NRASQ61R-driven atypical melanocytic tumor with blue nevus-like morphology: A case report.

NRAS Q61 mutations are driver genetic alterations associated with common melanocytic nevi. Herein, we describe a case of NRAS-mutant melanocytic tumor with a blue nevus-like morphology. A 71-year-old Japanese man presented with a 4.6-mm nodule on his back. Histopathological examination revealed a dense distribution of spindle-shaped melanocytes in the upper dermis and a sparse distribution of dendritic melanocytes in the mid-dermis. The vertical periadnexal extension reached the deep dermis at the center of the tumor. A small junctional component, hyperpigmentation, sclerotic stroma, mild nuclear atypia, and a few mitotic figures were observed. Immunohistochemical examination revealed no PRAME expression and preserved p16 expression. Diffuse RASQ61R immunoreactivity was observed in these tumor cells. Nuclear ß-catenin expression was not observed. Targeted RNA sequencing revealed two mutations, NRAS c.182A>G (Q61R) and FGFR2 c.-157A>G, but no other pathogenic alterations such as BRAF, GNAQ, GNA11, CTNNB1, PRKAR1A, or IDH1 mutations or kinase gene fusions. The histopathology fits that of compound-type blue nevus, which is called "Kamino nevus"; however, this tumor was genetically considered to be on the spectrum of conventional acquired melanocytic nevi but not on that of blue nevi. Morphologically, NRAS-driven melanocytic nevi resemble blue nevi without IDH1R132C coexistence.

Impact of the FIGO2023 staging system on endometrial cancer in Japan: differences between next-generation sequencing and simplified surrogate marker analysis.

BACKGROUND: The International Federation of Gynecology and Obstetrics (FIGO) revised the staging system of endometrial cancer in 2023. In this study, we aimed to determine stage transitions and prognosis of endometrial cancer using FIGO2008, FIGO2023 without molecular classification (FIGO2023), and FIGO2023 with molecular classification (FIGO2023m). METHODS: Eighty-three patients diagnosed with endometrial cancer who underwent surgery and next-generation sequencing (NGS) molecular profiling as part of the Project HOPE cohort study were enrolled. Each case was staged according to the FIGO2008 and FIGO2023 criteria, and we evaluated changes in stage and disease-specific survival (DSS). Molecular classification based on NGS was performed to evaluate FIGO2023m, and the concordance rate with immunohistochemical marker analysis was assessed. RESULTS: Transitioning from FIGO2008 to FIGO2023 resulted in the restaging of 18 cases. Conversely, transitioning from FIGO2008 to FIGO2023m led to the restaging of 15 cases. The concordance rate between FIGO2023 and FIGO2023m staging was 96.4%. With FIGO2023m, the 5-year DSS was 97.6% for stage I (95% confidence interval [CI] 83.9-99.7), 83.3% for stage II (95% CI 56.8-94.3), 100% for stage III (95% CI NA), and 25.0% for stage IV (95% CI 0.9-66.5). Discrepancies in disease staging due to discordance between simplified surrogate marker analysis and NGS evaluation occurred in two cases. CONCLUSIONS: The revision of the staging system from FIGO2008 to FIGO2023 and FIGO2023m resulted in the restaging of several cases, with significant changes between stages I and II.

Loss of p16 Immunoexpression and Deletions of CDKN2A in the Progression of Extramammary Paget Disease: An Immunohistochemical and Genetic Study of 24 Invasive/Metastatic Cases.

ABSTRACT: Information regarding the genetic alterations in extramammary Paget disease (EMPD) is scarce. This study investigated the significance of CDKN2A and MTAP alterations in EMPD progression using immunohistochemistry and panel DNA sequencing. In total, 24 invasive/metastatic EMPD cases were included in this study. The immunoexpression of p16 and MTAP in the primary in situ, primary invasive, and metastatic tumor components was evaluated. Panel DNA sequencing was performed for metastatic tumor components in 5 of the 24 cases. Immunoexpression of p16 in the in situ tumor component was at least partially preserved in all 19 tested cases (100%). By contrast, the invasive tumor component was diffusely or partially lost in 18 (81.8%) of 22 tested cases. Regarding the foci of lymph node metastasis, 13 (81.2%) of the 16 patients showed a significant loss of p16 expression. Loss of MTAP immunoexpression was observed less frequently compared with the loss of p16 expression. CDKN2A homozygous deletions were confirmed in all 5 tested cases by sequencing, whereas MTAP deletions were detected in only 2 cases. In conclusion, p16 expression loss and CDKN2A deletions can be frequently seen in invasive/metastatic cases of EMPD.

Recurrent GATA3 P409Afs*99 Frameshift Extension Mutations in Sweat-gland Carcinoma With Neuroendocrine Differentiation.

Sweat-gland carcinoma with neuroendocrine differentiation (SCAND) was recently proposed as a new cutaneous adnexal neoplasm with neuroendocrine differentiation; however, its genetics are not well known. Herein, we performed clinicopathologic and genetic analyses of 13 SCAND cases and 5 control cases of endocrine mucin-producing sweat gland carcinoma (EMPSGC). The SCAND group included 11 males and 2 females with a median age of 68 years (range, 50 to 80 y). All SCAND lesions occurred in the ventral trunk or genital area. Of the 13 SCAND cases, 9 and 5 exhibited lymph node and distant metastases, respectively. Three (23.1%) patients with SCAND died of the disease. In contrast, neither metastasis nor mortality was confirmed in the EMPSGC cases. Immunoexpression of the androgen receptor, c-Myb, and MUC2 was limited in SCAND, whereas EMPSGC frequently expressed these immunomarkers. GATA3 P409Afs*99 extension mutations were detected in 7 (53.8%) of the 13 SCAND cases, using Sanger or panel sequencing. All 7 SCAND cases with GATA3 mutations were located in the genital, inguinal, or lower abdominal regions, whereas 5 of the other 6 SCAND cases were located in the anterior upper to mid-trunk. No GATA3 mutations were detected in the EMPSGC cases (0/5, 0%). These clinicopathologic and genetic findings support SCAND as a tumor entity distinguishable from EMPSGC. In addition, the characteristic frameshift extension mutations in GATA3 contribute to the establishment of the tumor-type concept of SCAND.

Apocrine carcinoma with marked sebocyte-like cytological features: A report of two cases.

Apocrine carcinoma cases with sebaceous differentiation have not been reported and can be misdiagnosed as sebaceous carcinoma. We present two cases of apocrine carcinoma with marked sebocyte-like cytological features. Tumors were observed in the left axilla of a 68-year-old man (Case 1) and the right axilla of a 72-year-old man (Case 2). Both patients presented with multiple lymph node metastases. Histopathology revealed densely distributed solid nests of tumor cells containing foamy cytoplasm and enlarged round nuclei with prominent nucleoli. The tumor cells diffusely expressed adipophilin, PRAME (cytoplasmic pattern), androgen receptor, BerEP4, and GCDFP15 but did not express p63 in both cases. PIK3CA E726K and H1047R mutations were detected in Cases 1 and 2, respectively. Tumor location in the axilla, the presence of eosinophilic granular cytoplasm, prominent nucleoli, and PIK3CA mutations, immunoreactivity for BerEP4 and GCDFP15, and lack of p63 immunoexpression findings matched apocrine carcinoma characteristics, but not sebaceous carcinoma. Thus, apocrine carcinoma can demonstrate intracytoplasmic lipid accumulation and rarely exhibit sebocyte-like cytological features. Apocrine carcinoma should be distinguished from sebaceous carcinoma due to the former's higher metastatic potential and lack of association with Muir-Torre syndrome.

A Case of Superficial Papular Neuroma: A Rare Neural Neoplasm.

ABSTRACT: A case of 67-year-old male patient with superficial papular neuroma (SPN) on the occiput is reported. This is the second report of SPN and the first with clinical images. Histologically, in the superficial dermis and periadnexa, the specimen exhibits a nodule of bland spindle cells with an S-shaped and spindle nucleus, surrounded by eosinophilic collagen fibers and scattered mast cells, which forms focally peripheral nerve-like structures. Lichen simplex chronicus-like changes are observed. Immunostaining result revealed that the tumor cells are positive for S-100, neurofilament, collagen IV, and CD34 but negative for Melan A, epithelial membrane antigen, and glial fibrillary acidic protein. Histological differential diagnosis includes prurigo nodularis, neurotized nevus, benign peripheral nerve sheath tumor, such as neurofibroma or schwannoma, a type of neuroma, such as traumatic neuroma, mucosal neuroma, and palisaded encapsulated neuroma, or a type of neural hamartoma. A careful histological investigation will enable dermatopathologists to make a diagnosis of SPN.

BHLHE41/DEC2 Expression Induces Autophagic Cell Death in Lung Cancer Cells and Is Associated with Favorable Prognosis for Patients with Lung Adenocarcinoma.

Lung cancer constitutes a threat to human health. BHLHE41 plays important roles in circadian rhythm and cell differentiation as a negative regulatory transcription factor. This study investigates the role of BHLHE41 in lung cancer progression. We analyzed BHLHE41 function via in silico and immunohistochemical studies of 177 surgically resected non-small cell lung cancer (NSCLC) samples and 18 early lung squamous cell carcinoma (LUSC) cases. We also examined doxycycline (DOX)-inducible BHLHE41-expressing A549 and H2030 adenocarcinoma cells. BHLHE41 expression was higher in normal lung than in lung adenocarcinoma (LUAD) tissues and was associated with better prognosis for the overall survival (OS) of patients. In total, 15 of 132 LUAD tissues expressed BHLHE41 in normal lung epithelial cells. Staining was mainly observed in adenocarcinoma in situ and the lepidic growth part of invasive cancer tissue. BHLHE41 expression constituted a favorable prognostic factor for OS (p = 0.049) and cause-specific survival (p = 0.042) in patients with LUAD. During early LUSC, 7 of 18 cases expressed BHLHE41, and this expression was inversely correlated with the depth of invasion. DOX suppressed cell proliferation and increased the autophagy protein LC3, while chloroquine enhanced LC3 accumulation and suppressed cell death. In a xenograft model, DOX suppressed tumor growth. Our results indicate that BHLHE41 expression prevents early lung tumor malignant progression by inducing autophagic cell death in NSCLC.

Histopathological variation in the demyelinating sentinel lesion of primary central nervous system lymphoma.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is one of the least common malignant brain tumors. It is usually diagnosed initially as diffuse large B cell lymphoma (DLBCL). In rare cases, however, a demyelinating lesion referred to as a "sentinel lesion" precedes the actual diagnosis, which usually depicts two distinct patterns of inflammatory cells during histological analysis. This case report describes a unique histological finding and describes the recognized variations in sentinel lesion histopathology. CASE DESCRIPTION: A 78-year-old female patient was found to have multiple white matter lesions of various degrees of enhancement on post-contrast T1-weighted magnetic resonance imaging. A stereotactic biopsy of a heterogeneous lesion in the left occipital lobe was performed, which revealed demyelination along with lymphocytic infiltration, reactive astrocytosis, abundant T cells, and foamy macrophages. There was no evidence of monoclonality, rapid regression of all lesions occurred, and the patient was thus treated for tumefactive demyelination. Three months later, all of the residual lesions had enlarged and were homogeneously enhancing. An endoscopic-guided biopsy of the right periventricular lesion showed diffuse atypical lymphoid cells. CONCLUSION: The sentinel lesion of PCNSL expresses a variable histological pattern of inflammatory cells. This case demonstrates a unique and rare picture of mixed perivascular and parenchymal infiltration of inflammatory cells, highlighting the importance of repeated biopsies and/or radiological examinations to obtain an accurate diagnosis.

Breast cancer with an intraductal component that was proven genetically to be metastasis of contralateral breast cancer: a case report.

BACKGROUND: When diagnosing patients with bilateral breast cancer, it is challenging to determine the relationship between multiple breast cancer lesions at the individual patient level with certainty. CASE PRESENTATION: A 35-year-old Japanese woman was diagnosed with a left breast cancer. She was previously diagnosed with right pT3N3M0 stage IIIC breast cancer and underwent chemotherapy with targeted therapy, radiotherapy, and endocrine therapy as adjuvant treatment after mastectomy and axillary lymph node dissection. Approximately 2 years after the first surgery, her left breast cancer was preoperatively diagnosed as a contralateral primary breast cancer, and left mastectomy and axillary lymph node dissection were performed. Histopathologically, the tumor was determined to be invasive ductal carcinoma accompanied with several intraductal components. After a second surgery, mutation analysis of her bilateral breast cancer was performed in a clinical study, which revealed that her metachronous bilateral breast tumors had the same GATA3 and CSMD1 mutations. Thus, mutation analysis strongly supported her latter left breast cancer being a metastatic lesion from the former right breast cancer. Some difficulties in diagnosing bilateral breast cancer exist when determining whether they are double primary cancers or represent contralateral breast metastasis. The existence of intraductal components is a critical piece of information for suspecting primary lesions. However, this case demonstrated that metastatic contralateral breast lesions can have intraductal components. CONCLUSION: Herein we report a genetically proven contralateral breast metastasis with some intraductal components.

A tailored next-generation sequencing panel identified distinct subtypes of wildtype IDH and TERT promoter glioblastomas.

Central nervous system tumors are classified based on an integrated diagnosis combining histology and molecular characteristics, including IDH1/2 and H3-K27M mutations, as well as 1p/19q codeletion. Here, we aimed to develop and assess the feasibility of a glioma-tailored 48-gene next-generation sequencing (NGS) panel for integrated glioma diagnosis. We designed a glioma-tailored 48-gene NGS panel for detecting 1p/19q codeletion and mutations in IDH1/2, TP53, PTEN, PDGFRA, NF1, RB1, CDKN2A/B, CDK4, and the TERT promoter (TERTp). We analyzed 106 glioma patients (grade II: 19 cases, grade III: 23 cases, grade IV: 64 cases) using this system. The 1p/19q codeletion was detected precisely in oligodendroglial tumors using our NGS panel. In a cohort of 64 grade Ⅳ gliomas, we identified 56 IDH-wildtype glioblastomas. Within these IDH-wildtype glioblastomas, 33 samples (58.9%) showed a mutation in TERTp. Notably, PDGFRA mutations and their amplification were more commonly seen in TERTp-wildtype glioblastomas (43%) than in TERTp-mutant glioblastomas (6%) (P = .001). Hierarchical molecular classification of IDH-wildtype glioblastomas revealed 3 distinct groups of IDH-wildtype glioblastomas. One major cluster was characterized by mutations in PDGFRA, amplification of CDK4 and PDGFRA, homozygous deletion of CDKN2A/B, and absence of TERTp mutations. This cluster was significantly associated with older age (P = .021), higher Ki-67 score (P = .007), poor prognosis (P = .012), and a periventricular tumor location. We report the development of a glioma-tailored NGS panel for detecting 1p/19q codeletion and driver gene mutations on a single platform. Our panel identified distinct subtypes of IDH- and TERTp-wildtype glioblastomas with frequent PDGFRA alterations.

Next-generation sequencing analysis of endometrial screening liquid-based cytology specimens: a comparative study to tissue specimens.

BACKGROUND: Liquid-based cytology (LBC) is now a widely used method for cytologic screening and cancer diagnosis. Since the cells are fixed with alcohol-based fixatives, and the specimens are stored in a liquid condition, LBC specimens are suitable for genetic analyses. METHODS: Here, we established a small cancer gene panel, including 60 genes and 17 microsatellite markers for next-generation sequencing, and applied to residual LBC specimens obtained by endometrial cancer screening to compare with corresponding formalin-fixed paraffin-embedded (FFPE) tissues. RESULTS: A total of 49 FFPE and LBC specimens (n = 24) were analyzed, revealing characteristic mutations for endometrial cancer, including PTEN, CTNNB1, PIK3CA, and PIK3R1 mutations. Eight cases had higher scores for both tumor mutation burden (TMB) and microsatellite instability (MSI), which agree with defective mismatch repair (MMR) protein expression. Paired endometrial LBC, and biopsied and/or resected FFPE tissues from 7 cases, presented almost identical mutations, TMB, and MSI profiles in all cases. CONCLUSION: These findings demonstrate that our ad hoc cancer gene panel enabled the detection of therapeutically actionable gene mutations in endometrial LBC and FFPE specimens. Endometrial cancer LBC specimens offer an alternative and affordable source of molecular testing materials.

A sellar neuroblastoma showing rapid growth and causing syndrome of inappropriate secretion of antidiuretic hormone: A case report.

BACKGROUND: Sellar neuroblastoma is a very rare entity. We report a rare case of arginine vasopressin (AVP)- producing sellar neuroblastoma presumed to have originated from the lower part of sellar turcica, which grew very rapidly. CASE DESCRIPTION: A 33-year-old woman was found to have a sellar lesion with a diameter of 18 mm invading into the bilateral cavernous sinus on magnetic resonance imaging (MRI) performed for dizziness. Six years later, when she visited the clinic due to bilateral visual disturbance, MRI showed a rapid growth of the tumor, with a maximal diameter of 56 mm at the current state, strongly compressing the optic nerve and chiasm. Transsphenoidal decompression of the optic chiasm revealed an intact pituitary gland on the top of the tumor. The tumor was composed of neoplastic cells that were immunohistochemically positive for neuronal markers and arginine vasopressin (AVP), but negative for all anterior pituitary hormones, glial fibrillary acidic protein, or thyroid transcription factor-1; these findings were suggestive of sellar neuroblastoma. She underwent 50-Gy radiation therapy, which has controlled the growth for the past 3 years. CONCLUSION: Awareness of rare sellar neuroblastomas will allow the accumulation of clinicopathologic information that may facilitate the understanding of their origin, clinical features, neuroimaging characteristics, and pertinent adjuvant treatment.

Peroxiredoxin 4 promotes embryonal hepatoblastoma cell migration but induces fetal cell differentiation.

Hepatoblastoma (HB) is the leading primary hepatic malignancy in children and likely emerges due to failure of hepatic progenitor cells to properly differentiate. The peroxiredoxin (PRDX) family is frequently linked to cancer. In our previous study, we demonstrated that expression of the only secreted family member, PRDX4, was correlated with hepatocellular carcinoma. The aim of this new study was to investigate PRDX4's role in HB. We collected 87 HB specimens and performed PRDX4 immunohistochemistry staining. Clinical analysis was conducted and the effect of PRDX4 overexpression on two HB cell lines (Huh6 and HepG2) was also examined. Clinical data revealed elevated PRDX4 expression in embryonal component was correlated with advanced stage (IV) and metastasis. In comparison, increased PRDX4 expression in fetal component was associated with well differentiation. In vitro experiments showed PRDX4 overexpression enhanced migration in embryonal-like HB cells (Huh6), which was accompanied by epithelial-mesenchymal transition (EMT). By contrast, PRDX4 overexpression inhibited proliferation, decreased stemness markers, and increased hepatic markers in fetal-like HB cells (HepG2), which indicated induction of tumor cell differentiation. In conclusion, PRDX4 promotes embryonal hepatoblastoma cell migration but induces fetal cell differentiation. It can be adopted as an important marker for HB prognosis and a potential treatment target.

Comparison of HER2 Status Before and After Trastuzumab-based Chemotherapy in Patients With Advanced Gastric Cancer.

BACKGROUND/AIM: The aim of the present study was to compare human epidermal growth factor receptor 2 (HER2) expression before and after trastuzumab-based chemotherapy in patients with advanced HER2-positive gastric cancer. MATERIALS AND METHODS: We assessed HER2 expression using immunohistochemistry and/or fluorescence in situ hybridization in pre-treatment biopsied specimens and post-treatment resected specimens obtained from seven patients with advanced HER2-positive gastric cancer receiving trastuzumab-based chemotherapy. RESULTS: Four patients maintained the HER2-positive status and three patients had a change in HER2 expression from positive to negative. In patients showing the loss of HER2 expression after treatments, HER2-positive tumor cells with a dominant histological type disappeared, and HER2-negative tumor cells with another dominant histological type were identified. CONCLUSION: HER2 expression can change after trastuzumab-based chemotherapy in patients with advanced HER2-positive gastric cancer. Continuous monitoring of HER2 expression after treatments may be utilized to determine whether the continued use of trastuzumab is advisable.

Predicted Prognosis of Patients with Pancreatic Cancer by Machine Learning.

PURPOSE: Pancreatic cancer remains a disease of high mortality despite advanced diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic cancers. MUC1 and MUC4 expression are related to the aggressive behavior of human neoplasms and a poor patient outcome. In contrast, MUC2 is a tumor suppressor, and we have previously reported that MUC2 is a favorable prognostic factor in pancreatic neoplasia. This study investigates whether the methylation status of three mucin genes from postoperative tissue specimens from patients with pancreatic neoplasms could serve as a predictive biomarker for outcome after surgery. EXPERIMENTAL DESIGN: We evaluated the methylation status of MUC1, MUC2, and MUC4 promoter regions in pancreatic tissue samples from 191 patients with various pancreatic lesions using methylation-specific electrophoresis. Then, integrating these results and clinicopathologic features, we used support vector machine-, neural network-, and multinomial-based methods to develop a prognostic classifier. RESULTS: Significant differences were identified between the positive- and negative-prediction classifiers of patients in 5-year overall survival (OS) in the cross-validation test. Multivariate analysis revealed that these prognostic classifiers were independent prognostic factors analyzed by not only neoplastic tissues but also nonneoplastic tissues. These classifiers had higher predictive accuracy for OS than tumor size, lymph node metastasis, distant metastasis, and age and can complement the prognostic value of the TNM staging system. CONCLUSIONS: Analysis of epigenetic changes in mucin genes may be of diagnostic utility and one of the prognostic predictors for patients with pancreatic ductal adenocarcinoma.

Granulomatous/sarcoid-like reactions in the setting of programmed cell death-1 inhibition: a potential mimic of disease recurrence.

Nivolumab and pembrolizumab are humanized IgG4 monoclonal antibodies against programmed cell death 1 (PD-1). Although these agents are effective in treating advanced melanoma, non-small-cell lung carcinoma, and other types of cancers, various adverse events have been reported. Cutaneous adverse events are particularly prevalent and, while granulomatous/sarcoid-like reactions are uncommon, they are increasingly recognized as immune-related adverse events associated with immune checkpoint inhibitors. Herein, we report two cases of granulomatous/sarcoid-like reaction with foreign material, mimicking metastatic malignancy after PD-1 inhibitor treatment. Clinicians should be aware of the existence of cutaneous lesions and perform biopsy if needed to prevent misdiagnosis and unnecessary adjustments to immunotherapy.

Prominent dermal Langerhans cells in an Omenn syndrome patient with a novel mutation in the IL2RG gene.

Prominent dermal infiltration by Langerhans cells (LC) is a rare finding in patients with Omenn syndrome (OS). Here, we report the case study of a 7-month-old boy with OS and with prominent dermal infiltration by LC, which is a rare histological manifestation of the skin. Striking erythroderma appeared in the patient 2 weeks after birth. We also noted alopecia, lymphadenopathy, hepatosplenomegaly, eosinophilia and an elevated serum immunoglobulin E level with hypogammaglobulinemia. Peripheral blood flow cytometry showed the Tlow NK+ B+ immunophenotype and genetic analysis, a novel mutation in the IL2RG gene (c.337_339delTCT, p.Ser113del). The final diagnosis was that of OS. He responded well to an allograft umbilical cord blood transplantation that was performed when the patient was 8 months of age. We speculate that the LC accumulated in the dermis will eventually migrate to the regional lymph node, then stimulate autoreactive T cells by overpresenting antigens, thus causing OS-specific skin symptoms.