S100A8 and S100A9 are associated with endometrial shedding during menstruation.

Matrix metalloproteinases (MMPs) and their major source, endometrial stromal cells (ESCs), play important roles in menstruation. However, other mechanisms in endometrial shedding may be unexplored. This study focused on four proteins: S100A8 and S100A9 (alarmins) are binding partners and induce MMPs, MMP-3 cycle-dependently plays a key role in the proteolytic cascade, and CD147, which has S100A9 as its ligand, induces MMPs. Immunostaining for these proteins was performed on 118 resected specimens. The percentage and location of each positive reaction in ESCs were measured and compared using Image J. The influence of leukocytes on S100A8 or S100A9 immunopositivity was also examined. From the premenstrual phase, S100A8 and MMP-3 began to have overlapping expressions in ESCs of the superficial layer, and ESC detachment was found within these sites. S100A9 was expressed from the late secretory phase and CD147 already from earlier. Later, the expression sites of S100A9 and CD147 included those of S100A8. Before menstruation, S100A8 or S100A9 expression was not affected by leukocytes. These results suggest that the local formation of S100A8/S100A9 complex, which occurs specifically in ESCs upon progesterone withdrawal, induces the local expression of MMP-3 and serves as a switch to the lysis phase.

A symptomatic intercalated duct lesion of the parotid gland: a case report with immunohistochemical and genetic analyses.

Intercalated duct lesions (IDLs) are usually asymptomatic. We report a case of IDL, in which a palpable mass formed. The patient was a 45-year-old Japanese male, who noticed a mass in the left parotid region. The nodular lesion was well-circumscribed, but did not have a fibrous capsule or exhibit infiltrative growth. It contained a small cystic space and consisted of basaloid cells arranged in a cribriform pattern and inner ductal cells. It had some solid areas of nest-like proliferation displaying mild cellular atypia. Immunohistochemically, the luminal cells were positive for cytokeratin (CK)7 and epithelial membrane antigen, and the abluminal cells were positive for CK5/6, p63, and DOG1. S-100 protein-positive stromal cells were also seen. The lesion's cells were all positive for SOX10, and the nuclei of some basaloid cells were positive for ß-catenin. The Ki-67 labeling index was 3.8%. The ductal cells contained diastase-digestion-resistant, Periodic acid Schiff-positive zymogen granules. Genetically, the lesion harbored a missense mutation in the CTNNB1 gene. We diagnosed the lesion as an IDL. As IDLs are usually small non-neoplastic lesions, symptomatic cases are rare. Based on its common immunohistochemical and genetic features, IDL may be a precursor of basal cell adenoma/adenocarcinoma, such as intercalated duct adenoma.

Epithelial-myoepithelial carcinoma ex-pleomorphic adenoma of the parotid gland: report of a rare case with immunohistochemical and genetic analyses.

Epithelial-myoepithelial carcinoma (EMCa) is a rare low-grade salivary malignancy. It is rare for EMCa to occur as the carcinomatous component of carcinoma ex-pleomorphic adenoma (PA). We examined one additional case of EMCa ex-PA, immunohistochemically and genetically. The patient was an 83-year-old female, who suffered from swelling of the right parotid region. Histologically, the tumor contained a hyalinized nodule, which displayed elastosis. The main tumor exhibited a bi-layered structure, involving inner ductal cells and clear outer myoepithelial cells. Immunostaining indicated that the inner cells were positive for epithelial membrane antigen, whereas the outer cells were positive for p40. On the genetic level, the carcinoma harbored no HRAS gene mutations, whereas fluorescence in situ hybridization (FISH) of the Pleomorphic Adenoma Gene1 showed splitting signals in the carcinomatous component. We diagnosed this case as EMCa ex-PA. It is necessary to differentiate EMCa ex-PA from myoepithelial carcinoma and clear cell carcinoma, and FISH is useful for such purposes.

Basaloid squamous cell carcinoma with adenoid cystic-like features of the head and neck region: A report of two cases.

The histology of basaloid squamous cell carcinoma (BSCC) can resemble that of adenoid cystic carcinoma (AdCC). Herein, we report two cases of BSCC with adenoid cystic-like features (BSCC-AdC). We collected cases of AdCC and BSCC of the head and neck region, extracted two cases with unusual histology, and reexamined them histologically and immunohistochemically. Case 1 involved an 81-year-old Japanese male, who had an elastic-hard mass on the left side of his tongue, and a biopsy examination suggested AdCC. Case 2 involved a 63-year-old Japanese male, who had a polypoid mass on his right hypopharynx. He was diagnosed with AdCC with high-grade transformation. Histologically, atypical cells in a myxoid stroma, which exhibited trabecular, nest-like, and/or cribriform growth patterns, and necrosis were observed in both cases. Case 2 displayed more marked cellular atypia than Case 1. Immunohistochemically, the tumor cells were diffusely positive for cytokeratin 5/6, p63/p40, SRY-related HMG-box 10 and Ki-67, but negative for other myoepithelial markers and p16. Finally, both cases were rediagnosed as BSCC-AdC. It is known that esophageal BSCC displays adenoid cystic-like features, and BSCC-AdC also sometimes occurs in the head and neck region. Clinicians should carefully differentiate BSCC-AdC from AdCC of the minor salivary glands and human papillomavirus-related carcinoma.

Membranous S100A10 involvement in the tumor budding of colorectal cancer during oncogenesis: report of two cases with immunohistochemical analysis.

BACKGROUND: Tumor budding (TB) and poorly differentiated clusters (PDCs) are a sequence of histologic findings that predict worse prognosis and node metastasis in colorectal cancer (CRC). TB and PDC (TB/PDC) are caused by cancer cell detachment and are distinguished by the number of cancer cells that constitute a cell cluster. In short, PDC is regarded as the previous step of TB. TB/PDC and epithelial-mesenchymal transition (EMT) are closely linked, but its pathogenic mechanisms are still unclear. S100A10, a member of the S100 protein family, forms a heterocomplex with annexin A2 (ANX A2) and then translocates to cell membrane from the cytoplasm and plays various roles in cell dynamics, including plasminogen activation. S100A10 is the activation modulator of the heterocomplex and promotes cell invasion. S100A10 is involved in the remodeling of both actin and extracellular matrix (ECM), which is also associated with EMT. CASE PRESENTATION: In two representative cases of conventional advanced CRC, we immunohistochemically examined S100A10 and ANX A2 expressions in which both TB and PDC were prominent. Both CRCs metastasized to multiple regional lymph nodes. In both cases, a membranous positivity for S100A10 was diffusely found in both tumor buds and PDCs and was observed in the tumor cells protruding toward the stroma, giving rise to TB/PDC. However, even in tumor glands with TB/PDC, the tumor cells with a smooth border around the stroma showed either cytoplasmic fine-granular expression or no positivity. The immunoreactivity for ANX A2 was almost the same as that for S100A10. In the main tumor components without TB/PDC, no distinct positivity was detected at their smooth borders. CONCLUSIONS: During oncogenesis, membranous S100A10 has the potential to be related to TB of CRC. This may be due to plasminogen activation, actin remodeling, and interaction with an altered ECM. However, further study is required to confirm this hypothesis.

Membranous overexpression of S100A10 is associated with a high-grade cellular status of breast carcinoma.

S100A10 promotes tumor invasion in various cancers. Although genetic studies on S100A10 in breast carcinoma (BC) have been used for molecular biological classification, immunohistochemical studies are lacking. We aimed to identify the correlation between S100A10 expression in BC and various pathological parameters, including morphological features to determine histological grade (HG). Immunostained serial paraffin-embedded tissue sections from 176 cases of resected BC or normal mammary ducts (controls) were assessed for the membrane expression of S100A10. Of the 176 cases, 125 conventional infiltrating ductal carcinomas were chosen, comprising 67 (53.6%) S100A10-positive tumors, whereas normal mammary ducts were S100A10-negative. S100A10 immunoreactivity in ductal carcinoma in situ (n = 51) was similar to that of invasive carcinoma. The distinct membrane-immunopositivity was correlated with high HG, severe nuclear pleomorphism, frequent mitotic counts, high Ki-67 labeling index, HER2/neu overexpression, and low estrogen receptor status (P < 0.05), but not with tubular formation, pT categories, node metastasis, vessel permeation, and pStage. Membrane overexpression of S100A10 in BC correlates with the high-grade morphological and molecular status of the carcinoma cell rather than stromal invasion and architectural deviation. Evidence points to the use of S100A10 as a biomarker representing a high-grade cellular status of BC.

S100A10 upregulation associates with poor prognosis in lung squamous cell carcinoma.

S100A10 is one of the members of the S100 protein family and is a key plasminogen receptor. Its upregulation has been reported in many types of tumors. In lung cancer, an association between upregulation of S100A10 and poor prognoses has been reported only in adenocarcinoma. We pursued the possibility of significance in lung squamous cell carcinoma (SCC). We first examined S100A10 protein expression by immunohistochemistry in 120 primary resected lung SCCs; 33 (27.5%) tumors showed strong membranous-immunopositivity particularly at the invasive front, i.e., the cancer-cell surface in contact with the stroma. Expression levels were significantly associated with higher pathological TNM stage (P = 0.0119), tumor size (P = 0.0003), lymphatic invasion (P = 0.0005), lymph node metastasis (P = 0.0006), and poorer prognosis (P = 0.0064). Our present results suggest that high S100A10 expression of the lung SCC cells, particularly adjacent to stroma, plays an important role in tumor progression, probably caused by lymphatic invasion and nodal metastasis.

[Three cases of enteroenteric intussusception examined by three-dimensional computed tomography enteroclysis].

Three-dimensional computed tomography (3D CT) enteroclysis or virtual enteroscopy is a novel technique to explore the entire small bowel using a modified protocol of virtual colonoscopy by inflating the small bowel with air. In our hospital, the procedure is performed routinely for cases with suspected gross lesions. We performed 3D CT enteroclysis for three cases with enteroenteric intussusception bowel. The lesions associated with intussusception were identified, single-incision laparoscopic surgery was performed, and diagnoses of lipoma and Peutz-Jeghers polyp were made in two cases. 3D CT enteroclysis did not reveal any associated lesion in the third case. This was followed by an intraoperative exploration during gastrectomy for stomach cancer, but no intestinal lesion was found. A diagnosis of idiopathic intussusception and its spontaneous release was made, and no recurrence was observed during the follow-up period. 3D CT enteroclysis seems to be an appropriate modality for the evaluation of enteroenteric intussusception.

[Virtual enteroscopy for the evaluation of stenosis in a case of chronic multiple ulcers of the small intestine].

A 39-year-old female presented to our hospital with diarrhea, vomiting, anemia, and hypoalbuminemia. Virtual enteroscopy was performed to evaluate the small bowel; we found annular stenoses at 89, 100, 116, 147, and 154 cm from the ligament of Treitz. Small bowel resection was performed, and annular ulcers were confirmed at 58, 71, 90, 130, 138, 218, and 225 cm from the ligament of Treitz. Clinical records and pathological examination failed to determine the cause of these ulcers, and we diagnosed chronic multiple ulcers of the small intestine. Thus, we believe that virtual enteroscopy can be beneficial in preoperatively diagnosing multiple ulcers and stenoses in the small bowel.

Complexities in Adjuvant Endocrine Therapy for Breast Cancer in Female-to-Male Transgender Patients.

Introduction: Managing breast cancer in female-to-male (FtM) transgender patients is complicated and challenging. Androgens play a crucial role in the development of secondary sexual identity in FtM transgender patients, but their effectiveness in breast cancer remains unclear. Furthermore, the considerations for adjuvant endocrine therapy in this population are highly intricate and warrant thorough discussion. Case Presentation: We describe the case of a 44-year-old FtM transgender diagnosed with breast cancer 3 years after initiating androgen receptor agonist therapy as part of his gender identity transition. After mastectomy, adjuvant endocrine therapy was initiated, consisting of a combination of an aromatase inhibitor and a gonadotropin-releasing hormone agonist, along with a cross-sex hormone. Conclusion: Estradiol levels were significantly reduced, and male-typical levels of sex hormones were attained.

Complete Regression of an 8-cm Desmoid Fibromatosis After Treatment With Tamoxifen.

We report a case of a relatively large desmoid fibromatosis that responded completely to tamoxifen as a single drug therapy. A 47-year-old Japanese man underwent laparoscopy-assisted endoscopic submucosal dissection for a duodenal polyp. He developed postoperative generalized peritonitis and underwent an emergency laparotomy. Sixteen months after the surgery, a subcutaneous mass was found on the abdominal wall. Biopsy of the mass revealed estrogen receptor alpha-negative desmoid fibromatosis. The patient underwent total tumor resection. Two years after the initial surgery, he was found to have multiple intra-abdominal masses, with the largest mass measuring 8 cm in diameter. Biopsy revealed fibromatosis, as in the case of the subcutaneous mass. Complete resection was impossible due to the proximity of the duodenum and superior mesenteric artery. Tamoxifen was administered for three years, resulting in complete regression of the masses. No recurrence was observed for the following three years. This case indicates that relatively large desmoid fibromatosis can be successfully treated with a selective estrogen receptor modulator alone and that its effect is not dependent on the estrogen receptor alpha status of the tumor.

Acquired Treatment Resistance in a Patient with Metastatic PD-L1-Positive Breast Cancer and Germline BRCA1 Mutation.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer associated with higher rates of relapse and mortality compared to other subtypes. Chemotherapy has been a mainstream treatment approach for TNBC due to the lack of therapeutic targets. Recent advances have led to the introduction of novel agents against specific patients with programmed death-ligand 1 (PD-L1)-positive TNBC who harbor germline BRCA mutations. However, some patients who respond to PD-L1 or poly (ADP-ribose) polymerase PARP inhibitors often develop resistance. Additionally, treatment strategies are more complicated for patients with PD-L1-positive TNBC and germline BRCA mutations. Here, we report a patient with metastatic PD-L1-positive TNBC who harbored a germline BRCA1 mutation. The patient sequentially received combination treatment regimens, including PD-L1 inhibitors with chemotherapy and the PARP inhibitor olaparib, acquiring resistance to the treatments in a couple of months. Further investigations are warranted to elucidate the mechanisms underlying resistance to PD-L1 antibodies and PARP inhibitors to improve treatment outcomes while preventing emergence of treatment resistance in patients with TNBC.

Esophageal ulcer related to zinc deficiency following a total gastrectomy.

A 76-y-old Japanese man who had undergone gastrectomy 4.5 y earlier experienced 2 wk of sore throat, heartburn, and difficulty swallowing. Endoscopy showed deep, craterlike, longitudinal ulcers in the lower and middle esophagus. Immunohistochemistry and blood tests were negative for herpes simplex virus and cytomegalovirus infections. The patient reported no other symptoms affecting the gastrointestinal tract. Although his symptoms ameliorated after initial hospitalization and treatment, they re-emerged a few days after being discharged. Fifty-one days after being first admitted, he complained of glossalgia. The serum zinc level was found to be 38 µg/dL, which was below the reference range; the patient was diagnosed with zinc deficiency. After oral zinc administration, the patient was relieved of the symptoms, and his pain was alleviated. Upper gastrointestinal endoscopy after symptom relief showed improvement in the esophageal ulcers. He has continued taking zinc supplementations, and has not developed similar symptoms in the 5 y since being treated. To the best of our knowledge, this is the first case report of esophageal ulcers related to zinc deficiency.

Enrichment of Immune-Related Genes in Aggressive Primary Breast Angiosarcoma: A Case Report.

Primary breast angiosarcoma is an extremely rare disease with a poor prognosis. Primary angiosarcoma is distinct from secondary angiosarcoma, which usually occurs in patients who have been previously treated for breast cancer. The low incidence of primary breast angiosarcoma has hindered the elucidation of its etiology and potential therapies. Here, we report a case of a patient with primary breast angiosarcoma who experienced recurrence after surgery. The tumor was refractory to systemic treatments, and the patient died 18 months after the surgery. We used RNA sequencing for gene expression profiling of the tumor. A high tumor inflammation signature score indicated enrichment in immune-related signaling. CIBERSORTx, a tool used to characterize the cellular composition of complex tissues based on gene expression, indicated that the immune cells in the tumor were predominantly macrophages, and this was confirmed using immunohistochemical analysis. These findings indicate the possible use of checkpoint immunotherapy for the treatment of primary breast angiosarcoma.

[Large serous cystic adenoma at the pancreas tail mimicking mucinous cystic neoplasm].

A 62-year-old woman presented with left abdominal pain. A large and multi-cystic lesion at the pancreas tail was recognized on imaging examinations. MRI revealed low and high signal intensity on T1- and T2-weighted imaging, with focal and bright components in the nodule adjacent to the septum on T2-weighted imaging. Distal pancreatectomy was performed, and the cystic lesion was diagnosed as serous cystic adenoma with hemorrhage. The characters of serous cystic components on imaging examinations could help to distinguish the lesion from mucinous cystic neoplasm.

A Case of Colonic Micropapillary Carcinoma with a High Frequency of Apoptosis.

Colorectal micropapillary carcinoma (MPC) exhibits aggressive biological characteristics, with empty spaces and reversed polarity, similar to the poorly differentiated clusters (PDCs) formed from detached cancer cells. Epithelial-mesenchymal transition, which is involved in the cancer cell acquisition of apoptosis resistance, is closely linked with histological findings of MPC, PDCs, and tumor buds (TBs), with MPC and TBs considered as apoptosis-resistant features. However, we encountered a case of colonic MPC with frequent apoptosis. We examined the case using immunohistochemistry. In many of the tumor glands (TGs) of the MPC, empty spaces and tumor cell detachment toward the gland interior were observed. Moreover, TG ruptures were scattered, with PDCs adjacent to them. Apoptosis occurred mainly at the TG and PDC peripheries in the middle and deep tumor layers, and transforming growth factor beta 1 (TGF-ß1) positivity was evident in those tumor cells. Cells positive for apoptosis-related M30 were distributed mainly in the deep layer with a significant PDC and TB presence. However, apoptosis and M30 positivity were low in the TBs. Non-tumorous bud components, especially those in the deep layer, had poor ability to promptly acquire apoptosis resistance. No nuclear ß-catenin positivity was found in any of the tumor cells. Apoptosis has the potential to reciprocally produce MPC, PDCs, and TBs, with TGF-ß1 involvement.

Hybrid Carcinoma of the Parotid Gland: An Extremely Rare Three Cases with an Immunohistochemical Analysis and a Review of the Literature.

Salivary hybrid carcinoma (HC) is defined as when two or more kinds of carcinoma exist at the same location in a single mass. We reestimated and examined three cases of salivary gland HC. Case 1 involved a 76-year-old male. Case 2 involved a 74-year-old female. Case 3 involved a 66-year-old male. Histologically, case 1 involved a combination of salivary duct carcinoma (SDC) and squamous cell carcinoma (SqCC). Immunohistochemically, the former was positive for gross cystic disease fluid protein (GCDFP)-15 and androgen receptor (AR). Case 2 involved a combination of SqCC and neuroendocrine carcinoma. Immunohistochemically the latter was positive for synaptophysin and neural cell adhesion molecule (NCAM). Case 3 involved a combination of SDC and epithelial-myoepithelial carcinoma (EMC). Immunohistochemically, the former was positive for GCDFP-15 and AR, whereas the inner cells of the latter were positive for cytokeratin 7, and the outer cells of the latter were positive for actin. Because of the transitional zone between SDC and EMC, it was speculated that high-grade SDC arose from low-grade EMC.

The implicated clinical factors for outcomes in 304 patients with salivary duct carcinoma: Multi-institutional retrospective analysis in Japan.

BACKGROUND: Salivary duct carcinoma (SDC) is a high-grade salivary malignancy that frequently occurs as the carcinomatous component of carcinoma ex pleomorphic adenoma. We herein examined the clinical factors affecting outcomes in a large cohort of SDC. METHODS: We selected 304 SDC cases and investigated clinical characteristics and the factors affecting outcomes. RESULTS: The median age of the cases examined was 68 years, the most common primary site was the parotid gland (238 cases), and there was a male predominance (M/F = 5:1). Outcomes were significantly worse when the primary tumor site was the minor salivary glands (SG) than when it was the major SG. Outcomes were also significantly worse in pN(+) cases (161 cases) than in pN0 cases, particularly those with a metastatic lymph node number ≥11. The cumulative incidence of relapse and distant metastases was significantly higher in stage IV cases than in stage 0-III cases. CONCLUSIONS: The absolute number of lymph node metastases, higher stages, and the minor SG as the primary tumor site were identified as factors affecting the outcome of SDC.

Periostin expression and its supposed roles in benign and malignant thyroid nodules: an immunohistochemical study of 105 cases.

BACKGROUND: Thyroid tumors are often difficult to histopathologically diagnose, particularly follicular adenoma (FA) and follicular carcinoma (FC). Papillary carcinoma (PAC) has several histological subtypes. Periostin (PON), which is a non-collagenous extracellular matrix molecule, has been implicated in tumor invasiveness. We herein aimed to elucidate the expression status and localization of PON in thyroid tumors. METHOD: We collected 105 cases of thyroid nodules, which included cases of adenomatous goiter, FA, microcarcinoma (MIC), PAC, FC, poorly differentiated carcinoma (PDCa), and undifferentiated carcinoma (UCa), and immunohistochemically examined the PON expression patterns of these lesions. RESULTS: Stromal PON deposition was detected in PAC and MIC, particularly in the solid/sclerosing subtype, whereas FA and FC showed weak deposition on the fibrous capsule. However, the invasive and/or extracapsular regions of microinvasive FC showed quite strong PON expression. Except for it, we could not find any significant histopathological differences between FA and FC. There were no other significant histopathological differences between FA and FC. Although PDCa showed a similar PON expression pattern to PAC, UCa exhibited stromal PON deposition in its invasive portions and cytoplasmic expression in its carcinoma cells. Although there was only one case of UCa, it showed strong PON immunopositivity. PAC and MIC showed similar patterns of stromal PON deposition, particularly at the invasive front. CONCLUSIONS: PON may play a role in the invasion of thyroid carcinomas, particularly PAC and UCa, whereas it may act as a barrier to the growth of tumor cells in FA and minimally invasive FC.

Nivolumab-induced liver injury with a steroid-refractory increase in biliary enzymes, in a patient with malignant mesothelioma: An autopsy case report.

This is the first autopsy report of hepatotoxicity from nivolumab immunotherapy for malignant mesothelioma. The increase in levels of biliary enzymes and randomly distributed endothelial damage were steroid-refractory, but second-line option was abandoned because of cachexia. Further discussions are needed regarding the customized management of immune-related toxicities.