Local Delivery of SBRT and IL12 by mRNA Technology Overcomes Immunosuppressive Barriers to Eliminate Pancreatic Cancer.

The immunosuppressive milieu in pancreatic cancer (PC) is a significant hurdle to treatments, resulting in survival statistics that have barely changed in 5 decades. Here we present a combination treatment consisting of stereotactic body radiation therapy (SBRT) and IL-12 mRNA lipid nanoparticles delivered directly to pancreatic murine tumors. This treatment was effective against primary and metastatic models, achieving cures in both settings. IL-12 protein concentrations were transient and localized primarily to the tumor. Depleting CD4 and CD8 T cells abrogated treatment efficacy, confirming they were essential to treatment response. Single cell RNA sequencing from SBRT/IL-12 mRNA treated tumors demonstrated not only a complete loss of T cell exhaustion, but also an abundance of highly proliferative and effector T cell subtypes. SBRT elicited T cell receptor clonal expansion, whereas IL-12 licensed these cells with effector function. This is the first report demonstrating the utility of SBRT and IL-12 mRNA in PC. Statement of significance: This study demonstrates the use of a novel combination treatment consisting of radiation and immunotherapy in murine pancreatic tumors. This treatment could effectively treat local and metastatic disease, suggesting it may have the potential to treat a cancer that has not seen a meaningful increase in survival in 5 decades.

A Case of a Beta-Catenin-Activated Hepatic Adenoma in a Male Patient With Familial Adenomatous Polyposis.

Hepatocellular adenoma is a benign liver tumor often diagnosed incidentally in women of reproductive age who are taking oral contraceptives. In this study, we present a unique case of an 18-year-old man with known familial adenomatous polyposis who presented with sepsis in the setting of a recent total proctocolectomy and was incidentally found to have multiple large hepatic lesions. A biopsy of a liver lesion confirmed the diagnosis of a beta-catenin-activated hepatic adenoma. To the best of our knowledge, this is the first known case of beta-catenin-activated hepatic adenoma in a patient with a known familial adenomatous polyposis mutation. Beta-catenin is one of the many subtypes of hepatocellular adenomas, which carries a high risk of malignant transformation.

Acute Myeloid Leukemia in a Cholecystectomy Specimen.

A 76-year-old man was admitted into the ER for upper abdominal pain. Physical exam and CT scan confirmed acute cholecystitis with multiple cholelithis, and a cholecystectomy was performed. The cholecystectomy specimen showed chronic cholecystitis with exuberant inflammatory infiltrate. On careful examination of the specimen, large atypical cells with vesicular chromatin, folded nuclei, and inconspicuous red nucleoli were noted percolating into the gallbladder wall and lining vascular spaces. These cells were positive for CD117, CD43, and myeloperoxidase and negative for CD20 and CD3 stains. Further workup including peripheral blood flow cytometry confirmed a population of circulating immature myeloid precursors comprising about 38% of events. This is a rare case of acute myeloid leukemia that came to clinical attention by incidentally involving the gallbladder.

Liver Histology in Septic Patients: Is It All About Ductular Cholestasis?

CONTEXT.­: Cholestasis within bile ductules is touted as a key histologic finding in septic patients but is not entirely sensitive or specific. The spectrum of other histopathologic findings in septic patients has not been thoroughly studied. OBJECTIVE.­: To evaluate histologic features in liver biopsies from septic patients, as well as mimics. DESIGN.­: For 121 liver samples where sepsis was mentioned in provided clinical information or in the pathologic differential diagnosis, we compiled patient outcome, clinical impression (sepsis or not), and blood culture results. We evaluated each case for inflammatory and cholestatic histologic findings, comparing them between patients with and without clinical sepsis, and between patients with gram-positive versus gram-negative results on blood culture. RESULTS.­: Cases from clinically septic patients (n = 77) showed portal mononuclear inflammation (52 cases, 68%), lobular neutrophilic inflammation (45, 58%), ductular reaction (58, 75%), lobular cholestasis (68, 88%), ductular cholestasis (52, 68%), and acidophil bodies (36, 47%). Findings between clinically septic and nonseptic patients were similar, though the latter more often had lobular mononuclear inflammation (19% versus 45%, P = .004). Ductular cholestasis rates were similar in both groups (68% versus 55%, P = .17). Ductular cholestasis had a sensitivity of 68%, a specificity of 45%, a positive predictive value of 68%, and an accuracy of 60% for the diagnosis of sepsis. Gram-positive and gram-negative sepsis caused comparable findings. CONCLUSIONS.­: Ductular cholestasis can be present in septic and nonseptic liver samples, though its presence does suggest the possibility of sepsis. Other common findings in sepsis include lobular cholestasis, ductular reaction, portal mononuclear inflammation, and lobular neutrophilic inflammation.

Merkel cell carcinoma in the setting of hematologic disease is associated with unique features and potential pitfalls.

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine carcinoma of the skin, often associated with polyomavirus and ultra-violet light exposure. Immunosuppression is associated with increased risk of development of MCC, including that associated with hematolymphoid disorders such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We sought to determine whether MCC arising in patients with hematologic disorders showed unique features. Searching archived material at three institutions, we identified 13 patients with MCC and at least one hematologic malignancy and 41 patients with MCC with no reported hematologic malignancy. CLL/SLL was the most common hematologic disorder in this setting (9/13 cases). Clinical history, variation in morphologic appearance, unusual site distribution and concern for progression of underlying hematologic disease all contributed to potential diagnostic challenges. Overlapping marker expression between MCC and hematologic neoplasms created potential diagnostic pitfalls (e.g. CD138, Pax5, TdT, Bcl2, CD56, and CD117). In addition, we newly identify expression of CD5 and LEF-1 in a subset of MCC, including in patients with CLL/SLL. MCC in patients with hematologic malignancy were more common in men (92% versus 59%, p < 0.05) and showed an unusual site predilection to non-sun exposed sites (3/13 on the buttocks) with none presenting on the face or scalp. By contrast, face or scalp lesions were common in MCC without an associated hematologic malignancy (17/41, p < 0.05). Our findings reaffirm the need for skin surveillance in the setting of immune deficiency and for vigilance to identify unusual presentations of MCC in patients with or without hematologic disorders.

Immunoglobulin-G4-related skin disease.

Immunoglobulin-G4-related disease (IgG4-RD) is an autoimmune-mediated spectrum of diseases, characterized by infiltration of IgG4+ plasma cells into one or multiple organs, with the pancreas being the most commonly affected organ. The disease mostly affects middle-aged to elderly men. Diagnosis requires an integration of clinical, radiologic, pathologic, and serologic studies. Histologically, there is an increased infiltration of IgG4+ plasma cells, elevated ratio of IgG4+/IgG plasma cells of more than 40%, and a storiform pattern of fibrosis. There may be eosinophilia, along with elevated IgG4 levels. IgG4-RD can mimic several diseases and should be differentiated from inflammatory and neoplastic processes. Recently, there has been increased awareness of cutaneous involvement by IgG4-RD either as an isolated lesion or primary involvement or as a secondary involvement from a systemic disease. Clinically, cutaneous IgG4+-related disease presents as papules, plaques, and nodules involving the head and neck areas. We have provided a systematic review of the literature of this new and challenging entity of cutaneous IgG4-RD.

An Unusual Case of Human Papillomavirus-Related Anorectal Adenocarcinoma With Progression to Perianal Paget's Disease.

Primary adenocarcinoma of the anorectum, compared with squamous cell carcinoma, is a rarer and more aggressive malignant neoplasm. Infection with human papillomavirus (HPV) has been identified as a causal agent in a variety of tumors, including those of the cervix, head and neck, and anogenital region, especially squamous cell carcinoma. However, the relationship between HPV and anorectal adenocarcinoma has not been well studied. In this article, we report an HPV-related anorectal adenocarcinoma arising in a tubulovillous adenoma in a 76 years old female who presented initially with lower gastrointestinal bleeding. The carcinoma cells were positive for cytokeratin 7 and p16 by immunohistochemistry. High-risk HPV RNA in situ hybridization was positive. A follow-up examination of the anal area showed perianal plaques. Histologically, the excision of the perianal lesion showed intraepithelial infiltration by sheets and clusters of large atypical neoplastic cells. The neoplastic cells showed the same immunoprofile compared with the anorectal adenocarcinoma with p16 and high-risk HPV positivity. The findings are consistent with extramammary perianal Paget's disease secondary to anorectal adenocarcinoma. HPV-related adenocarcinoma in the anorectum is a newly recognized entity and was previously considered clinically indolent. Our case uniquely exhibits adenoma-carcinoma-perianal Paget's disease sequence, which has not been reported before. Our findings suggest that evaluation of the patient's lower genital tract for any HPV-associated lesions and long-term follow-up are required to monitor the disease progression in this type of malignancy.

Malignant tumors in hernia sac: Clinicopathological and immunohistochemical studies of 21 cases at a single institution.

Malignant tumors presented in hernia sac are very rare and the clinicopathological features are not well studied. We retrospectively reviewed 21 patients with cancers identified in surgically resected hernia sac specimens at our institution, including 14 males and 7 females, with a median age of 65 years (range 35-93). Fourteen patients (66.7%) carried a synchronous or metachronous cancer diagnosis elsewhere and the tumors in hernia sac were proven to be metastasis. Of the remaining seven (33.3%) cases, hernia sac tumors were the initial presentation of malignancy, and a panel of immunohistochemistry markers were applied in combination with clinical information to identify tumor origin. The final classification of all 21 cases was as follows: 11 gastrointestinal tract tumors including 10 adenocarcinomas and 1 gastrointestinal stromal tumor, 5 pancreatobiliary adenocarcinomas and 5 gynecological serous carcinomas. Compared to other tumor types, pancreatobiliary adenocarcinomas were more likely to involve hernia sac as initial presentation before a primary site was identified (P = 0.0307) and had worse survival (P < 0.005). As the first and largest cohort of malignant tumors in hernia sac, our study provides critical data on frequency, distribution, clinicopathological features and applicability of immunohistochemical markers to determine tumor origin in cases with unknown primary.

Giant Inflammatory Polyps in Diverticular Disease Mimicking a Colonic Mass: A Potential Malignant Masquerader.

BACKGROUND Inflammatory pseudopolyps (IPPs) are a common manifestation in inflammatory bowel disease (IBD) with more cases reported with ulcerative colitis than Crohn's disease. IPPs can grow to form large polyps which are called giant inflammatory polyps (GIPs). These polyps may cause an obstruction and form a mass-like lesion and surgical resection may be warranted. CASE REPORT A 65-year-old male without a previous history of IBD presented with abdominal discomfort, poor appetite, constipation, weight loss, and hematochezia. Due to the high suspicion of malignancy, a computed tomography (CT) scan was performed and showed a fixed lesion in the mid sigmoid colon highly concerning for a primary colon carcinoma, with scattered diverticula, and associated with elevated carcinoembryonic antigen (CEA). Colonoscopy was done but the scope could not be passed due to obstruction. Sigmoidectomy was performed which showed a huge noninvasive lesion, which looked like pseudopolypoid serpiginous mass as giant inflammatory polyp, with scattered diverticula. On microscopic examination, pathology showed a villous polyp with numerous inflammatory cells, without any dysplasia or carcinoma. CONCLUSIONS GIPs are rarely reported without a history of IBD. Diagnosis of GIPs can be very challenging, and surgery is sometimes indicated for definitive diagnosis.

Concurrent Polycythemia of Undetermined Etiology and Smouldering Plasma Cell Myeloma.

The combination of polycythemia and plasma cell myeloma occurring concurrently is very rare and few cases have been reported in the literature. Further, the vast majority of these cases are cases of polycythemia vera and myeloma. Here, we present a case of polycythemia of undetermined etiology and myeloma. The patient is a 48-year-old Caucasian male who was originally diagnosed with polycythemia of undetermined etiology. Twelve years later, when a bone marrow biopsy was performed in an attempt to determine the etiology of the polycythemia, findings diagnostic of plasma cell myeloma were discovered. Subsequent serum studies were also consistent with a plasma cell neoplasm, while evaluation for end-organ damage was negative. A battery of genetic and biochemical tests ruled out various congenital polycythemias, leading to a final diagnosis of polycythemia of undetermined etiology and smouldering plasma cell myeloma. This case highlights that while being unusual, polycythemia and plasma cell myeloma can occur concurrently, and, in this report, we discuss both entities and potential mechanisms of the pathophysiology of the concurrent presentation.