Differential gene expression profiling of aggressive and nonaggressive follicular carcinomas.

The classification of follicular thyroid neoplasms requires surgical resection for histologic evaluation of malignancy. Because variable clinical behavior exists, genomic expression profiling may lead to the identification of novel markers that facilitate better biologic classification. We performed for the first time gene expression analysis on clinically aggressive and nonaggressive follicular carcinomas (FCs) from patients for whom long-term follow-up data were available. We examined matched fresh-frozen tissue from 15 histopathologically diagnosed follicular carcinomas (7 patients with documented distant metastasis and/or death from disease and 8 patients without recurrence). For categorical comparison, we analyzed 4 follicular adenomas (FAs). The biologic control comprised 11 normal thyroid tissue specimens. High-quality RNA was extracted from the tissues, labeled, and hybridized to an Affymetrix (Santa Clara, CA) oligonucleotide microarray (HG-U133A). With the exceptions of 1 follicular adenoma and 1 follicular carcinoma, unsupervised hierarchical cluster analysis revealed 2 distinct groups--one containing normal thyroid tissue and follicular adenomas and another containing follicular carcinomas. We identified 421 genes that were differentially expressed between histologically normal thyroid tissues and all follicular neoplasms (P < 0.01; fold-change >2), 94 genes that distinguished follicular carcinomas from follicular adenomas (including PBP and CKS2), and 4 genes that distinguished aggressive follicular carcinomas from nonaggressive follicular carcinomas (NID2, TM7SF2, TRIM2, and GLTSCR2). Comparative genomic groupings identified differentially expressed genes that may lead to better classification of follicular thyroid neoplasms. Such genes may be used in future prospective validation studies to establish clinically useful and complementary diagnostic markers.

Growth factor receptors expression in anaplastic thyroid carcinoma: potential markers for therapeutic stratification.

Anaplastic thyroid carcinoma is a rare and universally fatal disease. Therefore, novel biomarkers are needed as surrogate end points in triaging patients for novel and selective biologic treatments. Up-regulation of several growth factor receptors has been shown to be associated with the biologic progression and response to targeted therapy of several malignancies. To determine the role of growth factor receptors in the biologic stratification of anaplastic thyroid carcinoma, we studied the expression of epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor beta, and HER-2 receptor in a large cohort of anaplastic thyroid carcinomas by immunohistochemical techniques. The percentage of positive cells, staining intensity and localization of staining in the anaplastic component, and coexisting well-differentiated thyroid carcinoma and adjacent nonneoplastic thyroid were evaluated for these markers. EGFR, platelet-derived growth factor receptor beta, and HER-2 were overexpressed in 58%, 16%, and 16% of anaplastic carcinomas, respectively. In tumors with adjacent normal thyroid parenchyma and/or differentiated carcinoma components, overexpression of all 3 markers was noted exclusively in the anaplastic component. Mutational analysis of exons 18, 19, and 21 of the EGFR gene showed no mutations in all anaplastic carcinomas. We conclude that the expression of these markers (1) may play a role in a subset of thyroid tumorigenesis and anaplastic transformation and (2) can be validated for potential use in the stratification of patients for targeted therapy.

Fine-needle aspiration biopsy of Hurthle cell lesions of the thyroid gland: A cytomorphologic study of 139 cases with statistical analysis.

BACKGROUND: Lesions of the thyroid gland composed of Hurthle cells encompass pathologic entities ranging from hyperplastic nodules with Hurthle cell metaplasia to Hurthle cell carcinomas. The cytologic distinction between these entities can be diagnostically challenging. Many cytologic features of Hurthle cell lesions that distinguish neoplastic Hurthle cell lesions requiring surgery from those that are benign and nonneoplastic have been described, but with variable usefulness. This is due, in part, to the small numbers of cases examined in previous studies and the limited application of statistical analysis. A morphologic study was made of 139 Hurthle cell lesions of the thyroid gland and statistical analysis applied to identify a set of cytomorphologic features that distinguish benign Hurthle cell lesions (BHCL) from Hurthle cell neoplasms (HCN). METHODS: Fine-needle aspiration biopsies (FNABs) of thyroid nodules with a predominant Hurthle cell component and corresponding histologic followup were included in the study. Cases were divided into BHCL and HCN groups on the basis of the histologic diagnosis. All cases were reviewed to assess the following 14 cytologic features: overall cellularity, cytoarchitecture, percentage of Hurthle cells, percentage of single cells, percentage of follicular cells observed as naked Hurthle cell nuclei, background colloid, chronic inflammation, cystic change, transgressing blood vessels (TBV), intracytoplasmic lumina, presence of multinucleated Hurthle cells, nuclear to cytoplasmic ratio, nuclear pleomorphism/atypia, and nucleolar prominence. The results were evaluated by using univariate and stepwise logistic regression (SLR) analysis; statistical significance was achieved at P-values < 0.05. RESULTS: One hundred thirty-nine FNAB specimens, corresponding to 56 HCN and 83 BHCL, fulfilled the study criteria. Six of the 14 cytologic features evaluated were shown by univariate analysis to be statistically significant in predicting HCN: nonmacrofollicular architecture (P < 0.001), absence of background colloid (P < 0.001), absence of chronic inflammation (P < 0.001), presence of TBV (P < 0.001), > 90% Hurthle cells (P < 0.001), and >10% single Hurthle cells (P = 0.014). The first four of these features were also shown to be statistically significant in the SLR analysis (P = 0.005, 0.010, 0.016, and 0.045, respectively), and when all four of these features were present HCN was correctly identified 86% of the time. CONCLUSIONS: In the current study of 139 FNAB specimens of thyroid Hurthle cell nodules, 14 cytologic features were examined and 6 were found to be statistically significant in identifying HCN. The following four features, when found in combination, were found to be highly predictive of HCN: nonmacrofollicular architecture, absence of colloid, absence of inflammation, and presence of TBV.

The utility of fine-needle aspiration in the diagnosis of gastrointestinal stromal tumors: a cytomorphologic and immunohistochemical analysis with emphasis on malignant tumors.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the tubular gut and mesentery. Fine-needle aspiration biopsy (FNAB) currently is a useful tool in the diagnosis of GIST because of various mutations of the KIT protooncogene that are recognized as characteristic of these tumors. Despite such advances, the malignant potential of GIST remains variable, and few studies have reported their findings in patients with malignant GIST. Therefore, in the current study, the authors have reported their experience with FNAB as a diagnostic tool in one of the largest series of malignant GISTs and have analyzed the cytomorphologic features of the tumors relative to their clinical behavior to determine which, if any, cytologic features are indicators of malignancy. METHODS: All patients with histologically confirmed GIST who were diagnosed by image-guided FNAB and confirmed with positive CD117 staining from 1998 to 2003 were included in the study. All tumors were reviewed for various cytomorphologic features. For study purposes, the patients were divided into two groups: Group A included all patients with malignant tumors, defined as those with metastatic disease or recurrent disease after adequate surgery with or without chemotherapy; Group B included all other patients. RESULTS: In total, 26 tumors from 23 patients (8 males and 15 females) with a mean age of 60.9 years were available for review. There were 14 primary tumors, 7 metastases (to the liver), and 5 recurrences. Twenty-one tumors were unequivocally malignant and were placed into Group A; the remaining 5 tumors were placed into Group B. The tumors in both groups were characterized by spindled or epithelioid cells with minimal nuclear atypia or pleomorphism and a moderate amount of cytoplasm. None of the cytologic features that were evaluated could distinguish reliably between benign tumors and malignant tumors, as expected. However, on cytologic examination, all tumors that demonstrated mitoses (n = 7 tumors) and/or pretreatment necrosis (n = 3 tumors) were identified as malignant. CONCLUSIONS: FNAB remains a reliable method for the diagnosis of GIST. Immunohistochemical staining of cytologic material with CD117 has been reliable in establishing this diagnosis by FNAB, provided adequate tissue is procured. In the current study, the presence of necrosis or mitoses in cytologic specimens was correlated with a diagnosis of malignant GIST.

Determining optimal clinical target volume margins in head-and-neck cancer based on microscopic extracapsular extension of metastatic neck nodes.

PURPOSE: To determine the optimal clinical target volume margins around the gross nodal tumor volume in head-and-neck cancer by assessing microscopic tumor extension beyond cervical lymph node capsules. METHODS AND MATERIALS: Histologic sections of 96 dissected cervical lymph nodes with extracapsular extension (ECE) from 48 patients with head-and-neck squamous cell carcinoma were examined. The maximum linear distance from the external capsule border to the farthest extent of the tumor or tumoral reaction was measured. The trends of ECE as a function of the distance from the capsule and lymph node size were analyzed. RESULTS: The median diameter of all lymph nodes was 11.0 mm (range: 3.0-30.0 mm). The mean and median ECE extent was 2.2 mm and 1.6 mm, respectively (range: 0.4-9.0 mm). The ECE was <5 mm from the capsule in 96% of the nodes. As the distance from the capsule increased, the probability of tumor extension declined. No significant difference between the extent of ECE and lymph node size was observed. CONCLUSION: For N1 nodes that are at high risk for ECE but not grossly infiltrating musculature, 1 cm clinical target volume margins around the nodal gross tumor volume are recommended to cover microscopic nodal extension in head-and-neck cancer.

Langerhans cell histiocytosis presenting as a thyroid gland mass.

We report 2 cases of Langerhans cell histiocytosis (LCH) presenting as a thyroid mass. The first case is a 45-year-old woman with a 13-year history of diabetes insipidus who presented with an enlarging thyroid mass with substernal extension. The second case is a 29-year-old man who presented with an enlarging thyroid mass and skin lesions. Histologic evaluation of the thyroid gland in both cases revealed extensive involvement by LCH, confirmed by immunohistochemical analysis showing Langerhans cells that were positive for CD1a and S-100 protein. Langerhans cell histiocytosis can rarely involve the thyroid gland in adults, and we have identified 30 cases reported in literature. Most patients had evidence of LCH involving other anatomic sites, as was true in these 2 cases, and the diagnosis was initially established by examination of other sites in a subset of patients. Affected patients frequently have diabetes insipidus, as was true in case 1. Thyroid gland involvement as the initial presentation of LCH is a rare phenomenon that can result in misdiagnosis.

Metastatic acinic cell carcinoma in a neurofibroma mistaken for carcinosarcoma.

BACKGROUND: Tumor-to-tumor metastasis is a rare, but well-recognized, entity most commonly involving metastatic carcinoma to a mesenchymal neoplasm. We report a case of acinic cell carcinoma of the parotid gland metastatic to a neurofibroma. METHODS AND RESULTS: A 55-year-old man with a history of a high-grade acinic cell carcinoma of the parotid was seen with a mass at the surgical site and metastatic foci in the scalp 10 months postoperatively. The resection specimen revealed a spindle cell lesion with metastatic foci of high-grade adenocarcinoma, initially diagnosed as a carcinosarcoma. The bland morphology and S-100-positive expression of the spindle cell lesion confirmed the diagnosis of neurofibroma. The high-grade features of the carcinomatous foci and their similarity to the primary tumor confirmed the presence of a tumor-to-tumor metastasis. CONCLUSION: To our knowledge, this is the first reported case of acinic cell carcinoma metastatic to a neurofibroma, an important entity in the differential diagnosis of biphasic tumors of the head and neck.

Genetic analysis of sinonasal adenocarcinoma phenotypes: distinct alterations of histogenetic significance.

Sinonasal adenocarcinomas, a relatively rare entity, are composed of distinctly different morphologic subtypes with variable biological behavior. To investigate the genetic events associated with their development and clinicopathologic features, we analyzed the alterations in K-ras, APC, beta-catenin, hMLH1 and hMSH2 and p53 genes expression in a cohort of 15 primary tumors comprising the two main sinonasal adenocarcinoma subtypes (enteric and seromucinous). The patients consisted of 13 men and two women, who ranged in age from 50 to 87 years. Tumors were predominantly located in the ethmoid sinus. Eight tumors were Enteric-type, and seven were seromucinous type. Nine patients were smokers and four were nonsmokers; and no information was available on two patients. Two of the eight enteric-type, had K-ras mutation at codons 12A and 12B, and one showed microsatellite instability at BAT-25. Two patients with enteric-type tumors had a history of wood-dust exposure, and one had a K-ras mutation at 12A codon as well as p53 overexpression. No patients with the seromucinous type had any genetic abnormalities, except for overexpression of p53 in two tumors. Our results show that (1) a subset of enteric-type sinonasal adenocarcinoma shares certain genetic alterations with colonic adenocarcinomas, (2) the seromucinous-type sinonasal adenocarcinoma lacks alterations and may develop through a different pathway, (3) high p53 expression is associated with aggressive tumor features in both subtypes and (4) the enteric-type runs a more malignant course than the seromucinous counterpart.