Case 4 22 year old female presented with asymmetric enlargement of the left lobe of the thyroid gland. No information available relative to a prior fine needle aspiration biopsy. A left lobectomy was performed. Intraoperative consultation diagnosis was "Follicular pattern lesion, defer to permanent section."
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Case 4 Diagnosis - Noninvasive poorly-differentiated thyroid carcinoma - Encapsulated thyroid tumor of follicular cell origin (EFHG) with high-grade features
Poorly-Differentiated Thyroid Carcinoma Definition Thyroid neoplasm with histologic and biologic features intermediate between those of differentiated thyroid carcinomas and undifferentiated (anaplastic) carcinoma Synonyms: Insular Carcinoma
Poorly-Differentiated Thyroid Carcinoma Clinical Features Predominantly middle-aged and elderly adults (mean 54 years) F > M Enlarging neck mass: de novo preceding history of long-standing thyroid mass with transformation from differentiated carcinoma Often present with locally advanced disease
Poorly-Differentiated Thyroid Carcinoma Pathology Often large (>4cm), encapsulated or invasive Histopathology: insular, solid, diffuse sheets, trabeculae, festoons, follicular, papillary Cytomorphology: Uniform, small and monotonous to enlarged and pleomorphic tumor cells Coarse nuclear chromatin Increased mitotic activity and necrosis Colloid-filled follicles can be seen
Poorly-Differentiated Thyroid Carcinoma Pathology Continued Invasive growth including: Capsular invasion Lymph-vascular invasion Extrathyroidal extension
Poorly-Differentiated Thyroid Carcinoma Immunohistochemistry Cytokeratins, thyroglobulin and TTF1 Calcitonin negative Absence of neuroendocrine markers Bcl-2 positive Increased proliferation rate (Ki67 or MIB1)
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Poorly-Differentiated Thyroid Carcinoma Turin Proposal* Presence of solid, trabecular or insular growth Absence of nuclear features diagnostic for papillary carcinoma Presence of at least one of the following: Convoluted nuclei; Mitotic activity 3 mitoses per 10 HPF; Tumor necrosis * Volante et al. AJSP 2007;31:1256-1264
Poorly-Differentiated Thyroid Carcinoma Validation of Turin Proposal* Validate criteria for diagnosis Evaluate prevalence and prognostic behavior * Asioli et al. Modern Pathol 2010;23:1269-1278
Poorly-Differentiated Thyroid Carcinoma Validation of Turin Proposal* 56 cases from Mayo Clinic Prevalence USA cases = 1.8% (56/2138) N. Italy = 6.7% (96/1442) Tumor characteristics similar: USA cases extensive vascular invasion (84% v 57%) N. Italy - prevalent insular growth (68% v 41%) * Asioli et al. Modern Pathol 2010;23:1269-1278
Poorly-Differentiated Thyroid Carcinoma Validation of Turin Proposal* Overall 5- year survival: USA = 68.6% N. Italy = 73.6% Total = 71.6% Overall 10-year survival: USA = 45.9% N. Italy = 45.7% Total = 46.3% * Asioli et al. Modern Pathol 2010;23:1269-1278
Poorly-Differentiated Thyroid Carcinoma (PDTC) PDTC not limited to tumors with insular/solid/trabecular growth: Hiltzik D, et al. Cancer 2006;106:1286-95: PDTC defined on basis of mitotic activity and/or tumor necrosis Rivera M, et al. Cancer 2008;113:48-56: Necrosis and/or mitotic index ( 5 x 10HPF)
Thyroid Lesions with Insular Growth Not restricted to Follicular Carcinoma: Thyroid Papillary Carcinoma Follicular Adenoma Non-neoplastic Lesions Not an indicator of: more aggressive neoplasm a neoplastic proliferation Jorda et al: Arch Pathol Lab Med 1993117:631-635 Ashfaq et al: Cancer 1994; 73:416-23
Poorly-Differentiated Thyroid Carcinoma Differential Diagnosis Papillary carcinoma, solid variant Thyroid medullary carcinoma Undifferentiated (anaplastic) carcinoma Benign follicular lesions/neoplasms with atypia
Solid Variant Papillary carcinoma > 50% solid growth Common in children including those with exposure to radiation (adults, too) Solid sheets of tumor cells with fibrovascular stroma (insular pattern) and typical nuclear features: lack increased mitotic activity, necrosis TGB, TTF1 +; CAL, NE markers negative Lymph-vascular invasion, extrathyroidal extension and nodal metastases
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Undifferentiated (Anaplastic) Clinical Presentation: Thyroid Carcinoma Rapidly enlarging neck mass Long-standing history of thyroid-based mass Pathology: Absence of follicular differentiation by light microscopy and IHC Prognosis: Rapid death due to locally uncontrollable disease: median survival 3-4 months 5-year survival 3.6-10%
Poorly-Differentiated Thyroid Carcinoma Treatment and Prognosis Total thyroidectomy and radioactive iodine Extrathyroidal extension at presentation in >50% Nodal and distant metastasis at presentation in 40% and 30%, respectively Recurrence and metastasis occur after treatment in a high percentage of cases 5-year survival approximately 50% Poor prognosis: advanced age, large tumor size, extrathyroidal extension, metastasis
Poorly-Differentiated Thyroid Carcinoma Validation of Turin Proposal* Overall 5- year survival: USA = 68.6% N. Italy = 73.6% Total = 71.6% Overall 10-year survival: USA = 45.9% N. Italy = 45.7% Total = 46.3% * Asioli et al. Modern Pathol 2010;23:1269-1278
Poorly-Differentiated Thyroid Carcinoma Validation of Turin Proposal* Prognosis Univariate analysis, risk of death higher: 45 years 4cm IMP3 immunoreactivity Multivariate analysis, risk of death higher: 45 years * Asioli et al. Modern Pathol 2010;23:1269-1278
Encapsulated or Noninvasive PDTC Meets criteria of mitotic index and tumor necrosis Encapsulation (non-noninvasive)? Diagnostic terminology? Treatment? Prognosis
Encapsulated or Noninvasive Aggressive Thyroid Carcinomas Cell type: Columnar cell Tall cell Growth: Solid Insular
Encapsulated or Noninvasive Aggressive Thyroid Carcinomas Undifferentiated (Anaplastic) Carcinoma Encapsulated thyroid tumors of follicular cell origin (EFHG) with highgrade features: Rivera M, et al: Hum Pathol 2010:41:172-80
EFHG with High-Grade Features Diagnostic criteria: At least 5 mitoses/10 HPF Tumor necrosis
EFHG with High-Grade Features 25 cases: F = 17; M = 8 Age: 16-84 (median, 49 years) Noninvasive = 8 (32%) Invasive = 17 (68%): Vascular: Extensive = 6 (24%); Focal = 8 (32%) Capsular: Extensive = 1 (4%); Focal = 11 (44%)
EFHG with High-Grade Features Size: All cases 2-7cm (mean, 3.6cm; median 3.5cm) Noninvasive: median, 3.6cm; mean 4.3cm Invasive: median, 3.2cm; mean, 3.2cm
EFHG with High-Grade Features Prognosis 88% (22) free of disease: Mean, 8.5 yrs; Median, 8.9 yrs Noninvasive (8): No recurrence, median follow-up 11.9 yrs
EFHG with High-Grade Features Invasive: Prognosis Without vascular invasion did not recur or metastasize Focal vascular invasion did not recur or metastasize Extensive vascular invasion increased risk of recurrence &/or metastasis
EFHG with High-Grade Features Treatment Lobectomy 48% (12/25) Total thyroidectomy: 52% (13/25) Radioactive iodine (RAI): 32% (8/25) Noninvasive 63% (5/8) total thyroidectomy 25% (2/8) RAI
EFHG with High-Grade Features* Noninvasive: Indolent outcome Excellent prognosis Conservative management Invasive: Tumors with extensive angioinvasion at risk of recurrence/metastasis * Rivera M, et al: Hum Pathol 2010:41:172-80
Poorly-Differentiated Thyroid Carcinoma Conclusion Distinct entity defined by histologic features that may not include insular/solid growth Oncocytic variant of PDTC Biologic behavior that is distinct and intermediate between differentiated thyroid carcinomas and undifferentiated (anaplastic) carcinoma
Rare Noninvasive EFHG with High-Grade Features Meet criteria of mitotic index and tumor necrosis Adverse effect that tumor necrosis and high mitotic rate have on survival in invasive thyroid carcinomas does not hold true in encapsulated noninvasive tumors Conservative treatment Excellent prognosis
EFHG with High-Grade Features Molecular Genetics Mutations found in 45% (10/22): 8 NRAS codon 61 1 KRAS codon 61 1 BRAF V600E and AKT1 2 PAX8-PPARγ rearrangements No RET rearrangement Higher frequency of RAS (41%) than BRAF (4.5%) Mutational rate significantly higher in patients > 45 years (P =.042)
Noninvasive EFHG with High-Grade Features Preinvasive precursors of thyroid carcinomas Low-stage PDTC With necrosis Thyroid carcinoma With mitoses Follicular adenoma (with atypia)
Case 4 Diagnosis - Noninvasive Poorly-Differentiated Thyroid Carcinoma - Encapsulated thyroid tumor of follicular cell origin (EFHG) with high-grade features