Pancreatic Neuroendocrine Tumors: Signaling Pathways and Epigenetic Regulation.

Pancreatic neuroendocrine tumors (PNETs) are characterized by dysregulated signaling pathways that are crucial for tumor formation and progression. The efficacy of traditional therapies is limited, particularly in the treatment of PNETs at an advanced stage. Epigenetic alterations profoundly impact the activity of signaling pathways in cancer development, offering potential opportunities for drug development. There is currently a lack of extensive research on epigenetic regulation in PNETs. To fill this gap, we first summarize major signaling events that are involved in PNET development. Then, we discuss the epigenetic regulation of these signaling pathways in the context of both PNETs and commonly occurring-and therefore more extensively studied-malignancies. Finally, we will offer a perspective on the future research direction of the PNET epigenome and its potential applications in patient care.

Small Cell Carcinoma of the Rectum-An Unexpected Diagnosis: Current Treatment Options for a Rare and Aggressive Entity.

Rectal small cell carcinoma is a rare and aggressive cancer subtype for which a consensus of optimal treatment has not yet been reached. This cancer presents a difficult surgical problem, and thus, the mainstay of treatment tends to mirror that of small cell carcinoma of the lung (chemotherapy, radiation therapy, and immune modulators). This brief report highlights current treatment options available for this rare and difficult entity. There is a significant need for large-center clinical trials and prospective studies to help determine the best treatment regimen to effectively care for patients with small cell carcinoma of the rectum.

Herpes Simplex Virus Pseudotumor Masking as Gastric Malignancy.

Herpes simplex virus (HSV) pseudotumor is a rare presentation of HSV and has not been previously reported in the stomach. A 51-year-old man with a medical history of HIV presented with new-onset dysphagia. Endoscopy revealed an HSV-positive mass at the gastroesophageal junction. After antiviral treatment, the patient returned with a 100-pound unintentional weight loss. Computed tomography showed an infiltrative mass with enlarged lymph nodes. The mass had progressed despite HSV treatment, and a repeat set of biopsies were negative for HSV with cells concerning for B-cell lymphoma. The patient was taken to the operating room for a full-thickness biopsy because of increasing concern for malignancy. The procedure was complicated by gastric perforation, leading to a total gastrectomy. Final pathology demonstrated an HSV-positive pseudotumor, negative for malignancy. It is important to diagnose gastric masses, especially in HIV-positive patients at high risk of infection and malignancy. However, immunocompromised patients with an HSV-positive mass should be treated for HSV pseudotumor with a longer than standard duration of antiviral therapy.

Novel treatment strategy of targeting epigenetic dysregulation in pancreatic neuroendocrine tumors.

BACKGROUND: Epigenetic dysregulation is an integral step in the progression of pancreatic neuroendocrine tumors. We hypothesized that tumor suppressor repression by DNA methyltransferase 1 in pancreatic neuroendocrine tumors could be targeted with epigenetic treatment. METHODS: Resected pancreatic neuroendocrine tumors from 32 patients were stained for DNA methyltransferase 1 and scored. Human (BON1) and murine (STC) pancreatic neuroendocrine tumor cells were treated with DNA methyltransferase 1 inhibitor 5-azacytidine and chemotherapeutic agents 5-fluorouracil and temozolomide. Cell proliferation assay and tumor suppressor gene analysis were performed with qRT-PCR and Clarion S microarray. Tumor measurements were compared in a murine treatment model. RESULTS: High DNA methyltransferase scores were associated with high Ki-67 (6.7% vs 70.6% P < .01), mitotic rate (0.0% vs 31.3%), and grade (20.0% vs 80.4%, P < .01). Treatment with 5-azacytidine and chemotherapy resulted in a reduction of cell proliferation compared to chemotherapy alone in BON1 (77.3% vs 53.1%, P < .001) and STC (73.4% vs 34.2%, P < .001). Treatment with 5-azacytidine and chemotherapy resulted in upregulation of tumor suppressors CDKN1A (7.6 rel. fold, P < .001), BRCA2 (4.3 rel. fold, P < .001), and CDH1 (6.0 rel. fold, P = .026) in BON1 and CDKN1a (14.5 rel. fold, P < .001) and CDH (17.5 rel. fold, P < .001) in STC. In microarray, 5-azacytidine drove global genetic changes in combination treatment. In vivo tumors treated with chemotherapy measured 88.6 ± 19.54 mm3 vs 52.89 ± 10.51 mm3 in those treated with combination therapy (P = .009). CONCLUSION: Epigenetic dysregulation with DNA methyltransferase 1 is associated with pancreatic neuroendocrine tumors and is a potential targetable strategy. 5-azacytidine and chemotherapy in combination can reduce cell proliferation, upregulate silenced tumor suppressor genes, and decrease in vivo tumors in pancreatic neuroendocrine tumors.

Identification and Treatment of SMARCA4 Deficient Poorly Differentiated Gastric Carcinoma.

Loss of expression of the SMARCA4 gene, a subunit of the SWI/SNF complex, has been historically associated with thoracic sarcomas. This loss of expression is extremely rare in gastric cancers, and its role in gastrointestinal tract carcinomas has not been fully elucidated. We report a case of a 73-year-old male with poorly differentiated, SMARCA4-deficient gastric cancer, showing that this immunophenotype is not limited to thoracic sarcomas or advanced-stage tumors. These tumors are often resistant to conventional FLOT chemotherapy and have poor prognoses, necessitating the need for early identification and alternative therapeutic approaches. New therapies such as EZH2 inhibitors and etoposide should be considered in cases where standard treatments are ineffective.

The Spectrum of Mucinous Lesions of the Breast.

CONTEXT.­: Mucinous lesions of the breast encompass many entities ranging from benign to malignant and nonneoplastic to neoplastic. Lesions discussed under this category are mucocele-like lesion, mucinous carcinoma, mucinous micropapillary carcinoma, solid papillary carcinoma, mucinous cystadenocarcinoma, mucoepidermoid carcinoma, invasive lobular carcinoma with extracellular mucin, mucinous ductal carcinoma in situ, and metastasis. OBJECTIVE.­: To review clinical, pathologic, and molecular features of mucinous lesions of the breast, their differential diagnoses, and challenging features on core needle biopsies. DATA SOURCES.­: The existing scientific and clinical literature as of December 2021. CONCLUSIONS.­: The category of mucinous lesions of the breast is vast and the differential diagnosis can be challenging, especially on core needle biopsies. In all cases, clinical, radiologic, and pathologic correlation is necessary to reach a comprehensive diagnosis. Given that the prognosis and management of each entity is different, being aware of these entities and their nuances is critical for a pathologist to guide accurate management.

Intrapancreatic Accessory Spleen Diagnosed As Neuroendocrine Tumor: The Dangers of False Positives and Their Implications in Subsequent Management.

This case serves as a reminder to consider ectopic splenic tissue in the differential diagnosis of pancreatic masses. The literature shows a lack of awareness and overtreatment of this condition due to clinical and radiologic concern for malignancy, namely neuroendocrine tumors (NETs) identified on positron emission tomography (PET)-CT NETSPOT. Given the vast difference in management and prognosis of ectopic splenic anomalies and malignant neoplasms involving the pancreas, accurate diagnosis is imperative to avoid unnecessary invasive procedures such as Whipple or distal pancreatectomy and splenectomy, which are associated with increased morbidity and mortality.

Cellular localization of PD-L1 expression in mismatch-repair-deficient and proficient colorectal carcinomas.

Blockade of the interaction between PD-1 and its ligands PD-L1 has shown clinical efficacy across several tumor types, especially in mismatch-repair-deficient colorectal carcinoma. The aim of this study was to examine the pattern and cellular localization of PD-L1 expression in the different molecular subtypes of mismatch-repair-deficient colorectal cancers vs. their mismatch-repair-proficient counterparts. PD-L1/SATB2 double-antibody-immunohistochemistry was utilized to distinguish tumor cell from immune cell staining. We observed in our series of 129 colorectal adenocarcinomas that PD-L1 expression occurred primarily in tumor-associated-immune cells and most prominently at the tumor-stroma-interface of the invasive front. The level of invasive front immune cell staining was significantly higher in mismatch-repair-deficient tumors compared to mismatch-repair-proficient tumors (p < 0.001), but no difference was observed among the different subtypes of mismatch-repair-deficient tumors: Lynch syndrome-associated vs. MLH1-methylated vs. unexplained. While selected mismatch-repair-proficient tumors exhibited unusually high tumor-infiltrating-lymphocytes and had high level immune cell PD-L1 expression, a positive correlation between PD-L1 expression and high lymphocyte count was detected only in mismatch-repair-deficient tumors (r = 0.39, p < 0.001) and not in mismatch-repair-proficient tumors. Notably, true tumor cell PD-L1 expression in colorectal carcinoma was rare, present in only 3 of 129 tumors (2.3%): 2 MLH1-methylated and 1 mismatch-repair-proficient with high tumor-infiltrating-lymphocytes; and the staining in the tumor cells in all 3 was diffuse (>=50% of the tumor). These findings may serve to inform further efforts aiming to evaluate PD-L1 immunohistochemistry vis-à-vis molecular sub-classification as predictive biomarkers in the treatment of colorectal carcinoma.

The Results of Hemoglobin Variant Analysis in Patients Revealing Microcytic Erythrocytosis on Complete Blood Count.

BACKGROUND: Microcytic erythrocytosis is an underrecognized and underevaluated complete blood count (CBC) finding. The literature pertaining to the determination of its etiology specifically by hemoglobin variant analysis is limited. METHODS: We performed hemoglobin variant analysis by high performance liquid chromatography on 137 patients who revealed microcytic erythrocytosis on CBC, and reviewed the results for the diagnosis of hemoglobin-associated disorders. RESULTS: A diagnosis of thalassemia trait and/or a hemoglobinopathy was established in 93 of 137 (67.9%) patients. Amongst these, ß-thalassemia trait topped the list with 69 cases (74.1%), followed by hereditary persistence of fetal hemoglobin with 5 cases (5.5%), Hemoglobin E disease with 4 cases (4.3%), and ∂/ß-thalassemia with 2 cases (2.1%). Compound heterozygous conditions with 1 or more hemoglobinopathies and/or thalassemias were diagnosed in 13 cases (14.0%). Abnormal hemoglobins in the compound heterozygosity group included C, S, HPFH, and 2 unknowns. CONCLUSION: Hemoglobin variant analysis provided a very high positive yield in determining the etiology of microcytic erythrocytosis.

Evaluation of the BacterioScan 216Dx for Standalone Preculture Screen of Preserved Urine Specimens in a Clinical Setting.

BACKGROUND: The BacterioScan 216Dx laser microbial growth monitoring system was evaluated as an option for preurine culture screening of preserved urine specimens at an acute care medical center. METHODS: The BacterioScan 216Dx system performance characteristics and the economic impact (cost effectiveness) for the laboratory were assessed. Urinalysis performance compared to urine culture was assessed if urinalysis was ordered as part of the patient care set. RESULTS: When compared to urine culture, the BacterioScan had an overall performance with corresponding 95% confidence intervals of 76% (68-83) sensitivity, 84% (80-87) specificity, 55% (48-63) positive predictive value, and 93% (90-95) negative predictive value for 610 randomly selected preserved urine specimens. Urinalysis compared to urine culture overall performance was 59% (48-69) sensitivity, 87% (83-90) specificity, 53% (43-63) positive predictive value, 89% (86-92) negative predictive value for 414 urine specimens. CONCLUSIONS: While the system did improve the turnaround time to a negative report, adoption of the BacterioScan system would increase the reagent budget for laboratory urine culture by 2.34 times the current cost, potentially making BacterioScan prohibitive in a budget restricted environment. Additionally, performance when compared to traditional urine culture was less than acceptable for a diagnostic laboratory to use as a stand-alone urinary tract infection screen.

Thoracic spinal osteochondroma: A rare presentation of spinal cord compression.

Osteochondromas are the most common benign bone tumor typically seen in the appendicular skeleton and are rarely found in the spine. We present a case of an osteochondroma of the spine presenting with spinal cord compression. 27-year-old male presented with lower extremity weakness and paresthesia, decreased lower extremity sensation, and decreased proprioception. MRI showed a heterogeneous mass with minimal peripheral enhancement and without restricted diffusion. CT demonstrated a calcified mass extending from the left facet joint of T11-T12 with medial extension, resulting in severe central canal stenosis and cord compression. The patient underwent surgical resection with pathology demonstrating an osteochondroma.

Microscopic lymphovascular invasion is an independent predictor of survival in resected pancreatic ductal adenocarcinoma.

Background and Objectives Despite routine inclusion of lymphovascular invasion (LVI) status in pathologic reports of resected pancreatic ductal adenocarcinomas (PDA), the clinical implications of LVI have not been well characterized. Methods This study is a retrospective review of 2640 patients who underwent a pancreatectomy for PDA at Thomas Jefferson University Hospital, Massachusetts General Hospital, or Johns Hopkins Hospital (2003-2014). Clinical and pathologic records were extracted from institutional databases. Results The median post-resection survival for the total cohort was 19.2 months with a 5-year survival rate of 15.2%. In a multivariate Cox proportional hazards model including conventional pathologic features, LVI was an independent predictor of survival (HR = 1.14, P = 0.017). In a stratified Kaplan-Meier survival analysis, patients with N0, LVI- PDA had a significantly improved overall survival compared to those with N0, LVI+ PDA (median 31 vs 24 mo, P = 0.020). Similarly, patients with N1, LVI- PDA had superior survival to patients with N1, LVI+ disease (18.6 vs 16.5 mo, P = 0.001). Conclusions As the first large scale study focused on the clinical impact of LVI status in PDA, these data indicate that this routinely reported pathologic feature is a bona fide and independent adverse prognostic factor.

Comprehensive profiling of metaplastic breast carcinomas reveals frequent overexpression of programmed death-ligand 1.

AIMS: Metaplastic breast carcinoma (MBC) is a rare subtype of breast carcinoma less responsive to conventional chemotherapy than ductal carcinoma. In molecular terms, MBCs usually cluster with triple-negative breast cancers (TNBCs), but have a worse prognosis than TNBCs. Studies investigating MBCs for specific biomarkers of therapy response are rare and limited by the methodological approaches. The aim of the present study was to characterise MBCs on a molecular level and test programmed death-ligand 1 (PD-L1) biomarker expression in MBCs for future therapeutic interventions. METHODS: We profiled 297 samples (MBC (n=75), TNBC (n=106), human epidermal growth factor receptor 2 (HER2)-positive breast cancers (n=32) and hormone-positive breast cancers (n=84)) by next-generation sequencing. Immunohistochemistry for PD-L1 and programmed cell death 1 (PD-1) expression was performed using automated procedures. RESULTS: The most commonly mutated genes in MBCs included TP53 (56%) and PIK3CA (23%). Pathogenic mutations in other genes, including HRAS, FBXW7, PTEN, AKT1 and SMAD4, were rare. PD-L1 expression was detected in a significantly higher proportion of MBCs (46%) than in other subtypes (6% each in hormone-positive and HER2-positive breast cancers, and 9% in TNBC, not otherwise specified, p<0.001). PD-1-positive tumour infiltrating lymphocytes (TILs) varied greatly in MBCs. CONCLUSIONS: Comprehensive profiling of a large cohort of this rare subtype of breast carcinoma highlighted the predominance of TP53 mutation and increased PD-L1 expression in carcinoma cells. These results can be exploited in clinical trials using immune checkpoint inhibitors.

Postpartum Granulomatous Hypophysitis: A Case Study, Review of the Literature, and Discussion of Pathogenesis.

Hypophysitis is a rare inflammatory condition of the pituitary gland that has three main histologic subtypes: lymphocytic hypophysitis (LH), granulomatous hypophysitis (GH), and xanthomatous hypophysitis (XH). Among these, LH is the most common and is strongly associated with the postpartum state, while XH is the least common. Many hypophysitis cases have been reported in the literature but only a few cases of postpartum GH have been discussed. Here, we describe a case of GH in a 24-year-old female presenting eleven days postpartum. We also review the current literature on postpartum GH and discuss the possible alterations in the immune environment during and after pregnancy that could explain this phenomenon. With more cases of GH being reported, the commonalities of female predominance, postpartum time of presentation, and occasional spontaneous resolution between LH and GH lend support to the theory that these two diseases likely represent spectrums of a single immunologic disorder.

Disseminated tuberculosis with prostatic abscesses in an immunocompromised patient-A case report and review of literature.

We describe a case of disseminated Mycobacterium tuberculosis (mTB) with prostatic abscess in a newly diagnosed HIV patient in the United States. The patient is a 34 year-old male who presented with respiratory symptoms and was diagnosed with HIV/AIDS complicated by disseminated mTB infection of the lungs, liver, and prostate. His prostate showed abscess formation on imaging that required drainage however he did not present with any genitourinary complaints. Our literature review revealed that prostatic involvement in mTB in the form of granulomatous prostatitis is uncommon; however, abscess formation is extremely rare and only few such cases have been published. Nearly 50% of the patients with prostatic abscess formation present without symptoms and therefore a high level of suspicion should be maintained; imaging should be performed early and prophylactic antibiotics for non-specific urinary symptoms should be avoided as this may lead to drug resistance of mTB to flouroquinolones.

Pathologic Spectrum of Secretory and Mucinous Breast Lesions.

CONTEXT: -The morphologic spectrum of secretory breast lesions encompasses benign, borderline, and malignant lesions. They are characterized by luminal pink, proteinaceous secretions and variable degrees of cytologic atypia ranging from low grade to high grade, with frequent papillary formations. Other lesions, benign and malignant, can also show luminal and extraluminal secretions and share similar features with secretory lesions, making them diagnostically challenging. OBJECTIVE: -To discuss the differential diagnosis of secretory breast lesions, emphasizing the most important diagnostic features of benign and malignant lesions. Lesions with intraluminal secretions discussed at length in this review include pregnancy-like hyperplasia, cystic hypersecretory hyperplasia, collagenous spherulosis, microglandular adenosis, hypersecretory carcinoma, and secretory carcinoma. Lesions with extravasated mucin, such as mucocele-like lesions and mucinous carcinoma, are also briefly discussed. DATA SOURCES: -Published articles obtained from a PubMed search of the English literature were the primary source for this review. CONCLUSIONS: -Lesions with secretory features described in this review show a pathologic spectrum, sometimes even within the same lesion. As a consequence, one should employ a low threshold for recommending reexcision on a core biopsy containing benign-appearing hypersecretory glands and use all ancillary data, including clinical presentation, imaging findings, morphology, immunohistochemistry, and molecular pathology, to render a final diagnosis.

Identification of the phosphorylation sites in the survival motor neuron protein by protein kinase A.

The survival motor neuron (SMN) protein plays an essential role in the assembly of uridine-rich small nuclear ribonuclear protein complexes. Phosphorylation of SMN can regulate its function, stability, and sub-cellular localization. This study shows that protein kinase A (PKA) phosphorylates SMN both in vitro and in vivo. Bioinformatic analysis predicts 12 potential PKA phosphorylation sites in human SMN. Mass spectrometric analysis of a tryptic digest of SMN after PKA phosphorylation identified five distinct phosphorylation sites in SMN (serines 4, 5, 8, 187 and threonine 85). Mutagenesis of this subset of PKA-phosphorylated sites in SMN affects association of SMN with Gemin2 and Gemin8. This result indicates that phosphorylation of SMN by PKA may play a role in regulation of the in vivo function of SMN.