WISCONSIN SOCIETY OF PATHOLOGISTS
2008 ANNUAL MEETING

Problem Cases in Thyroid Pathology

Saul Suster, M.D.
Medical College of Wisconsin
Milwaukee, WI

Case Histories

CASE 1:
Clinical History: A 56 year old woman was seen for sudden enlargement of her neck. On physical exam there was a mass in her right neck attached to underlying structures. At surgery, the tumor was deeply infiltrating the neck muscles. A subtotal resection of the right thyroid lobe was done.

CASE 2:
Clinical History: An 85 year old woman was seen for a large palpable thyroid nodule. A FNA was non-diagnostic. A right lobectomy was performed. Cut section of the specimen showed a large, apparently well-encapsulated nodule with extensive hemorrhage and infarction.

CASE 3:
Clinical History: A 54 year old man was seen for progressive enlargement of his neck. An FNA of the thyroid showed numerous lymphocytes and scant follicular cells consistent with Hashimoto’s thyroiditis. A total thyroidectomy was performed.

CASE 4:
Clinical History: A 53 year old woman was seen for a "cold" thyroid nodule in her right lobe of thyroid. A FNA yielded follicular cells with scant colloid consistent with a follicular neoplasm. A right thyroid lobectomy and isthmusectomy were done.

CASE 5:
Clinical History: A 70 year old woman with a history of previous "thyroid cancer" was seen for a recurrent mass in the right neck. The mass was resected.

CASE 6:
Clinical History: A 35 year old woman presented with a palpable neck mass. A large rubbery nodule was found in her left thyroid lobe, and a smaller nodule was noticed near the isthmus. An FNA yielded "few oxyphilic cells and scattered lymphocytes – follicular neoplasm cannot be ruled out." A thyroidectomy was performed.

CASE 7:
Clinical History: A 67 year old woman was seen for the development of a large nodule in her left neck, which had progressively enlarged over a period of 3 years. A fine needle aspiration showed oncocytic cells. A total thyroidectomy was performed.

CASE 8:
Clinical History: A 50 year old man was found to have a small palpable nodule in his left lobe of thyroid. The nodule was "cold” on scintiscan. A thyroid lobectomy with frozen section examination was undertaken.

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CASE HISTORY 1

Clinical History: A 56 year old woman was seen for sudden enlargement of her neck. On physical exam there was a mass in her right neck attached to underlying structures. At surgery, the tumor was deeply infiltrating the neck muscles. A subtotal resection of the right thyroid lobe was done.

Summary of IHC Stains

• Cytokeratin +
• Vimentin +
• Ki-67 +
• Thyroglobulin –
• Calcitonin –
• Chromogranin –
• TTF-1 –
• FVIII/CD31 -

DX:
Anaplastic Carcinoma of the Thyroid

Anaplastic Carcinoma

• Affects older individuals (>65 years)
• Female predilection
• Rapidly-enlarging, firm mass in the neck
• Dysphagia, hoarseness & dyspnea
• Hx of long-standing goiter or thyroid nodule
• Highly aggressive; median survival: 4 months

Histology

• Sarcomatoid
  • Storiform, MFH-like
  • Spindle, fibrosarcoma-like
• Epithelioid
  • Squamoid
  • Anaplastic

Differential Diagnosis for Paucicellular Variant of ATC

• Riedel’s struma
• Sclerosing variant of Hashimoto's

Riedel’s vs. Hashimoto

Riedel’s Struma:

• Idiopathic
• Irregular distribution
• Keloidal collagen
• No atypical cells
• Scant inflammation
• No extension beyond the thyroid capsule

Sclerosing HT:

• Autoimmune
• Diffuse involvement
• Irregular fibrosis with entrapped residual follicles
• Entrapped follicles with oxyphilic changes

IHC Markers in Anaplastic Ca

• Keratin + (< 50%)
• Vimentin + (100%)
• Ki-67 + (100%)
• P53 + (>50%)
• Thyroglobulin, TTF-1, Calcitonin, Chromogranin,
  CEA, CD31, S-100 protein – all negative

Pathogenesis

• De-nuovo growth
• "De-differentiation" from PTC, FTC or Hurthle cell tumors

Arch Otolaryngol Head & Neck Surg Vol.129: 96-100, 2003.

Differential Diagnosis

• Primary sarcomas of the thyroid
  • Leiomyosarcoma
  • Synovial sarcoma
  • Angiosarcoma
  • Fibrosarcoma
  • Malignant fibrous histiocytoma
• Metastatic sarcomas to the thyroid

Word of Caution….

• Pleomorphic and spindle cell tumors of the thyroid are best considered as examples of anaplastic carcinoma until proven otherwisE...

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CASE HISTORY 2

Clinical History: An 85 year old woman was seen for a large palpable thyroid nodule. A FNA was non-diagnostic. A right lobectomy was performed. Cut section of the specimen showed a large, apparently well-encapsulated nodule with extensive hemorrhage and infarction.

Summary of IHC Stains

• CD31 +
• Factor VIII +/–
• Vimentin +
• Thyroglobulin –
• CD34 –
• Keratin –
• EMA –
• CEA –
• S-100 –

DX:
Angiosarcoma of the Thyroid

Thyroid Angiosarcoma

• Extremely rare tumor
• Affects elderly patients (>65 years)
• Slight male predilection
• Symptoms: dyspnea, dysphagia
• Highly aggressive tumor; median survival 4.5 months

*Switzerland and other Alpine Countries

Histology

• Conventional type:
  Anaplastic tumor cells lining vascular spaces
• Epithelioid type:
  Composed of large epithelioid cells with abundant eosinophilic cytoplasm

Epithelioid angiosarcoma

Epithelioid angiosarcoma

Differential Diagnosis

• Anaplastic thyroid carcinoma with pseudoangiosarcomatous areas
• Medullary carcinoma with pseudoangiosarcomatous areas
• Metastatic carcinoma

Differential Diagnosis

Reactive Conditions that can Mimic Angiosarcoma
in the Thyroid

• Florid endothelial hyperplasia (Masson’s pseudoangiosarcoma)
• Post-FNA changes (hemorrhage, thrombosis, vascular proliferation)

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CASE HISTORY 3

Clinical History: A 54 year old man was seen for progressive enlargement of his neck. An FNA of the thyroid showed numerous lymphocytes and scant follicular cells consistent with Hashimoto’s thyroiditis. A total thyroidectomy was performed.

Summary of IHC Stains

• CD3-
• CD5-
• CD10-
• CD20+
• CD23-
• CD30-
• CD43-
• CD45RO-
• Bcl-1-
• Bcl-2+
• Kappa ~
• Lambda ~
  

DX:
Extranodal Marginal Zone
(MALT) lymphoma of the Thyroid

Thyroid Lymphoma

• Rare disease (~5% of all thyroid malignancies)
• More common in adults, with female predominance
• Patients present with slow enlargement of the gland
• Associated with Hashimoto’s thyroiditis
  

Histologic Types of Lymphoma of the Thyroid

• Hodgkin lymphoma
• DLBC lymphoma
• Follicular center cell lymphoma
• Mantle-cell lymphoma
• MALT lymphoma

Thyroid Lymphoma

• Associated with lymphocytic thyroiditis in >80% of patients
• ~80% patient have thyroid auto-antibodies
• Increased incidence of lymphoma is observed in patients with Hashimoto’s thyroiditis
• Majority are of large cell type (DLBCL), and are thought to be derived from low-grade MALT precursors

Extranodal Marginal Zone(MALT) Lymphoma

• Neoplastic proliferation of parafollicular (marginal zone) B-cells at mucosal sites
• Accounts for a minority of thyroid lymphomas (~3-5%)
• Affects middle-aged individuals, with no sex predilection
• Indolent growth, mainly asymptomatic
• Low-grade malignancy with good prognosis

Oncogenic Pathway in MALTomas

1. Lymphoid infiltrate in lymphocytic thyroiditis is composed of activated
2. T-helper cells T-helper cells stimulate autoreactive B-cells
3. Chronic antigenic stimulation of B-cells leads to clonal expansion and lymphoma

Morphologic Features of MALT Lymphoma in the Thyroid

• Diffuse proliferation of small lymphocytes with plasmacytoid features
• Frequent reactive germinal centers
• Colonization of germinal centers by neoplastic lymphocytes
• Formation of “lymphoepithelial” lesions
• Plugging of follicle lumens by small lymphocytes

Differential Diagnosis for MALT lymphoma of Thyroid

• Mantle-cell lymphoma
• Small lymphocytic lymphoma
• FCC lymphoma
• Florid Hashimoto’s thyroiditis

Am J Clin Pathol, Vol. 110: 327, 1998.

Molecular Studies in MALT

• Kappa/lambda light chain restriction by IHC, flow cytometry or DNA-ISH
• Heavy and light chain Ig rearrangements and VH family rearrangement by PCR

Diffuse Large B-cell Lymphoma

• Most common lymphoma of the thyroid (>80%)
• May arise in the background of MALT lymphoma
• Increased incidence in Hashimoto’s thyroiditis
• Aggressive behavior (5 year survival: 50-70%)
• Tumor deaths correlate with stage at presentation

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CASE HISTORY 4

Clinical History: A 53 year old woman was seen for a "cold" thyroid nodule in her right lobe of thyroid. A FNA yielded follicular cells with scant colloid consistent with a follicular neoplasm. A right thyroid lobectomy and isthmusectomy were done.

DX:
Follicular Variant of Papillary Thyroid Carcinoma

Follicular Variant of PTC

• Definition: a tumor with a predominant or exclusive follicular growth pattern displaying the characteristic nuclear features of PTC
• First described by Lindsay in 1960 (“Lindsay tumor”)
• Same prognosis and behavior as conventional PTC
• Two histologic types:
  • Encapsulated FVPTC
  • Widely invasive FVPTC

FVPTC: Morphologic Features

• Nuclear clearing of chromatin (“Orphan-Annie nuclei”)
• Longitudinal nuclear grooves
• Cytoplasmic invaginations into the nucleus (“nuclear pseudoinclusions”)
• Crowding and overlapping of nuclei
• Additional features: stromal fibrosis, dense colloid with scalloping, elongated and irregular shapes of the follicles, multinucleated giant cells within follicle lumens, psammoma bodies

Laryngoscope, Vol. 110:1431-1436, 2000.

Follicular Variant of Papillary Carcinoma: The Diagnostic Limitations of Preoperative Fine-Needle Aspiration and Intraoperative Frozen Section Evaluation

• 47 patients with PTC studied who had both FNA and FS done
• 24/47 patients had a final diagnosis of FVPTC
• Sensitivity for FNA in cases of FVPTC was 25%
• Sensitivity of FS in cases of FVPTC was 29%
• Sensitivity of conventional PTC for FNA was 74%
• Sensitivity of conventional PTC for FS was 87%
• CONCLUSION: “The thyroid surgeon needs to realize that, like follicular carcinoma, FVPTC is often diagnosed only on final pathological examination”

Laryngoscope, Vol.110:1432-1436, 2000.

Encapsulated FVPTC: a well-circumscribed, encapsulated follicular neoplasm with or without evidence of capsular invasion but with nuclear features of PTC.

Problem Areas in the Diagnosis ofEncapsulated FVPTC:

• Wide variation in pathologist’s perception of what constitutes the “nuclear features of PTC”
• Tumors in which the nuclear features of PTC are only seen focally within the tumor
• Tumors in which multiple microscopic foci with nuclear features suggestive of PTC are present
• Tumors in which the nuclei adopt a “pseudoclear” appearance, but no other features of FVPTC are present

Am J Surg Pathol Vol.28:1336-1340, 2004.

Percentage of Diagnoses by 10 Reviewers
in 87 Follicular Tumors

Observer Variation in the Diagnosis of Follicular Variant of Papillary Thyroid Carcinoma

• All 10 experts agreed on the diagnosis in only 39% of all cases
• All 10 experts agreed on the diagnosis in 66.7% of cases that were widely invasive and metastasized
• The lowest concordance was for well-circumscribed, non-invasive and encapsulated tumors
• CONCLUSION: “Since most cases with metastatic disease had obvious invasion, caution should be used in making a diagnosis of FVPTC in the absence of the major histopathologic features of clear-cut invasive growth”

Am J Surg Pathol 28:1336-1340, 2004.

“Strict Criteria Should be Applied in the Diagnosis of Encapsulated FVPTC”

• Major Criteria:
  1. Oval rather than round nuclei
  2. Crowding of nuclei, with lack of polarization
  3. Clear or pale nuclear chromatin or nuclear grooves
  4. Psammoma bodies
• Subsidiary Criteria:
  1. Presence of abortive papillae
  2. Predominantly elongated or irregular follicles
  3. Dark-staining colloid
  4. Presence of rare nuclear pseudoinclusions
  5. Multinucleated histiocytes within lumen of follicles

Chan JKC – Am J Clin Pathol 117:16-18, 2002

Encapsulated FVPTC –Clinical Behavior

Chernobyl Pathologists GroupInt J Surg Pathol 8:181-183, 2000.

• There are a small number of tumors in this category in which there is no vascular invasion and genuine doubt exists about capsular invasion.
• Since follicular tumors with only capsular invasion carry an extremely good prognosis, as do encapsulated FVPTC, these cases should not be subjected to further treatment (i.e., total thyroidectomy + radioactive iodine); lobectomy with clear margins is generally curative
• The terminology of “Well-differentiated tumor of uncertain malignant potential” or “Follicular tumor of uncertain malignant potential” is proposed for these lesions to avoid over-treatment and overdiagnosis

Role of Special Techniques for the Diagnosis of PTC

• “Although some IHC markers have been reported to be more commonly expressed in PTC….the “gold standard” for diagnosis is still the morphologic features” Chan JKC, Am J Clin Pathol 117, 2002.
• “One should be cautious in diagnosing PTC on the basis of IHC stains only, because some of these markers are expressed in benign thyroid lesions such as hyperplastic nodules and follicular adenoma” LiVolsi V, Adv Anat Pathol 11, 2004.
  

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CASE HISTORY 5

Clinical History: A 70 year old woman with a history of previous "thyroid cancer" was seen for a recurrent mass in the right neck. The mass was resected.

Summary of IHC Stains

• Cytokeratin AE1/AE3 +
• Thyroglobulin +
• Bcl-2 +
• Ki-67 + (~30%)
• TTF-1 +
• Calcitonin –
• Chromogranin –
• CEA -
  

DX:
Poorly-Differentiated(“Insular”) Carcinoma

Insular Carcinoma of the Thyroid

• First described by Langhans in 1907 as “wuchernde Struma” (proliferating goiter)
• Intermediate morphology between well-differentiated follicular carcinoma and anaplastic carcinoma
• Adults with female predilection
• High incidence of lymph node metastases (>60%)
• Aggressive behavior (5-year survival rate: 40%)

Morphologic Features

• Islands (“insulae”) of tumor cells with abortive follicles
• Trabecular and solid growth patterns
• Cribriform and “nested” growth
• Extensive areas of necrosis surrounding peritheliomatous tumor clusters
• Small round “primitive” cells with uniform hyperchromatic nuclei and scant cytoplasm
• Few scattered mitotic figures

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CASE HISTORY 6

Clinical History: A 35 year old woman presented with a palpable neck mass. A large rubbery nodule was found in her left thyroid lobe, and a smaller nodule was noticed near the isthmus. An FNA yielded "few oxyphilic cells and scattered lymphocytes – follicular neoplasm cannot be ruled out." A thyroidectomy was performed.

DX:
Dominant “Adenomatoid” Nodule in Nodular Hyperplasia

Nodular Hyperplasia

• Endemic goiter (iodine deficiency)
  • Parenchymatous goiter (tall follicular epithelium with scant colloid)
  • Colloid goiter (follicular atrophy with colloid accumulation)
• Sporadic goiter
  • (unknown etiology)
    

Adenomatoid Nodules with Hurthle Cell Features

• Absence of a capsule
• Multiple instead of single
• Admixed with non-oncocytic, conventional hyperplastic nodules
• Background of Hashimoto’s thyroiditis

DD of Adenomatoid Nodules

• Follicular adenoma/carcinoma
• Papillary carcinoma
• Insular carcinoma
• Hurthle cell adenoma/Ca
• Hyalinizing trabecular adenoma
• Dyshormonogenic goiter

Tips for Distinguishing Adenomatoid Nodules from other Conditions:

• Absence of a well-developed fibrous capsule
• Presence of other nodules within the gland displaying “hyperplastic” features
• Presence of Hashimoto’s or lymphocytic thyroiditis (for oncocytic adenomatoid nodules)
• Always look at the scanning magnification for features of nodular hyperplasia

Summary

• Adenomatoid nodules in nodular hyperplasia may adopt a wide variety of morphologic appearances
• The main differential diagnosis is with follicular adenomas (no clinical significance)
• Main diagnostic criterion is absence of a well-formed fibrous capsule
• Some features such as clearing of the nuclei, papillary formations, and mitotic activity may be potentially mistaken for malignancy
• Overall assessment of the entire specimen and identification of other features of hyperplasia are most helpful clues to correct diagnosis

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CASE HISTORY 7

Clinical History: A 67 year old woman was seen for the development of a large nodule in her left neck, which had progressively enlarged over a period of 3 years. A fine needle aspiration showed oncocytic cells. A total thyroidectomy was performed.

Diagnosis:

Follicular Carcinoma, Oxyphilic Cell Type (Hurthle cell carcinoma)

Hurthle cell carcinoma:

• Well-differentiated thyroid cancer of follicular cells with oxyphilic cytoplasm
• Same criteria for diagnosis as any other oxyphilic neoplasm
• Capsular and vascular invasion are indispensable for diagnosis
• Same prognosis as other comparable non oxyphilic follicular cancers
  

Hyperplasia vs. Adenoma

“A diagnosis of nodular goiter is favored over that of adenoma when a lesion occurs against a background of any significant damage to the thyroid (i.e., “nodularity”) and if the interior of the lesion is variable or shows evidence of degeneration”….

DeMay RM. Follicular lesions of the thyroid. Whither follicular carcinoma? Am J Clin Pathol 114:681-683, 2000.

“Adenoma is a lesion that shows a distinct growth pattern (which may be microfollicular, macrofollicular or trabecular), is confined within the boundaries of its capsule, and shows a different growth pattern from the surrounding thyroid parenchyma”

Baloch ZW, LiVolsi VA. Follicular-patterned lesions of the thyroid. The bane of the pathologist. Am J Clin Pathol 117:143-150, 2002.

Adenoma vs. Hyperplastic Nodule

• ADENOMA: “An encapsulated, solitary follicular lesion that does not show evidence of hyperplastic changes in the rest of the thyroid”…
• HYPERPLASTIC NODULE: “Any follicular lesion that is not encapsulated and shows hyperplastic changes elsewhere in the gland, regardless of its cell composition, regressive changes, or dissimilarity with the surrounding parenchyma”…

Adenoma Nodule

• A well circumscribed but unencapsulated follicular nodule in which the follicular cell population is different from that of the surrounding uninvolved normal parenchyma, and which is generally associated with hyperplastic changes in the rest of the gland…
  

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CASE HISTORY 8

Clinical History: A 50 year old man was found to have a small palpable nodule in his left lobe of thyroid. The nodule was "cold” on scintiscan. A thyroid lobectomy with frozen section examination was undertaken.

Diagnosis:
Hyalinizing Trabecular Adenoma of Carney

Hyalinizing Trabecular Adenoma

• Well-circumscribed and encapsulated
• Prominent trabecular or “neuroendocrine” growth pattern
• Prominent stromal and cytoplasmic hyalinization
• Longitudinal grooves, pseudonuclear inclusions and psammoma bodies
• Benign clinical behavior

Differential diagnosis:

• Neuroendocrine neoplasms:
  • Paraganglioma
  • Medullary carcinoma
• Papillary thyroid carcinoma due to:
  • Psammoma bodies
  • Longitudinal grooves
  • Nuclear pseudoinclusions

IHC Stains:

• Thyroglobulin +
• TTF1 +
• MIB-1 + (membranous pattern)
• Chromogranin –
• Calcitonin –
• NSE -

Am J Surg Pathol 32:622-634, 2008.

Hyalinizing Trabecular Adenoma

• Well-circumscribed and encapsulated lesion
• 0.3 – 4 cm. in size
• Population of oval or polygonal cells with trabecular arrangement
• May have a paraganglioma-like growth pattern
• Abundant hyalinized amyloid-like stroma
• Nuclear features resemble papillary carcinoma (grooves, pseudoinclusions)
• Psammoma bodies
• Lesions are not invasive, do not recur or metastasize

Ultrastructural Observations

• Abundant cytoplasmic intermediate filaments
• Abundant extracellular basement membrane material
• Lysosomal dense bodies present but no membrane-bound dense-core granules
• Giant secondary lysosomes of multivesicular body-type correspond to pale yellow cytoplasmic inclusions seen on H&E

IHC Observations

• Collagen type-IV stains hyalinized material (=basement membrane material produced by the epithelial cells)
• Thyroglobulin and TTF1 positive
• Calcitonin negative
• Occasional tumors have shown isolated positivity for chromogranin, somatostatin and argyrophilic stains
• Diffuse MIB-1 cytoplasmic positivity
• CK19 and HMW-CK negative
• HBME-1 negative or rarely positive
• Galectin-3 negative in 60% of cases

Molecular Genetic Findings

• RET/PTC1 rearrangements found in 3 cases (Papotti et al, 2000)
• RET/PTC1 rearrangements by PCR in 8 cases (Cheung, 2000)
• BRAF mutations not found in HTA but in 35% of PTC (Trovisco, 2004)

Controversies:

• “Hyalinizing trabecular tumor” (HTT) proposed by Franc in 1989, and adopted by WHO (Pathology & Genetics of Tumors of Endocrine Organs, DeLellis et al, IARC, 2004)
• “Hyalinizing trabecular neoplasm” (LiVolsi) proposed to indicate uncertain malignant potential
• “Papillary carcinoma, hyalinizing trabecular type”
• “Hyalinizing trabecular carcinoma”
• V. LiVolsi: “I believe that that hyalinizing trabecular tumors of the thyroid are neoplasms of very low malignant potential because I have yet to encounter a classic one that has behaved in a malignant fashion”
• R. Lloyd: “Since most of the cases of hyalinizing trabecular tumors in the literature are benign, these tumors should probably only be considered malignant when there is obvious invasion through the capsule, blood vessels or metastasis”
• A. Carney: “The clinical and pathological findings in my collection of more than 100 cases with long-term follow-up provide persuasive evidence for the existence of a hyalinizing trabecular tumor with a benign natural history, in other words, a hyalinizing trabecular adenoma”

Hyalinizing Trabecular Carcinoma

• Requires clear cut evidence of complete penetration and invasion of the capsule or vascular invasion
• Recurrence
• Metastasis
• Very few cases described; some may correspond to other entities
• According to A. Carney, he’s only witnessed 1 case that qualifies for that diagnosis from more than 100 cases studied

Is HTT a form of PTC?

• “Histologic, immunocytochemical, and molecular genetic studies show similarities and dissimilarities between them. The tumors share properties that may or may not indicate a molecular genetic connection between them. HTA likely has not accumulated sufficient genetic abnormalities to result in malignant transformation as manifested by invasion and metastasis”
  J. Aidan Carney, Am J Surg Pathol, 2008.
  

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