Elsevier

Human Pathology

Volume 41, Issue 2, February 2010, Pages 172-180
Human Pathology

Original contribution
Encapsulated thyroid tumors of follicular cell origin with high grade features (high mitotic rate/tumor necrosis): a clinicopathologic and molecular study

https://doi.org/10.1016/j.humpath.2009.08.011Get rights and content

Summary

Encapsulated thyroid tumors of follicular cell origin with high-grade features (EFHG) are unusual neoplasms. In current classification schemes, they are called atypical adenomas or follicular, papillary, or poorly differentiated carcinoma. When noninvasive, EFHG create a major therapeutic/diagnostic dilemma stemming from their rarity, low-stage, high-grade appearance, and lack of long-term follow-up studies. All cases of EFHG were defined as encapsulated tumors of follicular cell origin with at least 5 mitoses per 10 high-power fields and/or tumor necrosis. Available tissues were subjected to a thyroid carcinoma platform for mass spectrometry high-throughput genotyping, which consisted of 111 known mutations in 16 different genes: BRAF, RET, NRAS, HRAS, KRAS, PIK3CA, AKT1, and other related genes. Twenty-five cases met the selection criteria. Tumor necrosis was present in 56.0% (n = 14). Extensive vascular invasion was identified in 24.0% (n = 6). Eight (32%) of 25 tumors were noninvasive. Twenty-two patients (88%) were free of disease (median follow up: 8.5 years). All 8 noninvasive tumor did not recur despite focal/extensive tumor necrosis in 3 cases and a median follow-up of 11.9 years. EFHG with no vascular invasion did not recur. In patients without distant metastases at presentation (n = 24), 33% (2/6) of patients with extensive angioinvasion relapsed, whereas none of 18 with absent/focal vascular invasion recurred (P = .054). Mutations were found in 10 (45%) of 22 cases tested: 8 had NRAS codon 61, 1 KRAS codon 61, and 1 had coexistent BRAF V600E and AKT1. There was a higher frequency of RAS (9/22, 41%) than BRAF mutations (1/22, 4.5%) (P = .009). Noninvasive EFHG have an indolent behavior even in the presence of extensive tumor necrosis. EFHG with absent vascular invasion have an excellent prognosis despite the frequent occurrence of tumor necrosis. NRAS mutations are the most frequent oncogenic event in EFHG.

Introduction

Encapsulated thyroid tumors of follicular cell origin are generally thought to behave in an indolent fashion. The classification of these tumors is based on the recognition of a combination of cytologic and invasive features. The latter include invasion of the tumor capsule and angioinvasion. These tumors are designated as the follicular variant of papillary carcinoma when they contain nuclear features of classical papillary thyroid carcinoma (ie, grooves, pseudoinclusions and clearing). Encapsulated follicular variant of papillary carcinoma without significant vascular and capsular invasion have been shown to have an indolent course with infrequent recurrences and metastases [1]. When the nuclear features of papillary thyroid carcinoma (PTC) are absent, the presence of capsular or vascular invasion categorize the tumor as follicular carcinoma. Follicular carcinomas showing minimal capsular invasion recur or metastasize infrequently [2]. When the nuclear features of PTC are absent in a noninvasive tumor, the diagnosis of follicular adenoma is rendered.

On occasion, increased mitotic activity and/or tumor necrosis has been noted in encapsulated thyroid tumors. In noninvasive tumors without nuclear features of PTC, necrosis, and high mitotic rate can be a source of difficulty in making a benign diagnosis. Indeed, these high-grade features seem at odds with what otherwise could be regarded as an adenoma. In the first half of the 20th century, the term atypical adenoma was proposed to define noninvasive, nonpapillary encapsulated follicular-derived neoplasms with unusual disturbing histologic features. These “atypical adenomas” were defined on the basis of worrisome architecture (eg, solid hypercellular growth) or a combination of hypercellularity and increased mitotic activity [3], [4]. No recurrences were reported after long-term follow-up (up to 20 years) in “atypical adenomas” defined based on architecture [3]. Unfortunately, the latter studies included tumors with very low mitotic rate or in which the number of mitoses was not mentioned [3], [4]. Hence, the outcome of encapsulated non-invasive follicular-derived tumors with high-grade features (ie, high mitotic rate and/or tumor necrosis) has not been reported. This is important because several studies support the notion that the presence of tumor necrosis and increased mitoses are adverse prognostic indicators in thyroid malignancies [5], [6], [7], [8]. In fact, patients with invasive thyroid carcinomas harboring increased mitoses and/or necrosis have a greater chance of becoming refractory to radioactive iodine and to die of disease [9]. The presence of tumor necrosis and/or increased mitotic activity in a non-invasive tumor can create major anxiety on the part of the patient and physicians (pathologist and clinician) involved in his/her care. This uncertainty in regard to outcome obviously creates a major therapeutic dilemma.

To address these issues, 25 cases of encapsulated follicular-derived lesions with increased mitoses and/or necrosis were studied extensively at the histological and molecular level. In addition to the noninvasive cases, we have included similar high-grade but invasive encapsulated tumors in order to assess the value of invasive features while stratifying for mitosis and necrosis. The purpose of this study is not to create another entity or a new terminology but, rather, to help pathologists and clinicians understand the behavior and treat these rare tumors.

Section snippets

Patient population and inclusion criteria

The institutional database was searched for all cases with a diagnosis of thyroid carcinomas treated at Memorial Sloan-Kettering Cancer Center between January 1980 and December 2000. Additional cases were supplied from the personal file of one of us (R.A.G). The slides from the cases included in the study were examined by 2 head and neck pathologists with special interest in thyroid neoplasia (R.A.G. and M.R.). The pathologists were blinded to the clinical outcome of all patients studied. This

Clinical and histopathologic features

Slides from 980 patients were obtained for review, of which 19 satisfied the selection criteria. Six additional cases were supplied from the personal files of R.A.G., for a total of 25 cases. A minimum of one section per centimeter of tumor was examined in each patient with an average of 12 tumor sections examined per case. Seventeen women and 8 men were present in the cohort with a median age of 49 years (range, 16-84 years). The mean and median tumor size for all cases was 3.6 and 3.5 cm,

Discussion

Noninvasive EFHG are quite rare. Indeed, in this series derived from a major cancer center, these tumors constituted <1% of thyroid carcinomas. It is not possible to compare the incidence and demographics of these neoplasms to previous studies [3], [4] on “atypical adenomas” since our definition for worrisome histology differ significantly. Indeed, our definition is based on mitosis and tumor necrosis rather than architectural grading. All noninvasive EFHG tumors showed no evidence of disease

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    This work was presented in part at the annual meeting of the United States and Canadian Academy of Pathology in March 2009.

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