Acute acalculous cholecystitis as an early manifestation of COVID-19: case report and literature review.

Background: The novel coronavirus disease 2019 (COVID-19) has rapidly spread worldwide since the outbreak in Wuhan, China, in 2019, becoming a major threat to public health. The most common symptoms are fever, dry cough, shortness of breath, but subjects with COVID-19 may also manifest gastrointestinal symptoms, and in a few cases an involvement of the gallbladder has been observed. Case report: Here we present a case of 50-year-old male with SARS-CoV-2 infection who had abdominal pain, vomiting and diarrhea without respiratory symptoms and was finally diagnosed as acute acalculous cholecystitis (AAC). Laparoscopic cholecystectomy was performed and found a gangrenous gallbladder; the real-time reverse transcription polymerase chain reaction SARS-CoV-2 nucleic acid assay of the bile was negative. We also made a review of the literature and try to understand the hypothetic role of SARS-CoV-2 in the pathogenesis of AAC. Conclusions: We highlighted that it is noteworthy to look at gastrointestinal symptoms in patients with SARS-CoV-2 infection and take into account AAC as a possible complication of COVID-19. Although more evidence is needed to better elucidate the role of the pathogenic mechanisms of the SARS-CoV-2 in AAC, it is conceivable that the hepatobiliary system could be a potential target of SARS-CoV-2.

COVID-19 pandemic impact on cytopathology practice in the post-lockdown period: An international, multicenter study.

BACKGROUND: In a previous worldwide survey, the authors showed a drastic reduction in the number of cytological specimens processed during the coronavirus disease 2019 "lockdown" period along with an increase in malignancy rates. To assess the continued impact of the pandemic on cytological practices around the world, they undertook a second follow-up worldwide survey collecting data from the post-lockdown period (2020). METHODS: Participants were asked to provide data regarding their cytopathology activity during the first 12 weeks of their respective national post-lockdown period (2020), which ranged from April 4 to October 31. Differences between the post-lockdown period and the corresponding 2019 period were evaluated, and the authors specifically focused on rates of malignant diagnoses. RESULTS: A total of 29 respondents from 17 countries worldwide joined the survey. Overall, a lower number of cytological specimens (n = 236,352) were processed in comparison with the same period in 2019 (n = 321,466) for a relative reduction of 26.5%. The overall malignancy rate showed a statistically significant increase (12,442 [5.26%] vs 12,882 [4.01%]; P < .001) during the same time period. Similar results were obtained if both malignancy and suspicious for malignancy rates were considered together (15,759 [6.58%] vs 16,011 [4.98%]; P < .001). CONCLUSIONS: The data showed a persistent reduction in the cytological specimen volume during the post-lockdown period (2020). However, the relative increase in the cytological workload in the late part of the post-lockdown is a promising finding of a slow return to normality.

The histomorphological and molecular landscape of colorectal adenomas and serrated lesions.

The 2019 WHO classification of digestive system tumors significantly reformed the classificatory definition of serrated lesions of the colorectal mucosa and added new essential diagnostic criteria for both conventional adenomas and hereditary gastrointestinal polyposis syndromes. Histopathological examination of colorectal adenocarcinoma precursors lesions represents an important segment of daily clinical practice in a pathology department and is essential for the implementation of current colorectal adenocarcinoma secondary prevention strategies. This overview will focus on a schematic histopathological and molecular classification of precursor lesions arising within colorectal mucosa.

Malignant epithelial/exocrine tumors of the pancreas.

Pancreatic malignant exocrine tumors represent the most important cause of cancer-related death for pancreatic neoplasms. The most common tumor type in this category is represented by pancreatic ductal adenocarcinoma (PDAC), an ill defined, stroma-rich, scirrhous neoplasm with glandular differentiation. Here we present the relevant characteristics of the most important PDAC variants, namely adenosquamous carcinoma, colloid carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, signet ring carcinoma, medullary carcinoma and hepatoid carcinoma. The other categories of malignant exocrine tumors, characterized by fleshy, stroma-poor, circumscribed neoplasms, include acinar cell carcinoma (pure and mixed), pancreatoblastoma, and solid pseudopapillary neoplasms. The most important macroscopic, histologic, immunohistochemical and molecular hallmarks of all these tumors, highlighting their key diagnostic/pathological features are presented. Lastly, standardized indications regarding gross sampling and how to compile a formal pathology report for pancreatic malignant exocrine tumors will be provided.

Global impact of the COVID-19 pandemic on cytopathology practice: Results from an international survey of laboratories in 23 countries.

BACKGROUND: To the authors' knowledge, the impact of the coronavirus disease 2019 (COVID-19) pandemic on cytopathology practices worldwide has not been investigated formally. In the current study, data from 41 respondents from 23 countries were reported. METHODS: Data regarding the activity of each cytopathology laboratory during 4 weeks of COVID-19 lockdown were collected and compared with those obtained during the corresponding period in 2019. The overall number and percentage of exfoliative and fine-needle aspiration cytology samples from each anatomic site were recorded. Differences in the malignancy and suspicious rates between the 2 periods were analyzed using a meta-analytical approach. RESULTS: Overall, the sample volume was lower compared with 2019 (104,319 samples vs 190,225 samples), with an average volume reduction of 45.3% (range, 0.1%-98.0%). The percentage of samples from the cervicovaginal tract, thyroid, and anorectal region was significantly reduced (P < .05). Conversely, the percentage of samples from the urinary tract, serous cavities, breast, lymph nodes, respiratory tract, salivary glands, central nervous system, gastrointestinal tract, pancreas, liver, and biliary tract increased (P < .05). An overall increase of 5.56% (95% CI, 3.77%-7.35%) in the malignancy rate in nongynecological samples during the COVID-19 pandemic was observed. When the suspicious category was included, the overall increase was 6.95% (95% CI, 4.63%-9.27%). CONCLUSIONS: The COVID-19 pandemic resulted in a drastic reduction in the total number of cytology specimens regardless of anatomic site or specimen type. The rate of malignancy increased, reflecting the prioritization of patients with cancer who were considered to be at high risk. Prospective monitoring of the effect of delays in access to health services during the lockdown period is warranted.

Very Rare Liver Neoplasm: Lymphoepithelioma-Like (LEL) Hepatocellular Carcinoma.

A case of lymphoepithelioma-like (LEL) hepatobiliary carcinoma is reported. To date, only 89 cases of this rare neoplasm have been reported, with both hepatocellular and cholangiocellular histotype. The case reported here could be classified as LEL mixed hepatobiliary carcinoma (Hepato-Cholangio), a histotype not reported so far in the LEL variant.

Evolving concepts and use of immunohistochemical biomarkers in flat non-neoplastic urothelial lesions: WHO 2016 classification update with diagnostic algorithm.

CONTEXT: The classification of flat non-neoplastic urothelial lesions has been evolved through the years in the attempt to better define a spectrum of morphologic entities with somewhat overlapping features. Differentiating these lesions is important because of differences in patient management and clinical outcome. Materials and methods and objective: A systematic review of the literature has been carried out in order to (1) assess the most striking clinical features of each lesion and (2) identify those morphological traits and immunophenotypical markers which may aid in the differential diagnosis. RESULTS AND CONCLUSION: Our results point out the importance of a proper definition of flat non-neoplastic urothelial lesions in order to predict clinical behaviour and allow tailored patient management; therefore, we attempted to construct a novel and "easy to use" algorithm for a clear, standardized and evidence-based pathological diagnosis.

The Tumor Entity Denominated "clear cell-papillary renal cell carcinoma" According to the WHO 2016 new Classification, have the Clinical Characters of a Renal Cell Adenoma as does Harbor a Benign Outcome.

The new WHO 2016 classification of renal neoplasia encounters the new entity called "clear cell papillary renal cell carcinoma" (ccpRCC). The ccpRCC has been long included as a subtype of clear cell RCC histotype and it actually ranges from 2 to 9% in different routinely available cohort of renal carcinomas. Of important note, ccpRCC does not show any recurrences or metastases or lymph-node invasion and the outcome is always good. We reviewed twenty-four publications with available follow-up for patients (no. 362) affected by clear cell papillary RCCs/renal adenomatoid tumours and notably ccpRCC harbors an indolent clinical behavior after a mean of 38 months (3,5 years) of follow-up. This paper reviews the histological, molecular and clinical features characterizing ccpRCC, with the goal of focusing the knowledge of the benign fashion of this new tumour entity, supporting the idea of a new renal cell adenoma recruited morphologically from ex conventional clear cell RCC tumours.

On a Rare Cutaneous Metastasis from a Sacrococcygeal Chordoma.

Chordomas are rare malignant tumors of notochordal origin and are rare locally aggressive ones with a metastatic potential. The skin rarely is seen as metastatic site. We describe a case of an adult woman with cutaneous metastasis of a primary sacral chordoma excised ten years before, which appeared as a painless cutaneous mass located in the dorsal region. Once removed, the surgical specimen was formalin fixed and in paraffin embedded. Sections were stained with haematoxylin-eosin, and histochemical and immunohistochemical investigations were performed. Histologically, the neoplasia was characterized by cords or single tumor cells with an abundant myxoid stroma, conspicuous pale vacuolated cytoplasm (the classic "physaliphorous cells"), and mild nuclear atypia. Mitotic activity was scanty. At immunohistochemistry, the tumor cells were diffusely positive for S-100 protein, pan-keratins, EMA, and vimentin. A diagnosis of cutaneous metastasis of chordoma was performed. This case illustrates a diagnostic challenge because of the unusual presentation of an already rare tumor.

Cathepsin K expression in castration-resistant prostate carcinoma: a therapeutical target for patients at risk for bone metastases.

BACKGROUND: The lysosomal cysteine protease cathepsin K is involved in bone remodeling and is also expressed in the peritumoral stroma of carcinomas arising from different organs. A new generation of cathepsin K inhibitors blocking the RANKL/RANK pathway are being developed. We sought to investigate cathepsin K expression in a cohort of castration-resistant prostate carcinomas. METHODS: Sixteen cases of castration-resistant disease with at least 5 years of follow-up were selected from a cohort of 280 patients who underwent surgery. Cathepsin K was evaluated on formalin-fixed and paraffin-embedded tissue microarrays with 5 tissue spots per case. These were scored as high 2+ (≥30% of cells), low 1+ (<30% of cells) or zero (absence), distinguishing tumor cells and peritumoral stroma cells. Low (1+) and absence (0) of scoring were interpreted as negative, and high (2+) as positive. RESULTS: The castration-resistant group was composed of 15 acinar adenocarcinomas and 1 neuroendocrine carcinoma, and all showed at least Gleason score 8 at prostatectomy. Two out of 16 cases (12%) scored positive for cathepsin K in tumor cells; and 5 of 16 cases (31%) scored positive in peritumoral stroma cells. The neuroendocrine and acinar subtypes of carcinoma with positive immunoexpression in neoplastic cells developed bone metastases after 4 and 5 years, respectively, and subsequently died. CONCLUSIONS: Patients affected by castration-resistant prostate carcinoma may be tested for cathepsin K, and a positive strong expression (2+) could be a useful predictive biomarker of response to targeted agents, aiding in the selection of patients eligible for these treatments.

Urine TMPRSS2: ERG Fusion Transcript as a Biomarker for Prostate Cancer: Literature Review.

Prostate cancer (PCa) is one of the most common male malignancies. Serum prostate-specific antigen (PSA) is one of the most valuable biomarkers in tumor biology and remains the standard marker in detecting and monitoring PCa. However, the high number of serum PSA false positive and false negative results make the identification of novel biomarkers extremely welcome to improve our diagnostic accuracy in detecting PCa and distinguishing the aggressive from the indolent ones. In this study, we analyzed the current role of urinary gene fusion transcripts involving v-ets erythroblastosis virus E26 oncogene homolog, commonly known as ERG, and the androgen-regulated gene transmembrane protease, serine 2 (TMPRSS2), as a biomarker for PCa. Used as a single marker, urinary TMPRSS2:ERG has low sensitivity but high specificity. However, its combination with the other urinary marker PCa antigen 3 (PCA3) has been reported to provide high specificity and sensitivity. Finally, a commercially available assay combining serum PSA with urinary PCA3 and TMPRSS2:ERG provides a 90% specificity and 80% sensitivity in diagnosing PCa. Urinary TMPRSS2:ERG also seems to be indicative of PCa aggressiveness upon biopsy. Should these findings be confirmed in larger studies, urinary TMPRSS2:ERG might become a valuable test not only for diagnosing PCa but also for distinguishing the aggressive tumors from the indolent ones.

Polypoid Carcinoma of the Oropharynx with Stromal Ossifying Myofibroblastic Proliferation: A Case Report and Literature Review.

A 76-year-old man reported a worsening difficulty in swallowing, leading to the inability to eat. Physical examination and CT scan revealed a polypoid mass on the posterior oropharynx and obstructing the oropharyngeal space. Histologically, the surface was ulcerated. In the underlying necrotic rim, there was active granulation tissue, and a proliferation of voluminous, globoid elements with hyperchromatic and irregular nucleus, sometimes arranged in a alveolar aggregate. The core of the lesion contained spindle-like myoid elements in interwoven bundles, with trabeculae of osteoid matrix maturing into calcified bone. Immunohistochemistry documented positivity for cytokeratins, epithelial membrane antigen, and P63 in the globoid elements beneath the necrotic rim; strong and diffuse expression of vimentin, smooth muscle actin, and CD99 and BCL2 in the spindle elements; and complete negativity for cytokeratin 5/6, high molecular weight cytokeratin (clone 34ßE12), S100, muscle-specific actin, desmin, CD117, and anaplastic lymphoma kinase. The lesion was morphologically and immunophenotypically classified as a polypoid oropharyngeal carcinoma with ossifying myofibroblastic stromal proliferation.

Methods to identify molecular expression of mTOR pathway: a rationale approach to stratify patients affected by clear cell renal cell carcinoma for more likely response to mTOR inhibitors.

Since target therapy with mTOR inhibitors plays an important role in the current management of clear cell renal cell carcinoma (RCC), there is an increasing demand for predictive biomarkers, which may help to select patients that are most likely to benefit from personalized treatment. When dealing with formalin-fixed paraffin-embedded (FFPE) cancer tissue specimens, several techniques may be used to identify potential molecular markers, yielding different outcome in terms of accuracy. We sought to investigate and compare the capability of three main techniques to detect molecules performing an active function in mTOR pathway in RCC. Immunohistochemistry (IHC), Western blot (WB) and immunofluorescence (IF) analyses were performed on FFPE RCC tissue specimens from 16 patients by using the following mTOR pathway-related: mTOR (Ser235/236), phospho-mTOR (p-mTOR/Ser2448), phospho-p70S6k (p-p70S6k/Thr389), both monoclonal and polyclonal, phospho-S6Rb (p-S6Rb) and phospho-4EBP1 (p-4EBP1/Thr37/46). No single molecule was simultaneously revealed by all three techniques. Only p-p70S6k was detected by two methods (IHC and IF) using a monoclonal antibody. The other molecules were detected exclusively by one technique, as follows: p-mTOR and polyclonal p-p70S6K by IHC, p70S6K, p-S6Rb and p-4EBP1 by WB, and, finally, mTOR by IF. We found significant differences in detecting mTOR pathway-related active biomarkers by using three common techniques such as IHC, WB and IF on RCC samples. Such results have important implications in terms of predictive biomarker testing, and need to be related to clinical end-points such as responsiveness to targeted drugs by prospective studies.

Analysis of the IgVH genes in T cell-mediated and antibody-mediated rejection of the kidney graft.

AIMS: Grafts have been shown to be sites where the alloimmune response develops in a direct interaction between the targeted tissue and the immune effectors. An important issue in renal rejection is B cell infiltrate that may contribute to the development or persistence of rejection. Analysis of gene-expression patterns also provides a window on the biology and pathogenesis of renal allograft rejection. METHODS: To better understand the role exerted by B cells in a renal acute rejection, the authors analysed the IgVH gene repertoire in six cases of transplanted kidneys with acute T cell-mediated rejection (TCMR), three of which were associated with antibody-mediated rejection (ABMR). RESULTS: The authors found mutated and unmutated sequences, without any evidence of clonal relationships, in all patients with TCMR alone and in two of the three cases with both acute TCMR and ABMR. The remaining patient showed glomerular inflammation and thrombosis, with diffuse C4d glomerular and peritubular capillary deposition, and hypermutated V region genes. CONCLUSIONS: These results suggest that there is more than one pathway to the onset and perpetuation of CD20 (+) B cells infiltration in acute rejection; furthermore, the CD20 (+) B cells' clonal expansion may be responsible for a more severe pattern of ABMR, through immune-mediated tissue damage.

Rare lymphoid neoplasms coexpressing B- and T-cell antigens. The role of PAX-5 gene methylation in their pathogenesis.

We report 3 cases of lymphoid neoplasms with mixed lineage features of T-, NK-, or B-cell marker expression and clonal gene rearrangement for both T-cell receptor and immunoglobulin light chain IgK. A characteristic of our cases was the lack of expression of the specific B-cell transcription factor, Pax5, which is essential for maintaining the identity and function of mature B cells during late B lymphopoiesis. In the absence of Pax5, B cells in vitro can differentiate into macrophages, dendritic cells, granulocytes, and T/NK cells. Methylation analysis of the Pax5 gene in our cases suggests that its inactivation by this epigenetic event in a committed or mature B cell, before plasma cell differentiation, may well be a common pathogenetic mechanism in mature lymphoid neoplasms with expression of multilineage antigens. In particular, case 1 may represent a mixed NK- and B-cell lineage; and cases 2 and 3 may represent mixed T and B-cell lineage, respectively. Aberrations in the DNA methylation patterns are currently recognized as a hallmark of human cancer. Cases with aberrant phenotypes require molecular analysis for lineage assignment. Studies of such cases may be helpful to better elucidate whether they represent a distinct entity with clinical, immunophenotypic, and molecular characteristics or an incidental phenomenon during malignant transformation. Interestingly, these cases were all characterized by poor clinical outcome.

Overlapping morphologic and immunophenotypic profiles in small B-cell lymphoma. A report of two cases.

We present two cases of small B-cell lymphomas of particular diagnostic interest because the histological patterns were at variance with their immunophenotype. One of these lymphomas, involving the gallbladder and duodenum, showed a marginal zone lymphoma-like (MALT type) pattern of cellular infiltration with CD5 negativity but (unexpectedly) Cyclin D1 positivity. Fluorescence in situ hybridization analysis of this case was performed because of the aberrant expression of Cyclin D1, and was clearly positive for the Cyclin D1 gene translocation. The second case, occurring in a lymph node, showed the typical growth pattern of a follicular lymphoma but it had an atypical immunophenotype, namely, expression of Cyclin D1, CD10, and Bcl2 and focally Bcl6, accompanied by a lack of CD5 and CD23. The Cyclin D1 gene translocation was detected by fluorescence in situ hybridisation (FISH), whereas c-myc and Bcl2 genes translocation were absent. Numerical chromosomal changes, which were visualized for chromosomes 8, 11, and 18 could be correlated to the aberrant immunoprofile. In this context, we discuss the diagnostic value of Cyclin D1, CD5, CD23, CD10, Bcl6 markers revealed by immunohistochemistry, as well as the significance of detection by FISH of chromosomal translocations such as t(11;14) and t(14;18). The question still remains as to whether such cases should be designated as specific lymphoma entities or reported as unclassifiable and the chromosome aberration reported.

Activity of rituximab monotherapy in refractory splenic marginal zone lymphoma complicated with autoimmune hemolytic anemia.

We describe the case of a 61-year-old patient with refractory splenic marginal zone lymphoma and secondary autoimmune hemolytic anemia, both successfully treated with rituximab. This case demonstrates that rituximab monotherapy might also be a valid therapeutic approach in marginal zone lymphoma and autoimmune hemolytic anemia after failure of first-line treatment. Maintenance therapy, although expensive, could be useful to improve event-free survival in patients with unfavorable clinical behavior.

Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 infection in reactive lymphoid tissues: a model for KSHV/HHV-8-related lymphomas?

We set out to analyze the presence of Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8 (HHV-8) in different neoplasms occurring in East Africa, a region characterized by a high KSHV/HHV-8 seroprevalence rate and endemic Kaposi's sarcoma (KS). Our results suggest that, in endemic regions of Africa, KSHV/HHV-8 is predominantly associated with KS, independently of HIV status. During the course of this study, other important information came to light. We found the presence of KSHV/HHV-8 in 2 cases of lymph nodes partially involved by Burkitt's lymphoma and KS and in 1 case of multicentric Castleman disease. Our immunophenotypic and molecular data seem to suggest 2 different mechanisms of viral infection are at work in lymphoid cells. On one hand, when B cells show a latent phase infection with KSHV/HHV-8, after the germinal center reaction, naive B cells become resting memory B cells, similarly to Epstein-Barr virus-infected B cells. On the other hand, when lytic genes such as vIL6 are expressed in naive B cells, they may be driven to differentiate into plasmablasts without undergoing germinal center reaction. Interestingly, among KSHV/HHV-8-positive cases, in those in which there was also lymphoma, the neoplastic cells were negative for KSHV/HHV-8. This further confirms that KSHV/HHV-8 is involved in the neoplastic transformation of only certain types of lymphoma, probably in relation to their precursor infected cell. In conclusion, the maturation stage of KSHV/HHV-8-positive B cells as well as the type of viral infection may well determine the morphological, phenotypic, and clinical characteristics of KSHV/HHV-8-associated lymphomas.