Pleomorphic high grade endometrial stromal sarcoma with YWHAE gene amplification may be a novel variant with poor prognosis.

Endometrial stromal neoplasms are classified by the World Health Organization (WHO) into endometrial stromal nodule (ESN), low grade (LGESS), high grade (HGESS), and undifferentiated uterine sarcoma (UUS). HGESS is subclassified based on molecular findings, YWHAE or BCOR. The HGESS with YWHAE::NUTM2A/B (alias YWHAE::FAM22A/B) fusion usually have relatively monomorphic (as with most fusion-associated malignancies) rounded to epithelioid cells with eosinophilic cytoplasm, vesicular nuclei, nucleoli, and mitotic figures >10/10 HPF. We present a 66-year-old woman with post-menopausal bleeding found to have a heterogeneous solid-cystic uterine mass on CT who underwent total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and pelvic lymph node dissection. A 15.0×9.0 cm variegated uterine mass with hemorrhage and necrosis was identified. Histologically, the tumor was hypercellular with haphazard fascicles, microcysts, and tongue-like destructive myometrial invasion. Tumor cells exhibited marked pleomorphism and high mitotic activity with atypical mitotic figures. There was extensive cyclin-D1 and subset CD10 immunopositivity. FISH showed YWHAE amplification but without rearrangement. Interestingly, we found only two other reported cases of pleomorphic HGESS with YWHAE gene amplification upon review of 259 cases from cBioPortal database, one of which was reported as carcinosarcoma with heterologous elements. Of note, all three YWHAE amplified cases were diagnosed at high-stage and succumbed to disease within six months. Our case appears to be the third case of YWHAE-amplified pleomorphic HGESS, possibly a new variant of uterine sarcoma with aggressive biologic behavior that needs further evaluation.

Clear Cell Odontogenic Carcinoma: A Series of Three Cases.

BACKGROUND: Clear cell odontogenic carcinoma (CCOC) is a rare malignant odontogenic epithelial neoplasm of the jaws. It is composed of irregular nests of clear to faintly eosinophilic cells resembling clear cell rests of primitive dental lamina and an intermixed hyalinized fibrous stroma. Most cases occur in the 5th and 6th decades of life, with a female predominance. The mandible is affected more than the maxilla. Clinical features vary from asymptomatic to non-specific pain, ill-defined radiolucency, root resorption, and sometimes soft tissue extension. Histology varies from bland to high grade. CCOC demonstrated a significant tendency to recur. Metastasis typically involves regional lymph nodes, which haves been reported in 20-25% of cases. Pulmonary metastasis rarely occurs. Differential diagnoses are broad and include odontogenic, salivary, melanocytic, and metastatic neoplasia. CCOCs are positive for cytokeratins, mainly AE1/AE3 and CK19. Most cases show EWSR1 rearrangement and rarely, the BRAFV600E mutation. DESIGN: Patient charts were reviewed at our institution. A total of three cases were found in electronic medical records, which were diagnosed as clear cell odontogenic carcinoma over a period of six years (2014-2019). Patient charts were reviewed for medical history and radiology data. The pathology slides were reviewed by one or more faculty members. RESULTS: We present three cases of CCOC, ranging in age from 40 to 69 years (two women and one man). Two cases involved the maxilla and one involved the mandible. Two presented with painful swelling and one with mass recurrence. Radiography results show that two had poorly defined radiolucent lesions, and one was heterogeneous with a small nodule projecting into the maxillary sinus. Histological examination revealed an epithelial neoplasm composed of irregular sheets, cords, and nests of polygonal cells with central hyperchromatic, mildly pleomorphic nuclei surrounded by clear to pale eosinophilic cytoplasm, with occasional mitotic figures. The tumor had infiltrated the bone and soft tissues. Two cases were immunopositive for CK5/6 and one case was positive for p63 and CK19. Interestingly, the eosinophilic dentinoid matrix interspersed among tumor cells in one case was consistent with its odontogenic origin. Histochemical staining showed PAS-positive and diastase-labile intracytoplasmic material consistent with glycogen. CONCLUSION: Our study highlights the potential diagnostic significance of dentinoid (although reportedly seen in only 7% of cases), along with CK5/6 immunopositivity, in supporting the histologic diagnosis of CCOC among a variety of neoplasia in its differential diagnosis.

Retrospective Validation of a 168-Gene Expression Signature for Glioma Classification on a Single Molecule Counting Platform.

Gene expression profiling has been shown to be comparable to other molecular methods for glioma classification. We sought to validate a gene-expression based glioma classification method. Formalin-fixed paraffin embedded tissue and flash frozen tissue collected at the Augusta University (AU) Pathology Department between 2000-2019 were identified and 2 mm cores were taken. The RNA was extracted from these cores after deparaffinization and bead homogenization. One hundred sixty-eight genes were evaluated in the RNA samples on the nCounter instrument. Forty-eight gliomas were classified using a supervised learning algorithm trained by using data from The Cancer Genome Atlas. An ensemble of 1000 linear support vector models classified 30 glioma samples into TP1 with classification confidence of 0.99. Glioma patients in TP1 group have a poorer survival (HR (95% CI) = 4.5 (1.3-15.4), p = 0.005) with median survival time of 12.1 months, compared to non-TP1 groups. Network analysis revealed that cell cycle genes play an important role in distinguishing TP1 from non-TP1 cases and that these genes may play an important role in glioma survival. This could be a good clinical pipeline for molecular classification of gliomas.

Progressive Osteolysis After Use of Synthetic Bone Graft Substitute.

Benign bone tumors are commonly treated with intralesional curettage and bone graft, with autogenous bone graft being the gold standard. However, autogenous bone graft has its limitation, and artificial bone graft substitutes were developed as an alternative. PRO-DENSE™ (Wright Medical Technology, Arlington, Tennessee) is a calcium sulfate and calcium phosphate mixed bone graft substitute that is biodegradable and osteoconductive, which has made them a popular choice among surgeons. However, long-term studies of this treatment method for benign tumors are still limited. In this report, we present a case of progressive femoral neck osteolysis caused by an inflammatory reaction to PRO-DENSE™ two years after intralesional curettage and bone grafting of a benign bone tumor.  A twenty-one-year-old female with fibrous dysplasia underwent intralesional curettage with the use of PRO-DENSE™ bone substitute to fill the cavitary defect. She developed an inflammatory reaction to the bone graft substitute leading to increasing pain and osteolysis requiring a reoperation. Bone graft substitute has many advantages; however, they should be used with discretion due to many unknown regarding their safety and long-term outcomes.

Comparative analysis of transcriptomic profile, histology, and IDH mutation for classification of gliomas.

Gliomas are currently classified through integration of histology and mutation information, with new developments in DNA methylation classification. However, discrepancies exist amongst the major classification methods. This study sought to compare transcriptome-based classification to the established methods. RNAseq and microarray data were obtained for 1032 gliomas from the TCGA and 395 gliomas from REMBRANDT. Data were analyzed using unsupervised and supervised learning and other statistical methods. Global transcriptomic profiles defined four transcriptomic glioma subgroups with 91.4% concordance with the WHO-defined mutation subtypes. Using these subgroups, 168 genes were selected for the development of 1000 linear support vector classifiers (LSVC). Based on plurality voting of 1000 LSVC, the final ensemble classifier confidently classified all but 17 TCGA gliomas to one of the four transcriptomic profile (TP) groups. The classifier was validated using a gene expression microarray dataset. TP1 cases include IDHwt, glioblastoma high immune infiltration and cellular proliferation and poor survival prognosis. TP2a is characterized as IDHmut-codel, oligodendrogliomas with high tumor purity. TP2b tissue is mostly composed of neurons and few infiltrating malignant cells. TP3 exhibit increased NOTCH signaling, are astrocytoma and IDHmut-non-codel. TP groups are highly concordant with both WHO integrated histology and mutation classification as well as methylation-based classification of gliomas. Transcriptomic profiling provides a robust and objective method to classify gliomas with high agreement to the current WHO guidelines and may provide additional survival prediction to the current methods.

Atypical Spindle Cell Lipomatous Lesion Resected From Patient With History of CLL.

Atypical spindle cell lipomatous neoplasm, also known as well-differentiated spindle cell liposarcoma, represents a newly discovered entity of adipocytic tumors. Recent research has shown this tumor variant to be more related to spindle cell lipoma, rather than the originally hypothesized atypical lipomatous tumor spectrum. Here we present a case of a 58-year-old man with a history of chronic lymphocytic leukemia with an enlarging mass on the posterior left shoulder, initially hypothesized to be a benign lipoma. However, magnetic resonance imaging showed a large, multiseptated, heterogeneous mass concerning for soft tissue sarcoma. After resection, pathologic analysis showed cells closely resembling spindle cell lipoma, with additional cellular and fascicular zones containing lipoblasts and mitotic figures. Molecular analysis showed no MDM2 amplification. This lack of amplification indicates this tumor is distinctly different from an atypical lipomatous tumor, which characteristically displays MDM2 amplification. However, tumor expression of RB1 was normal. The majority of atypical spindle cell lipomatous neoplasms are associated with RB1 deletions. We conclude that we have a unique example of an atypical spindle cell lipomatous tumor.

Polymorphous Low-Grade Neuroepithelial Tumor of the Young: A Case Report with Genomic Findings.

BACKGROUND: Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently recognized epileptogenic neuroepithelial tumor. Despite its distinctiveness, its polymorphous histology and the nature of its oligodendrocyte-like cells remain unclear. CASE DESCRIPTION: A 30-year-old, right-handed man was diagnosed with intractable epilepsy since 22 years of age. Magnetic resonance imaging revealed T2 signal hyperintensity and corresponding T1 signal hypointensity within the subcortical white matter of the right middle temporal gyrus. Positron emission tomography scan demonstrated hypometabolism in the right anterior temporal region. Electroencephalography and stereo-electroencephalography monitoring localized seizures to the right temporal lobe, allowing the patient to undergo right temporal lobectomy. Histologic sections demonstrated cortical dysplasia, white matter heterotopia, and hippocampal reactive gliosis without neuronal loss. Interestingly, an approximately 6-mm subcortical neoplasm was identified in the temporal lobectomy. It was composed of well-differentiated oligodendroglial-like cells but exhibited mild-to-moderate nuclear variability and pleomorphism, and mild infiltration into the overlying cortex without perineuronal satellitosis. No mitotic activity, microvascular proliferation, or necrosis was identified, and Ki-67 labeling index was less than 1%. The tumor was diffusely CD34 positive with moderate glial fibrillary acidic protein and retained ATRX staining, and demonstrated the presence of the BRAF V600E mutation. The tumor was negative for reticulin condensation, synaptophysin, SMI31, neuronal nuclei immunostains, and both the IDH1 mutation and 1p19q codeletion. Overall histologic findings were most consistent with PLNTY. CONCLUSIONS: The correct diagnosis of PLNTY and its distinction from closely resembling low-grade neuroepithelial tumors is important. We hope our proposed diagnostic features will aid in its proper diagnosis and management.

Atypical Intracranial Meningioma with Metastasis to C7 Vertebral Body: A Case Report.

BACKGROUND: Extracranial metastasis, mainly a feature of World Health Organization (WHO) grade III meningiomas, is only rarely reported in grade II meningiomas. CASE DESCRIPTION: We report a case of a 48-year-old man who was initially diagnosed in 2010 with an occipital convexity meningioma based on computed tomography scan/magnetic resonance imaging (MRI) and treated with surgical therapy and gamma knife. The first operation achieved a macroscopically complete resection. The tumor was histologically classified as an atypical meningioma. The patient had a recurrence in 2014 on the left tentorial leaflet as noted on postcontrast MRI. The patient was asymptomatic, without focal neurologic deficits. In 2016, the patient reported new-onset pain in the neck and left upper extremity. MRI indicated complete replacement of the C7 vertebral marrow, with a soft tissue component extending posteriorly into the epidural space that appeared to be flattening the thecal sac but without evidence of abnormal cord signal. Histopathology of resection confirmed atypical meningioma. CONCLUSIONS: This case represents a rare instance of intraosseous spine as the first site of metastasis of WHO grade II atypical meningioma and is the first reported case of extracranial metastasis of a meningioma to the C7 vertebral body.

The lifelong impact of fetal growth restriction on cardiac development.

BACKGROUND: Maternal nutrient restriction (MNR) is a widespread cause of fetal growth restriction (FGR), an independent predictor of heart disease and cardiovascular mortality. Our objective was to examine the developmental and long-term impact of MNR-induced FGR on cardiac structure in a model that closely mimics human development. METHODS: A reduction in total caloric intake spanning pregestation through to lactation in guinea pig sows was used to induce FGR. Proliferation, differentiation, and apoptosis of cardiomyocytes were assessed in late-gestation fetal, neonatal, and adult guinea pig hearts. Proteomic analysis and pathway enrichment were performed on fetal hearts. RESULTS: Cardiomyocyte proliferation and the number of mononucleated cells were enhanced in the MNR-FGR fetal and neonatal heart, suggesting a delay in cardiomyocyte differentiation. In fetal hearts of MNR-FGR animals, apoptosis was markedly elevated and the total number of cardiomyocytes reduced, the latter remaining so throughout neonatal and into adult life. A reduction in total cardiomyocyte number in adult MNR-FGR hearts was accompanied by exaggerated hypertrophy and a disorganized architecture. Pathway analysis identified genes related to cell proliferation, differentiation, and survival. CONCLUSIONS: FGR influences cardiomyocyte development during critical windows of development, leading to a permanent deficiency in cardiomyocyte number and compensatory hypertrophy in a rodent model that recapitulates human development.

Cervical superficial myofibroblastoma: Case report and review of the literature.

Superficial myofibroblastoma of the lower female genital tract is a rare benign, recently recognized neoplasm that mostly affects the vulvovaginal area. Our report discusses a case of cervical superficial myofibroblastoma of the lower female genital tract in a 45-year-old patient who is presented with menometrorrhagia. On examination, she had multiple uterine fibroids and a circumscribed submucosal mass lesion involving the anterior lip of cervix. At hysterectomy, histopathological examination of the cervical mass revealed a relatively hypocellular tumor consisted of bland spindled and stellate cells. An immunohistochemistry evaluation revealed reactivity for CD34, desmin, and smooth muscle actin. This neoplasm should be included in the differential diagnosis of cervical mass lesions. This tumor also needs to be differentiated from other mesenchymal lesions of lower female genital tract.

Persistent indolent pancolonic marginal zone lymphoma of MALT-type with plasmacytic differentiation - A rare post-transplant lymphoma?

Marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is associated with chronic inflammatory disorders. We present an indolent pancolonic MALT lymphoma occurring in a 39-year-old female with history of autoimmune hepatitis requiring liver transplant in 1997 and ulcerative colitis diagnosed in 2004. Random biopsies from a grossly unremarkable surveillance colonoscopy in 2015 revealed a dense monomorphic plasmacytoid infiltrate causing expansion of lamina propria without significant crypt infiltration or destruction. These cells were positive for CD79a and CD138 and showed lambda restriction; however, CD20, CD43, CD56, HHV8, and EBER were negative. A similar pancolonic infiltrate was identified in all prior colorectal biopsies from 2010 and 2012 upon retrospective review. Subsequent computed tomography of the abdomen revealed no bowel wall thickening nor enlarged lymph nodes. Bone marrow revealed involvement consistent with stage IV disease. Biopsies from 2010 and 2015 demonstrated clonal immunoglobulin gene rearrangement. MYD88 mutation was not detected. The overall features were indicative of MALT lymphoma. Although low-grade B-cell lymphomas are not considered part of the post-transplant lymphoproliferative disorder spectrum, such cases have been reported, and are typically EBV-negative. Patient underwent treatment with pentostatin for her MALT lymphoma reaching a sustained remission despite additional immunosuppression for resurgent hepatic dysfunction. To our knowledge, this is the first reported case of EBV-negative pancolonic MALT lymphoma with plasmacytic differentiation post liver transplant presenting in an indolent, asymptomatic fashion with persistence for greater than five years successfully managed without compromising the patient's liver transplant.

Anterior Gray Matter Pituicytic Heterotopia with Monomorphic Anterior Pituitary Cells: A Variant of Nonsecretory Pituitary Adenoma Neuronal Choristoma? Report of a Rare Case and Review of the Literature.

BACKGROUND: Mixed tumors of adenomatous and neuronal cells in the sellar region are an uncommon finding. The origins of these heterogeneous tumors are unknown, and management remains unsettled. We report a very rare case of anterior gray matter pituicytic heterotopia with monomorphic anterior pituitary cells that likely represents a variant of nonsecreting pituitary adenoma neuronal choristoma (PANCH) with no ganglion cells. We also review the current literature for the various clinical presentations of PANCH. CASE DESCRIPTION: A 49-year-old female complaining of headache, blurred vision, and hair loss was found to have a nonsecretory sellar mass with compression of the optic chiasm on magnetic resonance imaging (MRI). The mass was excised via a transsphenoidal procedure. Histological analysis of tissue sections revealed heterotopic gray matter with reactive gliosis without ganglion cells or Herring bodies. Only 1 smear exhibited characteristics of a pituitary adenoma. CONCLUSIONS: The overall findings were most consistent with a variant of PANCH. At a postoperative follow-up of 4.5 years, there was resolution of visual symptoms, and the residual sellar mass was stable on MRI. Neuronal choristoma is hypothesized to originate from embryonal pituitary or hypothalamus, or by differentiation from pituitary adenoma cells. Surgery is the cornerstone of management, and the clinical course appears to be similar to that of nonfunctioning pituitary adenoma in reported cases.

Combined Inhibition of DNMT and HDAC Blocks the Tumorigenicity of Cancer Stem-like Cells and Attenuates Mammary Tumor Growth.

Recently, impressive technical advancements have been made in the isolation and validation of mammary stem cells and cancer stem cells (CSC), but the signaling pathways that regulate stem cell self-renewal are largely unknown. Furthermore, CSCs are believed to contribute to chemo- and radioresistance. In this study, we used the MMTV-Neu-Tg mouse mammary tumor model to identify potential new strategies for eliminating CSCs. We found that both luminal progenitor and basal stem cells are susceptible to genetic and epigenetic modifications, which facilitate oncogenic transformation and tumorigenic potential. A combination of the DNMT inhibitor 5-azacytidine and the HDAC inhibitor butyrate markedly reduced CSC abundance and increased the overall survival in this mouse model. RNA-seq analysis of CSCs treated with 5-azacytidine plus butyrate provided evidence that inhibition of chromatin modifiers blocks growth-promoting signaling molecules such as RAD51AP1 and SPC25, which play key roles in DNA damage repair and kinetochore assembly. Moreover, RAD51AP1 and SPC25 were significantly overexpressed in human breast tumor tissues and were associated with reduced overall patient survival. In conclusion, our studies suggest that breast CSCs are intrinsically sensitive to genetic and epigenetic modifications and can therefore be significantly affected by epigenetic-based therapies, warranting further investigation of combined DNMT and HDAC inhibition in refractory or drug-resistant breast cancer. Cancer Res; 76(11); 3224-35. ©2016 AACR.

Two Cases of Chronic Intestinal Pseudo-obstruction: A Comparison of Staining Characteristics of Enteric Visceral Myopathy With Hirschsprung Disease.

Chronic intestinal pseudo-obstruction (CIPO), a rare, debilitating disorder of bowel motility dysfunction, is largely a clinical diagnosis, without any universally accepted diagnostic criteria. Three subgroups are generally acknowledged based on the cell-type affected: enteric visceral myopathy (the most common subgroup), neuropathy, and mesenchymopathy. A fourth subgroup includes abnormalities of neurohormonal peptides. Although immunohistochemical staining is reportedly useful for identifying the mesenchymopathic type, its role in diagnosing enteric visceral myopathy and neuropathy has been fraught with difficulties. We present two cases of chronic intestinal pseudo-obstruction that are clinically and histopathologically suggestive of type III visceral enteric myopathy, aiming to expound upon the diagnostic and pathogenic features. We found that the outer-longitudinal layer of the muscularis propria was more severely affected as compared with the inner circular layer. To investigate the value of this finding, we performed immunostains in the one case in which a paraffin block was available. We found increased peripherin and calretinin immunopositive nerve fibers in the outer layer as compared with inner, but without any significant increase in S-100 positivity or alteration in neuronal morphology of myenteric plexus, a novel finding. This differential staining pattern was completely different from Hirschsprung disease, in which we found rare to absent peripherin and calretinin staining. It is unclear if this increase in the outer layer in visceral myopathy reflects a reactive change or dysfunctional axons. In addition, the history of volvulus in one patient and transmural inflammatory changes in the second raise concerns about the higher propensity of clinical complications secondary to the attenuated outer muscular layer. This study suggests that enteric visceral myopathy has histologic and staining characteristics different from Hirschsprung disease, a finding of diagnostic significance in the differential diagnosis of bowel obstruction. Moreover, these features may have pathogenic value and need further confirmation.

A Paratesticular Serous Borderline Tumor in a Pediatric Patient With Proteus Syndrome.

Proteus syndrome is a rare disorder of asymmetric overgrowth of various tissues of the body and is associated with specific tumors appearing before the second decade. Although there have been reports of lesions of the genitourinary tract associated with Proteus syndrome, a case of serous borderline tumor of the paratestis has not been previously recorded. We report the first such case in a 20-month-old child who presented with a left-sided testicular mass that was found on histology to be a serous borderline tumor of the paratestis. Surgical management included a left inguinal radical orchiectomy and surveillance follow-up.