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

2. 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

3. 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

4. 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

5. 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

6. 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:

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

8. 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

9. Pictures courtesy of Dr Rasika Singh

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

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

18. 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

19. 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

20. 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

21. 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