Rare Tumor Types & Syndromes

Rare Tumors Indicating Genetic Counseling:

- generally think organs that dont typically have tumors &/or unusual pathology

• Endolymphatic sac tumor (ELST)

• Ependymomas (spine or brain)

• Gastrointestinal stromal tumor

• Gliomas

  • astrocytoma

  • oligodendroglioma

  • optic

• Hemangioblastoma

• Leiomyosarcoma

• Melanoma, Uveal

• Mesothelioma

• Malignant peripheral nerve sheath tumor

• Paraganglioma

• Pheochromocytoma

• Primitive neuroectodermal tumor (PNET)

• Renal cell carcinoma

  • chromophobe

  • papillary type 1

  • papillary type 2

  • tubule-papillary

• Renal tumors

  • oncocytomas

  • oncocytic hybrid tumors

• Retino hamartomas

• Schwannomatosis

• Vestibular Schwannomas

• Stomach cancer (e.g., diffuse)

• Thyroid cancer, medullary

4.1.2. Malignant

4.1.3. Significant Role of Benign Tumors

Benign Tumors as Indicators:

• Many rare tumor syndromes feature benign tumors as prominent indicators.

  • Examples include:

  • Dysplastic nevi (FAMMM)

  • Retinal angiomas (VHL)

  • Neurofibromas (neurofibromatosis)

  • Other physical cues may also suggest specific syndromes.

Associated Characteristics:

• Macrocephaly (PTEN syndrome)

• Café au lait macules (neurofibromatosis, CMMRD, BHD)

• Jaw cysts (Gorlin syndrome)

4.1.4. Multiple Tumors as Indicators

• Adrenal tumors

The development of multiple tumors (benign or malignant) is a hallmark of hereditary cancer syndromes.

• Examples include:

  • Bilateral retinoblastoma (hereditary retinoblastoma)

  • Bilateral Wilms tumor (Wilms tumor predisposition syndrome)

  • Multiple cancers within different organs (e.g., parathyroid carcinoma & pancreatic islet cell tumor in MEN1)

4.3. Clinical Features of Selected Rare Tumor Syndromes

4.3.1. BAP1 Tumor Predisposition Syndrome

• Gene: BAP1 on 3p21.1

• Criteria: Presence of $\ge$ 2 BAP1-related tumors in an individual, or 1 BAP1 tumor with a first-degree relative also having a BAP1-related tumor.

• Tumor Risks: High risks of mesothelioma, uveal melanoma, and renal cell carcinoma.

• Testing Recommendations: BAP1 testing for those with personal or family histories of specific tumors.

• Management and Screening Proposals:

  • Annual ocular exams starting at age 11

  • Annual full-body skin checks from age 20

  • Annual abdominal ultrasounds and possible MRI/urinalysis.

4.3.2. Birt–Hogg–Dubé Syndrome

• Gene: FLCN at 17p11.2

• Criteria: Combination of major and minor criteria. Major: multiple fibrofolliculomas or history of spontaneous pneumothorax. Minor: multiple renal cysts or family history of BHD-associated conditions.

• Tumor Risks: Increased risks of renal tumors (chromophobe or oncocytoma types) and benign skin tumors (fibrofolliculomas).

• Other Features: Pulmonary cysts, spontaneous pneumothorax, and management considerations.

4.3.3. Familial Atypical Multiple Mole Melanoma Syndrome

• Genes: CDKN2A (TP16) and CDK4

• Criteria: Strong family history of melanoma ($\ge$ 2 first-degree relatives), high number of atypical nevi, and specific histological features of nevi.

• Main Cancer Risks: High melanoma risk; pancreatic cancer correlations.

• Management Recommendations: Skin exams and pancreatic cancer screenings.

4.3.4. Familial Lung Cancer

• Genes: EGFR and ERBB2

• Criteria: Recommendations for genetic testing based on specific cancer history: early-onset lung cancer in non-smokers, multiple affected family members, or rare histological subtypes.

• Tumor Risks: Increased risk for lung cancers, especially in young nonsmokers and carriers.

4.3.5. Gorlin Syndrome

• Genes: PTCH1 and SUFU

• Diagnostic Criteria: Combination of major and minor criteria. Major: multiple BCCs (or 1 BCC before age 30), odontogenic keratocysts, palmar/plantar pits, skeletal abnormalities. Minor: macrocephaly, specific facial features, developmental anomalies.

• Tumor Risks: High incidence of BCC, medulloblastoma, and other tumors (e.g., ovarian fibromas).

4.3.6. Hereditary Leiomyomatosis Renal Cell Cancer

• Gene: FH at 1q43

• Diagnostic Criteria: Pathological confirmation of multiple cutaneous and/or uterine leiomyomas. Early-onset or multiple leiomyomas prompt genetic testing.

• Main Cancer Risks: High risks of renal cell cancer, specifically papillary type 2 renal cell carcinoma.

4.3.7. Multiple Endocrine Neoplasia, Types 1 & 2

• Genes: MEN1 (for MEN type 1), RET (for MEN type 2)

• Diagnostic Criteria: Presence of $\ge$ 2 tumors from a defined set of endocrine glands.

  • MEN1: Parathyroid gland (hyperparathyroidism), pituitary gland (adenomas), pancreas/duodenum (e.g., gastrinomas, insulinomas) tumors.

  • MEN2: Medullary thyroid carcinoma, pheochromocytoma, parathyroid hyperplasia.

• Main Tumors:

  • MEN1: Primary tumors include parathyroid adenomas, pancreatic neuroendocrine tumors, and pituitary adenomas.

  • MEN2: Characterized by medullary thyroid carcinoma, pheochromocytoma, and sometimes parathyroid gland hyperplasia (MEN2A) or ganglioneuromas (MEN2B).

4.3.8. Neurofibromatosis, Types 1 & 2

• Gene: NF1 (for Neurofibromatosis type 1) and NF2 (for Neurofibromatosis type 2)

• Diagnostic Criteria for NF1: Diagnosis with $\ge$ 2 of: $\ge$ 6 café au lait macules, $\ge$ 2 neurofibromas (or 1 plexiform), axillary/groin freckling, optic pathway glioma, $\ge$ 2 Lisch nodules, distinct bony lesion, or a first-degree relative with NF1.

• Main Tumors:

  • NF1: Characterized by benign neurofibromas, optic pathway gliomas, and other potential tumors like malignant peripheral nerve sheath tumors.

  • NF2: Primarily associated with bilateral vestibular schwannomas; other central nervous system tumors like meningiomas and schwannomas are common.

4.3.9. Schwannomatosis

• Genes: SMARCB1 and LZTR1

• Diagnostic Criteria: Presence of multiple schwannomas (benign nerve sheath tumors) without evidence of bilateral vestibular schwannomas (differentiating from NF2).

• Tumor Risks: Development of multiple schwannomas throughout the body (excluding vestibular nerves), mostly appearing in early adulthood.

4.3.10. Von Hippel-Lindau Syndrome

• Gene: VHL at 3p25.3

• Diagnostic Criteria: Multiple hemangioblastomas (retina, brain, spinal cord) OR 1 hemangioblastoma with an associated lesion (clear cell RCC, pheochromocytoma, ELST) OR family history of VHL disease.

• Tumor Risks: High risk of hemangioblastomas, clear cell renal cell carcinoma (RCC), pheochromocytoma, and endolymphatic sac tumors (ELST).