Annals of Diagnostic Pathology最新文献

Composite lymphoma, defined as two or more distinct well-defined entities involving the same anatomic site, is rare. Here we report a 79-year-old woman with composite mantle cell lymphoma (MCL) and lymphoplasmacytic lymphoma (LPL) involving bone marrow at the time of initial diagnosis. The patient presented with splenomegaly and lymphadenopathy and laboratory studies showed an elevated serum IgM level and IgM kappa paraprotein. Bone marrow evaluation showed concurrent involvement by MCL and LPL, supported by immunophenotypic studies that revealed two distinct aberrant B-cell populations. Next-generation sequencing analysis identified concurrent MYD88 and CXCR4 mutations and fluorescence in-situ hybridization showed CCND1 translocation, supporting the diagnosis of concomitant MCL and LPL. In conclusion, composite lymphoma can present in the bone marrow. The use of ancillary studies was essential in reaching the diagnosis in this case, as the results excluded the possibility of MCL lymphoma with plasmacytic differentiation, as well as other CD5- and CD10-negative small B-cell lymphomas.

Immunohistochemical staining with immunoglobulins and complements may aid the diagnosis of patients whose clinical and histological findings are consistent with autoimmune bullous dermatoses (AIBD). We aimed to investigate the diagnostic value of immunohistochemical markers in lesional biopsy and perilesional frozen samples in AIBD. We included 136 cases from whom lesional biopsies and perilesional samples for direct immunofluorescence (DIF) examination were collected with a preliminary diagnosis of AIBD between January 2019 and January 2023. All diagnoses were reconfirmed by evaluating the clinical, histopathological, and serological findings and DIF results (C3, IgG, IgA, or IgM positivity compatible with the clinical diagnosis) altogether, although DIF results were considered a priority. After confirming the diagnoses, the samples were categorized as AIBD or the others. The perilesional tissues obtained for DIF simultaneously with skin biopsy and stored at −80 °C were thawed, and FFPE tissues were prepared. We performed immunohistochemical staining (C4d, C3d, IgG, and IgG4) on FFPE tissues of both lesional and perilesional samples. Strong, linear, or granular staining patterns at the dermoepidermal junction or the intraepidermal blistering space were considered positive in line with the diagnosis of the case. Cases other than AIBD were used as negative control tissues to assess the specificity of immunohistochemical markers. Of the 136 cases, 52 were diagnosed with AIBD. In lesional samples, the sensitivity of C4d, C3d, IgG, and IgG4 was 80.6 %, 69.4 %, 75 %, and 5.7 % with corresponding specificity of 100 %, 98.7 %, 89.6 %, and 97.4 %, respectively in pemphigoid diseases compared to a sensitivity of 18.2 %, 9.1 %, 70 %, and 9.1 % and specificity of 98.7 %, 100 %, 89.6 %, and 97.4 %, respectively in pemphigus diseases. In frozen samples, we detected expression in a limited number of cases. The sensitivity of C4d, C3d, IgG, and IgG4 was 8.7 %, 2.2 %, 19.4 %, and 2.2 %, with corresponding specificity of 100 %, 100 %, 98.5 %, and 98.6, respectively. There was a none to slight concordance rate between the IHC results of lesional tissues and perilesional frozen samples. Kappa coefficients for C4d, C3d, IgG, and IgG4 were 0.120 (P = 0.029), 0.111 (P = 0.050), 0.203 (P = 0.003), and - 0.15 (P = 0.846), respectively. Immunohistochemical staining with C4d, C3d, IgG, and IgG4 on biopsy samples collected from lesions may guide the diagnosis of AIBD, thereby eliminating the need for an additional biopsy and accelerating the diagnostic process.

Mucosal melanomas often require a detailed differential diagnosis and immunochemical study due to their different morphology and pattern characteristics. The tumors may also show fibroblastic, schwannian, smooth muscle, rhabdomyosarcomatous, gangliocytic, epithelial, and neuroendocrine differentiation. All these features can lead to serious diagnostic difficulties. The study aimed to determine the frequency of neuroendocrine differentiation in melanomas of the sinonasal and oral regions and to assess whether there is any relationship between neuroendocrine differentiation and clinical, histopathological, and other immunophenotypic features of this neoplasm. The study included 18 cases diagnosed with oral or sinonasal malignant melanoma. Neuroendocrine differentiation was determined by immunohistochemistry using synaptophysin, chromogranin, CD56, and INSM-1. A cut-off defining neuroendocrine differentiation in malignant melanomas has not been established in the literature. Because of this, any degree of neuroendocrine marker expression was considered as indicative of “neuroendocrine differentiation” without setting any cut-off. Neuroendocrine differentiation was observed in 13 of 18 cases (72.2 %) when a single positive neuroendocrine marker was considered sufficient. The number of cases with at least two positive neuroendocrine markers was 8/18 (44.4 %). Synaptophysin, chromogranin A, CD56, and INSM1 were positive in 33.3 %, 13.3 %, 56.2 %, and 47.1 % of cases, respectively. The results of our study suggest that neuroendocrine differentiation is not uncommon in oral and sinonasal melanomas. Knowing that malignant melanomas can show neuroendocrine differentiation will prevent diagnostic pitfalls.

Papillary microcarcinomas (PMCs) are papillary carcinomas ≤1 cm in size, with an increasing incidence. Although generally indolent, some cases exhibit aggressive behavior. Recently, active surveillance has been recommended to avoid surgical treatment. Identifying molecular changes that predict aggressiveness in PMCs has gained importance, but studies are limited. We aimed to demonstrate TERT expression and BRAF V600E positivity immunohistochemically in PMCs and correlate them with histomorphological features, subtypes, and clinicopathological findings. We included 95 PMC cases diagnosed between 2010 and 2019 at the Department of Pathology, Faculty of Medicine, XXX University. We investigated TERT expression using RT-PCR. We evaluated BRAF V600E mutation immunohistochemically. We evaluated the relationship between genetic, histomorphological, and clinicopathological findings. In patients with multifocality and those with a tumor size ≥0.5 cm, the frequency of lymph node metastasis was significantly higher. A positive correlation was shown between BRAF V600E positivity and lymph node metastasis, lymphovascular invasion, advanced disease stage, and classical subtype by univariate analyses. We detected TERT expression in 18 of 95 patients (7.8 %). No relationship could be detected between TERT expression alone or combined with BRAF positivity and clinicopathological features. Although TERT mutations are associated with aggressiveness in thyroid cancers, this association was absent in PMCs. The presence of TERT expression was demonstrated in some cases. However, TERT expression could not be associated with clinicopathological findings, which is consistent with the literature suggesting that TERT plays a role in advanced stages of carcinogenesis.

Small/flat urothelial lesions are challenging and currently available ancillary immunohistochemistry testing often cannot reliably distinguish between reactive lesions and urothelial carcinoma (UCa). UCa has a characteristic molecular profile, but small/flat urothelial lesions are typically considered too small to perform next generation sequencing (NGS). Herein, we present our institution's experience with utilizing comprehensive DNA-based NGS to evaluate small/flat urothelial lesions (n = 13 cases). NGS was ordered on 7/13 small/flat urothelial lesions initially diagnosed as urothelial atypia, ordered by the pathologist to aid in further diagnosis; the remaining 6/13 cases were diagnosed as urothelial carcinoma in situ (uCIS), ordered by a treating oncologist. The test was considered as adding value if it yielded pathogenic or likely pathogenic alterations previously associated with urothelial carcinoma in the literature. Macroscopic dissection was determined necessary in all cases and obtained either by scraping (7), punch biopsy (5) or scooping (1) of paraffin tissue blocks. In 4/13 cases, tumor content was considered low (<25%); in 2/13 cases, DNA quantity yield was considered below optimal (<250 ng); all cases met required DNA quantity for testing (>50 ng). Mean target coverage ranged: 498 to 985 (optimal >500 reads). NGS testing identified mutations compatible with urothelial carcinoma in all 7 cases initially diagnosed as atypical; and in one case, the tumor recurred as a lung metastasis. All 6 uCIS had NGS testing results concordant with UCa. In conclusion, despite small sample quantity with low tumor content and DNA concentration yield, NGS testing with appropriate methodology can be considered in the setting of small/flat urothelial lesions to aid in diagnosis or per oncologist request and yield interpretable results.

In summary, the study's investigation of KMT2C and TSC2 variants in ACD-RCC marks a significant advancement in comprehending this distinct kidney tumor. By illuminating the molecular landscape of ACD-RCC, the research sets the stage for future studies aimed at revealing the complex mechanisms driving tumor development and progression. This understanding could eventually lead to more effective management and treatment strategies for renal cancer patients.

In 2020, acquired cystic disease-associated renal cell carcinomas (ACD-RCCs) were reported to harbor KMT2C and TSC2 variants: however, their carcinogenic implication has not yet been reported. This study aimed to explore the variant features of KMT2C and TSC2 in ACD-RCC and their implication in ACD-RCC tumorigenesis. Eleven ACD-RCCs, 10 ACD-RCC-like cysts, and 18 background kidneys were retrieved. The background kidneys consisted of atrophic thyroid follicle-like tubules. They included four with clustered cysts, two with eosinophilic changes, and one each with clear cell changes and sieve-like changes in the renal tubules. First, DNA-targeted sequencing of KMT2C and TSC2 whole exons was performed on eight ACD-RCC samples. Subsequently, a custom DNA panel was designed to include the recurrent KMT2C and TSC2 variants based on the sequencing results. Second, DNA-targeted sequencing was performed on the remaining samples using a custom panel targeting the recurrent variants. Additionally, immunohistochemistry was performed for KMTC, H3K4me1, H3K4me3, TSC2, and GPNMB on the ACD-RCCs. Six of the 11 ACD-RCC cases harbored KMT2C and TSC2 variants, including nine likely pathogenic variants. In contrast to ACD-RCC, 1 of the 9 ACD-RCC-like cysts harbored both variants. Immunohistochemical analysis did not support the loss of function in ACD-RCCs harboring KMT2C and TSC2 variants. KMT2C and TSC2 variant frequencies were higher in ACD-RCC than in other renal cell carcinomas. However, KMT2C and TSC2 are unlikely to be the primary drivers of ACD-RCC development.

The most common type of melanoma is cutaneous melanoma (CM). The predominant mutational signature is that of ultraviolet radiation (UVR) exposure. The Cancer Genome Atlas (TCGA) molecular classification includes four major subtypes of CM based on common genetic alterations involving the following genes: BRAF, NRAS, and NF1, with a small fraction being “triple” wild-type. The two main signaling pathway abnormalities in CM are the mitogen-activated protein kinase (MAPK) pathway and the phosphoinositol-3-kinase (PI3K) pathway. Other less common types include mucosal melanomas (MM) and uveal melanoma (UM), which have a significantly different genomic landscape. Although few studies reported rare cases with HPV-positive (HPV+) melanoma, the clinicopathological and molecular characteristic of this entity has not been well-described. Among the 2084 melanoma cases queried at our institution, we identified seven patients diagnosed with HPV+ melanoma (prevalence 0.03 %), including five instances of CM and two of MM. The majority of cases were positive for HPV16 (n = 6). Most of the patients were elderly and with advanced disease (n = 6), although this finding may be attributed to the relative frequency of our institution testing advanced-stage tumors. Histologically, most cases showed high degree of pleomorphism and high mitotic count (5 or more mitoses/mm²) (n = 6). UVR signature was present in the CM, but not in the MM cases. Alterations in either MAPK and/or PI3K pathways were detected in the majority of cases (n = 6). The most common genetic abnormalities detected in this study occurred in the TERT promoter (TERTp) (n = 5), a finding that has been reported to be associated with aggressive disease. Our data shows that while HPV+ melanoma is rare, identifying this disease entity could help guide therapy given the demonstrated genomic alterations.