Epstein-Barr virus (EBV)-positive inflammatory follicular dendritic cell sarcoma (EBV+ IFDCS) is a rare, indolent malignant neoplasm. Due to its rarity, a comprehensive assessment of its immunophenotypic spectrum and molecular analysis is still lacking. This study aimed to characterize the immunophenotypic and genetic alterations of EBV+ IFDCS to improve understanding of its cell of origin and molecular pathogenesis and to identify potential therapeutic targets. Immunohistochemical staining for a panel of follicular dendritic cell (FDC) and fibroblastic reticular cell (FRC) lineage markers, along with targeted next-generation sequencing, was performed. Nineteen cases of EBV+ IFDCS were classified into four immunophenotypes: nine FDC, two FRC, three biphasic and five null phenotypes. Morphologically, cases with a null phenotype more frequently exhibited a lymphoma-like growth pattern (4/5, 80%) compared with those with a definite FDC and/or FRC phenotype (1/14, 7.1%, P = 0.006). Moreover, a scattered distribution of neoplastic cells was more commonly observed in null phenotype cases (4/5, 80%) than in FDC and/or FRC phenotype cases (3/14, 21.4%, P = 0.038). Targeted sequencing revealed somatic variants in chromatin modifier-related genes in 60.0% (9/15), homologous recombination repair (HRR)-related genes in 53.3% (8/15) and Hippo pathway-relatedgenes (FAT2 and FAT1) in 26.7% (4/15) of cases. These findings demonstrate the wide morphological and immunophenotypic spectrum of EBV+ IFDCS. Furthermore, variants in chromatin modifier and HRR-related genes may participate in its pathogenesis, and PARP inhibition may represent a potential therapeutic strategy for patients with unresectable disease.

Extramammary Paget disease (EMPD) is an intraepidermal carcinoma that typically involves the urogenital, perineal and perianal skin. EMPD is classified as primary if arising directly in the skin, or secondary if spreading from another malignancy, most commonly urothelial carcinoma and colorectal adenocarcinoma. Prostein (p501s) immunoreactivity was initially described as sensitive and specific for prostatic epithelial cells including prostatic adenocarcinoma. Herein, we investigated the expression of prostein in primary EMPD of the external genitalia, secondary EMPD involving the external genitalia or perineum, and mammary Paget disease (MPD). Prostein was negative by immunohistochemistry in all cases of MPD (n = 0/11) and secondary EMPD (n = 0/5). Conversely, prostein was positive in all cases of primary EMPD (n = 11/11), including non-invasive and invasive components and including one nodal metastasis. Among these cases, 5/11 (45%) showed non-focal moderate-to-strong staining, 3/11 (27%) showed focal weak staining, and 3/11 (27%) cases showed weak diffuse staining. All cases of primary EMPD additionally showed diffuse 2-3+ staining for GATA3, and 10/11 cases of primary EMPD showed diffuse 2-3+ staining for androgen receptor (AR). These findings suggest that prostein may be a promising immunohistochemical marker for the diagnosis of primary EMPD.

Teratomas are the most common germ cell tumours in the gynaecological tract, the vast majority arising in the ovary. Limited information is available on uterine teratomas. We evaluated clinicopathological features of five uterine teratomas, fluorescence in situ hybridization for isochromosome 12p [i(12p)], short tandem repeat (STR) analysis, and targeted DNA sequencing in a subset. Patients' age ranged from 29 to 60 (median: 40) years. Three underwent hysterectomy and two conservative cervical excisions. All tumours were uterine confined with four centred in the cervix and one in the corpus, ranging from 2.4 to 6.5 (median: 3.75) cm. Three tumours only had mature elements with one associated with mature glial tissue in the peritoneum and endometrium. The other two tumours also showed immature neural tissue, warranting a diagnosis of Grade 2 immature teratoma based on ovarian criteria. Four patients were alive with no evidence of disease with median follow-up of 13 (range 2-42) years. i(12p) was not detected in two tumours with available material (one mature and one immature). STR analysis showed heterozygosity in one mature and complete homozygosity in one immature teratoma. Targeted DNA sequencing revealed no pathogenic or likely pathogenic alterations in one immature teratoma and a pattern consistent with genome-wide loss of heterozygosity. Uterine teratomas display either mature or an admixture of mature and immature elements and can rarely be associated with gliomatosis. Limited data show no association with i(12p). The malignant potential of immature uterine teratomas is not well established and they appear to be more akin to sacrococcygeal than ovarian teratomas based on limited STR results from this cohort and the literature.

The grading and staging of liver biopsies from patients with steatotic liver disease, in particular metabolic dysfunction-associated steatotic liver disease (MASLD), is of fundamental importance in the execution of clinical trials of new therapeutic agents in this condition. Several semi-quantitative scoring systems have been designed for this purpose, of which the most used is the NASH Clinical Research Network (NASH CRN) system, in which the grade of disease is assessed on the severity of steatosis, hepatocyte ballooning and lobular inflammation. There has been recent interest in the role of portal inflammation (PI) in MASLD. The arguments for and against the inclusion of a semi-quantitative score for PI in grading MASLD activity are discussed in detail.

Mucin-producing breast lesions encompass a diverse range of entities with varied morphologies, distinct molecular genetics and different outcomes. Mucocele-like lesions (MLLs) are being increasingly recognised and sampled due to advancements in imaging techniques. These lesions can present with or without epithelial proliferation and atypia, which hold prognostic significance. Diagnosing MLLs on limited core needle biopsy (CNB) samples can be challenging. Mucinous breast carcinoma (MuBC) generally has an excellent prognosis in its pure form. Recent studies indicate that mucin-producing invasive cancers with micropapillary growth pattern, high nuclear grade or HER2 overexpression/amplification may not fare as well as their pure counterparts, suggesting that they should be distinguished from pure MuBCs. Invasive lobular carcinoma with extracellular mucin (ILCEM) is an emerging subtype of ILC characterised by neoplastic cells in cords, nests and trabeculae, often with signet ring morphology, floating in extracellular mucin. This can lead to misdiagnosis as a ductal phenotype due to varied architectural patterns or a MuBC due to the presence of extracellular mucin. This review highlights the spectrum of mucin-producing breast lesions, focusing on the above-mentioned entities along with recent molecular updates, potential mimics and diagnostic pitfalls on CNB specimens. Awareness of these entities, a practical approach to their diagnosis, combined with judicious use of immunohistochemistry, are crucial for accurate diagnosis by pathologists, which is in turn essential for guiding clinical decision making for optimal patient outcomes.

Treatment and outcomes in colorectal carcinoma (CRC) depend on the UICC classification, depth of invasion, and distant metastases. However, it is not clear whether an extensive workup of lymph nodes (LNs) is important for the adequate determination of metastases. Therefore, we compared the number of LNs and metastases obtained by a standard protocol (SP) and an extended protocol (EP) in two series with a total of 105 CRC cases and 2417 LNs. In the first series, the EP included complete stepwise sectioning of all LN-bearing paraffin blocks in each case, increasing the total number of LNs from 1247 in the SP to 1333 in the EP and the number of metastases from 69 to 80. One pTNM pN1a case became pN1b, and two pN1b cases became pN2a. The staging, and thus the therapy, changed in none of them. Furthermore, no relevant effect of embedding one versus both halves of large LNs >5 mm was evident. In the second series, the EP included immunohistochemical staining for pan-cytokeratin (monoclonal antibodies AE1/AE3) of all LN-bearing paraffin blocks in a given case. The number of detected metastases rose from 82 to 89, with a constant total 1084 LNs. In two cases, the pTNM classification changed from pN2a to pN2b. Staging and therapy changed in none. An extensive workup of LNs is not mandatory in patients with CRC. A straightforward protocol is sufficient to guide clinicians to the appropriate therapy.

ASCL1, NEUROD1, POU2F3 and YAP1 are recently described markers of transcriptional subtypes in small cell lung carcinoma (SCLC), while DLL3, regulated by ASCL1, is a target of novel therapeutic agents in various neuroendocrine neoplasms. The expression of these markers in lung carcinoids is not well established. We examined these markers in 109 lung carcinoids and compared their expression with that in 191 enteropancreatic neuroendocrine tumours (EP-NETs) and with lung carcinoid markers (OTP, TTF1). ASCL1, NEUROD1, OTP and TTF1 were positive in 56%, 0%, 84% and 35% of lung carcinoids, respectively. Of the OTP-negative lung carcinoids (n = 18), 4 (22%) were ASCL1-positive, of which one was TTF1-positive. In contrast, 59% of EP-NETs were NEUROD1-positive, whereas only rare tumours focally expressed ASCL1 (1.1%) and OTP (0.5%) and none expressed TTF1. DLL3 was positive in 57 (52%) lung carcinoids versus 5 (2.6%) EP-NETs. All lung carcinoids and EP-NETs were completely negative for POU2F3 and YAP1. We also analysed clinicopathologic correlates of ASCL1, OTP, TTF1 and DLL3 expression in lung carcinoids, expanding on several previously suggested associations, including ASCL1 and TTF1 with peripheral location, OTP with low Ki67 (P = 0.002) and low stage (P = 0.002) and DLL3 with high Ki67 (P = 0.002). Unlike SCLC, lung carcinoids and EP-NETs completely lack the expression of POU2F3 and YAP1, which offers diagnostic applications. Our findings also nominate ASCL1 and NEUROD1 as site of origin markers for lung versus digestive NETs/carcinoids, respectively. Finally, the divergent expression of DLL3 in lung carcinoids and EP-NETs has therapeutic implications.