Ninety-four cases of encapsulated follicular variant of papillary thyroid carcinoma: A name change to Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features would help prevent overtreatment

Thompson, LD.
Mod Pathol. 2016 Jul;29(7):698-707.
Encapsulated follicular variant of papillary thyroid carcinoma is a common thyroid gland cancer, with a highly indolent behavior. Recently, reclassification as a non-malignant neoplasm has been proposed. There is no comprehensive, community hospital based longitudinal evaluation of encapsulated follicular variant of papillary thyroid carcinoma. Ninety-four cases of encapsulated follicular variant of papillary thyroid carcinoma were identified in a review of all thyroid gland surgeries performed in 2002 within the Southern California Permanente Medical Group. All histology slides were reviewed and follow-up obtained. Seventy-five women and nineteen men, aged 20-80 years (mean 45.6 years), had a single (n=61), multiple (same lobe; n=20), or bilateral (n=13) tumor(s), ranging in size from 0.7 to 9.5 cm in diameter (mean 3.3 cm). Histologically, all cases demonstrated a well-formed tumor capsule, with capsular and/or lymphovascular invasion in 17 and no invasion in 77 cases. Lymph node metastases were not identified. The tumors had a follicular architecture, without necrosis or 43 mitoses/10 high-power fields (HPFs). Classical papillary thyroid carcinoma nuclear features were seen in at least three HPFs per 3mm of tumor diameter, including enlarged, elongated, crowded, and overlapping nuclei, irregular nuclear contours, nuclear grooves, and nuclear chromatin clearing. Lobectomy alone (n=41), thyroidectomy alone (n=34), or completion thyroidectomy (n=19) was the initial treatment combined with post-op radioablative iodine in 25 patients. All patients were without evidence of disease after a median follow-up of 11.8 years. Encapsulated follicular variant of papillary thyroid carcinoma showed benign behavior, supporting conservative surgery alone and reclassification of these tumors to Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP).
PubMed ID: 27102347
Article Size: <1 MB

Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma: A Paradigm Shift to Reduce Overtreatment of Indolent Tumors.

Nikiforov YE, Seethala RR, Tallini G, Baloch ZW, Basolo F, Thompson LD, Barletta JA, Wenig BM, Al Ghuzlan A, Kakudo K, Giordano TJ, Alves VA, Khanafshar E, Asa SL, El-Naggar AK, Gooding WE, Hodak SP, Lloyd RV, Maytal G, Mete O, Nikiforova MN, Nosé V, Papotti M, Poller DN, Sadow PM, Tischler AS, Tuttle RM, Wall KB, LiVolsi VA, Randolph GW, Ghossein RA.
JAMA Oncol. 2016 Aug 1;2(8):1023-9.
IMPORTANCE: Although growing evidence points to highly indolent behavior of encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC), most patients with EFVPTC are treated as having conventional thyroid cancer.
OBJECTIVE: To evaluate clinical outcomes, refine diagnostic criteria, and develop a nomenclature that appropriately reflects the biological and clinical characteristics of EFVPTC.
DESIGN, SETTING, AND PARTICIPANTS: International, multidisciplinary, retrospective study of patients with thyroid nodules diagnosed as EFVPTC, including 109 patients with noninvasive EFVPTC observed for 10 to 26 years and 101 patients with invasive EFVPTC observed for 1 to 18 years. Review of digitized histologic slides collected at 13 sites in 5 countries by 24 thyroid pathologists from 7 countries. A series of teleconferences and a face-to-face conference were used to establish consensus diagnostic criteria and develop new nomenclature.
MAIN OUTCOMES AND MEASURES: Frequency of adverse outcomes, including death from disease, distant or locoregional metastases, and structural or biochemical recurrence, in patients with noninvasive and invasive EFVPTC diagnosed on the basis of a set of reproducible histopathologic criteria.
RESULTS: Consensus diagnostic criteria for EFVPTC were developed by 24 thyroid pathologists. All of the 109 patients with noninvasive EFVPTC (67 treated with only lobectomy, none received radioactive iodine ablation) were alive with no evidence of disease at final follow-up (median [range], 13 [10-26] years). An adverse event was seen in 12 of 101 (12%) of the cases of invasive EFVPTC, including 5 patients developing distant metastases, 2 of whom died of disease. Based on the outcome information for noninvasive EFVPTC, the name “noninvasive follicular thyroid neoplasm with papillary-like nuclear features” (NIFTP) was adopted. A simplified diagnostic nuclear scoring scheme was developed and validated, yielding a sensitivity of 98.6% (95% CI, 96.3%-99.4%), specificity of 90.1% (95% CI, 86.0%-93.1%), and overall classification accuracy of 94.3% (95% CI, 92.1%-96.0%) for NIFTP.
CONCLUSIONS AND RELEVANCE: Thyroid tumors currently diagnosed as noninvasive EFVPTC have a very low risk of adverse outcome and should be termed NIFTP. This reclassification will affect a large population of patients worldwide and result in a significant reduction in psychological and clinical consequences associated with the diagnosis of cancer.
PubMed ID: 27078145

Update on follicular variant of papillary thyroid carcinoma with an emphasis on new terminology: noninvasive follicular thyroid neoplasm with papillary-like nuclear features

Thompson, LDR.
Diagnostic Histopathology 2016.
The most common papillary thyroid carcinoma (PTC) variant is the follicular variant, representing w30% of all PTCs. The tumour is most common in middle aged (4th e 5th decades) women, who usually present with a single dominant nodule (about 3 cm). By definition, follicular architecture must be the dominant finding, while demonstrating the nuclear features of PTC. Papillary structures are <1% of volume, while necrosis, increased mitoses (>3/10 high power fields) and psammoma bodies are absent. The tumour category is divided into “encapsulated/well demarcated” and “invasive” types. The nuclear features include enlarged, elongated and overlapping nuclei; membrane irregularities (irregular contours, grooves and pseudoinclusions); chromatin clearing, margination and glassy nuclei. When the tumour is encapsulated/well demarcated without invasion, demonstrating the other inclusion and exclusion criteria, the new name of “Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features” (NIFTP) is used, a tumour that requires no additional treatment.
Article Size: 8.4 MB

A Clinicopathologic Series of 685 Thyroglossal Duct Remnant Cysts

Thompson LD, Herrera HB, Lau SK.
Head Neck Pathol. 2016 May 9. [Epub ahead of print]
The clinical features of thyroglossal duct remnant cysts (TGDC) have been well described, however the histopathologic aspects of these lesions have not been addressed in a detailed manner. In particular, there has been no large community practice based series evaluating TGDC histologically compared with management outcomes. A retrospective review of all TGDC diagnosed between 2005 and 2015 was performed. Six hundred eighty-five patients were identified (344 males; 341 females). Age at presentation was bimodal (first and fifth decades) and ranged from 0.8 to 87 years (mean 31.3 years). Males predominate in children (150:111); females in adults (230:194). Patients presented most frequently with a mobile midline neck mass in an infrahyoid location. An associated skin fistula (n = 67) was twice as common in pediatric as adult patients. The average cyst size was 2.4 cm (range 0.4-9.9 cm) by imaging studies and 2.6 cm (range 0.2-8.5 cm) by pathologic examination; pediatric patients had smaller cysts (mean 2.1 cm) than adults (mean 2.8 cm). Histologically, 257 (38 %) TGDC were lined by respiratory epithelium alone, 68 (10 %) squamous epithelium alone, 347 (51 %) exhibited both respiratory and squamous epithelium, and 13 (1 %) had no identifiable epithelial lining. Four hundred eighty-four (71 %) TGDC had associated thyroid gland tissue present within the cyst wall (n = 282), skeletal muscle (n = 71), adipose tissue (n = 34), or a combination of these sites (n = 97). The hyoid bone was identified in 647 (grossly and/or histologically), and absent in 38. Surgical management consisted of Sistrunk procedure (n = 647), cystectomy (n = 31), or thyroidectomy/thyroid lobectomy (n = 7). Treatment related complications were observed in 6 patients, which included vocal cord damage, seroma, and hematoma. Recurrences developed in 20 (3 %) patients, 14 of whom were managed initially by cystectomy. Papillary thyroid carcinoma was identified in 22 (3.2 %) TGDC. In summary, TGDC show a bimodal peak in the 1st and 5th decades, commonly presenting as a midline cervical lesion below the hyoid bone, associated with a skin fistula in 10 %. Histologically TGDC are most commonly lined by a combination of respiratory and squamous epithelium. Thyroid gland tissue is identified in 71 % of cases (0.45 cm mean size), although not limited to the cyst wall, but present in the surrounding soft tissues. Rare TGDC may harbor malignancy (3.2 %). TGDC are most effectively managed by Sistrunk procedure rather than excision, which carries low rates of complications (1 %) and recurrence (3 %).
PubMed ID: 27161104
Article Size: 2.7 MB

Thyroglossal Duct Cyst Carcinomas: A Clinicopathologic Series of 22 Cases with Staging Recommendations

Thompson LD, Herrera HB, Lau SK.
Head Neck Pathol. 2016 Oct 4. [Epub ahead of print].
Carcinomas arising from thyroglossal duct remnant cysts (TGDCs) are rare, without well-defined management and staging criteria. All TGDCs (n = 685) diagnosed between 2005 and 2015 were retrospectively reviewed, with 22 carcinomas identified (3.2 % incidence). Twenty-two patients (17 females, 5 males), aged 12-64 years (mean 39.9 years; median 39 years) were identified. An anterior, superior midline neck mass was the presenting symptom in all patients. A cancer diagnosis [all papillary thyroid carcinoma (PTC)] was made after the Sistrunk procedure (SP), with a Bethesda Category V or VI classification preoperatively by fine needle aspiration in 5 of 12 cases tested. A SP was performed in all patients, with total thyroidectomy concurrently (n = 4) or subsequently (n = 12). A selected neck dissection was performed in 5 patients, with metastases found in 3. Of the patients who had a thyroidectomy, synchronous PTC was identified in 6 (thus, 6 of 22 patients had synchronous thyroid gland primaries). This supports an origin from extra-thyroidal remnants (cyst origin) rather than metastatic tumor from a thyroid gland primary. Follow-up radioactive iodine therapy was performed in 13 patients. Metastatic disease to local lymph nodes 57 months after presentation was seen in 1 patient, with all others alive and disease free (mean 3.8 years; range 0.4-10.8 years). The TGDCs ranged from 0.8 to 5 cm (mean 2.3 cm), while the PTCs ranged from 0.1 to 3.8 cm (mean 1.4 cm). All of the tumors were classical PTC, showing a sclerotic and infiltrative pattern, with a capsule present in 11. Lymphovascular invasion was detected in 11; margins were positive in 6. Using currently defined criteria, the patients were separated into AJCC stage group I (n = 21) or II (n = 1). However, if extension into the adipose tissue (n = 11), skeletal muscle (n = 10), or perineural/perivascular tissues (n = 10) were used to stage the patients, interpreted to represent the equivalent of “extrathyroidal extension” (n = 13) as defined for thyroid gland primaries, there would be 15 group I and 7 group III cases. All seven group III patients were ≥45 years. Three of four patients with lymph node metastasis also showed soft tissue extension. In conclusion, TGDC carcinomas (TGDCCa) are uncommon, with all classical PTC. For “microcarcinomas” (≤1 cm), conservative management can be used for patients <45 years (i.e., Sistrunk procedure only); for >1 cm tumors, and due to the high incidence of concurrent papillary carcinoma and higher stage at presentation in older patients, completion thyroidectomy is recommended for patients ≥45 years. Thus, even though a good prognosis can be expected for PTC developing in TGDCs, staging is advocated to more appropriately match therapeutic interventions.
PubMed ID: 27704385
Article Size: 2.5 MB

A clinicopathologic study of minimally invasive follicular carcinoma of the thyroid gland with a review of the English literature.

Thompson LD, Wieneke JA, Paal E, Frommelt RA, Adair CF, Heffess CS.
Cancer. 2001 Feb 1;91(3):505-24.
BACKGROUND: The criteria for minimally invasive (low grade) follicular carcinoma of the thyroid (MI) remain controversial, often resulting in unnecessary treatment.
METHODS: The records of 130 patients with minimally invasive (MI) follicular thyroid carcinoma were retrieved from the files of the Endocrine Tumor Registry of the Armed Forces Institute of Pathology.
RESULTS: Ninety-five patients were confirmed to have MI based on the authors’ criteria of small-to-medium vessel invasion, capsular invasion of up to full thickness, no parenchymal tumor extension, and no tumor necrosis (patients with oxyphilic tumors were excluded). The remaining 35 patients had tumors that were reclassified as ‘not low grade’ based on large vessel invasion, extension into parenchyma, and tumor necrosis (oxyphilic cases excluded). The MI patients included 67 women and 28 men, ages 20-95 years (average, 42.0 years). Nearly all patients presented with a thyroid mass (n = 90 patients). The mean tumor size was 2.8 cm. Histologic features examined for tumor classification included cellularity, capsule nature, capsular invasion, vascular invasion, extension into parenchyma, cytoplasmic oxyphilia, mitotic activity, and necrosis. All patients were treated with surgical excision. Adjuvant radioactive iodine therapy was performed in 24 patients. Five patients developed recurrent disease: four were alive or had died without evidence of disease after additional treatment (mean, 18.1 years), and one patient died with disease (MI tumor) at 15.1 years. All of the remaining patients were disease free (mean follow-up, 16.5 years).
CONCLUSIONS: There are reproducible histologic criteria to diagnose patients with MI follicular carcinoma. The overall excellent long term prognosis and a good patient outcome suggests that no additional surgery is necessary. Copyright 2001 American Cancer Society.
PubMed ID: 11169933
Article Size: 2 MB

Malignant lymphoma of the thyroid gland: a clinicopathologic study of 108 cases.

Derringer GA, Thompson LD, Frommelt RA, Bijwaard KE, Heffess CS, Abbondanzo SL.
Am J Surg Pathol. 2000 May;24(5):623-39.
We report a retrospective clinicopathologic study of 108 primary thyroid gland lymphomas (PTLs), classified using the REAL and proposed WHO classification schemes. The patients included 79 women and 29 men, with an average age of 64.3 years. All patients presented with a thyroid mass. The PTLs were classified as marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) or MZBL (n = 30), diffuse large B-cell lymphoma (DLBCL) with MZBL (n = 36), DLBCL without MZBL (n = 41), and follicle center lymphoma (FCL; n = 1). Excluding the FCL, features of lymphomas of MALT-type were identified in all groups, despite a follicular architecture in 23% of cases. Lymphocytic thyroiditis (LT) was identified in 94%. Ninety-one percent of patients presented with stage IE or IIE disease, whereas 69% had perithyroidal soft tissue infiltration. All patients were treated with surgical excision followed by adjuvant therapy (76%): chemotherapy (15%), radiation (19%), or a combination of radiation and chemotherapy (42%). Disease-specific survival was 82% at last follow up (mean, 82.8 mos) and 79% at 5 years. Statistically, stages greater than IE, presence of DLBCL, rapid clinical growth, abundant apoptosis, presence of vascular invasion, high mitotic rate, and infiltration of the perithyroidal soft tissue were significantly associated with death with disease. No patients with MZBL or stage IE disease died with disease. In summary, PTLs typically occur in middle- to older-aged individuals as a thyroid mass, with a predilection for females. Despite their histologic heterogeneity and frequent simulation of other lymphoma subtypes, virtually all PTLs are lymphomas of MALT-type arising in the setting of LT. Mixed DLBCL and MZBL are common. Overall, PTLs have a favorable outcome with appropriate therapy, but prognosis depends on both clinical stage and histology. MZBL and stage IE tumors have an excellent prognosis, whereas tumors with a large cell component or DLBCL or stage greater than IE have the greatest potential for a poor outcome.
PubMed ID: 10800981
Article Size: 4 MB

Primary thyroid teratomas: a clinicopathologic study of 30 cases.

Thompson LD, Rosai J, Heffess CS.
Cancer. 2000 Mar 1;88(5):1149-58.
BACKGROUND: Primary thyroid teratomas are rare thyroid gland neoplasms of germ cell derivation that display features of trilineage differentiation.
METHODS: The histologic and immunophenotypic features of 30 cases of thyroid teratomas were reviewed, patient follow-up was obtained, and the results were analyzed statistically.
RESULTS: The patients included 15 females and 15 males ages newborn-56 years (mean, 12.4 years). All patients presented clinically with a mass in the thyroid, ranging in size from 2.0-13 cm in greatest dimension (mean, 6.0 cm). Histologically, the tumors usually were well circumscribed, although occasionally infiltrative into the thyroid parenchyma. Derivatives of all three germ layers (ectoderm, mesoderm, and endoderm) were present in varying degrees of maturity. The tumors were divided into benign (n = 7 tumors), immature (n = 14 tumors), and malignant (n = 9 tumors) as determined by an increasing percentage of tumor volume comprised of primitive mesenchymal or neural-type tissue. All the microscopically malignant tumors occurred in the adult population. Surgical excision was performed in 28 patients, followed by adjuvant therapy in 5 patients. Follow-up was obtained in 26 patients; 8 patients had died from or with tumor (5 neonates with immature histology and 3 adults with malignant histology; mean, 0.6 years) and 18 patients were alive with no evidence of disease at a mean of 16.9 years of follow-up.
CONCLUSIONS: Thyroid teratomas are rare neoplasms that can be divided into three types depending on the presence and proportion of the immature component. The outcome is dependent largely on the age of the patient, the size of the tumor at the time of initial presentation, and the presence and proportion of immaturity. Surgical excision is the treatment of choice, with adjuvant therapy reserved for the malignant cases. Copyright 2000 American Cancer Society.
PubMed ID: 10699906
Article Size: <1 MB

A rationale for conservative management of microscopic papillary carcinoma of the thyroid gland: a clinicopathologic correlation of 90 cases.

Rassael H, Thompson LD, Heffess CS.
Eur Arch Otorhinolaryngol. 1998;255(9):462-7.
Microscopic papillary carcinoma of the thyroid gland (MPC) measuring < or = 1.0 cm in diameter has a generally benign outcome, but is often overtreated with additional surgery. Ninety cases of MPC and 77 cases of nonmicroscopic papillary carcinoma of the thyroid gland (non-MPC) from 1970 to 1980 were retrieved from the Endocrine Registry of the Armed Forces Institute of Pathology (AFIP), Washington, D.C. Histologic features and patient follow-up were analyzed. Twenty-one patients with MPC had multifocal disease within the affected thyroid lobe, while a further 15 had either bilateral or intraglandular spread. Four of 10 patients who had additional surgery were found to have additional foci of tumor. Fourteen patients with lymph node metastases at initial surgery had no subsequent nodal metastases. All patients were either alive without disease or had died of unrelated causes after an average follow-up period of 17.3 years. Of the 77 non-MPC patients, 13 developed lymph node metastases or local recurrences, and one died of metastatic disease. Sixty-four of these patients were alive without evidence of disease after an average follow-up of 22 years. Present findings show that while MPC may present with perithyroidal lymph node metastases (15.56%), patients do not develop clinical tumors in the remaining thyroid tissue. Our experience indicates that close clinical follow-up without additional surgery is the preferable management for patients with MPC.
PubMed ID: 9833215
Article Size: <1 MB

Thyroid papillary carcinoma of columnar cell type: a clinicopathologic study of 16 cases.

Wenig BM, Thompson LD, Adair CF, Shmookler B, Heffess CS.
Cancer. 1998 Feb 15;82(4):740-53. — Comment in: Cancer. 1998 Dec 1;83(11):2421-3.
BACKGROUND: Thyroid papillary carcinoma of columnar cell type is considered an uncommon histologic subtype of papillary carcinoma characterized by its morphologic features and purportedly aggressive biologic course.
METHODS: Sixteen cases of thyroid papillary carcinoma of columnar cell type were identified from the Endocrine Tumor Registry at the Armed Forces Institute of Pathology and the Washington Hospital Center. Clinical records and follow-up were available in all cases. Paraffin blocks were available for histochemical and immunohistochemical studies in 15 of the 16 cases.
RESULTS: Of the 16 cases reported, 13 patients were female and 3 were male. The ages ranged from 16-76 years (average, 47 years; median, 40 years). An asymptomatic neck mass was the most common clinical presenting symptom. Macroscopically, the tumors varied from circumscribed or encapsulated to infiltrative, ranging in size from 1.5-6.5 cm. Histologically, the tumors had diverse growth patterns, including papillary, solid, microfollicular, and cribriform. A common pattern was the presence of markedly elongated follicles arranged in parallel cords. Colloid-filled follicles could be found, at least focally, in all cases. The characteristic histologic appearance included the presence of elongated cells showing nuclear stratification. Other features included the presence of vacuolated-appearing cells, spindle-shaped cells, and squamoid nests. Limited areas in the tumors showed morphologic features typical of thyroid papillary carcinoma. In 14 of the cases, the tumor was encapsulated, showed limited invasive growth, or was a microscopic tumor. In two of the cases, there was extrathyroidal invasion. Immunohistochemical studies showed consistent reactivity with cytokeratin and vimentin; varied reactivity with thyroglobulin, epithelial membrane antigen, carcinoembryonic antigen, and LeuM1; and no reactivity with calcitonin or chromogranin. Treatment was by surgical resection; supplemental radioactive iodine therapy was administered in eight patients. Follow-up was available for all patients, 13 of whom (81%) were alive and free of disease or had died of unrelated causes over periods ranging from 2-11 years (average, 5.8 years). All 13 of these patients had tumor confined completely to the thyroid gland. One patient died 4 months after diagnosis secondary to sepsis. Two patients (17%) had aggressive biologic courses. In both patients there was extrathyroidal invasion. One of these patients died of metastatic disease to the lungs 3 years after diagnosis; the other was alive with bilateral pulmonary metastases 9 years after the diagnosis.
CONCLUSIONS: The findings of the current study indicate that thyroid papillary carcinoma of columnar cell type is a distinct morphologic type but not a distinct clinical type of thyroid papillary carcinoma. The biologic behavior of this tumor is predicated on clinical stage, with the presence or absence of extrathyroidal invasion being the single most important parameter. Treatment of patients with these tumors should be based on the clinical stage and not on the morphologic appearance.
PubMed ID: 9477108
Article Size: 3 MB

Metastatic renal cell carcinoma to the thyroid gland: a clinicopathologic study of 36 cases.

Heffess CS, Wenig BM, Thompson LD.
Cancer. 2002 Nov 1;95(9):1869-78.
BACKGROUND: Clear cell tumors of the thyroid gland in general are uncommon. Metastatic renal cell carcinoma (RCC) to the thyroid gland is a rare occurrence but must be considered in the differential diagnosis of a thyroid gland clear cell neoplasm to prevent misclassification, potentially resulting in inappropriate clinical management.
METHODS: Thirty-six cases of metastatic RCC to the thyroid were retrospectively retrieved from the files of the Endocrine Registry of the Armed Forces Institute of Pathology.
RESULTS: The tumors occurred in 22 women and 14 men, ages 53-80 years (mean, 64.9 years). Symptoms were present for a mean of 13.0 months. The tumors generally affected a single lobe of the thyroid gland as a solitary mass (n = 30; 83%), measuring 1.0-15.0 cm in diameter (mean, 3.8 cm). Histologically, the tumors were composed of polygonal cells with clear cytoplasm, distinct cell membranes, and small compact eccentric nuclei within a rich vascular network. Diastase-sensitive, periodic acid-Schiff-positive material (n = 22; 61%) and/or Oil Red O-positive material (n = 5; 14%) were noted. Thyroglobulin immunohistochemistry was negative in the foci of metastatic RCC. Although the majority of the patients had documented previous evidence of an RCC (n = 23; 64%) as remotely as 21.8 years before the thyroid metastases (mean, 9.4 years), the metastatic tumor to the thyroid gland was the initial manifestation of RCC in 13 patients. The majority of patients (n = 23; 64%) died with disseminated disease (mean, 4.9 years), but 13 patients (36%) were alive or had died without evidence of disease (mean, 9.1 years).
CONCLUSIONS: In the presence of a clear cell tumor of the thyroid gland, the diagnostic considerations must include metastatic RCC. The light microscopic features may suggest this possibility and the diagnosis can be established by supplemental histochemical and immunohistochemical studies. Surgical treatment of the metastatic disease is suggested, as this may result in prolonged patient survival. Published 2002 by the American Cancer Society.
PubMed ID: 12404280
Article Size: 2 MB

Diffuse sclerosing variant of papillary thyroid carcinoma: a clinicopathologic and immunophenotypic analysis of 22 cases.

Thompson LD, Wieneke JA, Heffess CS.
Endocr Pathol. 2005 Winter;16(4):331-48.
BACKGROUND: The diffuse sclerosing variant of papillary thyroid carcinoma (DSV-PTC) is an uncommon tumor making up about 2% of all papillary thyroid carcinomas. Previous studies have not comprehensively evaluated these tumors in a large series of patients.
DESIGN: Twenty-two cases of DSV-PTC diagnosed between 1970 and 2000 were identified in the files of the AFIP. Histologic and immunohistochemical features were evaluated and patient follow-up was obtained.
RESULTS: The tumors affected 14 females and 8 males, aged 6 to 49 yr (mean, 18 yr), with males presenting at a mean older age than females (24 vs 14 yr). Symptoms included an enlarging mass in the thyroid, present for a mean of 9.5 mo. While a dominant tumor was identified in a single lobe, bilateral disease was common (n = 16). The dominant mass ranged in size from 1.7 to 5.8 cm in diameter (mean, 3.8 cm). Histologically, all cases demonstrated a papillary carcinoma (conventional, solid, or follicular pattern) diffusely involving the gland. Extrathyroidal extension, lymphocytic thyroiditis, squamous metaplasia, increased fibrosis/sclerosis, and psammoma bodies were present to a variable degree. Both the papillary carcinoma and squamous metaplasia cells were strongly immunoreactive with CK19, thyroglobulin, and TTF-1. An increased number of S-100 protein immunoreactive dendritic cells were recognized. p53 was increased (>15%) in the tumor cells in 12 patients, while Ki-67 was increased in the tumor cells in two patients. Perithyroidal and cervical lymph node metastasis occurred in 18 (82%) patients. All metastases demonstrated histologic features similar to the primary. Complete resection (thyroidectomy in 18 patients) with lymph node dissection, yielded a 95% 5-yr survival without evidence of disease. One patient died of disease after a malignant transformation of the squamous metaplasia into squamous cell carcinoma.
CONCLUSIONS: The recognition of DSV-PTC can be made with the following features: classic to solid foci of PTC, lymphocytic thyroiditis, squamous metaplasia, increased fibrosis, and innumerable psammoma bodies. DSV-PTC is more biologically aggressive than conventional PTC, but the patients’ survival is not significantly different. This diagnosis should lead the clinician to aggressively manage these patients (thyroidectomy and lymph node dissection) in an effort to achieve an excellent long-term clinical outcome.
PubMed ID: 16627920
Article Size: <1 MB

Peripheral Nerve Sheath Tumors of the Thyroid Gland: A Series of Four Cases and a Review of the Literature.

Thompson LD, Wenig BM, Adair CF, Heffess CS.
Endocr Pathol. 1996 Winter;7(4):309-318.
Primary peripheral nerve sheath tumors (PNSTs) of the thyroid gland are exceptionally rare. Two schwannomas and two malignant PNSTs (MPNSTs), arising primarily within the thyroid gland, were identified in the files of the Endocrine Tumor Registry at the Armed Forces Institute of Pathology. The patients included two females, age 69 and 80 yr, and two males, age 18 and 33 yr. The patients presented with a mass in the thyroid gland confined to a single lobe of the thyroid without involvement of the cervical neck region. None of the patients had a history of neurofibromatosis. The benign tumors were encapsulated, one of them cystic, with the characteristic cellular and nuclear features of schwannomas. The MPNSTs were invasive tumors, effacing the thyroid parenchyma, with a fascicular pattern of growth composed of neural appearing cells with increased cellularity, increased mitotic activity, and with focal necrosis. Immunoreactivity for 5100 protein and vimentin was seen in all tumors. The patients with schwannomas, treated only by surgical resection, were alive without evidence of disease, over a period of 5-33 yr. Both patients with MPNSTs died of the disease 8 mo and 42 mo, respectively, with widely disseminated disease. Primary thyroid PNSTs are exceptionally rare tumors. MPNSTs, in this limited experience, have a fatal outcome irrespective of aggressive adjuvant therapy.
PubMed ID: 12114802
Article Size: 5 MB

Inter-Observer Variation in the Pathologic Identification of Minimal Extrathyroidal Extension in Papillary Thyroid Carcinoma.

Su HK, Wenig BM, Haser GC, Rowe ME, Asa SL, Baloch Z, Du E, Faquin WC, Fellegara G, Giordano T, Ghossein R, LiVolsi VA, Lloyd R, Mete O, Ozbek U, Rosai J, Suster S, Thompson LD, Turk AT, Urken ML.
Thyroid. 2016 Apr;26(4):512-7.
BACKGROUND: Extrathyroidal extension (ETE) is a significant prognostic factor in papillary thyroid carcinoma (PTC). Minimal extrathyroidal extension (mETE) is characterized by involvement of the sternothyroid muscle or perithyroid soft tissue, and is generally identified by light microscope examination. Patients with mETE, identified pathologically, are automatically upstaged to pT3. However, the prognostic implications of mETE have been a source of controversy in the literature. Moreover, there is also controversy surrounding the identification of mETE on pathological specimens. The objective of this study was to determine the level of agreement among expert pathologists in the identification of mETE in PTC cases.
METHODS: Eleven expert pathologists from the United States, Italy, and Canada were asked to perform a review of 69 scanned slides of representative permanent sections of PTC specimens. Each slide was evaluated for the presence of mETE. The pathologists were also asked to list the criteria they use to identify mETE.
RESULTS: The overall strength of agreement for identifying mETE was slight (κ = 0.14). Inter-pathologist agreement was best for perithyroidal skeletal muscle involvement (κ = 0.46, moderate agreement) and worst for invasion around thick-walled vascular structures (κ = 0.02, slight agreement). In addition, there was disagreement over the constellation of histologic features that are diagnostic for mETE, which affected overall agreement for diagnosing mETE.
CONCLUSIONS: Overall agreement for the identification of mETE is poor. Disagreement is a result of both variation in individual pathologists’ interpretations of specimens and disagreement on the histologic criteria for mETE. Thus, the utility of mETE in staging and treatment of PTC is brought into question. The lack of concordance may explain the apparent lack of agreement regarding the prognostic significance of this pathologic feature.
PubMed ID: 26953223
Article Size: <1 MB

Inter-Observer Variation in the Pathologic Identification of Extranodal Extension in Nodal Metastasis from Papillary Thyroid Carcinoma

Du E, Wenig BM, Su HK, Rowe ME, Haser GC, Asa SL, Baloch Z, Faquin WC, Fellegara G, Giordano T, Ghossein R, LiVolsi VA, Lloyd R, Mete O, Ozbek U, Rosai J, Suster S, Thompson LD, Turk AT, Urken ML.
Thyroid. 2016 Jun;26(6):816-9.
Background: Extranodal extension (ENE) in lymph node metastases has been shown to worsen the prognosis of papillary thyroid cancer (PTC). Despite the clinical significance of ENE, there are no stringent criteria for its microscopic diagnosis, and its identification is subject to inter-observer variability. The objective of this study was to determine the level of agreement among expert pathologists in the identification of ENE in PTC cases.
Methods: Eleven expert pathologists from the United States, Italy, and Canada were asked to review 61 scanned slides of representative permanent sections of PTC specimens from Mount Sinai Beth Israel Medical Center in New York. Each slide was evaluated for the presence of ENE. The pathologists were also asked to report the criteria they use to identify ENE.
Results: The overall strength of agreement in identifying ENE was only fair (j = 0.35), and the proportion of observed agreement was 0.68. The proportions of observed agreement for the identification of perinodal structures (fat, nerve, skeletal, and thick-walled vessel involvement) ranged from 0.61 to 0.997.
Conclusions: Overall agreement for the identification of ENE is poor. The lack of agreement results from both variation in pathologists’ identification of features and disagreement on the histologic criteria for ENE. This lack of concordance may help explain some of the discordant information regarding prognosis in clinical studies when this feature is identified.
PubMed ID: 27089928
Article Size: <1 MB

Thyroid gland follicular carcinoma.

Thompson LD.
Ear Nose Throat J. 2015 Mar;94(3):100-102.
FIRST PARAGRAPH: Thyroid gland follicular carcinoma is a malignant epithelial neoplasm of follicular cell differentiation that exhibits capsular and/or lymphovascular invasion while lacking the nuclear features of thyroid papillary carcinoma. While rarely inherited, follicular carcinoma will develop in about 20% of patients with Cowden syndrome, related specifically to PTEN germline mutations. Previous radiation exposure and iodine deficiency are known environmental etiologic factors.
PubMed ID: tbd
Article Size: <1 MB

Hyalinizing trabecular adenoma of the thyroid gland.

Thompson LD.
Ear Nose Throat J. 2011 Sep;90(9):416-7.
FIRST PARAGRAPH: Hyalinizing trabecular ade-noma (HTA) is a very rare tumor (<1% of all primary thyroid gland tumors) of thyroid follicular cell origin with a trabecular pattern of growth and marked intratrabecular hyalinization. For all intents and purposes, this is a benign tumor, although there is a case report of pulmonary metastasis with invasion, suggesting the term tumor be used instead of adenoma. A few cases have occurred following radiation exposure, and there may be a relationship to thyroid papillary carcinoma, as there have been reports of RET/PTC rearrangements.
PubMed ID: 21938699
Article Size: <1 MB

Medullary thyroid carcinoma.

Thompson LD.
Ear Nose Throat J. 2010 Jul;89(7):301-2.
FIRST PARAGRAPH: Medullary thyroid carcinoma (MTC) is a malignant epithelial tumor of the thyroid gland that exhibits C-cell differentiation. C cells arise from the ultimobranchial body, which is derived from the fourth pharyngeal pouch, and they are found in the upper and middle areas of the thyroid lobes. These cells produce calcitonin, a hormone involved in calcium homeostasis. While a number (20%) of MTCs are associated with the autosomal-dominant inherited multiple endocrine neoplasia (MEN) syndromes (specifically MEN2A and MEN2B), most (80%) cases are sporadic. Germline or somatic mutations of the RET gene are characteristic of this tumor. They usually involve an activating point mutation of 10q11.2. Specifically, codon 634 in exon 11 is most common in MEN2A, while codon 918 in exon 16 is most common in MEN2B.
PubMed ID: 20628986
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Primary smooth muscle tumors of the thyroid gland.

Thompson LD, Wenig BM, Adair CF, Shmookler BM, Heffess CS.
Cancer. 1997 Feb 1;79(3):579-87.
BACKGROUND: Primary smooth muscle tumors of the thyroid gland are rare. To date, there are few cases reported of primary thyroid leiomyomas and leiomyosarcomas.
METHODS: One leiomyoma and four leiomyosarcomas arising within the thyroid gland were identified in the files of the Endocrine Tumor Registry of the Armed Forces Institute of Pathology. Histologic and immunohistochemical features were reviewed and follow-up obtained.
RESULTS: The patients included 2 females, ages 56 and 64 years, and 3 males, ages 45, 68, and 83 years. The patients presented with a mass in the thyroid gland that had increased in size over a number of months. All the tumors originated within a single lobe of the thyroid gland and measured from 1.1 to 9 cm in greatest dimension. Histologically, there was a fascicular pattern of growth comprised of spindle-shaped cells with blunt-ended nuclei. The leiomyoma was encapsulated, cytologically bland, and amitotic; the leiomyosarcomas were invasive with increased cellularity, pleomorphism, a high mitotic rate, necrosis, and hemorrhage. Immunohistochemical staining showed reactivity with vimentin, smooth muscle actin, muscle specific actin, and desmin. The patient with the leiomyoma was alive without evidence of disease 11 years after the initial presentation, with surgical resection as the only treatment. Three of the patients with leiomyosarcomas were dead within 2 years of diagnosis, in spite of aggressive therapeutic intervention. The remaining patient was still alive 10 months after initial presentation with multiple lung metastases.
CONCLUSIONS: Smooth muscle tumors of the thyroid gland are distinctive tumors. Leiomyosarcomas can be distinguished from anaplastic carcinoma, although patient outcome is uniformly unfavorable.
PubMed ID: 9028371
Article Size: 1 MB

Langerhans cell histiocytosis of the thyroid: a series of seven cases and a review of the literature.

Thompson LD, Wenig BM, Adair CF, Smith BC, Heffess CS.
Mod Pathol. 1996 Feb;9(2):145-9.
Langerhans cell histiocytosis is a rare disorder, with a few reports describing isolated thyroid gland involvement. We report seven cases, which included four females and three males ranging in age from 2 months to 55 years, with a median age of 37 years. Histologically, the cases demonstrated either diffuse or focal involvement of the thyroid gland by Langerhans cell histiocytes, characterized by bean-shaped, lobated, folded nuclei. In association with the histiocytic infiltrate, there was a prominent eosinophilic cellular component, as well as destruction of the thyroid follicles. All cases occurred in a background of lymphocytic thyroiditis. One case demonstrated adenomatoid nodules, whereas another had a microscopic papillary carcinoma. Immunohistochemical staining demonstrated positive reactivity with S-100 protein, lysozyme, and KP-1. Four patients with isolated thyroid disease, treated by surgical resection alone, are alive without systemic disease from 3 to 19 years after initial presentation. The three patients with systemic disease died within 1 year of the initial diagnosis with disease-related complications. Localized disease portends a favorable prognosis as compared to the thyroid involvement as part of systemic disease.
PubMed ID: 8657721
Article Size: 3 MB

Diffuse hyperplasia of thyroid gland (Graves’ disease)

Thompson LDR.
Ear Nose Throat J. 2007 Nov;86(11):666-7.
FIRST PARAGRAPH: Widely known by its eponym Graves’ disease, diffuse hyperplasia of the thyroid gland is an autoimmune condition in which excess thyroid hormone production is unchecked by the normal feedback loop between the thyroid and the pituitary gland. The immune-system abnormality is mediated by antibodies to the thyrotropin receptor found on follicular epithelial cells. When the most specific antibody, known as thyroid-stimulating immunoglobulin (TSI), is bound to the thyrotropin receptor, the TSI mimics the action of pituitary thyrotropin and stimulates the follicular epithelium to produce hormone. The clinical effect of this autoimmune process is (1) thyrotoxicosis accompanied by diffuse thyroid enlargement and an infiltrative ophthalmopathy and (2) a spectrum of the systemic effects of excessive thyroid hormone production.
PubMed ID: 18225623
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Papillary thyroid carcinoma.

Nelson BL, Thompson LD.
Ear Nose Throat J. 2004 Oct;83(10):675-6.
FIRST PARAGRAPH: Papillary thyroid carcinoma is the most common type of thyroid malignancy. The tumor occurs largely in adults, usually those between the ages of 20 and 50 years; the female-to-male ratio is 4:1. Papillary thyroid carcinoma is also the most common pediatric thyroid malignancy.
PubMed ID: 15586863
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Endoscopic management of intratracheal ectopic thyroid.

Pritchyk KM, Thompson LD, Malekzadeh S.
Otolaryngol Head Neck Surg. 2004 May;130(5):630-2.
CASE REPORT CONCLUSIONS: ITET is a rare cause of upper airway obstruction. CT scan of the neck without contrast should be performed to evaluate the location of obstruction. MRI scan should be used to assess the extent and vascular nature of the lesion. Endoscopic laser excision is an appropriate treatment option for benign and vascular ITET tissue.
PubMed ID: 15138431
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Subacute (de Quervain’s) thyroiditis.

Thompson LD, Heffess CS.
Ear Nose Throat J. 2002 Sep;81(9):623.
FIRST PARAGRAPH: Subacute (de Quervain’s) thyroiditis is a seasonal disorder that generally affects middle-aged women. It is characterized by neck pain and generalized malaise, fatigue, fever, and chills following an upper respiratory infection, usually of viral etiology. Thyroid gland palpation elicits exquisite tenderness of the firm gland, which can be involved either focally or diffusely. The stage the disease determines whether there is hyper- or hypothyroidism.
PubMed ID: 12353438
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Minimally invasive follicular thyroid carcinoma.

Heffess CS, Thompson LD.
Endocr Pathol. 2001 Winter;12(4):417-22.
Infiltration of the capsule, vascular invasion, and/or neoplastic extension into the adjacent parenchyma are regarded as prerequisites for the diagnosis of follicular carcinoma. In modern practice, most of these tumors fall into the category of follicular carcinoma, minimally invasive (FCMI) characterized by evidence of limited capsular or vascular invasion with an excellent long-term prognosis and a good patient outcome. Notwithstanding the wide acceptance of the diagnostic criteria established by the World Health Organization for the classification of follicular carcinomas in particular, they have been difficult to apply and have led to a great deal of confusion. This confusion is compounded when applied to ‘low-grade’ or ‘minimally invasive’ follicular carcinoma because of the poor reproducibility of the classification and the variable results reported in the literature. Our surgical colleagues face a similar lack of a standardized treatment for low-grade follicular carcinomas, which leads to unnecessary surgical treatment. Standardization of histologic criteria is necessary to promote confidence and uniformity in the therapeutic approach of these tumors. We believe that a FCMI is defined as an encapsulated follicular tumor (not papillary), with only small to medium vessel invasion within or immediately adjacent to the tumor capsule and/or up to full-thickness capsular transgression without accompanying extension into the thyroid parenchyma with intervening fibrosis. By using these criteria, patients can be managed with conservative surgical excision to yield an excellent long-term patient outcome.
PubMed ID: 11914475
Article Size: 1 MB

Intratracheal ectopic thyroid tissue: a case report and literature review.

Byrd MC, Thompson LD, Wieneke JA.
Ear Nose Throat J. 2003 Jul;82(7):514-8.
We discuss a case of intratracheal ectopic thyroid tissue (ETT) that was retrieved from the files of the Otorhinolaryngic–Head and Neck Pathology Registry at the Armed Forces Institute of Pathology. The patient was a 54-year-old man who had a history of papillary thyroid carcinoma, which had been treated with a subtotal thyroidectomy. During routine follow-up 4 years later, the patient’s primary care physician detected an elevated thyroglobulin level. Further referrals and evaluations revealed that the patient had intratracheal ETT. The patient refused to undergo surgical excision and remains without evidence of recurrent carcinoma. In a MEDLINE literature review, we found only 13 other well-documented cases of intratracheal ETT since 1966; in all but two cases, patients had benign disease. Once the possibility of thyroid carcinoma has been eliminated by histologic examination, intratracheal ETT can be managed by complete surgical excision with the prospect of an excellent long-term clinical outcome.
PubMed ID: 12955837
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Undifferentiated thyroid carcinoma.

Thompson LD.
Ear Nose Throat J. 2013 Oct-Nov;92(10-11):500-4.
FIRST PARAGRAPH: Histologically, undifferentiated thyroid carcinomas show a variety of patterns, from sheet-like, storiform, fascicular, angiomatoid, and meningothelial to solid, exhibiting extensive lymph-vascular invasion.
PubMed ID: 24170460
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Chronic lymphocytic thyroiditis (Hashimoto thyroiditis).

Thompson LD.
Ear Nose Throat J. 2014 Apr-May;93(4-5):152-3.
FIRST PARAGRAPH: Chronic lymphocytic thyroiditis, eponymically referred to as Hashimoto thyroiditis (named after Hakarum Hashimoto, who first described the disease in 1912), is an autoimmune thyroiditis that results from autoantibodies to thyroid-specific antigens. There is a poorly understood interaction between susceptibility genes and environmental triggers, resulting in antimicrosomal and antithyroglobulin antibodies. Many patients may have another simultaneous autoimmune disease (such as Sjögren syndrome, diabetes mellitus, or myasthenia gravis), while there is some overlap with Graves disease (diffuse hyperplasia). Hypothyroidism may also result from destruction of the thyroid epithelium by inflammatory cells.
PubMed ID: 24817227
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Neoplasms metastatic to the thyroid gland.

Thompson L.
Ear Nose Throat J. 2006 Aug;85(8):480, 483.
FIRST PARAGRAPH: Tumors that occur in the thyroid gland as a result of lymph or vascular spread from distant sites are considered to represent metastatic disease rather than a direct extension of a primary from an adjacent organ. Metastatic deposits are identified at a higher frequency in abnormal glands—that is, those with adenomatoid nodules, thyroiditis, and follicular neoplasms. Further, metastatic deposits may be found within primary thyroid tumors, such as a renal cell carcinoma metastatic to a thyroid papillary carcinoma. Although a thyroid gland mass may be the presenting clinical sign, it is more often the underlying thyroid gland disease (e.g., thyroiditis, adenomatoid nodules) that prompts clinical evaluation. The thyroid gland metastatic deposit is the initial presentation of an occult primary tumor in as many as 40% of patients. Carcinomas are the most common metastatic tumors from (in order of frequency) the kidney (figure 1), lung, breast (figure 2), and stomach; melanoma is less common.
PubMed ID: 16999049
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Dyshormonogenetic goiter of the thyroid gland.

Thompson LD.
Ear Nose Throat J. 2005 Apr;84(4):200.
FIRST PARAGRAPH: Dyshormonogenetic goiter is the name given to a family of inborn errors of metabolism that lead to defects in the synthesis of thyroid hormone. The prevalence of this disease is 1 in 30,000 to 50,000 live births, and it is the second most common cause (10 to 15%) of permanent congenital hypothyroidism.
PubMed ID: 15929313
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Template for Reporting Results of Biomarker Testing of Specimens From Patients With Thyroid Carcinoma.

Chiosea S, Asa SL, Berman MA, Carty SE, Currence L, Hodak S, Nikiforov YE, Richardson MS, Seethala RR, Sholl LM, Thompson LD, Wenig BM, Worden F; Members of the Cancer Biomarker Reporting Committee, College of American Pathologists.
Arch Pathol Lab Med. 2016 Sep 28. [Epub ahead of print]
The College of American Pathologists offers these templates to assist pathologists in providing clinically useful and relevant information when reporting results of biomarker testing. The College regards the reporting elements in the templates as important elements of the biomarker test report, but the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice.
The College developed these templates as educational tools to assist pathologists in the useful reporting of relevant information. It did not issue them for use in litigation, reimbursement, or other contexts. Nevertheless, the College recognizes that the templates might be used by hospitals, attorneys, payers, and others. The College cautions that use of the templates other than for their intended educational purpose may involve additional considerations that are beyond the scope of this document.
Completion of the template is the responsibility of the laboratory performing the biomarker testing and/or providing the interpretation. When both testing and interpretation are performed elsewhere (e.g., a reference laboratory), synoptic reporting of the results by the laboratory submitting the tissue for testing is also encouraged to ensure that all information is included in the patient’s medical record and thus readily available to the treating clinical team.
PubMed ID: 27681332
Article Size: 75 KB