Histopathology最新文献

Aims: Many studies have highlighted interobserver variability in histologic distinction between colorectal sessile serrated lesion (SSL) and hyperplastic polyp (HP). In 2019, the WHO updated their criteria for the diagnosis of SSL, requiring 'at least 1 unequivocal architecturally distorted serrated crypt'. Even with this simplified criterion, as well as experience accumulated in recognizing SSL over 25 years, SSL and HP remain difficult to distinguish in some instances. This study aimed to assess observer variability and preferred criteria in diagnosing SSL among gastrointestinal pathologists.

Methods and results: We retrospectively identified 60 serrated colorectal polyps, produced uniform H&E recuts, and created whole-slide images for each case. Cases were selected to cover a spectrum of non-dysplastic serrated lesions, as confirmed via review by four pathologists who individually interpreted each as SSL, HP, or serrated polyp NOS (SP-NOS). The cases were then reviewed by nine additional pathologists. A second round of review followed after a 5-month washout period. A third round of reviews was completed after 5 additional months, at which time reviewers were provided information regarding polyp size and site. Fleiss and Cohen kappa values were calculated to determine overall inter- and intra-observer agreement. The top three criteria pathologists used to favour a diagnosis of SSL over HP included crypt distortion (13/13), polyp location (8/13) and size (4/13). There was moderate agreement among all 13 pathologists when classifying the 60 cases for rounds 1 (κ = 0.50) and 2 (κ = 0.46), and good agreement for round 3 (κ = 0.63), the round using criteria beyond those of the WHO; stratification by location showed agreement was worst for transverse polyps. Twenty-one (35%) cases were called SSL >80% of the time, and 16 (27%) cases were classified as HP >80% of the time. Agreement was moderate (κ = 0.43) for polyps measuring ≥1.0 cm and was good (κ = 0.63) for polyps measuring ≤0.4 cm. In keeping with current WHO criteria, crypt distortion was the only feature all pathologists considered useful to diagnose SSL. Overall interobserver agreement improved from moderate to good when pathologists were aware of the polyp size and site. Pathologists had the worst agreement when classifying lesions in the transverse colon or polyps ≥1.0 cm.

Conclusions: Non-histologic criteria (e.g. polyp site and size) may be necessary to accurately and reproducibly distinguish SSL from HP, if properly validated.

Phyllodes tumours of the breast present challenges in their diagnosis, classification and management. Further understanding of the molecular changes underpinning these tumours may lead to more precise classification and potential treatment options. Similar to fibroadenomas, MED12 is the most frequently mutated gene in phyllodes tumour. However, in addition, there is a spectrum of molecular alterations from benign to malignant phyllodes tumours with increasing genomic complexity, high level copy number alterations and aberrations of cancer driver genes in malignant phyllodes tumours. This review summarizes the molecular pathology of phyllodes tumours, the use of these data in developing a model of phyllodes tumour pathogenesis, and how molecular pathology might be applied to aid diagnosis and guide treatment in this rare tumour type.

Aims: Accurate determination of tumour size is critical for pT staging in pancreatic ductal adenocarcinoma (PDAC), yet gross measurement alone often underestimates the true tumour extent because of the tumour's ill-defined and infiltrative nature. This study aimed to evaluate the diagnostic and prognostic value of incorporating microscopic rectification into tumour size assessment in PDAC.

Methods and results: A total of 342 therapy-naïve pancreatoduodenectomies were analysed using a grossing protocol that includes separate sampling of anterior and posterior soft tissues via the 'orange-peeling' technique to retrieve lymph nodes and document soft tissue involvement. Peripancreatic soft tissue involvement was present in 91% of cases, and isolated microscopic foci distant from the main mass in 48%. Of the 266 tumours grossly classified as pT1/T2 (≤4 cm), 39 (14%) showed carcinoma in both anterior and posterior soft tissues, and were reclassified as pT3. This subset showed significantly worse survival (P = 0.04) and higher nodal positivity (87% versus 69%, P = 0.02) than the remaining pT2 cases, comparable to conventional pT3 tumours (86%, P = 0.77). Multivariable Cox regression adjusted for age, sex, nodal status, margin, and lymphovascular/perineural invasion confirmed the survival disadvantage of this subgroup. Reclassification yielded a more balanced distribution of T categories (pT2 66% → 52%, pT3 22% → 34%) and modestly improved prognostic discrimination (C-index: 0.592 versus 0.574).

Conclusions: This study elucidates that PDAC frequently extends beyond the visible mass ('horses out of the barn' phenomenon); peripancreatic soft tissue involvement is common, and gross size often underestimates the true tumour extent, making microscopic correction crucial. Approximately one in six pT1/T2 tumours (≤4 cm) shows carcinoma in both anterior and posterior soft tissues and behave like pT3 in outcomes and nodal status. Therefore, gross-micro rectification is essential to avoid understaging, particularly for T2 tumours. The orange-peeling protocol should classify tumours with foci in both anterior and posterior soft tissues as pT3, while other approaches may employ mapping techniques to enable microscopic reconstruction and biologically accurate staging.

Background: Clear cell adenocarcinoma (CCA) of the urinary tract is a rare genitourinary malignancy that primarily arises in the urethra and bladder. Due to its rarity, the molecular landscape of these tumours remains poorly characterized. In this large series, we aimed to molecularly characterize CCA to gain insights into its pathogenesis and identify potential targets for therapy.

Design: Formalin-fixed, paraffin-embedded tumour tissue blocks from 19 cases of CCA were subjected to molecular profiling using a targeted next-generation sequencing (NGS) panel.

Results: The most common alteration was a gain-of-function mutation in PIK3CA (74%), followed by mutations in KRAS (26%), ERBB2 (21%), SMAD4 (21%), RB1 (16%), TP53 (5%), MET (5%) and APC (5%). Thirteen tumours harboured co-mutations. Five cases showed concurrent PIK3CA and KRAS mutations, while the remaining tumours had either isolated PIK3CA alterations or co-occurring loss-of-function mutations in tumour suppressor genes, including RB1 point mutation, SMAD4 inactivation, APC truncation or TP53 inactivation. Eight patients died of disease, with a mean follow-up of 14 months (range, 3-31 months). Notably, all eight deceased patients and two of the surviving patients harboured PIK3CA mutations.

Conclusions: In summary, we identified a distinct oncogenic pathway in CCA of the urinary bladder, most commonly involving activation of the PI3K/AKT/mTOR pathway through gain-of-function mutations in PIK3CA (74%) and/or KRAS (26%). These tumours frequently harbour loss-of-function mutations in tumour suppressor genes (TP53, SMAD4, RB1 and APC) and point/missense mutations of proto-oncogenes (ERBB2 and MET). Our study also highlights potential therapeutic targets for this aggressive malignancy.

Aims: Cutaneous plasmablastic lymphoma (cPBL) is a rare and aggressive neoplasm that presents as skin nodules. Despite occurring in ~5% of PBL cases, the World Health Organization (WHO) does not distinguish primary cutaneous PBL (pcPBL) from secondary cutaneous PBL (scPBL), and their clinical differences remain poorly defined. To determine whether pcPBL represents a distinct clinical entity, we compare the clinicopathologic features, immunohistochemical profiles, and survival outcomes of pcPBL and scPBL.

Methods and results: Retrospective comparative study analysing 40 cases of cPBL (6 newly identified institutional cases and 34 cases from the literature), categorized as pcPBL (n = 25; no extracutaneous disease at diagnosis) or scPBL (n = 15; concurrent extracutaneous disease). Patients with pcPBL were older than those with scPBL (median 62 vs. 43 years; Mann-Whitney P = 0.018). Leg involvement was significantly associated with pcPBL (OR = 6.22; 95% CI: 1.21-31.9; P = 0.031). Disease-specific survival (DSS) analysis included 17 evaluable cases (pcPBL n = 11; scPBL n = 6). Median DSS was 42.0 months in pcPBL and 8.0 months in scPBL (log-rank χ² = 3.98; p = 0.046). Median follow-up (reverse Kaplan-Meier) was 20.0 months in pcPBL and not reached in scPBL. Cox models were directionally consistent but underpowered.

Conclusion: In this pooled analysis, cases presenting with primary cutaneous involvement tended to occur in older patients and more often involved the legs. However, these observations should be interpreted cautiously given small numbers and heterogeneity of the available data. Within pcPBL, EBV positivity correlated with better survival. These hypothesis-generating findings provide a basis for prospective, multi-centre studies to clarify classification, staging implications, and management of this rare lymphoma.

Aims: 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.

Methods and results: 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-related genes (FAT2 and FAT1) in 26.7% (4/15) of cases.

Conclusions: 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.

Aims: 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).

Methods and results: 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).

Conclusions: These findings suggest that prostein may be a promising immunohistochemical marker for the diagnosis of primary EMPD.

Aims: 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.

Methods and results: 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.

Conclusion: An extensive workup of LNs is not mandatory in patients with CRC. A straightforward protocol is sufficient to guide clinicians to the appropriate therapy.

Introduction: 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.

Methods: 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.

Results: 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.

Conclusions: 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.