Stromal p16 and SATB2 Expression Does Not Distinguish Atypical Polypoid Adenomyoma (APA) From its Benign Mimics.

Atypical polypoid adenomyoma (APA) is a polypoid biphasic lesion of low malignant potential that arises in the lower uterine segment and uterine corpus. The diagnosis of APA is often challenging on biopsy and curettage specimens, and both benign and malignant processes need to be considered in the differential. Stromal expression of p16 and SATB2 have recently been shown to distinguish APA from myoinvasive endometrioid carcinoma. The authors hypothesized that p16 and SATB2 immunohistochemistry could also aid in the distinction of APA from benign adenomyomatous polyp and endometrioid adenomyoma. The study comprised 10 APAs, 7 adenomyomatous polyps, 11 endometrioid adenomyomas, and 10 myoinvasive endometrioid carcinomas. The majority of APAs showed moderate to strong, diffuse p16 and stromal expression. However, most adenomyomatous polyps and endometrioid adenomyomas also exhibited moderate to strong, focal to diffuse p16 stromal expression. SATB2 showed weak to moderate, focal to diffuse expression in the majority of APAs, adenomyomatous polyps and endometrioid adenomyomas. In contrast, p16 and SATB2 were negative to weak and focal in 90% of myoinvasive endometrioid carcinomas. Our findings demonstrate that p16 and SATB2 may be helpful in the differential diagnosis of myoinvasive endometrioid carcinoma and APA while not useful in separating APA from adenomyomatous polyp and endometrioid adenomyoma.

Human Epidermal Growth Factor Receptor 2 Overexpression/Amplification in Primary Ovarian Endometrioid Carcinoma.

Human epidermal growth factor receptor 2 (HER2) expression has become increasingly helpful in predicting responses to anti-HER2 agents in gynecological cancers. This study retrospectively analyzed HER2 expression in 48 primary ovarian endometrioid carcinomas. HER2 immunohistochemistry was performed using the Ventana platform (Clone 4B5 monoclonal predilute) following the manufacturer's protocol. HER2 expression was equivocal (score 2+) by image analysis in 2 cases (4.17%) based on the breast cancer criteria. Fluorescence in situ hybridization was negative for HER2 amplification in one case (International Federation of Gynecology and Obstetrics, grade 1) and positive in the other (International Federation of Gynecology and Obstetrics, grade 3). Our findings contribute to the growing evidence that HER2 is overexpressed in a small proportion of ovarian endometrioid carcinoma, and thus may serve as a potential therapeutic target in selected cases.

Mark Wick contributions to pathology of the mediastinum.

Mark Wick made a wide range of contributions to the field of mediastinal pathology. Early papers amplified the spectrum of neuroendocrine carcinomas of the thymus and brought attention to the aggressive nature of this tumor, also highlighting the occurrence of coexisting carcinoid tumor and small cell carcinoma of this organ. The controversial issue of thymoma classification was addressed in several papers and editorial comments, while also reporting a case of metastatic thymoma. A series of thymic carcinomas as well a report on the unusual clear cell variant bear his name as one of the authors. He summarized the topic of mediastinal cyst in a review published in 2005. Sarcomas arising in mediastinal germ cell tumors were also within the purview of his interests, with a publication of series of seven cases. He reviewed the topic of inflammatory myofibroblastic tumor of the heart and added a case to the existing literature. Two books dedicated to different aspect of mediastinal pathology also carry his name in the front cover in association with Drs Taazelar in one and Marchevsky in the other.

The Genetic Landscape of Fibroepithelial Lesions of the Breast.

Fibroepithelial lesions of the breast encompass a broad spectrum of lesions from fibroadenomas and their variants to phyllodes tumors, including their clinical range of benign, borderline, and malignant. Classification of this spectrum of neoplasms has historically and currently been based purely on morphology, although the nomenclature has shifted over the years largely due to the significant histologic overlap that exists primarily within the cellular fibroadenomas to borderline malignant phyllodes tumor categories. A review of the current diagnostic challenge, proposed ancillary studied and their value in prognostic significance, is provided. This article highlights the most recent molecular and genetic findings as well as the limitations of the studies, in the context of practical and available applications for the diagnostician and managerial implications for the clinician.

Gene Expression Profiling of Fibroepithelial Lesions of the Breast.

Fibroepithelial lesions of the breast (FELs) are a heterogeneous group of neoplasms exhibiting a histologic spectrum ranging from fibroadenomas (FAs) to malignant phyllodes tumors (PTs). Despite published histologic criteria for their classification, it is common for such lesions to exhibit overlapping features, leading to subjective interpretation and interobserver disagreements in histologic diagnosis. Therefore, there is a need for a more objective diagnostic modality to aid in the accurate classification of these lesions and to guide appropriate clinical management. In this study, the expression of 750 tumor-related genes was measured in a cohort of 34 FELs (5 FAs, 9 cellular FAs, 9 benign PTs, 7 borderline PTs, and 4 malignant PTs). Differentially expressed gene analysis, gene set analysis, pathway analysis, and cell type analysis were performed. Genes involved in matrix remodeling and metastasis (e.g., MMP9, SPP1, COL11A1), angiogenesis (VEGFA, ITGAV, NFIL3, FDFR1, CCND2), hypoxia (ENO1, HK1, CYBB, HK2), metabolic stress (e.g., UBE2C, CDKN2A, FBP1), cell proliferation (e.g., CENPF, CCNB1), and the PI3K-Akt pathway (e.g., ITGB3, NRAS) were highly expressed in malignant PTs and less expressed in borderline PTs, benign PTs, cellular FAs, and FAs. The overall gene expression profiles of benign PTs, cellular FAs, and FAs were very similar. Although a slight difference was observed between borderline and benign PTs, a higher degree of difference was observed between borderline and malignant PTs. Additionally, the macrophage cell abundance scores and CCL5 were significantly higher in malignant PTs compared with all other groups. Our results suggest that the gene-expression-profiling-based approach could lead to further stratification of FELs and may provide clinically useful biological and pathophysiological information to improve the existing histologic diagnostic algorithm.

Single-cell transcriptomic analysis of endometriosis.

Endometriosis is a common condition in women that causes chronic pain and infertility and is associated with an elevated risk of ovarian cancer. We profiled transcriptomes of >370,000 individual cells from endometriomas (n = 8), endometriosis (n = 28), eutopic endometrium (n = 10), unaffected ovary (n = 4) and endometriosis-free peritoneum (n = 4), generating a cellular atlas of endometrial-type epithelial cells, stromal cells and microenvironmental cell populations across tissue sites. Cellular and molecular signatures of endometrial-type epithelium and stroma differed across tissue types, suggesting a role for cellular restructuring and transcriptional reprogramming in the disease. Epithelium, stroma and proximal mesothelial cells of endometriomas showed dysregulation of pro-inflammatory pathways and upregulation of complement proteins. Somatic ARID1A mutation in epithelial cells was associated with upregulation of pro-angiogenic and pro-lymphangiogenic factors and remodeling of the endothelial cell compartment, with enrichment of lymphatic endothelial cells. Finally, signatures of ciliated epithelial cells were enriched in ovarian cancers, reinforcing epidemiologic associations between these two diseases.

Myofibroblastic stromal hyperplasia of the breast.

Myofibroblastic stromal hyperplasia (MSH) is the proposed name for a benign spindle cell proliferation of the mammary stroma, which often raises clinical and radiographic concern for a mass or a malignant process. Ten cases were retrieved from the files of our institution. All presented as a mammographic abnormality. Patients ranged in age from 24 to 67 years. Seven were <50 years old. The salient histopathologic aspect was the proliferation of benign appearing spindle cell within the intralobular stroma. The most common pattern was a diffuse proliferation of compact spindle cells with areas of perilobular/periductal accentuation. Mitotic activity and atypia were not seen. Tumor cells were positive for CD34 and SMA and negative for estrogen receptor, Beta-catenin, and p63. Only one of the cases demonstrated an associated lesion that explained the mammographic abnormality. Follow-up was available for four cases and was uneventful. MSH has overlapping features with the fascicular pattern of PASH and is likely related to pseudoangiomatous stromal hyperplasia (PASH) but differs in that does not demonstrate pseudovascular structures and it predominantly involves perilobular stroma. Recognition of this pattern will avoid discordant radiologic pathologic findings and unnecessary surgery/repeat biopsies.

Clinicopathologic and molecular features of six cases of phosphaturic mesenchymal tumor.

Phosphaturic mesenchymal tumors (PMT) are rare neoplasms characterized by secretion of FGF23, resulting in renal phosphate wasting and osteomalacia. This tumor-induced osteomalacia (TIO) is cured by complete resection; thus, diagnosis is important, particularly on biopsy. Although PMT have a classic histologic appearance of bland spindled cells with conspicuous vascular network and characteristic smudgy basophilic matrix, there is a broad histologic spectrum and variant histologic patterns can make recognition difficult. Recent studies have demonstrated FN1-FGFR1 and FN1-FGF1 gene fusions in PMT; however, approximately 50% of cases are negative for these fusions. We sought to characterize 6 cases of PMT in-depth, compare fusion detection methods, and determine whether alternative fusions could be uncovered by targeted RNA sequencing. Of the 6 cases of PMT in our institutional archive, 3 were not given diagnoses of PMT at the time of initial pathologic examination. We characterized the immunoprofile (SMA, D2-40, CD56, S100 protein, desmin, SATB2, and ERG) and gene fusion status (FN1 and FGFR1 rearrangements by fluorescent in situ hybridization (FISH) and two targeted RNA sequencing approaches) in these cases. Tumors were consistently positive for SATB2 and negative for desmin, with 5/6 cases expressing ERG and CD56. One specimen was acid-decalcified and failed FISH and RNA sequencing. We found FN1 gene rearrangements by FISH in 2/5 cases, and a FN1-FGFR1 fusion by targeted RNA sequencing. No alternative gene fusions were identified by RNA sequencing. Our findings suggest that IHC and molecular analysis can aid in the diagnosis of PMT, guiding excision of the tumor and resolution of osteomalacia.

Histopathologic, immunophenotypic, and proteomics characteristics of low-grade phyllodes tumor and fibroadenoma: more similarities than differences.

Distinguishing low-grade phyllodes tumor from fibroadenoma is practically challenging due to their overlapping histologic features. However, the final interpretation is essential to surgeons, who base their management on the final pathology report. Patients who receive a diagnosis of fibroadenoma might not undergo any additional intervention while lumpectomy with wide margins is the standard of care for phyllodes tumor, which can have significant cosmetic consequences. We studied the clinical, immunophenotypic, and proteomics profiles of 31 histologically confirmed low-grade phyllodes tumor and 30 fibroadenomas. Matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) and immunohistochemistry for Ki-67, p53, ß-catenin, and E-cadherin were performed on all cases. After the mass spectra for all 31 cases of low-grade phyllodes tumor and 30 cases of fibroadenoma were collected, an average peak value for all cases was generated. There was no significant difference in the overall mass spectra pattern in any of the peaks identified. There was also overlap in the percentage of cells staining positive for Ki-67, p53, ß-catenin, and E-cadherin. The two groups of patients showed no statistically significant difference in age, tumor size, or disease-free survival. Neither group developed malignant transformation, distant metastases, or disease-related mortality. We have demonstrated low-grade phyllodes tumor and fibroadenoma to show significant overlapping clinical and proteomics features.

Adenomyosis presenting as a molar pregnancy: A case report.

•We present a case of atypical adenomyosis with clinical, laboratory, and imaging findings suggestive of a molar pregnancy.•Adenomyosis causes uterine enlargement and may appear cystic on vaginal ultrasound.•Falsely elevated ß-hCG in the setting of obesity and hypothyroidism may complicate diagnosing abnormal uterine bleeding.

Clinicopathologic characteristics of de novo nodular regenerative hyperplasia in pediatric liver transplant.

Liver NRH is seen in all patients age; however, more frequently in those over the age of 60 years and associated with multiple systemic diseases. In liver allograft recipients, the development of DnNRH has been linked with the use of azathioprine or vascular abnormalities. We present the clinicopathologic characteristics of 17 pediatric patients who underwent liver transplantation and subsequently developed DnNRH. The patients were divided into early and late onset depending if DnNRH was diagnosed within or beyond 4 years after transplant. Eight patients (47%) presented as early onset, of which two had normal ultrasound at time of diagnosis. One patient (12.5%) with early onset lost the graft secondary to DnNRH. Nine patients (53%) presented as late onset, of which two (22%) had normal ultrasound at time of diagnosis. Two patients (25%) of the late onset lost their graft secondary to chronic rejection and DnNRH. Two patients (12%) died secondary to cytomegalovirus pneumonitis and pancolitis. Furthermore, both groups presented with symptoms differing from the adult population in prior studies and were not associated with the use of azathioprine or vascular abnormalities. Interestingly, episodes of acute cellular rejection were more common in the early-onset group compared to the late-onset group. In conclusion, DnNRH in the pediatric age group has a different clinical presentation, possibly reflecting a different pathogenesis compared to the adult population.

Primary osseous sacral neuroblastoma in an adult.

Neoplasms of the sacrum are rare. Given the non-specific imaging findings in sacral lesions, the imaging-based differential diagnosis is always difficult. This case is about an adult with primary sacral neuroblastoma and we have discussed imaging and histopathological findings of this rare tumor.

Association of Li-Fraumeni Syndrome With Small Cell Carcinoma of the Ovary, Hypercalcemic Type and Concurrent Pleomorphic Liposarcoma of the Cervix.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare, highly lethal malignancy predominantly affecting young adult females. We report a patient with widely metastatic SCCOHT and concurrent uterine cervical pleomorphic liposarcoma. Clinical targeted next-generation sequencing was performed on both neoplasms and demonstrated hemizygous stop-gain TP53 mutations (p.R196*), and wild-type SMARCA4 in both tumors. Microarray analyses of both tumors revealed similar but not identical widespread loss of heterozygosity over most chromosomes associated with loss of chromosomal copy number in the SCCOHT and pleomorphic liposarcoma tumors, amplification of FGFR1 in both tumors, and amplification of MYC in the SCCOHT. Immunohistochemistry demonstrated that SMARCA4 and SMARCB1 were retained in both tumors, and that SMARCA2 expression was retained but TP53 expression was lost in the SCCOHT. Germline testing using Sanger sequencing showed heterozygous TP53 mutation, confirming the diagnosis of Li-Fraumeni syndrome. These findings are novel and for the first time associate SCCOHT with Li-Fraumeni syndrome.

Acute graft-versus-host disease is more prevalent and severe in the lower than the upper gastrointestinal tract.

It is unclear whether acute gastrointestinal (GI) graft-versus-host disease (GVHD) affects all segments of the GI tract equally. Up to 45% patients reported showed discrepancy in involvement between upper GI (UGI) and lower GI (LGI) tract. We compared the prevalence and the severity of acute GVHD in UGI and LGI tract on histologic examination. A cohort of 110 cases of simultaneous UGI and LGI biopsies from 105 allogeneic hematopoietic stem cell transplantation recipients with clinically confirmed GI GVHD were reviewed retrospectively. The χ(2) test and 1-way analysis of variance test were used for statistical analysis. Most (75%) of the cases had GVHD involvement in both UGI and LGI tracts, whereas UGI-only GVHD was found in 6% and LGI-only GVHD in 19%. GVHD prevalence was the lowest in stomach (61%) and significantly increased toward duodenum/jejunum (81%; P = .0019). The LGI tract showed similar GVHD prevalence (P = .3648); the highest was in the sigmoid colon (97%). The histologic grade was lowest in the stomach (mean ± SD, 1.6 ± 0.8) and was similar across all UGI segments (P = .0883). The histologic grade in LGI significantly increased (P = .0265) from the terminal ileum (2.0 ± 1.3) to the rectum (2.9 ± 1.0). Overall, both the prevalence and the histologic grade of GVHD in LGI were significantly higher than those of UGI (P < .0001 for both). Our results show that acute GVHD had a higher prevalence and was more severe in the LGI than in UGI tract. A small subset of patients had only UGI involvement.

Hepatoid carcinoma of the pancreas: a case report and literature review of a heterogeneous group of tumors.

Hepatoid carcinomas are tumors that display, at least focally, cytologic and/or architectural features of hepatocellular carcinoma. They have been described in several organs, most notably in the stomach and ovary. We report a case of hepatoid carcinoma of the pancreas that developed in a 41-year-old woman in association with a pancreatic endocrine carcinoma. The fine needle aspiration material was characterized by the presence of monotonous, small-to-medium sized tumor cells with round nuclei and finely granular chromatin, intermixed with more atypical tumor cells displaying larger nuclei with coarse clumped chromatin, prominent nucleoli, and moderate amounts of foamy cytoplasm. The excised specimen displayed a poorly differentiated pancreatic endocrine carcinoma associated with well-defined islands of larger tumor cells growing in a perisinusoidal pattern which, based on their immunohistochemical profile and the demonstration of bile, proved to represent a hepatoid component. This case and prior examples in the literature suggest that hepatoid carcinomas of the pancreas appear to be a heterogeneous group of tumors (pure or associated with another histologic component) that are often associated with early liver metastasis and a short survival, although those arising as a component of endocrine tumors seem to fare slightly better. Hepatoid carcinoma of the pancreas should be included in the differential diagnosis of pancreatic tumors composed of large eosinophilic cells.

Peridiverticular colonic hyaline rings (pulse granulomas): report of two cases associated with perforated diverticula.

Hyaline ring (pulse granuloma) is a rare benign lesion of the oral cavity soft tissues characterized by round or oval structures with scalloped borders composed by a collagenous matrix variable associated with inflammatory and foreign bogy giant cells. Vegetable fragments are variably identified. Whereas most cases occur in the oral cavity, it has also been described in other sites such as the lung and rectum. It is thought by most to represent a reaction to foreign materials. We report two incidentally discovered cases of colonic hyaline rings associated with perforated diverticulitis. Vegetable residues were seen in both cases.

Perivascular epithelioid clear cell tumor of the common bile duct.

The perivascular epithelioid clear cell tumor (PEComa) has been described in a number of locations, including the pancreas, uterus, bladder, prostate, and gastrointestinal tract. We report the existence of a similar tumor occurring in the distal common bile duct of a 51-year-old man admitted for obstructive jaundice. The tumor had characteristic histologic features of a PEComa, including a richly vascular organoid architecture, tumor cells with clear to lightly eosinophilic cytoplasm, and variably prominent nucleoli. Immunohistochemically, the tumor cells were positive for HMB-45 and neuron specific enolase but negative for epithelial markers, smooth muscle markers, other neuroendocrine markers, vimentin, melan-A, and S-100 protein. PEComas appear to be ubiquitous tumors with characteristic histology and immunophenotype. Although most of these tumors have behaved in a benign fashion, they should be considered tumors of uncertain malignant potential given previous reports of recurrence and metastases. During a short follow-up period following a conservative local excision, our patient remains free of disease.

Spindle cell ossifying amyloidotic tumor of the fallopian tube.

We report a unique tumor of the fallopian tube that was an incidental finding in a 60-year-old woman. The tumor was characterized by nests of spindle cells embedded in a partially ossified, hyalinized stroma, that also contained amyloid and basement membrane-like material. The histologic appearance of the tumor cells suggested an epithelial nature, but no immunohistochemical or ultrastructural evidence of such was found. The circumscription of the tumor and its lack of mitotic activity and cytologic atypia suggest a benign nature, but the histogenesis and appropriate classification of the tumor remain unclear.