Non-small cell lung carcinomas with diffuse coexpression of TTF1 and p40: clinicopathological and genomic features of 14 rare biphenotypic tumours.

Thyroid transcription factor 1 (TTF1) and p40 are widely-utilized diagnostic markers of lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), respectively. Diffuse coexpression of TTF1 and p40 has been described in only rare case reports. In a multi-institutional study, we collected the largest cohort of these unusual tumours to-date (n = 14), with the goal of elucidating their clinicopathological and genomic characteristics. Lung tumours with diffuse coexpression (labelling 50-100% tumour cells) of TTF1 clone 8G7G3/1 and p40 clone BC28 were identified. Detailed clinicopathological and immunohistochemical parameters were analyzed. Eight tumours were analyzed by next-generation sequencing (NGS) and the results were compared to those in > 9 K LUAD and > 1 K LUSC. All tumours with diffuse TTF1/p40 coexpression were poorly differentiated non-small cell lung carcinomas (NSCLC), 42% of which had basaloid features. Some tumours exhibited focal keratinization (14%), napsin A and/or mucicarmine labelling (46%) or both squamous and glandular features (7%). NGS revealed a uniquely high rate of FGFR1 amplifications (70%) compared to either LUAD (0.7%, P < 0.0001) or LUSC (11%, P = 0.001). LUAD-type targetable driver alterations were identified in 38% of cases (one EGFR, two KRAS G12C). The tumours were clinically aggressive, exhibiting metastatic disease in most patients. Lung carcinomas with diffuse TTF1/p40 coexpression represent poorly differentiated NSCLCs with frequent basaloid features, but some show evidence of focal squamous, glandular or dual differentiation with a distinctly high rate of FGFR1 amplifications. The presence of targetable LUAD-type alterations (EGFR, KRAS G12C) emphasizes the importance of molecular testing in these tumours.

First Report of Thoracic Carcinoma With DEK::AFF2 Rearrangement: A Case Report.

DEK::AFF2 carcinomas of the head and neck region have been recently described and reported to have aggressive clinical behavior but exceptional sensitivity to immunotherapy. We report a case of a 26-year-old female, never smoker, with a 5.2-cm left lower lobe central lung mass, with morphologic features identical to those reported for DEK::AFF2 head and neck carcinomas, including mixed papillary exophytic and invasive components, squamous/basaloid features, and monomorphic cytomorphology. DEK (exon 7)::AFF2 (exon 9) fusion was identified by whole-transcriptome RNA sequencing. This is the first report of thoracic DEK::AFF2 carcinoma, indicating that these tumors are not confined to the head and neck region but can involve both upper and lower respiratory tracts. This entity should be considered in the differential diagnosis of squamous cell carcinomas in never smokers lacking other known oncogenic mutations.

Differentiation of pancreatic ductal adenocarcinoma and chronic pancreatitis using graph neural networks on histopathology and collagen fiber features.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. However, the symptoms and radiographic appearance of chronic pancreatitis (CP) mimics that of PDAC, and sometimes the 2 entities can also be difficult to differentiate microscopically. The need for accurate differentiation of PDAC and CP has become a major topic in pancreatic pathology. These 2 diseases can present similar histomorphological features, such as excessive deposition of fibrotic stroma in the tissue microenvironment and inflammatory cell infiltration. In this paper, we present a quantitative analysis pipeline empowered by graph neural networks (GNN) capable of automatic detection and differentiation of PDAC and CP in human histological specimens. Modeling histological images as graphs and deploying graph convolutions can enable the capture of histomorphological features at different scales, ranging from nuclear size to the organization of ducts. The analysis pipeline combines image features computed from co-registered hematoxylin and eosin (H&E) images and Second-Harmonic Generation (SHG) microscopy images, with the SHG images enabling the extraction of collagen fiber morphological features. Evaluating the analysis pipeline on a human tissue micro-array dataset consisting of 786 cores and a tissue region dataset consisting of 268 images, it attained 86.4% accuracy with an average area under the curve (AUC) of 0.954 and 88.9% accuracy with an average AUC of 0.957, respectively. Moreover, incorporating topological features of collagen fibers computed from SHG images into the model further increases the classification accuracy on the tissue region dataset to 91.3% with an average AUC of 0.962, suggesting that collagen characteristics are diagnostic features in PDAC and CP detection and differentiation.

Role of CD68 immunohistochemistry in categorizing benign nonmesothelial cell population and refining "atypical" category in serous fluid cytology.

BACKGROUND: Body fluids are rich in histiocytes and may mimic atypical epithelial cells morphologically. Histiocytes can pose a significant challenge in serous fluid cytology as they tend to appear atypical due to prolonged accumulation in serous fluids in vivo and processing by liquid-based cytology in vitro. Not many studies have documented the utilization of histiocytic marker such as CD68 in serous fluid cytology, which can subsequently reduce the "atypical" diagnostic category. METHODS: One thousand one hundred and twenty-nine cases of serous fluid cytology from 2016 to 2019 were reviewed and reclassified based on proposed classification of the international system for reporting serous fluid cytology. There were 133 cases with atypical diagnoses, out of which 51 cases had cellblocks. An immunohistochemistry (IHC) panel, including two mesothelial markers, two epithelial markers, and one histiocytic marker was applied to the atypical samples. Same IHC panel was utilized to evaluate 15 cases each from negative for malignancy (NFM), suspicious for malignancy (SFM), and malignant (MAL) categories for further comparison. RESULTS: After reevaluation of the cytology material with IHC stains, 924 (82%), 133 (12%), 23 (2%), and 49 (4%) of the cases were reclassified as NFM, atypia of uncertain significance, SFM, and MAL, respectively. Twenty-five out of 51 atypical cases (49%) were downgraded to "benign" after reevaluation with CD68 IHC. CONCLUSION: Histiocytes can mimic atypical epithelial cells in body fluids. Effective utilization of CD68 IHC will be beneficial in further refining the "atypical" diagnostic category in serous fluid cytology.

An Unusual Histopathological Presentation of Epidermotropic Metastatic Pharyngeal Squamous Cell Carcinoma.

Epidermotropic metastasis of head and neck squamous cell carcinoma is rare. We report a case of a 56-year-old white man with a history of oral squamous cell carcinoma who presented with multiple papules on the face, eyelid, and chest wall. The histopathologic examination of the skin lesions revealed nests of malignant cells with basaloid features and zones of cytoplasmic vacuolization predominantly within the dermis but focally involving the epidermis. Central necrosis, focal papilla formation, and lymph-vascular invasion were also seen. Two of these lesions, each read by different dermatopathologists, were initially diagnosed as sebaceous carcinoma. However, further evaluation, including adipophilin immunohistochemistry, confirmed the metastatic nature of the skin lesions. Cytoplasmic vacuolization in metastatic deposits of squamous cell carcinoma may mimic primary sebaceous carcinoma. This presentation highlights the need to consider the possibility of a metastatic deposit when making a diagnosis of primary sebaceous carcinoma.

Pancreatic lymphoma: A cytologic diagnosis challenge.

Very rarely lymphoma primarily or secondarily involves the pancreas. Involvement of the pancreatic parenchyma with lymphoma clinically may mimic pancreatic ductal adenocarcinoma (PDA) and other mass-forming pancreatic lesions. Endoscopic ultrasound fine needle aspiration (EUS-FNA) is the first step in the diagnostic pathway of managing these patients by providing a cytology specimen. Cytologically, lymphoma of pancreas can be misdiagnosed for a wide variety of pancreatic neoplastic and non-neoplastic lesions. Cytological differential diagnosis includes well-differentiated adenocarcinoma, acinar cell carcinoma, well differentiated neuroendocrine tumor, and autoimmune pancreatitis. Gastroenterologist's skills in providing adequate sample for preparing smears, cell blocks and/or performing flow cytometry, and also cytopathologist's skills in detecting atypical lymphocytic population are crucial factors. Although cytology examination has limitations to subclassify lymphoma, it plays a key role to redirect clinicians into the right patient-care pathway. In this article, we present two cases of pancreatic lymphoma with emphasis on the discriminating cytomorphological features, and we also review literatures with reports of primary pancreatic lymphoma (PPL) to better understand the characteristics of this rare lesion.

Neuroendocrine Neoplasia in Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT Lymphoma) of the Lung: A Case Report and Immunohistochemistry Analysis of Eight Pulmonary MALT Lymphomas.

Carcinoid tumorlets are peribronchiolar proliferations of neuroendocrine cells often associated with lung scars. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is a non-Hodgkin's lymphoma that frequently involves the gastrointestinal tract but less commonly is described in the lung. Simultaneous occurrence of neuroendocrine neoplasms and MALT lymphoma is extraordinarily rare and has predominately been reported in the gastrointestinal tract. In this article, we describe the case of a 73-year-old female with coexisting pulmonary MALT lymphoma and carcinoid tumorlets of the right middle lobe. Retrospective series of 8 pulmonary MALT lymphomas are evaluated for neuroendocrine neoplasia by immunohistochemistry. No correlation between MALT lymphoma and neuroendocrine neoplasia was identified in this case series. While the concurrence of these distinctive neoplasms is most likely coincidental, the presence of a common risk factor, or one neoplasm as a risk factor for the other, deserves study of a larger group of pulmonary MALT lymphomas.

Preservation of beta cell function after pancreatic islet autotransplantation: University of Chicago experience.

The aim of the study was to assess the rate of insulin independence in patients after total pancreatectomy (TP) and islet autotransplantation in our center. TP followed by islet autotransplantation was performed in 10 patients. Severe unrelenting pain associated with chronic pancreatitis was the major indication for surgery. Islets were isolated using the modified Ricordi method and infused through the portal vein. Exogenous insulin therapy was implemented for at least two months posttransplant to support islet engraftment and was subsequently weaned off, if possible. Median follow-up was 26 months (range, 2 to 60 months). Median islet yield was 158,860 islet equivalents (IEQ) (range, 40,203 to 330,472 IEQ) with an average islet yield of 2,478 IEQ/g (range, 685 to 6,002 IEQ/g) of processed pancreas. One patient developed transient partial portal vein thrombosis, which resolved without sequela. Five (50%) patients are currently off insulin with excellent glucose control and HbA1c below 6. Patients who achieved and maintained insulin independence were transplanted with significantly more islets (median, 202,291 IEQ; range, 145,000 to 330,474 IEQ) than patients who required insulin support (64,348 IEQ; range, 40,203 to 260,476 IEQ; P < 0.05). Patient body mass index and time of chronic pancreatitis prior transplant procedure did not correlate with the outcome. The remaining five patients, who require insulin support, had present C-peptide in blood and experience good glucose control without incidence of severe hypoglycemic episodes. Islet autotransplantation efficiently preserved beta cell function in selected patients with chronic pancreatitis and the outcome correlated with transplanted islet mass.

Islet autotransplantation and total pancreatectomy.

The goal of IAT is the preservation of beta-cell mass at the time of pancreatectomy. The majority of recipients have significant endogenous beta-cell function with positive blood C-peptide after surgery, even if only approximately one third achieve insulin independence. In appropriately selected patients, total pancreatectomy combined with IAT achieves relief of pain and improves quality of life with relatively easier-to-manage glycemic control and avoidance of hyper- and hypoglycemic episodes. Current research is focused on improving techniques of islet isolation and engraftment as well as long-term survival of autografted islets.

Chronic pancreatitis and primary sclerosing cholangitis--first report of intrahepatic autologous islet transplantation.

BACKGROUND: We are reporting first successful intrahepatic autologous islet transplantation after total pancreatectomy in a patient with chronic pancreatitis and primary sclerosing cholangitis. METHODS: Total pancreatectomy and subsequent islet autotransplantation were performed in a 16-year-old boy with intractable pain due to chronic pancreatitis in the setting of ulcerative colitis and primary sclerosing cholangitis (PSC). Liver biopsy revealed PSC with focal bridging fibrosis. The pancreas was surgically removed and digested, and islets were isolated, highly purified, and infused intraportally. RESULTS: Over 18-month follow-up, the patient did not show progression of chronic liver disease or signs of portal hypertension. Magnetic resonance cholangiopancreatography revealed no new changes, and liver biopsy did not show progression of the periportal fibrosis. Pain medication was weaned over 12 months at which time glycemic control was excellent without exogenous insulin supplementation. HbgA1c was 5.9. Fifteen months after the procedure, stimulation with a mixed meal led to a fourfold increase of serum C-peptide and an eightfold increase of insulin level. CONCLUSION: Pancreatic autologous islets can be successfully transplanted into a liver affected by PSC without compromising hepatic or graft function. Durability of the procedure may be limited in the future by the natural course of the liver injury caused by PSC.

Distinct function of the head region of human pancreas in the pathogenesis of diabetes.

The large size of the human pancreas challenges unbiased quantitative analyses that require a practical stereological approach. While many histological studies of the pancreas in the past lacked regional information, we have shown marked heterogeneity within an individual, where islet distribution/density is relatively low in the head and gradually increases through the body toward the tail region by>2-fold. Studies focusing on the tail region may be prone to overestimation of ß-cell/islet mass when normalizing measured values per person by using pancreas weight or volume. In this article, beyond technical issues, we discuss the pathophysiological importance of studying the head region of the human pancreas regarding its unique characteristics in early development, and the anatomical disposition that may lead to a preferential loss of ß-cells in patients with type 2 diabetes and the development of pancreatic cancer.