Histopathology最新文献

Aims: Lymphangioleiomyomatosis (LAM) is a PEComa that primarily affects premenopausal women and is associated with the cystic destruction of the lung. Although smooth muscle and melanocytic markers can be helpful, histologic diagnosis of LAM remains challenging, especially in small biopsies. Glycoprotein non-metastatic melanoma protein B (GPNMB) expression has recently been identified as a highly specific and sensitive immunohistochemical marker for PEComas. Nevertheless, only a few LAM cases have been studied so far. The aim of this study was to assess the utility of GPNMB immunohistochemistry as an ancillary marker in a larger cohort of LAM samples.

Methods and results: Immunohistochemistry for GPNMB was performed on cases of LAM (N = 15), potential differential diagnostic mimics (N = 30) and normal lung tissue (N = 2). Immunohistochemistry was assessed using the H-score method; an H-score above 100 was considered 'high'. All LAM cases showed strong cytoplasmic expression, with cell membrane accentuation in some areas. In contrast, differential diagnostic mimics were either negative or only weakly positive. Normal lung parenchyma was negative for GPNMB; however, weak-to-moderate expression was seen in alveolar macrophages in both the normal and diseased lung tissues in most cases. Considering only 'high' positivity, GPNMB immunohistochemistry showed 100% sensitivity and specificity for the diagnosis of LAM in our cohort.

Conclusions: Based on its 100% sensitivity and specificity, GPNMB appears to be a highly valuable immunohistochemical marker for the diagnosis of pulmonary LAM. Besides its diagnostic value, the membrane positivity of GPNMB on LAM cells may predict a response to glembatumumab vedotin, an antibody-drug conjugate targeting GPNMB.

Aims: Immunohistochemistry (IHC) for p16 is widely used as a surrogate marker for HPV involvement in oropharyngeal squamous cell carcinoma (OPSCC), among other tumours. Confirming HPV status in OPSCC is critical, as HPV-positive tumours have better overall survival and may require de-escalated therapy compared to HPV-independent OPSCC in the future. However, discordance exists between p16 and HPV, and direct HPV testing is occasionally required to ensure an accurate diagnosis. The aim of this study is to highlight the genomic basis behind the limitation of relying on p16 IHC as a surrogate marker for HPV involvement.

Methods and results: Through a multi-institutional collaboration, this case series compiled four patients with a 'false' negative p16 staining pattern in HPV-positive non-keratinizing head and neck squamous cell carcinoma. All cases demonstrated minimal to no p16 IHC staining and were positive for HPV by direct RNA in situ hybridization. Through CDKN2A fluorescence in situ hybridization testing, three patients demonstrated a homozygous deletion of CDKN2A and one demonstrated a heterozygous deletion.

Conclusions: This series highlights the genomic basis for the 'false' negative p16 results, raising awareness of a significant diagnostic pitfall while emphasizing the importance of careful consideration of clinicopathologic parameters in the clinical workup of these cases.

Aims: The molecular characteristics and intricate relationships between tumours exhibiting overlapping features of metanephric adenoma (MA) and epithelial Wilms tumour (WT), as well as their pure forms, remain largely enigmatic.

Methods and results: Herein, we conducted a comprehensive genetic analysis of nine epithelial-predominant Wilms tumours, focusing on genetic alterations through expanded targeted sequencing and RNA sequencing (RNA-seq) methodologies. The patients ranged in age from 13 to 61 years, with a mean and median age of 43 and 48 years, respectively. The cohort included seven males and two females. These tumours exhibited immune reactivity for BRAF, WT1, and CD57, and harboured frequent TERT promoter mutations (7/9) and BRAF V600E mutations (8/9). RNA sequencing-based clustering revealed a close similarity between the tumours and MAs, suggesting that they may represent a distinct subset within the Wilms tumour spectrum. Two patients were lost to follow-up, while the remaining seven (7/7) were alive without tumour recurrences or metastases at the time of analysis, with a mean follow-up duration of 78.1 months.

Conclusions: Our research supports the notion previously described that epithelial-predominant Wilms tumours, characterized by frequent TERT promoter and BRAF V600E mutations, represent a distinct subset within the Wilms tumour spectrum. These tumours display an expression profile closely resembling that of metanephric adenomas and are associated with a favourable prognosis.

Background: Autoimmune metaplastic atrophic gastritis (AMAG) causes pulmonary trans-differentiation of the gastric mucosa and is known to increase the risk of developing gastric adenocarcinoma. AMAG-associated gastric adenocarcinomas were examined for immunoreactivity for TTF-1 and Napsin A.

Design: Eighteen AMAG-associated gastric adenocarcinomas and 36 non-AMAG-associated gastric adenocarcinomas were stained for TTF-1 (clones SP141 and 8G7G3/1) and Napsin A (clone 1P64) by immunohistochemistry. AMAG stage and staining patterns were characterized.

Results: The AMAG group was older (mean age 74 vs. 65 years) and was not significantly different with regard to sex or tumour differentiation. Zero (0%) AMAG cases were classified as early phase, four (22%) as florid phase and 14 (78%) as end stage. AMAG-associated adenocarcinomas showed more frequent TTF-1 immunoreactivity compared to control adenocarcinomas in both clone SP141 (39% vs. 11%; P = 0.04) and 8G7G3/1 (22% vs. 6%; P = 0.17). AMAG-associated adenocarcinomas showed more frequent Napsin A immunoreactivity compared to control adenocarcinomas (28% vs. 0%; P < 0.01). Immunoreactivity in AMAG-associated adenocarcinomas was patchy, ranging from 1% to 20% of tumour cells staining positive (1+ to 3+ intensity). In the AMAG cases with background gastric mucosa (n = 14), the background showed TTF-1 positive foci in seven (50%) cases (both clones) versus one (3%; clone SP141) to two (6%; clone 8G7G3/1) of 33 controls (P < 0.01) and Napsin A positive foci in five (36%) cases versus zero (0%) controls (P < 0.01). Staining in background mucosa was also patchy, involving 1%-10% of gastric glands without intestinal metaplasia.

Conclusion: TTF-1 and Napsin A immunoreactivity was present in the background gastric mucosa almost exclusively in the AMAG-associated cases. This immunoreactivity is also present in AMAG-associated adenocarcinomas more commonly than non-AMAG-associated adenocarcinomas. This knowledge may aid pathologists in avoiding the pitfall of diagnosing metastatic lung cancer, as the expression is patchy and may also be seen in atrophic background mucosa.

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.