately one-half of the patients present with paraganglioma or pheochromocytoma, although multiple lesions occur in approximately only 20% of the cases. About 20% of the patients have all three tumor types; the remainder have two of the three, most commonly GIST and pulmonary chondromas. This triad doesn't appear to run in families and no responsible gene has been discovered.[44]
      • Carney-Stratakis syndrome (Carney dyad syndrome) is a condition that includes paraganglioma and GIST, but no pulmonary chondromas. It is inherited in an autosomal dominant manner with incomplete penetrance. It is equally common in men and women, with an average age of 23 years at presentation. The majority of patients with this syndrome have been found to carry germline mutations in the SDHB, SDHC, or SDHD genes.[44]
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