Head & Neck Flashcards
List 4 benign HPV-related lesions of the oral cavity.
Verruca vulgaris
Squamous papilloma
Condyloma acuminatum
Heck’s disease
List 5 syndromes associated with thyroid cancer.
PTEN (COWDEN)
Familial adenomatous polyposis
Carney Complex
Multiple Endocrine Neoplasia
Werner syndrome / progeria
Two risk factors for follicular thyroid adenoma
Radiation exposure (childhood/adolesence 15x)
Iodine deficiency
List syndromes associated with follicular thyroid adenoma
Carney complex (PRKAR1A) - multiple, +/- oncocytic adenomas - cardiac myxomas, myxoid fibroadenoma breast, lentigines, blue nevi, primary pigmented nodular adrenocortical disease (PPND), pituitary adenomas, large cell calcifying Sertoli cell tumor.
Cowden (PTEN) - multiple bilateral follicular adenomas.
(FAP gets pap Ca, adenomas, many of which “are likely” to be Follicular carcinoma - WHO).
List important molecular changes seen in follicular adenomas.
RAS (30%)
mostly NRAS, HRAS, least frequently KRAS.
PAX8/PPARG: 8% of adenomas (a feature of follicular carcinomas)
what features differentiate follicular adenoma from follicular carcinoma?
- absence of vascular invasion
- absence of capsular invasion
Must sample adequately, esp. the tumor-capsule interface to search for invasion.
grossly encapsulated = submit entire capsule.
list 4 positive immunos in follicular adenoma
Cytokeratin (basically all thyroid neoplasms are CK+)
TTF-1
Thyroglobulin (NB: medullary is negative)
Pax8
List histologic variants of follicular adenoma (8)
- Hyperfunctioning (hyperthyroidism; makes thyroxine; often columnar cells with vacuolated cytoplasm). NB. Follicular Tall cell is BRAF+, hyperfunctioning adenoma is not.
- Follicular adenoma with Papillary Hyperplasia: children/young; thick capsule, cystic, predominantly papillary. No ptc nuclear features.
- Lipoadenoma: mature adipose cells throughout; assoc. Cowden and radiation.
- Follicular adenoma with Bizarre nuclei: highly atypical cells; otherwise typical. esp. in oncocytic adenomas and tx with radioactive iodine. No necrosis, rare mits.
- Signet ring cell: thyroglobulin +; mucin +. Contain microvilli on EM.
- Clear cell: ballooning, accumulation of lipid or glycogen, deposition of thyroglobulin. Do TTF1 and thyroglobulin to ddx from metastatic clear cell RCC
- Spindle cell: rarely = predominantly spindle cells; CK+, TTF1+, thyroglobulin +; negative for calcitonin.
- Black follicular adenoma: tx with minocycline.
What is the typical patient profile and what is the prognosis of hyalinizing trabecular tumor of the thyroid?
Predominantly females, ~age 50, excellent prognosis.
slight predilection for right lobe
asymptomatic; benign findings on imaging, incidental
+/- risk with radiation, no other factors known
Molecular: RET/PTC1 ; no RAS, no BRAF
List 3 malignancy-related markers of follicular cells (markers that favour PTC over benign lesions, although they are not specific):
HBME1 : membranous
Galectin 3 : nuclear & cytoplasmic
CK19
**membranous HBME1 is the most specific.
What is the hyaline material in hyalinizing trabecular tumor of the thyroid?
Collagen IV, positive by IHC
List inclusion (3) and exclusion (7) criteria for NIFTP.
Inclusion:
- Encapsulated or well-demarcated
- Follicular patterned
- At least focal nuclear features of PTC
Exclusion:
- Infiltration/tumoral capsular invasion
- Solid/trabecular/insular growth >30%
- True papillae (even 1)
- Psammoma bodies
- Tall cell, hobnail, columnar cell, cribriform morular
- Necrosis
- Mitoses >3/10 hpf (in solid/microfollicular areas)
NB: Also, NO BRAF v600e mutation allowed!
source: CAP protocol
What are the three categories of nuclear features of PTC?
- Size and shape: enlargement, elongation, overlapping
- Membrane irregularities: irregular contours, grooves, pseudoinclusions
- Chromatin characteristics: chromatin clearing, margination of chromatin to membrane, glassy nuclei.
need at least 2-3 for dx of NIFTP
How do you differentiate NIFTP from follicular adenoma?
Nuclear features of PTC
How do you differentiate NIFTP from papillary carcinoma?
Absence of papillae in NIFTP
How do you differentiate NIFTP from invasive encapsulated FVPTC?
absence of capsular or vascular invasion
List risk factors for PTC
1 Ionizing radiation
WHO: other risk factors have been identified: obesity, diabetes, smoking, alcohol, dietary nitrates, dietary iodine excess, genetics.
List 3 familial syndromes associated with PTC
FAP: APC gene 5% of PTCs; CRIBRIFORM MORULAR
Carney complex
Werner
What molecular genetic pathway is activated in the majority of PTC cases?
MAPK (BRAF & NRAS)
BRAFv600E is the most common mutation in PTC - conventional papillary and tall cell variants.
What thyroid neoplasms display mutations in RAS?
More follicular = more Ras-like;
Mutations in RAS genes (NRAS, HRAS, KRAS) common in PTC; most are follicular variant.
NIFTP typically RAS-mutated.
RAS mutations are the most common type in Follicular carcinoma.
List histologic variants of PTC:
Papillary microcarcinoma (<1cm)
Encapsulated: architecturally and cytologically PTC with fibrous capsule; survival ~100%
Follicular: 2 types = infiltrative; encapsulated with invasion.
Diffuse sclerosing: F>M; may have serum anti-Thyroglobulin or antimicrosomal Ab; Background lymphocytic thyroiditis. Squamous metaplasia/morules; abrupt keratinization. RET/PTC rearranged! Nodal mets.
Tall cell: AGGRESSIVE VARIANT. 2-3x as tall as wide. Oncocytic cytoplasm. ++ nuclear pseudoinclusions. radio-iodine refractory. TERT promoter mutations 30%.
Columnar cell: pseudostratification (piled up on each other). Lacks PTC nuclear features. Subnuclear vacuolization (looks endometrioid). CDX2+ TTF1+. Invasion important prognostic.
Cribriform-Morular: FAP (multiple) or sporadic (solitary); almost exclusively females. Squamoid morules. Clear nuclei = biotin. TTF1 patchy. NUCLEAR BETA-CATENIN+.
Hobnail: >30% HOBNAIL. AGGRESSIVE VARIANT. >25% positive for p53. BRAF is most common mutation.
PTC with fibromatosis/fasciitis-like stroma
Solid/Trabecular: peds, ionizing radiation. All or nearly all solid, trabecular or nested and not another type. RET/PTC fusions in kids and radiation but not adults. ddx poorly diff: solid trabecular has PTC nuclear features, poorly diff does not + has necrosis/mits.
Oncocytic: pure form extremely rare. ddx tall cell.
Spindle cell: spindle cell metaplasia can be <5% or >95%. ddx biopsy tract, but it has no hemosiderin or reactive changes. no mitoses necrosis (ddx anaplastic spindle cell).
Clear cell: extremely unusual. ddx met RCC; clear cell medullary; parathyroid.
Warthin-like: unencapsulated, eosinophilic cells, lymphoplasmacytic infiltrate. Background hashimoto.
List syndromes associated with follicular thyroid carcinoma
Cowden/PTEN : follicular adenomas, PTC, follicular carcinoma, goitre, everything but medullary.
Werner syndrome (AR; WRN gene)
Carney complex
What are the three subclassifications of FTC?
- Minimally invasive
- Encapsulated angioinvasive
- Widely invasive
How does the WHO define vascular invasion in FTC?
Intravascular tumor cells should be adherent to the vessel walls, either covered by endothelium or in a context of thrombus or fibrin. Invasion must occur in vessels beyond or within the tumour capsule - cannot be intratumoral.
NB: Lymphatic invasion in FTC is virtually unknown. Same with nodal mets. Nodal mets = rethink your dx. probably follicular variant of PTC.
What is “extensive” vascular invasion in FTC?
> 4 vessels
List variants of FTC
Clear cell variant: >50% clear cells ; uniform nuclei, no substantial pleomorphism. Must exclude clear cell RCC, medullary thyroid, parathyroid tumors.
Other variants are unusual: signet ring, glomeruloid, spindle cell.
What is the cytology of FTC?
cannot distinguish benign from malignant follicular-patterened lesions! Cyto dx is “follicular neoplasm” because we cannot evaluate capsular and/or vascular invasion.
What molecular marker is an independent prognostic indicator in FTC?
TERT promoter mutation
what is the definition of widely invasive FTC?
Extensive invasion of FTC into thyroid and extra-thyroidal soft tissues.
Vascular invasion alone does not make it “widely invasive”
Extensive angioinvasion is WORSE.
What is in the cytoplasm of “Hurthle” cells?
Mitochondria
See numerous abnormally large mitochondria on EM
List features of Hurthle cell adenoma
Encapsulated
Follicles
Cells with characteristic oncocytic cells with large centrally located nuclei
NO INVASION
Many occur in setting of background lymphocytic thyroiditis
may have fibrous bands
tend to infarct when FNA’d
What is the metastatic pattern of Hurthle cell carcinoms?
Can metastasize to cervical nodes (FTC virtually never does this); can also invade veins and metastasize hematogenously.
Possible vascular invasion pattern: can present as multiple intravascular nodules in the neck.
Hematogenous spread is to liver, lungs, bone.
Mets can be many years later.
Liver mets can be mistaken for primary hepatocellular!
What is poorly differentiated Hurthle cell carcinoma?
Large, >4cm
Foci of tumor necrosis
numerous mitoses, including abnormal forms
foci of small tumor cells prominent
- small cell/poorly diff component may be dominant pattern in metastasis!
- can be TTF1 and thyroglobulin negative!
List prognostic factors in hurthle cell carcinoma
Prognosis depends on extent of vascular invasion: more veins is worse.
Even encapsulated HCC can met years later.
Widely invasive with extensive vascular invasion is associated with high mortality (>90% at 10 years).
What is the molecular profile of NIFTP?
Shares molecular features with other follicular-patterned tumors : high prevalence of RAS and sometimes PPARG.
NO BRAF
List the bethesda categories for Thyroid Cytology
- Unsat/nondiagnostic
- Benign
- AUS/FLUS
- Follicular neoplasm / suspicious for a follicular neoplasm, specify hurthle cell type
- Suspicious for malignancy
- Malignant
What is the risk of recurrence or other adverse events after NIFTP?
< 1% within first 15 years after resection.
Recurrence risks: Incomplete excision (positive margins)
What is the ddx for hurthle cell neoplasms in the thyroid?
Hurthle cell adenoma
Hurthle cell carcinoma
Medullary
Parathyroid
Papillary with hurthle cell changes
How is hurthle cell carcinoma classified?
Minimally invasive
Widely invasive
encapsulated angioinvasive
List 3 PTC variants with oncocytic cytoplasm:
tall cell
oncocytic variant
Warthin-like variant
What are the classic molecular alterations in follicular carcinoma?
RAS (N-RAS, K-RAS, H-RAS) (30-50%)
seen in 10-15% of hurthle cell carcinomas
PAX8-PPARG (20-50%)
RAS is rarely seen in PTC (0-10%)
PTC classically associated with BRAF v600E
What are the molecular alterations seen in hurthle cell neoplasms (two broad groups)?
- Abnormal number of chromosomes (near haploid);
- chromosome 7 heterozygosity
- +/- chromosomes 5 & 12 - Mitochondrial DNA mutations
- mutations in complex I of respiratory chain
Also known to have mutations in TERT promoter; not specific to HCCA, also seen in other aggressive neoplasms.
(Also MAPkinase and MTOR pathways in 55% of carcinomas… )
What are three types of invasion to be aware of in thyroid pathology?
Capsular invasion
Angioinvasion
Extrathyroidal extension (ETE)
List three thyroid tumors that are divided from a benign counterpart by the presence or absence of invasion of a capsule.
NIFTP vs (invasive) encapsulated follicular variant of PTC
Follicular adenoma vs follicular carcinoma
Hurthle cell adenoma vs hurthle cell carcinoma
