Keywords

7.1 Introduction

Identification of an inherited pheochromocytoma/paraganglioma (PPGL) has important implications for the patient, as the germline mutation may have an impact on treatment in advanced disease, may influence surgical strategy (sparing surgery vs adrenalectomy) and drive postoperative care. Care of the patient with hereditary PPGL also includes taking care of the family members who test positive on genetic testing. Patients with PPGL syndrome and asymptomatic carriers of mutations in PPGL susceptibility genes need an extensive and lifelong surveillance program which considers their risk of relapse or development of new PPGL and the risk related to the involvement of other organs [1].

Surveillance programs should consider the biological characteristics of the specific gene mutation (risk of malignancy, penetrance), but also the possible radiological risk and psychological impact of such a long-term follow-up, especially in healthy mutation carriers.

Since these are rare neoplastic syndromes, some of which have only recently been identified, surveillance programs are not always evidence-based but are rather suggestions based on expert opinion and recommendations issued by consensus conferences.

7.2 Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) is an autosomal dominant multisystem disease characterized by an extremely variable phenotype. The cutaneous phenotype presenting with multiple café-au-lait macules and cutaneous neurofibromas is most common and gives the disease its name. However, the clinical course of the disease is dependent on the involvement of other organs. The clinical diagnosis according to criteria developed by the United States National Institutes of Health (NIH) is based on the presence of at least two of the following [2]:

  • six or more café-au-lait macules (>5 mm in diameter prepuberty, or > 15 mm postpuberty);

  • at least 2 neurofibromas or 1 plexiform neurofibroma;

  • axillary or inguinal freckling;

  • optic glioma;

  • two or more Lisch nodules;

  • typical bony lesions (thickening of long bone cortex, pseudoarthrosis, sphenoid dysplasia);

  • first degree relative with NF1.

The extent of skin manifestations has often a modest influence on the quality of life of patients, except in cases of severe esthetic impact; similarly, optic glioma and astrocytoma have generally a favorable outcome. The patients’ quality of life is instead affected by the common behavioral disorders, specific learning disability and deep nodular neurofibromas or voluminous plexiform neurofibromas, which are responsible for neurologic deficits and severe neuropathic pain. Plexiform neurofibroma in 10% of cases may degenerate into malignant peripheral nerve sheath tumors: a rapid increase in volume, persistent pain, or exacerbation of existing pain with a change in consistency of the tumor are clues of malignant transformation. NF1 subjects have an increased risk of breast cancer and gastrointestinal stromal tumors (GIST). Surveillance in affected patients includes annual mammography from the age of 30 years and contrast-enhanced magnetic resonance imaging (MRI) in subjects with a family history of breast cancer. There are no clear indications for GIST surveillance: some authors propose abdominal ultrasound (US) every 24 months and annual complete blood count together with vitamin D and calcium metabolism assessment for the risk of osteoporosis. Currently, there is no consensus for PPGL screening in NF1 patients but, considering that affected subjects are often asymptomatic, biochemical assessment every 2 years starting at the age of 14 with 24-h urinary fractionated metanephrines could be a reasonable surveillance strategy and should also be considered prior to elective surgery and for women planning a pregnancy. Lifelong annual biochemical surveillance should be proposed for subjects with a prior diagnosis of PPGL [3].

Abdominal imaging (computed tomography [CT], MRI) and functional study with (123/131I-MIBG scintigraphy, or 18F-DOPA positron-emission tomography [PET]/CT) are indicated only if biochemistry is abnormal. NF1 mutated PPGLs belong to cluster 2 kinase signaling-related tumors (see Chap. 4); for these tumors 18F-DOPA PET/CT is the preferred functional imaging modality due to the high uptake by the tumoral tissue compared to normal adrenal gland, allowing detection of multiple lesions within the adrenal parenchyma [4].

7.3 Multiple Endocrine Neoplasia 2

Multiple endocrine neoplasia 2 (MEN2) is a disease with autosomal dominant transmission, characterized by three clinical variants (MEN2a, MEN2b, and FMTC) as a result of the variable aggregation of medullary thyroid cancer (MTC), pheochromocytoma (PHEO), primary hyperparathyroidism (PHPT) and syndromic features (marfanoid habitus, mucosal neuromas, hindgut hypergangliosis, and thick corneal nerves) (Table 7.1).

Table 7.1 Clinical features of multiple endocrine neoplasia 2 (MEN2) syndromes
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The different clinical manifestations of MEN2 are often metachronous and not always expressed, MTC is highest penetrant and mostly affects morbidity and survival. An almost exclusive feature of RET gene mutations is the genotype-phenotype correlation, which allows prediction of the clinical expression for the different RET mutations. The American Thyroid Association (ATA) guidelines have classified mutations with the highest risk for MTC as HST (patients with RET codon M918T mutation, associated with MEN2B), mutations with a high risk as H (patients with C634F/G/R/S/W/Y and A883F mutations), and mutations with a moderate risk as MOD (Table 7.2).

Table 7.2 Relationship between common RET mutations and the risk of aggressive MTC, PHEO and PHPT
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Surveillance for RET mutation carriers is then strongly conditioned by the risk of medullary thyroid cancer, and includes indication for prophylactic thyroidectomy, which is timed according to the ATA risk classification [5].

Due to the high penetrance of aggressive MTC also at very young age, prophylactic thyroidectomy is recommended in the first year of life for MEN2B subjects (HST-risk mutation) and by at the age of 5 years or earlier, based on calcitonin level and neck ultrasound for MEN2A subjects (H-risk mutations). For subjects with MOD-risk mutations the timing of prophylactic thyroidectomy should be optimized according to the family history and patient’s desires: follow-up involves annual neck US and serum calcitonin assay, with thyroidectomy being performed when the calcitonin level becomes elevated.

PHPT is usually mild and asymptomatic and occurs in 20–30% of MEN2A patients, mostly with mutation in codon 634.

Surveillance for PPGL with annual 24-h urinary fractionated metanephrines should start at the age of 11 years for HST-risk and H-risk mutations and at the age of 16 years for MOD-risk mutations; abdominal imaging (CT, MRI) is indicated only in the event of abnormal biochemistry. For a functional study, considering that RET-mutated PHEOs belong to cluster 2 kinase signaling-related tumors, 18F-DOPA PET/CT is considered the first choice in preference to the traditionally used 123/131I-MIBG scintigraphy. The second suggested functional imaging study is probably 68Ga-DOTA PET/CT.

7.4 Von Hippel Lindau Syndrome

Von Hippel Lindau (VHL) syndrome is a hereditary neoplastic disease with autosomal dominant transmission. It is characterized by multiorgan involvement with predisposition to benign and malignant neoplasia; the tumors which mostly impact the clinical course of disease are central nervous system and retinal hemangioblastomas, clear cell carcinoma, neuroendocrine tumors and PPGL.

VHL syndrome was in the past classified into type 1 and type 2, according to the risk of developing PHEO: lower for type 1 (<10%) and higher (40–60%) for VHL type 2. VHL type 2 was further classified into subtype 2A (lower risk of renal cancer), subtype 2B (high risk of renal cancer), and subtype 2C with only risk for PHEO without other manifestations of VHL syndrome. Application of genetic screening in clinical practice has excluded the presence of a genotype/phenotype association, so the patient’s possible attribution to a clinical phenotype should never influence the follow-up. Surveillance programs should consider all possible organ involvement, with the aim of achieving a preclinical diagnosis and early treatment of lesions. The surveillance protocol for VHL-mutated subjects is summarized in Table 7.3.

Table 7.3 Surveillance protocol for von Hippel-Lindau disease
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Surveillance for PPGL should start at the age of 4 years considering that VHL mutations are often involved in pediatric PHEOs (about 40%) and consists of annual blood pressure monitoring and plasma-free metanephrine, normetanephrine, 3-methoxytyramine and/or measurement of 24-h urinary metabolite excretion. Annual abdominal US and MRI every 2 years are suggested also for early detection of kidney cancer and neuroendocrine tumors. Functional studies are indicated only in the case of abnormal biochemistry and/or suspected abnormality at imaging: VHL-related PPGL have lower expression of somatostatin receptor 2 (SSTR2), so the most sensitive functional imaging study is probably 18F-DOPA PET/CT where available; otherwise, 123/131I-MIBG scintigraphy and, as a second choice, 68Ga- DOTA PET/CT can be used.

7.5 SDHx-associated Hereditary PPGL

PPGL is the most common and characteristic expression of SDHx mutations, but mutations in these genes also predispose to renal cancer and to wild GIST (GIST without mutation in the KIT and PDGFRA genes). The surveillance protocol for SDHx mutations is not easy to devise: in fact, if on the one hand the risk of malignancy associated with SDHB, SDHD and probably SDHA mutations would warrant an intensive surveillance protocol, on the other hand the low penetrance of SDHB and SDHA mutations could suggest lengthening the intervals between follow-up assessments. Follow-up for gene mutation carriers comprises annual blood pressure measurement and physical examination, plasma free metanephrine, normetanephrine, 3-methoxytyramine and/or measurement of the 24-h urinary metabolite excretion, and MRI from the base of the skull to the pelvis every 2 or 3 years. Intensity of screening should be stronger for patients with a history of PPGL: MRI is recommended every 2 years. Whole-body MRI should be replaced with MRI of the skull base, neck, abdomen and pelvis, and low-dose chest CT.

SDHx-related PPGLs intensely express the SSTR2, so 68Ga-DOTATATE PET/CT is considered the most sensitive functional imaging test. This could be performed at initial screening and subsequently only if abnormal findings are detected at biochemistry or MRI; there is no consensus on the hypothesis of alternating the MRI study with 68Ga-DOTATATE PET/CT every 2–3 years. The surveillance protocol for VHL-mutated subjects is summarized in Table 7.4.

Table 7.4 Surveillance protocol for SDHx mutation carriers
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7.6 TMEM127- and MAX-associated PPGL

Follow-up surveillance for TMEM127 and MAX gene mutations involves annual physical examination, blood pressure measurement, annual plasma free metanephrine, normetanephrine, 3-methoxytyramine and/or measurement of the 24-h urinary metabolite excretion. Abdominal MRI could be performed every 2–3 years.

7.7 FH-associated PPGL

FH gene mutations are responsible for hereditary leiomyomatosis and papillary renal cell carcinoma (HLRCC), a complex neoplastic syndrome with autosomal dominant transmission, characterized by predisposition to cutaneous and uterine leiomyomata and papillary kidney cancer. PPGL have been described in only a small number of families. Often massive uterine leiomyomatosis causes severe bleeding and hysterectomy is necessary. Penetrance for renal cancer is fairly low (20%), and usually the cancer is a solitary but rapidly aggressive lesion. Also FH-PPGL may have an aggressive behavior [6]. Due to the small number of families studied until now, penetrance for PPGL is unknown, but is probably low.

Mutation carriers need annual gynecologic evaluation from the age of 20 years and abdominal annual MRI from the age of 8 years [7]. Biochemical screening for PPGL could probably start in young adulthood (after 18 years).