Papillary Carcinoma of the Thyroid

 

Common sites:

    •  

 

Gross features:

    • solitary or multifocal
    • may have ill-defined or well-defined margins (even encapsulated)
    • pale tan to white
    • often cystic
    • may contain areas of fibrosis and calcification
    • often granular on cut surface

 

Histologic features:

    • nuclear features (consensus nuclear features, diagnostic nuclear score, Nikiforov et al. 2016):
      • size and shape (score 0 or 1)
        • Enlargement, crowding/overlapping
        • Elongation
      • Nuclear membrane irregularities (score 0 or 1)
        • Irregular contours
        • Grooves
        • Pseudoinclusions (not required / uncommon in EFVPTC)
      • Chromatin characteristics (score 0 or 1)
        • Chromatin clearing (margination of chromatin / “glassy nuclei” / “Orphan Annie” nuclei)
    • note that these nuclear features can be seen in setting of thyroiditis
    • Consensus diagnostic criteria for the encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC)
      • Major features:
        • Encapsulation or clear demarcation
        • Follicular growth pattern
        • Nuclear features of papillary carcinoma (PTC)
          • Enlargement, crowding/overlapping
          • Elongation
          • Irregular contours
          • Grooves
          • Pseudoinclusions (not required / uncommon in EFVPTC)
          • Chromatin clearing (margination of chromatin / “glassy nuclei” / “Orphan Annie” nuclei)
      • Exclusion criteria:
        • “true” papillae > 1%
        • Psammoma bodies
        • Infiltrative border
        • Tumour necrosis
        • High mitotic activity (at least 3 per 10 HPF)
        • Cell / morphologic characteristics of other variants of PTC (tall cell, cribriform-morular, solid)
      • Minor features:
        • Dark colloid
        • Irregularly shaped follicles
        • Intratumoral fibrosis
        • “sprinkling” sign (Vanzati et al.)
        • Follicles cleft from stroma (Vanzati et al.)
        • Multinucleated giant cells within follicles
    • Proposed reclassification of encapsulated follicular variant papillary carcinoma (EFVPTC):
      • NIFTP – non-invasive follicular thyroid neoplasm with papillary-like nuclear features
      • Diagnostic criteria for NIFTP:
        • Encapsulation or clear demarcation
        • Follicular growth pattern
          • < 1% papillae
          • No psammoma bodies
          • 30% solid/trabecular/insular growth pattern
        • Nuclear score 2-3/3 (see above)
        • No vascular or capsular invasion
        • No tumour necrosis
        • No high mitotic activity (3 per 10 HPF)
    • may contain complex branching papillae with a fibrovascular stalk covered by single or multiple layers of cuboidal epithelial cells
    • psammoma bodies often found within cores of papillae (fairly specific for papillary carcinoma)
    • important prognostic factors:
      • capsular invasion
      • LVI in capsule or outside of capsule
    • cytology (Kinney’s Criteria):
      • intranuclear (pseudo)-inclusions
      • nuclear grooves
      • architecture – crowded sheets, papillary caps, papillae
      • micronucleoli
      • powdery altered chromatin
    • papillary microcarcinoma:
      • focus less than 1cm
      • probably no clinical importance (although cases of mets from these lesions are known)
    • tall cell variant:
      • cells are 3 times as long as they are wide
      • should comprise more than half of the tumour
      • tend to be large (>6cm)
      • tends to exstend extrathyroidally with vascular invasion more often
      • older patients
    • columnar cell variant:
      • papillary
      • tall columnar cells with nuclear stratification
      • unique nuclear features
        • hyperchromatic with punctate chromatin
      • scant clear cytoplasm
      • frequent mitoses
      • psammoma bodies rare
      • tends to be large (>6cm) with extrathyroidal extension and distant metastases
    • diffuse sclerosis variant:
      • children and young adults
      • bilateral goiter
      • squamous metaplasia associated with tumour papillae
      • numerous psamomma bodies
      • lymphocytic infiltrates around tumour foci
      • tend to recur
      • associated with radiation exposure (Chernobyl)
      • extracapsular extension, distant and nodal metastases often
    • clear cell variant:
    • solid variant:
      • solid pattern >50% of tumour
      • children
      • associated with radiation exposure (Chernobyl)

 

Immunophenotype:

Marker:

Sensitivity:

Specificity:

Cytokeratins 

 

 

Thyroglobulin

Good (negative in pulmonary primaries)

TTF-1

Also positive in pulmonary maliganncies

Synaptophysin (neg)

Chromogranin (neg)

Associated with malignancy (but not very useful…):

S100

HLA-DR

ER

HMWK

CK19

Not very – may be found in thyroiditis and reactive FNA sites

RET

HBME-1

Good

Not very

Galactin-3

Good

Not very

P27 (loss)
    • p53+, p27 underexpressed, and cyclin D1 overexpressed are more likely to metastasize

 

Molecular features:

    • RET or NTRK1 rearrangements (mutually exclusive to activating BRAF mutations):
      • Both are receptor tyrosine kinases
        • neither are normally expressed on the surface of thyroid follicular cells
        • downstream activates the ubiquitous MAP kinase pathway
      • RET/PTC fusion genes (13-40%)
        • At least 11 types
          • Vast majority are RET/PTC1 and RET/PTC3
        • significantly higher percentage in children with history of radiation exposure
          • Prevalence varies geographically as well
          • Low prevalence in poorly-differentiated and undifferentiated thyroid carcinoma
        • either paracentric inversion of chr 10, or t(10;17)
        • PTC genes (H4 – PTC-1, PKA – PTC-2, and ELE – PTC-3) fuse, by translocation, with the tyrosine kinase domain of the ret protooncogene
        • Typically involve intron 11 of RET
          • ALL known translocations lead to juxtaposition of intracellular tyrosine kinase domain (3’ end of RET, from exon 12 to the 3’-ter) to 5’ portion of different donor genes constitutively expressed in the thyroid
            • Exons 1-11 are excluded from the (active) fusion transcript
          • creates a novel amino-terminal portion to intracellular domain of Ret, making Ret activation ligand independent
          • Results in a constitutive activation of RET gene
        • RNA can be recovered from paraffin-formalin-fixed tissue to test for this fusion transcript
        • ?present in many Hashimotos and some follicular adenomas
          • Some argue these are either false positives or detecting micropapillary carcinomas
          • Lower transcript levels by qPCR than PTC cases
        • Heterogeneity within the tumour maybe
        • H4(CCDC6)-RET (RET/PTC1) (most common):
          • H4 (D10S170) gene
          • Paracentric inversion on chromosome 10
        • ELE1-RET (RET/PTC3) (next most common):
          • NCOA4 (ELE1, RFG, ARA70) gene
          • Paracentric inversion on chromosome 10
        • PKA-RET (RET/PTC2)
          • t(10;17)
        • Cell lines:
          • TPC-1
            • 3-way translocation involving chromosomes 1, 10, and 21
      • NTRK1/PTC fusion genes (5-10%)
        • Only 3% post-Chernobyl
        • Neurotrophic receptor-tyrosine kinase (aka TRKA) (1q22)
          • Transmembrane tyrosine-kinase receptor for nerve growth factor
          • Typically restricted to neurons of sensory spinal and cranial ganglia
          • Initiates ERK, PI3K, and PLC-gamma pathways
        • Fusion partners:
          • TPM3 (TRK-T1)
            • More frequent post-Chernobyl than others
          • TPR (TRK-T2)
          • TFG (TRK-T3)
        • either paracentric inversion or translocation
    • BRAF gene activating mutations (29-69%) (mutually exclusive to RET or NTRK1 rearrangements)
      • Aggressive behaviour association
      • Not prevalent in post-Chernobyl (0-12%) and sporadic childhood papillary thyroid CA (20%) (see AKAP9-BRAF rearrangement)
      • High prevalence in tall-cell variant (55-100%)
      • Low prevalence in follicular variant (7-14%)
      • Not in follicular thyroid carcinoma
      • Only 13% of poorly differentiated thyroid CA
      • 35% of undifferentiated thyroid CA
        • Those with a papillary thyroid CA component (60-78%)
        • Those without such a component (0-4%)
      • point mutation V600E (45%)
      • BRAF is an intermediary in the MAP kinase pathway
        • Results in activation of MAP kinase pathway
      • DNA can be recovered from paraffin-formalin-fixed tissue to test for this mutation
        • PRC to amplify up region using 2 sets of primers
        • Capillary electrophoresis on products to detect size of DNA products
    • AKAP9-BRAF rearrangement :
      • Seen post-radiation papillary thyroid CA
    • RAS family mutations (10-20%)
    • FAP patients are prone to development of a type of papillary thyroid cancer
      • Cribriform pattern
      • Nesting
    • Age is very important – if patient is <45y, stage is 1 for any T, any N

 

Other features:

    • Variants with a worse prognosis:
      • Tall cell variant
      • Columnar cell variant
      • Diffuse sclerosis variant
    • Clinical Management – pathologic factors taken into consideration (Thyroid Cancer Symposium in Toronto, Jan. 2017)
      • See ATA guidelines 2015
        • CCO endorses ATA guidelines but with comments (pathway coming this year hopefully)
      • FLUS – 3 options:
        • surgery
          • lobectomy
          • total thyroidectomy if genetic predisposition, radiation exposure, or > 4 cm
        • gene expression classifiers on FNAs (patients pay $800 US – Nikiforov’s test)
          • Afirma Vercarte
          • Assuragen
        • surveillance
      • NIFTP  - working group recommends no further surgery or RAI
        • UHN decided they would not reclassify older lesions as NIFTP
      • ATA guidelines – lobectomy or total thyroidectomy are sufficient if:
        • < 4 cm
        • No ETE (I think gross involvement of strap muscles; microscopic ETE is ok)
        • No lymph node metastases
      • Node dissection determining factors:
        • LVI (Ozgur says even 1 focus is enough if it meets their strict criteria including thrombus associated)
        • ETE (?gross only)
        • T3 or T4
      • RAI factors to consider:
        • ETE (gross / extensive / strap muscle involvement)
        • Margins
        • Nodes (still considered low risk if low volume in central / ?lateral compartment)
        • > 2cm size
        • Multifocality (even microcarcinomas)
        • Widely invasive growth pattern
        • High risk histology (see above)
      • Active surveillance criteria:
        • Size < 2.0 cm
        • Limited to thyroid
        • No ETE (?gross)
        • No cervical adenopathy (?minimal central neck node involvement ok?)
        •  

 

References:

    • Robbins & Cotran Pathologic Basis of Disease (2005)
    • WHO Tumours of Endocrine Organs (2004)
    • Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat. Rev. Cancer. 2006;6(4):292-306.
    • Chen F, Clark DP, Hawkins AL, Morsberger LA, Griffin CA. A break-apart fluorescence in situ hybridization assay for detecting RET translocations in papillary thyroid carcinoma. Cancer Genet. Cytogenet. 2007;178(2):128-134.
    • Nikiforov YE. Thyroid carcinoma: molecular pathways and therapeutic targets. Mod. Pathol. 2008;21 Suppl 2:S37-43.
    • Tallini G, Asa SL. RET oncogene activation in papillary thyroid carcinoma. Adv Anat Pathol. 2001;8(6):345-354.
    • Rhoden KJ, Unger K, Salvatore G, et al. RET/papillary thyroid cancer rearrangement in nonneoplastic thyrocytes: follicular cells of Hashimoto's thyroiditis share low-level recombination events with a subset of papillary carcinoma. J. Clin. Endocrinol. Metab. 2006;91(6):2414-2423.
    • Nikiforov et al.  Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma.  A paradigm shift to reduce overtreatment of indolent tumors.  JAMA Oncol. doi:10.1001/jamaoncol.2016.0386  (April 14, 2016)