Interobserver Variability in the Histopathologic Assessment of Extrathyroidal Extension of Well Differentiated Thyroid Carcinoma Supports the New American Joint Committee on Cancer Eighth Edition Criteria for Tumor Staging.

Background: Extrathyroidal extension (ETE) by papillary and follicular thyroid carcinoma can be associated with increased risk of tumor recurrence and mortality. In the seventh edition of its Cancer Staging Manual, the American Joint Committee on Cancer (AJCC) defined minimal ETE as the involvement of skeletal muscle (i.e., strap muscles) or perithyroidal soft tissue. The eighth edition of the AJCC Cancer Staging Manual has changed the criteria so that only grossly evident (macroscopic) ETE involving strap muscles (not microscopic ETE involving perithyroidal soft tissue) affects tumor staging. Summary: Concordance of identifying microscopic ETE (as well as extranodal extension by carcinoma metastatic to lymph nodes) was previously evaluated among 11 expert endocrine pathologists. The overall agreement rate was slight when rendering a diagnosis of ETE. Concordance was highest when pathologists assessed the spatial relationship of carcinoma to skeletal muscle. This article discusses the significance of these findings. It also reviews relevant anatomic and developmental considerations related to the boundaries of the thyroid. Conclusions: The results of the concordance study provide additional rationale supporting stringent criteria for diagnosing ETE, as proposed by the eighth edition of the AJCC Cancer Staging Manual. It is expected that these rigid morphologic criteria will potentially reduce interobserver variability and enhance consistency in the diagnosis and staging of thyroid carcinoma.

A prospective assessment defining the limitations of thyroid nodule pathologic evaluation.

BACKGROUND: Clinical management of thyroid neoplasms is based on light microscopic diagnosis, but its accuracy and precision are poorly defined. OBJECTIVE: To assess inter- and intraobserver variability of preoperative cytopathologic and postoperative histopathologic thyroid diagnoses. DESIGN: Samples were collected in a prospective, multicenter trial validating a gene expression classifier between June 2009 and December 2010. SETTING: 14 academic and 35 community clinical sites. PATIENTS: 653 patients with 776 surgically resected thyroid nodules of 1 cm or greater. MEASUREMENTS: Intraobserver concordance among 2 or more central histopathologists who independently read histopathology slides was calculated. Interobserver concordance between the diagnoses made by the central histopathologists and those made by local pathologists were calculated. Intra- and interobserver concordance for cytopathology was similarly calculated by comparing diagnoses made by local pathologists with those made by a central panel of 3 cytopathologists. RESULTS: Concordance on the histopathologic distinction between benign and malignant diagnoses was 91% comparing local with central histopathologists and 90% comparing 2 central histopathologists. Using the 6-category Bethesda System, 64.0% of diagnoses made by local and central cytopathologists and 74.7% of intraobserver diagnoses were concordant. Central cytopathologists made fewer indeterminate diagnoses than local pathologists (41.2% vs. 55.0%). LIMITATIONS: Many local pathologists did not use the Bethesda System, so their reports were translated to allow comparison. The study required histopathology, and the study population and specimens did not encompass all newly evaluated patients with a thyroid nodule. CONCLUSION: Substantial inter- and intraobserver variability exists in the cytopathologic and histopathologic evaluation of thyroid nodules, confirming an inherent limitation of visual microscopic diagnosis. PRIMARY FUNDING SOURCE: Veracyte.

Medicolegal liability in pathology: an international perspective.

An inevitable outcome of modern Medicine in any country is that some patients will experience adverse events, some of which would have been preventable. Different nations have developed various approaches to such cases; their legal efficacies are probably dissimilar and dependent on a number of disparate variables. An international "snapshot" of the results of the interacting forces can be obtained by asking physicians in several countries how they view selected subjective facets of their tort systems. In the U.S., many physicians view the structure of malpractice torts as unfair, and that belief is shared by at least some pathologists. The American Medical Association has declared that a multiregional malpractice "crisis" exists which raises medical costs and threatens access to care. Furthermore, malpractice tort decisions are often flawed scientifically because lay jurors and judges cannot properly evaluate the quality of "expert" testimony given by adversarial witnesses. Despite these factors, there has been little effort to investigate the views of pathologists on malpractice actions outside the U.S. In this paper, the authors have collected the responses of an international group of pathologists to a questionnaire on that topic. The respondents practice in academic centers in 15 countries outside the U.S. As expected, a range of views was represented, with some pathologists reporting that malpractice litigation was uncommon and others noting a worrisome trend toward its growth. Interestingly, so-called "defensive medicine" was found to be relatively common in pathology in many countries.

Assessment of RET/PTC oncogene activation and clonality in thyroid nodules with incomplete morphological evidence of papillary carcinoma: a search for the early precursors of papillary cancer.

Noninvasive thyroid nodules that exhibit borderline morphological signs of papillary cancer are difficult to diagnose and we do not know if they represent papillary carcinoma precursor lesions. Forty-six such nodules were analyzed for RET activation by immunohistochemistry and, in selected cases, by reverse transcriptase-polymerase chain reaction performed on RNA extracted after laser capture microdissection (LCM) of the tumor foci with and without papillary carcinoma features and positive RET immunoreactivity. RET immunoreactivity was identified, at least focally, in 30 of 46 (65.2%) of the nodules where it closely paralleled the morphological changes. Enough RNA was obtained after LCM in seven samples. RET/PTC1 or RET/PTC3 were detected in microscopic foci with papillary carcinoma features in most of the thyroid nodules (five of seven cases). No RET/PTC1 or RET/PTC3 rearrangements were detected in areas of the same tumors that lacked the cytological alterations. Analysis of clonality in the same nodules selected for LCM demonstrated that two were monoclonal and six were polyclonal. We conclude that RET activation closely parallels the morphological changes, that it is restricted to those areas of the tumor with the cytological alterations and that it is detectable in both mono- and polyclonal tumors. Although the finding of microscopic foci indicative of papillary carcinoma in a hyperplastic or adenomatous nodule does not justify the interpretation of the entire lesion as papillary carcinoma, it is possible that such foci may precede the development of invasive papillary cancer.

Hu Immunolabeling as a Marker of Neural and Neuroendocrine Differentiation in Normal and Neoplastic Human Tissues: Assessment Using a Recombinant Anti-Hu Fab Fragment.

The recombinant antibody fragment Fab GLN 495 recognizes an epitope shared by members of the neuron-associated Hu protein family (including HuC, HuD, and HelNl). This novel reagent labels the nuclei of neurons throughout the peripheral and central neuraxes and has been shown to recognize pulmonary small cell carcinomas and central nervous system (CNS) tumors of mature neuronal phenotype or neuronogenic differentiating capacity. Using this Fab fragment, we have undertaken a systematic survey of normal human tissues and an assessment of 554 non-CNS tumor samples for immunohistochemical evidence of Hu expression. Adrenomedullary cells, pancreatic islet cells, paraganglial chief cells, isolated adenohypophyseal cells, and spermatogonia were the only nonneuronal normal tissue elements to bind Fab GLN 495. In addition to labeling all 10 small cell carcinomas studied (six of which were extrapulmonary in origin), this recombinant anti-Hu Fab proved immunoreactive with neuroblastomas (four/four), esthesioneuroblastomas (one/one), typical (three/four) and atypical (one/four) pulmonary carcinoids, pancreatic islet cell tumors (two/six), large-cell neuroendocrine carcinoma of lung (one/four), Merkel cell tumors (two/three), medullary carcinomas of the thyroid (four/six), pheochromocytomas (two/four) and paragangliomas (four/four). Nonneural/neuroendocrine tumor labeling was restricted to the neuronal and immature neuroepithelial components of teratomas, to extraskeletal myxoid chondrosarcomas (three/four) and to small subsets of cells within examples of renal rhabdoid tumor (one/four), desmoplastic small cell tumor (one/four), alveolar rhabdomyosarcoma (two/four), Ewing sarcoma/PNET (two/nine), and Wilms tumor (one/four). Immunoreactivity was principally nuclear, with variable cytoplasmic labeling. Our findings support the largely restricted expression of Hu by neural/neuroendocrine neoplasms, suggest a potential role for Fab GLN 495 in the identification of small cell carcinomas irrespective of primary site, and support a recent proposal that at least some extraskeletal myxoid "chondrosarcomas" actually represent neuroendocrine tumors of soft parts. Int J Surg Pathol 8(2):109-117, 2000