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.

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.

Pediatric Sloughing Esophagitis: A Case Report and Discussion.

BACKGROUND: Sloughing esophagitis is an uncommon entity with an unclear pathogenesis characterized by desquamating sheets of squamous mucosa. It has been associated with bullous dermatologic disorders, other autoimmune diseases and has been most commonly reported in elderly, debilitated individuals on multiple medications. CASE REPORT: We report sloughing esophagitis in a previously healthy 17 year-old girl. While the initial trigger of her esophagitis is unclear, she improved with proton pump inhibitor therapy and swallowed fluticasone, with complete resolution after 6 months. CONCLUSIONS: Sloughing esophagitis can occur in the pediatric population. We discuss the presentation, differential diagnosis, and treatment of sloughing esophagitis in adolescents.

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.

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.

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.

Differential diagnosis of solid carcinoma in situ.

Although most cases of carcinoma in-situ are easily classified as either ductal or lobular on the basis of their pattern of involvement and the nature of their cell-to-cell relation, a few pose diagnostic problems. Attention to the presence of associated lesions and the results of immunohistochemical staining for E-cadherin and, to a lesser extent, cytokeratin can help to categorize problematic cases. This article reviews the histological criteria employed to separate ductal carcinoma in situ from lobular carcinoma in situ, the role of immunohistochemistry in the diagnosis of equivocal lesions, and the evidence suggesting the existence of combined and truly hybrid forms.

Endoscopic bile duct brushing of malignant pancreatic biliary strictures: retrospective study with comparison of conventional smear and ThinPrep techniques.

Endoscopic bile duct brushing (EBDB) is carried out to differentiate benign from malignant biliary strictures in patients who have pancreaticobiliary disease. The sensitivity of this method for the diagnosis of malignancy is relatively low. The aim of this study is to analyze the cytomorphologic features that are helpful in increasing the sensitivity of detecting these lesions on cytologic samples. These features are compared with slides prepared with the ThinPrep technique. The study included 142 patients with bile duct obstruction or pancreatic mass who underwent EBDB and follow-up surgery or biopsy between 1997 to 2000. Twenty-five (18%) of these cases were positive for malignancy in both EBDB and follow-up surgical biopsy; 20 of these cases were used as positive controls (PC). Sixty-one (43%) were negative in both EBDB and follow-up surgical biopsy specimens, and 21 of those cases were used as negative controls (NC). Fifty-six (39%) cases were negative/atypical in EBDB cytology but were suspicious or positive in the surgical or biopsy specimens (false-negative). We identified the cytologic criteria that were helpful in differentiating our positive and negative control groups and applied these criteria to our false-negative group to see whether our sensitivity could be increased, using well-defined cytologic criteria alone. Of the 56 false-negative cases, 9 (16%) were upgraded to suspicious/positive based on the presence of the following features: three-dimensional (3D) micropapillae (95% PC vs 19% NC, P < 0.0001), anisonucleosis (90% PC vs 5% NC, P < 0.0001), high nuclear-to-cytoplasmic (N/C) ratio (95% PC vs 9% NC, P < 0.0001), nuclear contour irregularity (65% PC vs 24% NC, P = 0.0079), and prominent nucleoli (70% PC vs 38% NC, P = 0.0406). Cytomorphologic features which were not helpful in distinguishing positive and negative cases were: single naked nuclei (50% PC vs 28% NC, P = 0.1597), chromatin granularity (50% PC vs 62% NC, P = 0.54), and necrosis (10% PC vs 5% NC, P = 0.5197). Improvement in diagnostic sensitivity for carcinoma of pancreaticobiliary tract in EBDB samples may be achieved by identifying the key malignant cytomorphologic features: 3D micropapillae, anisonucleosis, nuclear contour irregularity, prominent nucleoli, and high N/C ratio. The sensitivity in detecting malignant biliary strictures increased from 31% to 42% based on these criteria in our current study.