EWSR1 translocation in primary hyalinising clear cell carcinoma of the thymus.

AIMS: In thymic carcinomas, focal clear cell change is a frequent finding. In addition to a prominent, diffuse clear cell morphology, some of these carcinomas show an exuberant hyalinised extracellular matrix, and therefore probably represent a separate entity. However, a characteristic genomic alteration remains elusive. We hypothesised that, analogous to hyalinising clear cell carcinomas of the salivary gland, hyalinising clear cell carcinomas of the thymus might also harbour EWSR1 translocations. METHODS AND RESULTS: We identified nine archived cases of thymic carcinoma with focal clear cell features and two cases that showed remarkable hyalinised stroma and prominent, diffuse clear cell morphology. These two cases expressed p40 and were negative for Pax8, CD5, and CD117. Programmed death-ligand 1 was highly positive in one case (70%), and negative in the other one. EWSR1 translocation was identified in both cases of hyalinising clear cell carcinoma, and was absent in all nine carcinomas that showed clear cell features without substantial hyalinisation. In one of the EWSR1-translocated cases, a fusion between exon 13 and exon 6 of EWSR1 and ATF1, respectively was identified by next-generation sequencing. CONCLUSIONS: These findings suggest that the EWSR1 translocation and possibly the EWSR1-ATF1 fusion might be unifying genomic alterations for thymic clear cell carcinomas with prominent hyalinised stroma, for which we propose the term 'hyalinising clear cell carcinoma of the thymus'. Because the immunophenotype is unspecific, testing for the EWSR1 translocation might be helpful in discriminating this entity from other thymic neoplasms or metastases, in particular those with clear cell change.

Preoperative diagnosis of benign thyroid nodules with indeterminate cytology.

BACKGROUND: Approximately 15 to 30% of thyroid nodules evaluated by means of fine-needle aspiration are not clearly benign or malignant. Patients with cytologically indeterminate nodules are often referred for diagnostic surgery, though most of these nodules prove to be benign. A novel diagnostic test that measures the expression of 167 genes has shown promise in improving preoperative risk assessment. METHODS: We performed a 19-month, prospective, multicenter validation study involving 49 clinical sites, 3789 patients, and 4812 fine-needle aspirates from thyroid nodules 1 cm or larger that required evaluation. We obtained 577 cytologically indeterminate aspirates, 413 of which had corresponding histopathological specimens from excised lesions. Results of a central, blinded histopathological review served as the reference standard. After inclusion criteria were met, a gene-expression classifier was used to test 265 indeterminate nodules in this analysis, and its performance was assessed. RESULTS: Of the 265 indeterminate nodules, 85 were malignant. The gene-expression classifier correctly identified 78 of the 85 nodules as suspicious (92% sensitivity; 95% confidence interval [CI], 84 to 97), with a specificity of 52% (95% CI, 44 to 59). The negative predictive values for "atypia (or follicular lesion) of undetermined clinical significance," "follicular neoplasm or lesion suspicious for follicular neoplasm," or "suspicious cytologic findings" were 95%, 94%, and 85%, respectively. Analysis of 7 aspirates with false negative results revealed that 6 had a paucity of thyroid follicular cells, suggesting insufficient sampling of the nodule. CONCLUSIONS: These data suggest consideration of a more conservative approach for most patients with thyroid nodules that are cytologically indeterminate on fine-needle aspiration and benign according to gene-expression classifier results. (Funded by Veracyte.).

Desmoplastic small round cell tumor 20 years after its discovery.

Desmoplastic small round cell tumor (DSRCT) was proposed as a distinct disease entity by William L Gerald and Juan Rosai in 1991. Over 850 patients have been reported in the medical literature. A specific translocation, t(11;22)(p13;q12), is seen in almost all cases, juxtaposing the EWS gene to the WT1 tumor suppressor gene. DSRCT is composed of nests of small round cells with polyphenotypic differentiation, typically a mixture of epithelial, mesenchymal and neural features, surrounded by a prominent desmoplastic stroma. DSRCT has a predilection for adolescent and young adult males, and primarily involves the abdominal cavity and pelvis. Survival is low despite their initial response to multimodal treatment. Most patients relapse with disseminated disease that is unresponsive to further therapy.

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.

The origin of neuroendocrine tumors and the neural crest saga.

In this essay, the role of the neural crest in the development of the vertebrate embryo is briefly described. The techniques used to document the neural crest origin of various cell types and the tumors arising from them are discussed, with emphasis on Le Douarin's quail-chick chimera model. The current dogma on the origin of the cells of the diffuse endocrine system is presented, and some personal conjectures based on the microscopic appearances of various types of normal, vestigial and neoplastic human tissues are offered to the reader as 'food for thought.'

Squamous cell carcinoma arising in an ovarian mature cystic teratoma: a case report.

Malignant transformation in a mature cystic teratoma of the ovary is rare. The most common malignancy is squamous cell carcinoma, which consists of about 75% of malignant transformations. In the present report, we describe a case of advanced-stage squamous cell carcinoma arising in a mature cystic teratoma. A postmenopausal 63-year-old woman with squamous cell carcinoma arising in a mature cystic teratoma is presented. The initial investigation by ultrasound showed a left adnexal mass with mixed echo pattern, which arose the suspension of malignancy. She underwent a laparotomy and left oophorectomy. Histopatholog was compatible with squamous cell carcinoma arising in a mature cystic teratoma. After a few episodes of intestinal obstruction and colostomy, she underwent partial resection of the ileum and sigmoid colon four months after the initial oophorectomy. Histopathologic study showed metastatic poorly-differentiated squamous cell carcinoma. Subsequently, she underwent two courses of combination chemotherapy with cisplatin, leucovorin, and 5-fluorouracil with no response. She died from progression of the disease nine months after the initial operation.

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.

Morphologic characteristics of Chernobyl-related childhood papillary thyroid carcinomas are independent of radiation exposure but vary with iodine intake.

BACKGROUND: The Chernobyl accident caused an unprecedented increase in papillary thyroid carcinoma (PTC) incidence with a surprisingly short latency and unusual morphology. We have investigated whether unexpected features of the PTC incidence after Chernobyl were radiation specific or influenced by iodine deficiency. METHODS: PTCs from children from Belarus, Ukraine, and the Russian Federation exposed to fallout from Chernobyl were compared with PTCs from children not exposed to radiation from the same countries, from England and Wales (E&W) and from Japan. The degree and type of differentiation, fibrosis, and invasion were quantified. RESULTS: There were no significant differences between PTCs from radiation-exposed children from Belarus, Ukraine, and the Russian Federation and PTCs from children from the same countries who were not exposed to radiation. Childhood PTCs from Japan were much more highly differentiated (p < 0.001), showed more papillary differentiation (p < 0.001) and were less invasive (p < 0.01) than "Chernobyl" tumors, while tumors from E&W generally showed intermediate levels of degree and type of differentiation and invasion. There was a marked difference between the sex ratios of children with PTCs who were radiation exposed and those who were not exposed (F:M exposed vs. unexposed 1.5:1 vs. 4.2:1; chi(2) = 7.90, p < or = 0.01005). CONCLUSIONS: The aggressiveness and morphological features of Chernobyl childhood PTCs are not associated with radiation exposure. The differences found between tumors from the Chernobyl area, E&W, and Japan could be influenced by many factors. We speculate that dietary iodine levels may have wide implications in radiation-induced thyroid carcinogenesis, and that iodine deficiency could increase incidence, reduce latency, and influence tumor morphology and aggressiveness.

PEComa: another member of the MiT tumor family?

We report 2 cases of PEComa, one occurring in the colon of an 11-year-old boy and the other in the bone (fibula) of a 92-year-old woman. Both tumors consisted of nests of large epithelioid cells surrounded by a fibrovascular stroma. The nuclei were large and vesicular, with prominent centrally located nucleoli. The cytoplasm was eosinophilic, with a fine to coarse granularity. Mitoses and individual cell necrosis were infrequent. Immunohistochemically, both tumors showed strong cytoplasmic expression of HMB-45 and intense nuclear positivity for TFE3. To our knowledge, nuclear positivity for TFE3 has been previously reported in only 5 cases of PEComa. Reactivity to this marker suggests that PEComa should be added to the growing list of human tumors of the so-called MiT family gene.

Ovarian mature cystic teratoma with florid vascular proliferation and Wagner-Meissner--like corpuscles.

An ovarian mature cystic teratoma featuring florid vascular proliferation and Wagner-Meissner-like corpuscles is presented. The vascular proliferation is analogous to that seen in other tumors having a prominent neural component. The Wagner-Meissner-like corpuscles are viewed as evidence of a specialized type of differentiation of this neural component. To the best of our knowledge, they had not been previously reported in this setting.

Extraneural hemangioblastoma: a report of 5 cases.

Hemangioblastoma is a morphologically distinctive tumor that can occur sporadically or in association with von Hippel-Lindau disease, and which involves the central nervous system in the majority of the cases. Rare occurrences of hemangioblastoma in peripheral nerves and extraneural tissues have been reported. The histogenesis of this tumor remains uncertain. Various cell lineages such as vascular, glial, neural, fibrohistiocytic, and smooth muscle/myofibroblastic have been proposed for the so-called stromal cells, which are thought to represent the neoplastic component of these lesions. We report on 5 cases of hemangioblastoma arising in extraneural tissues. Two of the tumors were located in the presacral region, and one each in the maxilla, kidney, and adrenal glands. All 5 cases were morphologically indistinguishable from central nervous system hemangioblastoma. The existence of these cases suggests that the "stromal" cells of hemangioblastoma can demonstrate a variety of mature specific lineages, such as smooth muscle/myofibroblastic, or neuroendocrine, depending on the location and possibly the microenvironment.

Thymic tumor with adenoid cystic carcinomalike features: a clinicopathologic study of 4 cases.

Thymic carcinomas are rare malignant neoplasms which comprise several histologic subtypes. Adenoid cystic carcinoma (ACC) is included among these subtypes even if it has never been formally reported. We evaluated the clinical, radiologic, morphologic, immunohistochemical, and genetic features of 4 cases of thymic neoplasms with ACC-like features retrieved from the authors' consult files. Most cases affected adult/elderly males (mean 68.5 y; range: 63 to 77 y; M:F ratio=3:1), and were asymptomatic. The clinical history (no evidence of ACC in other sites), radiologic findings (a mass in the thymic region), and morphologic features (residual thymic tissue at the periphery of the neoplasm) strongly supported their primary thymic nature. Grossly, most of the tumors presented as multicystic lesions. On microscopic examination there were true glandular spaces filled with periodic acid-Schiff+material, and pseudocysts containing stromal mucin, collagen IV, and laminin. Features favoring malignancy were overtly infiltrative margins (2/4), mitotic figures (2/4), cytologic atypia (1/4), vascular invasion (1/4), absence of organoid thymuslike pattern (4/4), and absence of immature (TdT+) T lymphocytes (3/3). Necrosis and nerve invasion were not observed. The tumor cells showed the following immunophenotype: p63+(3/3), CK34betaE12+(3/3), CD5+ in scattered cells (1/3), CD117- (3/3), chromogranin-(2/2), synaptophysin-(2/2), and CD56- (2/2). MIB-1 ranged from 1% to 10%. Comparative genomic hybridization revealed an isolated gain of chromosome 8 in 1/3 cases. One patient is alive and well after 20 months, 1 died of another cause 5 years later, and 2 were lost at follow-up. Exceptionally, primary thymic tumors may exhibit histologic features resembling those of ACC of salivary glands. They may be well circumscribed and cytologically bland or invasive and cytologically atypical. In either case they lack an organoid thymuslike pattern and immature T lymphocytes. We have interpreted them as a microscopic subtype of well-differentiated thymic carcinoma of low-grade malignancy, an impression supported by the admittedly limited follow-up information.

Poorly differentiated thyroid carcinoma: the Turin proposal for the use of uniform diagnostic criteria and an algorithmic diagnostic approach.

Poorly differentiated (PD) thyroid carcinomas lie both morphologically and behaviorally between well-differentiated and undifferentiated (anaplastic) carcinomas. Following the original description of this entity, different diagnostic criteria have been employed, resulting in wide discrepancies and confusion among pathologists and clinicians worldwide. To compare lesions occurring in different geographic areas and the diagnostic criteria applied in those countries, we designed a study with a panel of internationally recognized thyroid pathologists to develop consensus diagnostic criteria for PD carcinomas. Eighty-three cases were collected from Europe, Japan, and the United States, and circulated among 12 thyroid pathologists. Diagnoses were made without any knowledge of the clinical parameters, which were subsequently used for survival analysis. A consensus meeting was then held in Turin, Italy, where an agreement was reached concerning the diagnostic criteria for PD carcinoma. These include (1) presence of a solid/trabecular/insular pattern of growth, (2) absence of the conventional nuclear features of papillary carcinoma, and (3) presence of at least one of the following features: convoluted nuclei; mitotic activity >or=3 x 10 HPF; and tumor necrosis. An algorithmic approach was devised for practical use in the diagnosis of this tumor.

Expression of p63 in thymomas and normal thymus.

The p63 gene, a member of the p53 family, is an epithelial marker expressed in embryonic ectoderm, breast myoepithelium, prostate, oral epithelium, epidermis, and urothelium. The DeltaN-p63 isoforms of p63, which are believed to behave as oncogenes, are expressed in squamous cell carcinoma, basal cell carcinoma, and transitional cell carcinoma. Only a few authors have looked for p63 expression in thymomas and normal thymus. We, therefore, thought of undergoing such a search by taking advantage of our archival material. We studied 66 cases of thymoma (1 type A, 8 type AB, 12 type B1, 19 type B2, 12 type B3, and 14 type C/thymic carcinoma) and 10 specimens of normal human thymus arranged in tissue microarrays. All thymomas (including thymic carcinomas) were positive for p63 regardless of type. Most of the epithelial cells of the normal thymus were also positive for this marker.

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.

Extramedullary erythropoiesis in chronic subdural hematoma simulating metastatic small round cell tumor.

We report two cases of extramedullary erythropoiesis within chronic subdural hematoma that caused diagnostic confusion. In both cases, the initial favored diagnosis by the submitting pathologists was that of a metastatic malignant tumor, including lymphoma, carcinoma, and malignant melanoma. In both cases, the subdural chronic hematoma contained cohesive clusters of small round blue cells with scant cytoplasm and round hyperchromatic nuclei. In both cases, some mitotic figures were identified. There was no gross or microscopic evidence of a meningeal mass lesion. The erythroblastic nature of the cells was confirmed using immunohistochemistry for CD43, glycophorin A, and erythropoietin A. It is important for surgical pathologists to be aware of this benign process and not to overinterpret it as either a primary or metastatic malignant tumor.

Solid Papillary Breast Carcinomas Resembling the Tall Cell Variant of Papillary Thyroid Neoplasms: A Unique Invasive Tumor With Indolent Behavior.

Thirteen cases of invasive solid papillary breast carcinomas resembling the tall cell variant of papillary thyroid neoplasms (BPTC) are reported here. Some cases had long-term follow-up. BPTC is a special type of primary breast neoplasm showing a triple-negative profile but low aggressive potential. Knowledge on BPTC is still scanty; therefore, the aim of the present paper was to report on the features of an additional 13 cases. All the patients were female individuals, and the mean age at presentation was 62.6 years; nodule sizes ranged from 0.6 to 2.5 cm (average, 1.6 cm). All the cases were characterized on histology by papillary, follicular as well as solid structures. The cells were columnar, eosinophilic mostly with granular cytoplasms, rich in mitochondria, with the features of oncocytes in no fewer than 7 cases. Estrogen and progesterone receptors as well as HER2 were consistently negative. The Ki67 proliferative index was low. Markers consistent with thyroid origin, such as TTF1 and thyroglobulin, were negative. Five cases stained for mammoglobin and GATA 3 were positive. All cases proved to be invasive and 2 cases each experienced metastases to 1 lymph node (axillary and intramammary). One case of the latter had a local recurrence. Nevertheless, all the patients are alive, free of disease 24 to 132 months after surgery, of which 8 are without further treatment The present series confirms that BPTC is a primary breast tumor of low malignant potential.

Distinctive Histogenesis and Immunological Microenvironment Based on Transcriptional Profiles of Follicular Dendritic Cell Sarcomas.

Follicular dendritic cell (FDC) sarcomas are rare mesenchymal tumors with variable clinical, morphologic, and phenotypic characteristics. Transcriptome analysis was performed on multiple FDC sarcomas and compared with other mesenchymal tumors, microdissected Castleman FDCs, and normal fibroblasts. Using unsupervised analysis, FDC sarcomas clustered with microdissected FDCs, distinct from other mesenchymal tumors and fibroblasts. The specific endowment of FDC-related gene expression programs in FDC sarcomas emerged by applying a gene signature of differentially expressed genes (n = 1,289) between microdissected FDCs and fibroblasts. Supervised analysis comparing FDC sarcomas with microdissected FDCs and other mesenchymal tumors identified 370 and 2,927 differentially expressed transcripts, respectively, and on the basis of pathway enrichment analysis ascribed to signal transduction, chromatin organization, and extracellular matrix organization programs. As the transcriptome of FDC sarcomas retained similarity with FDCs, the immune landscape of FDC sarcoma was investigated by applying the CIBERSORT algorithm to FDC sarcomas and non-FDC mesenchymal tumors and demonstrated that FDC sarcomas were enriched in T follicular helper (TFH) and T regulatory (TREG) cell populations, as confirmed in situ by immunohistochemistry. The enrichment in specific T-cell subsets prompted investigating the mRNA expression of the inhibitory immune receptor PD-1 and its ligands PD-L1 and PD-L2, which were found to be significantly upregulated in FDC sarcomas as compared with other mesenchymal tumors, a finding also confirmed in situ Here, it is demonstrated for the first time the transcriptional relationship of FDC sarcomas with nonmalignant FDCs and their distinction from other mesenchymal tumors.Implications: The current study provides evidence of a peculiar immune microenvironment associated with FDC sarcomas that may have clinical utility. Mol Cancer Res; 15(5); 541-52. ©2017 AACR.