Fibrosing cholestatic hepatitis after kidney transplantation from HCV-viremic donors to HCV-negative recipients: A unique complication in the DAA era.

Fibrosing cholestatic hepatitis (FCH) posttransplantation can lead to graft failure and death. In the era of direct acting antiviral therapy (DAA), several studies have demonstrated the efficacy and safety of transplanting hepatitis C virus (HCV)-positive allografts into HCV-negative recipients. In this case series, we present two cases of HCV-negative recipients who underwent kidney transplantation from viremic donors and developed FCH. Both patients presented after transplant with abnormal liver function tests and HCV viral loads of greater than 100 000 000 IU/mL. FCH was diagnosed by histology and/or clinical data. Both patients were started on DAA therapy within 24 hours of admission with improvement in LFTs. One patient has undetectable HCV 12 weeks after completing treatment and the other patient has undetectable HCV after completing DAA treatment. The introduction of DAAs has changed the landscape of solid organ transplantation with the potential to expand the donor pool and increase access to organs. While HCV viremic organs have tremendous potential to increase access to a scarce resource, FCH is a potentially fatal complication and therefore clinicians must maintain a high index of suspicion for this unique complication.

An Extradigital Glomus Tumor of the Median Antebrachial Vein.

Glomus tumors are benign vascular neoplasms that arise from specialized dermal arteriovenous anastomoses called glomus bodies. These tumors are most often found in the digital pulp and subungual region of the fingertips; however, a review of the literature suggests that extradigital glomus tumors may occur more often than is generally recognized. Although most extradigital glomus tumors arise within subcutaneous tissues, glomus tumors have occasionally been found within bones, nerves, and blood vessels. An intravascular glomus tumor of the forearm is a very rare occurrence and only a few cases have been reported in the literature. Here we describe a 55-year-old right-handed man with a 10-year history of exquisite tenderness and dysesthesia of his right proximal forearm. Surgical exploration revealed the presence of a mass arising from the median antebrachial vein, which was confirmed histologically to be a glomus tumor.

Judging pathological assessment in cancer specimens.

The pathologist plays a critical role in the multidisciplinary team in charge of treating cancer patients, as many of the therapeutic decisions rely on the information conveyed through the pathology reports. The task of the pathologist includes not only an accurate assessment of pathological T and N categories, but also the evaluation of other indicators of prognosis including quality of surgery, margins of resection, as well as additional histopathological and molecular markers that influence prognosis and could predict response to therapy.

Colorectal Carcinoma With Sarcomatoid Components: Report of 15 Cases and Literature Review of an Exceedingly Rare Carcinoma Subtype.

Colorectal carcinoma with sarcomatoid components (which includes so-called carcinosarcomas and sarcomatoid carcinomas) is a rare subtype with 50 reported cases in the literature and overlapping criteria with undifferentiated carcinoma. We collected and described 15 cases from 10 men and 5 women, with a mean age of 66 years. Symptoms included abdominal pain and gastrointestinal bleeding. Most tumors presented in the rectosigmoid region, with a mean size of 8.2 cm. The sarcomatoid component, on average, represented 58% of the tumors and took many forms, including spindled (10 cases), anaplastic (9 cases), and rhabdoid (3 cases); one case showed osteoid matrix. Tumor budding was usually high, and tumor-infiltrating lymphocytes were usually low. The sarcomatoid component was keratin-positive in 10 cases. One case showed loss of mismatch repair protein expression, and 2 cases showed SMARCA4 loss (1 also with SMARCA2 loss). Molecular testing identified mutations in KRAS (n=1), NRAS (n=2), BRAF (n=2), APC (n=1), and TP53 (n=1) in a few cases. Tumors often presented at advanced stage, with 11 cases pT4, 9 cases with nodal metastases, and 7 cases with distant metastases. Follow-up was available for 10 cases (median: 2 months), with 2 alive without disease, 3 alive with disease, and 5 dead. Our findings roughly corresponded with those in previously reported cases. Colorectal carcinoma with sarcomatoid components is rare and aggressive, with a poor prognosis for many patients. We suggest that spindled cells, anaplasia, heterologous elements, and/or a component with definable sarcomatous lineage be used to distinguish colorectal carcinoma with sarcomatoid components from undifferentiated carcinoma.

Potential clinical complications of Orise™ gel use, a new submucosal lifting agent: experience from a tertiary care center and review of the literature.

Background: Endoscopic mucosal resection (EMR) involves forming a fluid cushion in the submucosal area with a lifting agent, followed by superficial resection. Orise™ gel is one of the commonly used lifting agents for EMR. We present a case series and literature review that analyzes the characteristic histopathological findings and clinical implications observed where Orise™ gel was used before EMR. Methods: Colon resection specimens and prior EMR specimens where Orise™ gel was used were reviewed for patients undergoing EMR between January 2018 and December 2020. The literature review included relevant studies from the Medline and Cochrane databases from January 2018 to December 2020. Results: A total of 12 colon polyp EMRs using Orise gel were performed during the study period. Seven patients (58.34%) underwent surgical resection. Histological examination revealed that, after the EMR procedure, the Orise™ gel material changed its morphological characteristics over time from a basophilic (bluish) non-inflamed pattern to an eosinophilic (pink) type pattern, eliciting a foreign body reaction. The endoscopic appearance and examination of the excised specimens weeks after injection gave the impression of a mass in some cases. The material was also present transmurally and in some cases in the peri-intestinal adipose tissue. Conclusions: It was observed that Orise™ gel use elicits a foreign body-type granulomatous reaction. This potential side effect may lead to overdiagnosis of a mass/lesion and unnecessary surgical interventions. This case series and review of the literature aims to increase awareness of the changes caused by Orise™ gel in the gastrointestinal tract.

A case of cardiac sarcoidosis with successful heart transplantation after COVID-19 infection.

Arrhythmogenic right ventricular cardiomyopathy and cardiac sarcoidosis can both present with ventricular tachycardia. We report a case of a patient whose histological diagnosis was not only confirmed by the transplanted heart but who also underwent successful transplantation after overcoming COVID-19. .

Combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma: outcome after liver transplantation.

BACKGROUND: Combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma is a rare hepatobiliary malignancy incorporating components derived from both hepatocyte and intrahepatic bile duct epithelium. The natural history, treatment, and prognosis of this distinct cancer differ from hepatocellular carcinoma (HCC) or cholangiocarcinoma (CC) and are not completely understood. There is considerable controversy about the classification, treatment, and survival, which in turn is related to the rarity of the condition. Treatment options include surgical resection and the prognosis is believed to be better than CC but worse than HCC alone. METHODS: We report a single-center liver transplantation experience with the management of three patients with combined HCC-ICC with LT. Two patients were transplanted with presumed HCC within Milan criteria and the other patient was noted to have an incidental nodule in the explanted liver. Histomorphology and immunohistochemical studies revealed the presence of combined HCC-ICC in all three explants. RESULTS: One patient died 144 days after LT due to metastatic tumor. The second patient is alive and is tumor free at 8.5 years post-LT, and the third patient died of metastatic tumor at 155 days after LT. CONCLUSION: Good long-term survival can be achieved in at least some patients with this combined tumor type.

Sildenafil therapy and exercise tolerance in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a form of idiopathic interstitial pneumonia characterized by temporally and spatially heterogeneous fibroblast proliferation and poor prognosis. No therapies have been shown in randomized clinical trials (RCT) to influence survival. Twenty-nine subjects were assigned randomly in a pilot study to a double-blind, placebo-controlled, RCT to test sildenafil in patients with IPF with forced vital capacity 40-90% and diffusing capacity 30-90% of predicted. During the 6-month experimental treatment period, patients underwent 6-min walk tests and estimation of dyspnea using the Borg scale at baseline (0 months), 3 months, and 6 months. Participants had moderate impairment of pulmonary function, and there were no significant differences between placebo (n = 15) and sildenafil (n = 14)-treated groups. Sildenafil did not significantly increase 6-min walk test distance (mean distance +/- SD after 6-month protocol: placebo 355 +/- 82 m, sildenafil 324 +/- 41 m; p = 0.256) nor did it lessen dyspnea after exercise (mean Borg score after 6-month protocol: placebo 3.4 +/- 1.6, sildenafil 4.1 +/- 2.3; p = 0.492). Adverse reactions were few and minor in nature. In this trial, sildenafil did not significantly increase 6-min walk test distance or decrease the Borg dyspnea index in patients with clinically typical IPF. This trial was registered at clinicaltrials.gov as NCT00359736.

Cystic lesions of the pancreas: clinical and pathologic review of cases in a five year period.

CONTEXT: Cystic lesions of the pancreas represent an important subgroup of pancreatic tumors. The characterization of these lesions has evolved in recent years, and will continue to change according to the increasing number of biopsies and resections performed. DESIGN: Pancreatectomy specimens containing cystic lesions collected over a five-year period were reviewed. MAIN OUTCOME MEASURES: Demographic and pathologic features were recorded. SETTING: Cases were subclassified in diagnostic categories and were grouped according to the nature of the lesion (non-neoplastic vs. neoplastic). RESULTS: Of 361 pancreatic lesions, 97 cysts corresponding to 95 patients were studied. The patients' mean age was 60 years. Sixty two cysts (63.9%) occurred in women. Among the 97 cysts, five (5.2%) were non-neoplastic and 92 (94.8%) were neoplastic (59.8% benign, 17.5% borderline, 17.5% malignant). Intraductal papillary mucinous neoplasm was the most common diagnosis (n=51; 52.6%) followed by serous cystic neoplasm (n=20; 20.6%) and mucinous cystic neoplasm (n=13; 13.4%). Frequency of female gender was higher and age was lower in the borderline lesions (P=0.001 and P=0.002, respectively). Tumor size was significantly lower in benign neoplastic lesions (P=0.045). Incidental identification was more frequent in benign lesions (P=0.028), whereas malignant lesions were more frequently symptomatic (P=0.001). CONCLUSION: Cystic lesions are found in 20.6% of all pancreatectomy specimens. Among this heterogeneous group, benign neoplasms predominate, particularly those with mucinous lining. Age at presentation, gender, location and tumor size are highly variable, with the exception of solid pseudopapillary tumor. Clinical presentation, diagnostic imaging and laboratory data should be consistently reported to improve the therapeutic approach.

Eosinophilic cholangiopathy with concurrent eosinophilic colitis in a patient with idiopathic hypereosinophilic syndrome.

Eosinophilic cholangiopathy is a rare cholestatic disorder of unknown etiology. Simultaneous histologic documentation of eosinophilic involvement of the bile ducts and gastrointestinal tract has been reported previously in only a few well-documented cases. We report a 52-year-old man with a history of idiopathic hypereosinophilic syndrome who presented with acute diarrhea and cholestatic hepatitis. Colonoscopy revealed colitis, and a biopsy showed eosinophilic infiltrates in the colonic mucosa. Liver biopsy showed dense eosinophilic inflammation in the portal areas with bile duct damage. This case demonstrates the entity of hepatic involvement in idiopathic hypereosinophilic syndrome and the difficulties related to diagnosis and treatment.

Rectal cancer and the pathologist.

Examination of the rectum by pathologists is instrumental in the management of patients affected by rectal carcinoma. That role includes evaluation of multiple gross and microscopic features that convey prognostic implications. The analysis is based on the authors' experience handling rectal specimens along with review of the pertinent literature in these areas: margins of excision, quality of the mesorectum, diligence and techniques to sample lymph nodes, tumor budding, grading of residual amount of carcinoma after preoperative therapy, vascular/perineural invasion, and staging the tumor. Pathologists must communicate the findings in a clear manner. Evaluation of margins and completeness of mesorectum are markers of the quality of surgical excision. The number of lymph nodes obtained and examined is dependent in great part on the diligence of the pathologist finding them in the mesenteric adipose tissue. There are grades for budding and response to prior chemoradiation therapy. The location of vascular invasion (extramural vs. intramural) may predict aggressive behavior. Pathologists proactively are to choose sections of tumor for molecular testing. Meticulous macro- and microscopic evaluation of specimens for rectal carcinoma by pathologist is needed to determine an accurate assessment of staging and other prognostic factors. The modern pathologists play a pivotal part in the care and management of patients suffering from rectal adenocarcinoma. That role goes from the initial histological diagnosis to the gross and microscopic examination of the excised specimens. Based on that examination pathologists issue statements that not only evaluate the quality of the surgical procedure, but also through the application of molecular tests they give light on prognostic factors and information for therapeutic purposes.

Mesothelial cells in transbronchial biopsies: a rare complication with a potential for a diagnostic pitfall.

The presence of pleural tissue in transbronchial biopsies (TBs) is an incidental finding that has been rarely reported in the literature. It has the potential for causing wrong histologic diagnoses. Clinically, the significance of unintended pleural sampling by bronchoscopy is unknown. TBs containing mesothelial cells from 6 adult patients were studied using immunohistochemical stains. Clinical information was obtained with emphasis on the immediate postbronchoscopy period. The TBs were performed by 6 different bronchoscopists at 4 institutions because of pulmonary infiltrates in 5 patients and a mass lesion in 1 patient. All samples contained lung parenchyma and bronchial wall. They showed clusters of medium to large size polygonal cells with pink to amphophilic dense cytoplasm, round to oval nuclei, and prominent nucleoli. Some of the cells lined stroma and others were detached forming ribbons. They were initially disregarded, interpreted as carcinoma, judged as mesothelial cells, or interpreted as drug-induced reactive epithelial cells. They were positive for cytokeratin and showed nuclear staining for calretinin. They were negative for TTF-1, S100, CEA, and CD68. However, in 1 case, CD-68 positive histiocytes were admixed with enlarged reactive mesothelial cells corresponding to the so-called nodular histiocytic mesothelial hyperplasia. Chest x-ray films performed the same day after bronchoscopy showed no pneumothorax. Incidental sampling of the pleura may occur during the performance of TB and mesothelial cells may mimic carcinoma, pneumocytes, or macrophages. It is important to be aware of the presence of mesothelial cells in clinically uncomplicated TB to avoid an erroneous diagnosis of malignancy.

Adenomyomatous hyperplasia of the gallbladder with perineural invasion: revisited.

We report 9 examples of segmental adenomyomatous hyperplasia of the gallbladder with perineural invasion. Five patients were women and 4 men. Their ages ranged from 49 to 81 years (mean age 64 y). Eight patients had gallbladder calculi. The original pathologic diagnosis of adenocarcinoma was made in 5 patients and of "adenoma malignum" in one. Six patients are disease-free for 2 to 11 years following cholecystectomy, 1 patient died of unrelated causes and 2 were lost to follow-up. Histologically 2 types of adenomyomatous hyperplasia were recognized. The first one characterized by numerous Rokitansky-Aschoff sinuses (RASs) was accompanied by smooth muscle hyperplasia and an expanded subserosal layer containing numerous nerve trunks (6 cases). The second type was characterized by an extensively fibrotic gallbladder wall with numerous RASs but with few or no smooth muscle bundles and an expanded subserosal layer containing abundant nerve-trunks (3 cases). Perineural (7 cases) and intraneural invasion (2 cases) was identified only in the subserosal layer. The lack of p53 reactivity and the very low MIB-1-labeling index provide additional support to the non-neoplastic nature of the lesion. The pseudoinvasive pattern of the RASs, reactive epithelial atypia, and the perineural and intraneural invasion probably contributed to the erroneous diagnosis of adenocarcinoma or "adenoma malignum." The mechanism by which the epithelial structures "invaded" the perineural spaces and the nerves is unclear. We favor the hypothesis that the migration of the benign glandlike structures into the nerves is related to the production of chemotactic factors or signaling substances and the activation of cell receptors.

Oncocytic papillary neoplasms of the biliary tract: a clinicopathological, mucin core and Wnt pathway protein analysis of four cases.

AIMS: Oncocytic change in papillary neoplasms of the biliary tract is a very uncommon finding with little known about pathogenesis, immunophenotype and prognosis, especially in comparison to similar lesions in the pancreatic ductal system. We report four cases of oncocytic biliary intraductal papillary neoplasms (IPNs), highlighting the clinicopathological characteristics of these tumours, the immunohistochemical profile with regard to Wnt pathway proteins and mucin core protein (MUC) status, and compare these findings with the oncocytic variant of intraductal papillary mucinous neoplasm (IPMN) of the pancreas. METHODS: Four cases of oncocytic IPN of the extrapancreatic, biliary tree (two with accompanying invasive carcinomas) were examined for mucin profiles and Wnt signalling proteins. The cases were stained for: beta-catenin, c-myc, glutathione synthase kinase (GSK), E-cadherin, cyclin D1, and adenomatous polyposis coli (APC), and MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC5B and MUC6, using standard immunohistochemistry. RESULTS: The cases occurred in three males and one female, ranging in age from 59 to 81 years. The lesions caused obstructive symptoms related to the biliary tree as well as non-specific abdominal symptoms. Typically, cystic lesions were noted grossly. All four of the IPNs were composed of distinctive oncocytic cells. The invasive carcinomas accompanying two of the cases were also composed of oncocytes. None of the cases showed aberrant expression of the Wnt signalling proteins, although cyclin D1 was markedly over-expressed in all four cases. Three of four cases showed the following mucin profile: MUC3, MUC4, MUC5AC, MUC5B and MUC6 positive. CONCLUSIONS: The Wnt pathway proteins (especially beta-catenin and E-cadherin) are expressed normally in oncocytic variants of intraductal papillary neoplasms of the biliary tree, and the mucin profile is similar to their counterparts in the pancreas.

Tumor of the liver (hepatocellular and high grade neuroendocrine carcinoma): a case report and review of the literature.

We describe a rare hepatic collision tumor composed of a hepatocellular carcinoma and a high-grade neuroendocrine carcinoma. The patient, a 50-year-old man, underwent a partial hepatectomy because of a 5.0-cm mass. The tumor had two distinctive patterns. The majority of the tumor was a high-grade neuroendocrine carcinoma with features of a small cell carcinoma that was positive for chromogranin, synaptophysin, and cytokeratin 19 and negative for hepatocellular antigen and alpha-fetoprotein (AFP). The second component was a moderately differentiated hepatocellular carcinoma that was positive for hepatocellular antigen and AFP and negative for neuroendocrine markers. The two tumors were separated by fibrous bands. In areas where they collided, there was no transition or intermingling of cells between the two components, thus, it is different from the combined type of tumors. After removal of the tumor, the patient had intrahepatic and mesenteric recurrences within a follow-up period of 16 months.

Liver glycogen bodies: ground-glass hepatocytes in transplanted patients.

Ground-glass hepatocytes have been described in Lafora's disease, fibrinogen deposition, hepatitis B, type IV glycogenosis, and alcohol aversion (cyanamide) therapy. We encountered ground-glass hepatocytes with intracytoplasmic inclusions in four liver biopsies from three transplanted patients who had none of the above-mentioned underlying diseases. One patient was a 4-year-old boy who had a kidney transplant for severe ureterovesical reflux. Patient 2 was a 52-year-old man who had two liver transplants because of hepatitis C. The third patient was a 7-month-old girl who underwent a multivisceral transplant because of necrotizing enterocolitis and liver failure induced by total parenteral nutrition. The patients developed liver abnormalities from 45 days to 4 years after their transplants. The livers showed conspicuous ground-glass hepatocytes in 90% of the children's samples and 30% of the adult liver cells. The cytoplasmic bodies stained strongly for Gomori methenamine-silver; they were positive for periodic acid-Schiff without diastase, but negative after diastase digestion. They were negative for colloidal iron and hepatitis B core and surface antigens. Electron microscopy revealed non-membrane bound aggregates of glycogen. Idiopathic ground-glass hepatocytes occur in transplanted patients and represent accumulation of altered glycogen. However, their clinical significance and cause are not entirely elucidated.

Pulmonary Empty Spaces: Silicone Embolism-A Decade of Increased Incidence and Its Histological Diagnosis.

Pulmonary embolism (PE) is a critical complication related to multiple disorders and different medical or cosmetic procedures. This case report presents two patients who were admitted for respiratory symptoms in the setting of previously receiving silicone injections for cosmetic purposes and were diagnosed with silicone pulmonary embolism. The relevance of including questions about all cosmetic procedures as a part of a medical history is highlighted, in particular about silicone injections. The diagnosis is confirmed by histological means. Additionally, our review showed the change of most common sites of silicone injections and a significant increase in cosmetic procedures causing silicone embolism during the past twelve years.

Determination of GP88 (progranulin) expression in breast tumor biopsies improves the risk predictive value of the Nottingham Prognostic Index.

BACKGROUND: The Nottingham Prognostic Index (NPI), which combines numerical values for nodal status, tumor size and histological grade, is used in the standard of care to provide predictive value information on post-surgery survival for patients with primary breast cancer. Attempts to improve the performance of the NPI algorithm have been carried out by testing the inclusion of other biomarker expression and morphological features such as vascular invasion. In the present study, we investigated whether expression of the autocrine growth and survival factor GP88 (progranulin), known to be overexpressed in breast cancer, would improve NPI's predictive value. METHODS: We examined by immunohistochemistry (IHC) the GP88 expression in 508 cases of estrogen receptor positive invasive ductal carcinoma with known clinical outcomes and for which NPI had been determined. GP88 IHC expression was scored by two board certified pathologists and classified into two score groups of GP88 <3+ (0, 1+, 2+) and GP88 = 3+. The correlation between GP88 scoring, NPI and disease-free (DFS) or overall survival (OS) outcomes was then examined by Kaplan-Meier analysis, Cox proportional Hazard (CPH) ratio and Pearson's X (2) test. RESULTS: Kaplan-Meier survival graphs of cases categorized by their NPI scores (<3.4, 3.4-5.4, >5.4) and GP88 expression showed that for patients within the same NPI subgroup, patients having tumors with a high GP88 expression (GP88 IHC score of 3+) had a worse DFS than patients with tumors that had a low GP88 expression (GP88 IHC score <3+). When adjusted for NPI, high GP88 score was significantly associated with recurrence with a hazard ratio of 3.30 (95 % CI 2.12 to 5.14). CONCLUSIONS: The data suggest that the determination of GP88 tumor expression at time of diagnosis for early stage breast cancer patients can provide additional survival information to that provided by NPI alone and thus may be useful for risk management of patients diagnosed with breast cancer.

Role of liver function tests in detecting methotrexate-induced liver damage in sarcoidosis.

BACKGROUND: Methotrexate has become a standard second-line agent for the treatment of sarcoidosis. Because sarcoidosis has a high frequency of liver involvement, we routinely perform a liver biopsy after each cumulative gram of methotrexate therapy in patients with sarcoidosis in whom we plan to continue therapy. METHODS: Following a previously described protocol for methotrexate therapy, we have performed 100 liver biopsies on 68 patients with chronic sarcoidosis at our institution. On the basis of the liver biopsy results, we identified the following 4 groups: sarcoidosis (47 cases), toxic effects of methotrexate (14 cases), hepatitis C (2 cases), and normal liver tissue (37 cases). RESULTS: We found no difference among the groups in terms of age, weight at time of biopsy, the number of patients receiving corticosteroids at the time of biopsy, cumulative dose of methotrexate, race, or sex. The 14 cases of toxic reactions to methotrexate included 5 patients who had undergone 1 or more previous liver biopsies in which the results did not show toxic effects. We found a significant difference between groups for levels of alkaline phosphatase and asparate aminotransferase at the time of starting (or restarting) methotrexate therapy (analysis of variance, P<.05). This finding was also true for the liver function tests performed at the time of the biopsy (analysis of variance, P<.05). The highest values were for those whose biopsy findings showed sarcoidosis. CONCLUSIONS: Toxic reactions to methotrexate eventually occurred in more than 10% of patients with sarcoidosis treated for more than 2 years with methotrexate. Because of hepatic involvement owing to sarcoidosis, results of serial liver function tests were not useful in determining which patients would have this reaction to methotrexate.