Familial Thyroid Carcinoma Based on “Diagnostic Histopathology” – Familial thyroid carcinoma: the road less travelled in thyroid pathology – an update

Sporadic Thyroid Carcinomas Majority of thyroid cancer sporadic Best established risk factor for papillary thyroid carcinoma is ionizing radiation, low to intermediate dose – a/w ret/PTC proto-oncogene mutation Other risk factors poorly understood 45% papillary carcinomas have BRAF mutations Female: Male 3:1

Familial Thyroid Carcinoma A minority of thyroid cancers Gender incidence equal Two main groups – Follicular cell origin - Derived from parafollicular C cells Those derived from parafollicular C cells – medullary carcinomas – much better understood on a molecular level than follicular cell tumours

General characteristic of familial thyroid carcinoma Young patients Positive family hx of thyroid cancer/nodules, esp. multinodular goitre Multifocal tumours Bilateral tumours Possible precursor lesions e.g. c-cell hyperplasia

Medullary carcinoma Majority sporadic but 10-20% familial Recognised in 1951 by Robert Horn, previously classified as either “atypical adenomas” or grouped with anaplastic carcinomas Mid twentieth century C cells identified in human thyroid and calcitonin discovered In 1961 case report by Sipple described an individual with medullary thyroid carcinoma and bilateral pheochromocytomas Robert Horn described medullary carcinoma is seven cases – noted that these lesions were clinically aggressive but did not follow as aggressive a course as anaplastic carcinomas, Previously classified as atypical adenomas if well differentiated or if spindle cell grouped as anaplastic carcinoma

In 1960s ret mutations discovered in medullary carcinomas and in the germline of familial cases Multiple point mutations in ret gene on chromosome 10 can give rise to medullary carcinoma Ret gene is located on chromosome 10, it is a proto oncogene, it codes a receptor tyrosine kinase for members of GDNF family of extracellular signalling molecules, loss of function mutations lead to Hirschprung disease, gain of function mutations lead to medullary thyroid carcinoma, multiple endocrine neoplasias type 2A and 2B, pheochromocytoma and parathyroid hyperplasia Source: http://www.endocrinesurgeon.co.uk/index.php/what-causes-multiple-endocrine-neoplasia

Gain of function mutations in RET cause: Medullary carcinoma Multiple neuroendocrine carcinoma syndromes (type 2A and 2B) Pheochromocytoma Parathyroid hyperplasia

Medullary Carcinoma Pathology Usually in lateral upper two thirds of gland (area of highest C cell concentration) Often yellow/tan in colour Nest of cells separated by varying amounts of stroma Round/oval/spindle shaped cells Uniform cells with salt and pepper chromatin Intra-nuclear cytoplasmic inclusions common

Pictures courtesy of Dr Rasika Singh

Stroma “typically” contains amyloid but 25% do not (presence of amyloid thought to confer better prognosis but does not affect treatment – RCPATH thyroid dataset) Where present amyloid often calcifies Positive for CK, neuroendocrine markers, calcitonin, TTF – 1. calcitonin gene related peptide (CGRP) and CEA May stain for peptide hormones leading to clinical syndromes e.g. ACTH

C cell hyperplasia – ?precursor to medullary carcinoma Current definition of normal C cells in adult human thyroid Isolated spindle cells in a parafollicular location <50 per low power field <6 per any follicle

C cell hyperplasia is poorly defined, generally considered as: Increase in number Abnormal morphology (e.g. large, round amphophillic) Intra-follicular location (calcitonin staining can help highlight C cells) Source: Pathologyoutlines.com

May be difficult to distinguish C cell hyperplasia from lower limit of medullary carcinoma: Delellis and Wolfe state that: C cell hyperplasia ranges from diffuse increase to nodules of C cells replacing follicles, if BM of follicle is breached this becomes a medullary carcinoma RCPATH guidelines acknowledge C cell hyperplasia not well defined and would only diagnose this when nodules of C cells found in blocks not containing main tumour Diagnosis of C cell hyperplasia in resection specimens now optional and not in core dataset Difficult to know when basement membrane has been breached . All patients with medullary carcinoma should now be offered ret mutation testing for familial syndromes

Syndromes associated with familial thyroid carcinoma Features MEN 2 (AKA MEN2A, AKA Sipple syndrome) Medullary thyroid carcinoma Associated C cell hyperplasia Adrenal pheochromocytoma Adrenal medullary hyperplasia Parathyroid hyperplasia and adenomas Ret mutation MEN 2B Neuromas of oral cavity and GI tract MSK abnormalities (Marfinoid) Eye lens abnormalities Different ret mutation FMTC (familial medullary thyroid carcinoma) Subtype of MEN 2b Medullary thyroid carcinoma and associated C cell hyperplasia without other features

Familial Papillary Carcinoma To be considered familial cancer at least 3 first degree relatives should be affected Histology may be the same as non-familial classic or follicular variant of papillary carcinoma though multifocal and bilateral lesions are found Some series indicate more aggressive behaviour – lymphatic invasion, mets and recurrences increased Most investigators have not found BRAF mutations (conversely 40% of sporadic have BRAF mutations) Follicular derived familial tumours are less well understood on a molecular level

Papillary thyroid ca, adenomatoid nodules, papillary renal neoplasia Familial Non-Medullary Thyroid Carcinoma as the predominant lesion of a familial tumor syndrome Disorder Chromosome location Features Familial papillary thyroid carcinoma/ Papillary renal neoplasm (FPTC/PRN) 1q21 Papillary thyroid ca, adenomatoid nodules, papillary renal neoplasia Familial non – medullary thyroid carcinoma (FNMTC) With oxyphilia – 19qp13.2 Without oxyphilia – 19p13 Papillary thyroid carcinoma with/without oxyphilia and adenomatoid nodules FNMTC1 2q21 Papillary thyroid carcinoma and benign thyroid nodules Familial multi-nodular goitre syndrome 14q Multi-nodular goitre with cyst formation, papillary thyroid carcinoma, follicular adenoma, FNMTC – oxyphilia version associated with multiple oncocytic tumours of the thyroid, 1/3 are malignant and without increased risk of non-thyroid carcinoma to family members

Other familial tumour syndromes a/w non-medullary thyroid carcinoma

PTEN – hamartoma tumour syndrome (PHTS) – Cowden syndrome, Bannayan – Riley – Ruvalcaba syndrome and Proteus syndrome Cowden syndrome Benign and malignant tumours of breast, thyroid, endometrium Multiple skin hamartomas – trichilemmomas Recently described PTEN hamartoma of soft tissue 35% develop thyroid tumours, 60% thyroid nodules Bannayan – Riley – Ruvalcaba – multiple GI hamartomas and macrocephaly, proteus syndrome – overgrowth of tissues, ovarian cystadenomas, testicular tumours Bilateral, multifocal breast cancers as young age, thyroid nodules and tumours typically oncocytic, These syndromes were all originally thought to be due to mutations in PTEN suppressor genes, however other genes more recently implicated Source - wikipedia

Some patients lack PTEN alterations but have hereditary epigenetic changes to KILLIN promoter hypermethylation of PTEN promoter Hence different mutations leading to same syndrome – some patietns have preserved PTEN staining Clinically important as certain therapies e.g. sirolimus targeted at Akt-mTOR pathway targeted at PTEN mutations

Carney Complex Autosomnal dominant Skin and mucosal pigmentation Diverse pigmented skin lesion Endocrine neoplasias – pituitary adenoma, pigmented nodular adrenal disease, Sertoli and Leydig cell tumors, thyroid tumours http://www.regionalderm.com/Regional_Derm/files/qr_face.html

Werner syndrome AKA adult progeria Autosomnal Recessive connective tissue disease Premature aging, bilateral cataracts, gray hair and skin atrophy Benign thyroid lesions and PTC Mutation in WRN gene – RecQ helicase – ensures DNA stability