Testicular teratomagenesis from primordial germ cells with overexpression of germinal center-associated nuclear protein.

Testicular teratomas are the major histologic type of testicular germ cell tumors and their incidence continues to grow. Moreover, teratomas can develop from undifferentiated cells in induced pluripotent stem (iPS) cell transplantation therapy, seriously hampering the progress of regenerative medicine. Germinal center-associated nuclear protein (GANP) is thought to be important to the biogenetic control of primordial germ cells and is among the genes susceptible to testicular germ cell tumors. Thus, we analyzed the expression of GANP in human testicular postpubertal-type teratomas and established a novel mouse model to reveal the association between GANP and teratomagenesis. We analyzed 31 cases of human testicular postpubertal-type teratomas and, in all cases, GANP was overexpressed. The aberrant expression was also detected in germ cell neoplasia in situ accompanied by the teratoma. GANP expression was particularly high in the epithelia of the epidermis, cutaneous appendages, and trachea-like ciliated epithelium. To further clarify the association between GANP and teratomagenesis, we established a novel teratomagenesis mouse model (CAG-ganpTg mice). In the GANP-teratoma mice, GANP-overexpressing teratomas were more frequent at the testes and the middle portion of the uterus than has been seen in the previously established mouse models. In conclusion, GANP is overexpressed in testicular postpubertal-type teratomas and is an essential teratomagenic factor. We also found that CAG-ganpTg mice are useful mouse models of teratomagenesis that mimics human midline teratomas and that teratomas may originate from the overexpression of GANP in primordial germ cells.

Evaluation of the widths of the mucosal strips in pathological examination of specimens of endoscopic submucosal dissection for early gastric cancer.

BACKGROUND: Endoscopic submucosal dissection (ESD) is the standard treatment for early gastric cancer in Japan. Pathological evaluation of ESD specimens is considered essential to determine if additional gastrectomy is necessary. Usually, specimens resected by ESD are sliced into 2-3 mm wide sections, and each section is examined for depth of tumor and lymphovascular invasion. Nevertheless, in most cases of additional gastrectomy, lymph node metastasis is not present. Given that there are few-studies on how clinical-decisions based on the pathologic-evaluation-method, in particular the specimen cut-width, influence patient outcomes, we retrospectively evaluated whether reducing the number of cuts to one-half or one-third would result in underestimation of the real need for additional surgery. The effect of the actual cut-width on recommended treatment (referral to operation) and patient-outcomes was also assessed. METHODS: Pathological records of 498 lesions from 439 patients were reviewed and re-evaluated. All pathological descriptions are based on the gastric cancer classification system of the Japanese Gastric Cancer Association, 15th edition. RESULTS: In 5.8% and 8.5% of the total specimens, underdiagnosis of tumor-depth and lymphovascular invasion occurred when the number of sections was reduced to one-half and one-third, respectively. Significantly more submucosal invasions were found in the group in which the cut-with was between 3 and 4 mm than in the group in which the cut width was less than 3 mm. CONCLUSION: Evaluation of the appropriate cut-width is important and should be discussed from the standpoint of labor costs and lost opportunities to search for molecular markers in ESD materials.

Effectiveness of radiation therapy on brain invasion by human papillomavirus-related multiphenotypic sinonasal carcinoma: A case report.

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC) is newly suggested and characterized by HPV-related tumors. HMSC has a relatively good prognosis. No cases of brain invasion have been reported to date. We encountered a case of brain invasion by HMSC, in which we assessed the effectiveness of radiotherapy in comparison with biopsy and autopsy. A 69-year-old man was referred to a hospital three months after intracerebral hemorrhage (ICH). Contrast magnetic resonance imaging revealed a tumor in the ethmoid sinus involving the brain. We performed transnasal biopsy and intensity-modulated radiotherapy for sinonasal and intracranial lesions. Despite radiotherapy, the patient died on day 41 after radiation. Biopsy specimens displayed mixed findings of epithelial and mesenchymal components. The tumor was immunoreactive for p16, and the RNA in situ hybridization for HPV was positive. Finally, we diagnosed the patient as having HMSC. Autopsy of the sinonasal tissue revealed a reduction in the number of tumor cells. There was a marked reduction in the number of tumor cells in the sinonasal tissue compared to that in the invaded brain tissue. The effectiveness of radiotherapy could depend on the histopathological components and location of the lesion, even in the same patient.

[Sarcoidosis diagnosed by a tiny esophageal lesion:a case report].

A woman in her 60s was referred to the Department of Gastroenterology with anemia. She had a recurrent transient loss of consciousness 11 years ago, and she was examinated at the cardiology and neurology departments, but the cause was not identified. Epileptic seizures were suspected. Sodium valproate medication was started, and the patient's condition progressed with no recurrence. Esophagogastroduodenoscopy showed a tiny submucosal tumor-like lesion with mild depression in a 21cm thoracic esophagus. Biopsy revealed epithelioid granulomas with multinucleated giant cells in the subepithelial stroma. Computed tomography (CT), positron emission tomography-computed tomography (PET-CT), and magnetic resonance imaging (MRI) showed multiple lesions in the hilar lymph nodes, spleen, and heart that are typical of sarcoidosis. These findings led to the diagnosis of esophageal lesion associated with sarcoidosis. The patient had no subjective symptoms;however, treatment with prednisolone 30mg was started because cardiac sarcoidosis is a risk of death. Gastrointestinal tract involvement in sarcoidosis is rare;esophageal sarcoidosis is particularly rare, and there are few reports on superficial lesions. Here, we report a case of sarcoidosis that was diagnosed from a tiny esophageal lesion.

Epilepsy in patients with focal cortical dysplasia may be associated with autism spectrum disorder.

INTRODUCTION: Patients with epilepsy associated with focal cortical dysplasia (FCD) may be associated with autism spectrum disorder (ASD). Therefore, the purpose of this study was to compare surgically treated patients with epilepsy secondary to FCD and normal volunteers without epilepsy and to review the neuropathological findings of patients with FCD. METHODS: This study involved 38 patients with medically intractable focal onset epileptic seizures who underwent epilepsy surgery (Group 1). All patients had epilepsy associated with FCD. These patients and 38 normal volunteers without epilepsy (Group 2) were administered the autism spectrum quotient (AQ) test, and the groups were compared. RESULTS: The 38 patients in Group 1 included 16 females and 22 males (age range 20-60, mean age, 33.0; standard deviation (SD), 11.8 years). The normal volunteers in Group 2 included 22 females and 16 males (age range 20-57, mean age, 30.6 years; SD, 8.8 years). Total AQ scores were significantly higher in Group 1 than Group 2 (p = 0.027). Patients with FCD I showed a higher AQ score than those with FCD II in the AQ test (p ≤ 0.001). CONCLUSION: Patients with epilepsy secondary to FCD were associated with higher ASD score than normal volunteers. This tendency was seen more strongly in patients with FCD I than FCD II.

High PD-1 expression level is associated with an unfavorable prognosis in patients with cervical adenocarcinoma.

PURPOSE: The effectiveness of immunotherapy for cervical adenocarcinoma (CA) has not been demonstrated yet. Programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and CD8 may be used as biomarkers of response to immune therapy in CA patients. In the present study, we aimed to investigate whether the expression levels of PD-1, PD-L1, and CD8 can predict the prognosis of patients with CA and their response to immune checkpoint inhibition therapy. METHODS: In the present study, the clinical stage for all 82 patients with cervical adenocarcinoma was classified according to the guidelines of the International Federation of Gynecology and Obstetrics (FIGO); there were 5, 48, 5, 14, 8, and 2 patients with stage IA, IB, IIA, IIB, IIIB, and IVB disease, respectively. The levels of PD-1, PD-L1, and CD8 were analyzed by the immunohistochemical analysis of the formalin-fixed paraffin-embedded tumor samples. The correlation between the expression levels and patient prognosis was analyzed using the Kaplan-Meier method and univariate and multivariate Cox proportional hazard regression models. RESULTS: We observed a significant inverse correlation between the expression of PD-1 and CD8 (p = 0.001, chi-square test). We also found a significant inverse correlation between the expression of PD-L1 and CD8 (p = 0.027). The overall survival and progression-free survival rates were significantly worse in patients with positive PD-1 expression (p = 0.031; p = 0.087, respectively). CONCLUSION: Our results suggest that a high PD-1 expression is associated with a poor prognosis in patients with CA. Further research is necessary to identify the molecular mechanisms that mediate this association.

[Squamous Cell Papilloma of the Urinary Bladder].

We report a case of squamous cell papilloma of the urinary bladder, which is an extremely rare disease with only 15 cases reported in the Japanese and English literature. The case was in a 76-year-old woman. She was referred to the department of urology because multifocal tumors of the urinary bladder were found by computed tomographic scan during an examination for acute enteritis. Cystoscopy showed a nonpapillary flat tumor with whitish plaque on the left posterior wall, measuring 3 cm. Urinalysis and urine cytology revealed no abnormalities. Transurethral resection was performed. Histology revealed a papillary noninvasive squamous cell tumor with extensive keratinization on its surface. There were no nuclear atypia or evidence of koilocytotic change. Immunohistochemically, the tumor cells were negative for both p16 and p53. Based on the pathological findings, the tumor was diagnosed as squamous cell papilloma. The tumor recurred three month after the operation and she is being followed with no change observed for two and a half years.

Dedifferentiated Endometrial Carcinoma Could be A Target for Immune Checkpoint Inhibitors (Anti PD-1/PD-L1 Antibodies).

Dedifferentiated endometrial carcinoma (DDEC) is defined as an undifferentiated carcinoma admixed with differentiated endometrioid carcinoma (Grade 1 or 2). It has poor prognosis compared with Grade 3 endometrioid adenocarcinoma and is often associated with the loss of mismatch repair (MMR) proteins, which is seen in microsatellite instability (MSI)-type endometrial cancer. Recent studies have shown that the effectiveness of immune checkpoint inhibitor therapy is related to MMR deficiency; therefore, we analyzed the immunophenotype (MMR deficient and expression of PD-L1) of 17 DDEC cases. In the undifferentiated component, nine cases (53%) were deficient in MMR proteins and nine cases (53%) expressed PD-L1. PD-L1 expression was significantly associated with MMR deficiency (p = 0.026). In addition, the presence of tumor-infiltrating lymphocytes (CD8+) was significantly associated with MMR deficiency (p = 0.026). In contrast, none of the cases showed PD-L1 expression in the well-differentiated component. Our results show that DDEC could be a target for immune checkpoint inhibitors (anti PD-L1/PD-1 antibodies), especially in the undifferentiated component. As a treatment strategy for DDEC, conventional paclitaxel plus carboplatin and cisplatin plus doxorubicin therapies are effective for those with the well-differentiated component. However, by using immune checkpoint inhibitors in combination with other conventional treatments, it may be possible to control the undifferentiated component and improve prognosis.

Mesenteric inflammatory veno-occlusive disease occurring during the course of ulcerative colitis: a case report.

BACKGROUND: Mesenteric inflammatory veno-occlusive disease (MIVOD) is difficult to diagnose because of its rarity, nonspecific clinical findings, and frequent confusion with other diseases including inflammatory bowel disease. This report presents a very rare case of MIVOD that occurred during the course of ulcerative colitis (UC). CASE PRESENTATION: A 32-year-old man, who had been diagnosed with UC at the age of 29 and was in remission maintained by oral administration of 5-aminosalicylic acid (5-ASA), showed exacerbation of diarrhea and was admitted to the hospital. Since it was deemed an exacerbation of UC, intravenous steroid therapy and oral administration of tacrolimus were initiated, but his condition continued to worsen. Abdominal computed tomography (CT) was performed and showed intraperitoneal free air, leading to a diagnosis of gastrointestinal perforation and the performance of emergency surgery (subtotal colectomy and ileostomy). Histopathological examination of the resected colon of the patient showed mucosal inflammatory findings that were not typical of UC, including multiple organized thrombi with recanalization in the veins existing in the submucosal layer to the subserosal layer and an increased infiltration of inflammatory cells. These findings led to the pathological diagnosis of MIVOD. CONCLUSION: We report a very rare case in which MIVOD occurred during the course of UC.

Clinical course of disseminated intravascular coagulopathy-type amniotic fluid embolism: A report of three cases.

Amniotic fluid embolism (AFE) is a rare complication of pregnancy and its mortality rate is high. There have been few reports of AFE with presence of severe coagulopathy and incoagulable bleeding, and absence of cardiopulmonary symptoms or limited cardiopulmonary symptoms, followed by massive blood loss during delivery. Such cases have been referred to as disseminated intravascular coagulopathy-type AFE, and the characteristics of this condition have been presented previously. Here we report three cases that fulfilled the diagnostic characteristics of disseminated intravascular coagulopathy-type AFE.

[Angiomyolipoma with Epithelial Cysts (AMLEC) of the Kidney].

A 49-year-old man was demonstrated to have two tumors in the right kidney by computed tomographic scan during an examination for cholelithiasis. One was a fat rich solid tumor which was clinically diagnosed as angiomyolipoma, and the other was an unconfirmed cystic tumor. Cholecystectomy and radical nephrectomy were performed. Based on pathological findings, the solid tumor was diagnosed as common angiomyolipoma and the cystic tumor as angiomyolipoma with epithelial cysts (AMLEC). The cystic tumor consisted of 3 components : an epithelial cyst lined with single flat to cuboidal cells, a subepithelial compact stroma and an external layer of muscle predominant angiomyolipoma. Immunohistochemical examinations showed strong intense staining of pan-cytokeratin in the epithelium lining the cyst. The subepithelial compact stroma was stained with both CD10 and HMB45. The muscle predominant angiomyolipoma exhibited expression of HMB45. AMLEC is a recently recognized rare variant of angiomyolipoma.

[A Case of Poorly Differentiated Adenocarcinoma of the Colon with Rapid Postoperative Progression Suggestive of Peritoneal Dissemination].

A 62-year-old man was admitted to our hospital because of pain in the right lower abdomen and was diagnosed with cecal cancer and an associated abscess. The patient subsequently underwent right hemicolectomy. Histopathological examination was positive for por1, se, bd3, ly3, v0, PM0, and DM0. He was discharged from the hospital 21 days postoperatively. He was hospitalized with bloating of the right lower abdomen and inflammation 31 days postoperatively. He was later diagnosed with recurrence of the initial abscess, but his symptoms did not improve, and he was considered to have peritoneal dissemination. His general condition deteriorated rapidly, and he died approximately 1.5 months postoperatively. Histopathological and anatomical examination later confirmed multiple organ failure with peritoneal dissemination. It is reported that prognosis of poorly differentiated adenocarcinoma is worse than that for well- or moderately differentiated adenocarcinoma. Poorly differentiated adenocarcinoma may recur immediately after curative surgery.

Skull involvement in a pediatric case of chronic recurrent multifocal osteomyelitis.

An 11-year-old boy was diagnosed with chronic recurrent multifocal osteomyelitis (CRMO) and presented with right sacro-femoral and occipital lesions. Initially, a tumor was suspected. However, the bone biopsy showed osteomyelitis with a negative bacterial culture. Bone scintigraphy revealed inflammatory changes on multiple bone lesions. The slight elevation in inflammatory markers such as C-reactive protein was of little clinical value. He was diagnosed with CRMO by sacral biopsy, and the clinical course progressed, with the presence of a new occipital lesion observed after the 1-year follow-up. The administration of non-steroidal anti-inflammatory drugs successfully improved his clinical symptoms. The presence of a skull lesion in the occipital bone of a pediatric patient with CRMO has not been previously reported.

Total number of lymph node metastases is a more significant risk factor for poor prognosis than positive lateral lymph node metastasis.

PURPOSE: Lateral lymph nodes (LLNs) along the iliac vessels are an important indicator of local recurrence; however, we are unaware of any study that investigates whether the number of LLN metastases influences the prognosis of patients with lower rectal cancer. METHOD: We analyzed retrospectively the records of 154 patients who underwent radical resection of T1-4 lower rectal adenocarcinoma at a single institution. RESULTS: Among the 88.3 % of patients who underwent LLN dissection, 13 (8.4 %) had LLN metastasis. The Cox proportional hazard model indicated that sex, histological grade, lymphatic or venous invasion, and LLN metastasis were not significantly associated with tumor recurrence, whereas tumor depth and more than three lymph node metastases were risk factors for recurrence (p = 0.002 and p = 0.02, respectively). Of the 13 patients with LLN metastasis, 6 whose mesenteric lymph nodes (MLNs) had been well dissected and examined did not have MLN metastasis. CONCLUSIONS: The presence of one or two LLN metastases in patients who have undergone LLN dissection with surgery for lower rectal cancer is not associated with poor prognosis. The number of LLN metastases is a more significant risk factor for poor prognosis.

Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly.

OBJECTIVE: Recently, COL4A1 mutations have been reported in porencephaly and other cerebral vascular diseases, often associated with ocular, renal, and muscular features. In this study, we aimed to clarify the phenotypic spectrum and incidence of COL4A1 mutations. METHODS: We screened for COL4A1 mutations in 61 patients with porencephaly and 10 patients with schizencephaly, which may be similarly caused by disturbed vascular supply leading to cerebral degeneration, but can be distinguished depending on time of insult. RESULTS: COL4A1 mutations were identified in 15 patients (21%, 10 mutations in porencephaly and 5 mutations in schizencephaly), who showed a variety of associated findings, including intracranial calcification, focal cortical dysplasia, pontocerebellar atrophy, ocular abnormalities, myopathy, elevated serum creatine kinase levels, and hemolytic anemia. Mutations include 10 missense, a nonsense, a frameshift, and 3 splice site mutations. Five mutations were confirmed as de novo events. One mutation was cosegregated with familial porencephaly, and 2 mutations were inherited from asymptomatic parents. Aberrant splicing was demonstrated by reverse transcriptase polymerase chain reaction analyses in 2 patients with splice site mutations. INTERPRETATION: Our study first confirmed that COL4A1 mutations are associated with schizencephaly and hemolytic anemia. Based on the finding that COL4A1 mutations were frequent in patients with porencephaly and schizencephaly, genetic testing for COL4A1 should be considered for children with these conditions.

Positive peritoneal washing cytology is a potential risk factor for the recurrence of curatively resected colorectal cancer.

PURPOSES: Whether free peritoneal cancer cells should be considered peritoneal dissemination in colorectal cancer patients remains controversial. The aim of this study was to investigate the clinical significance of positive peritoneal washing cytology (PWC) in patients with colorectal cancer. METHODS: We retrospectively analyzed the records of 771 sequential patients diagnosed with stage 0-III colorectal cancer who underwent R0 resection and had no distant metastases or peritoneal dissemination. RESULTS: PWC was performed on all 771 patients. Sixty-eight patients experienced metastasis recurrence, 10 of whom experienced peritoneal recurrence. Of the 10 patients with peritoneal recurrence, 6 had positive PWC. Out of the 771 patients, 21 had positive PWC. Of these 21 patients, 6 had peritoneal recurrence, while 4 had distant metastasis and no peritoneal recurrence during the observation period. The 5-year disease-free survival was 89.0 % in the patients with negative PWC vs. 46.8 % in the patients with positive PWC (p < 0.0001, log-rank test). A Cox proportional hazards model revealed that positive PWC was the strongest independent risk factor for cancer-specific recurrence. CONCLUSIONS: Our study highlights PWC as a useful prognostic tool in patients undergoing curative surgery for colorectal cancer, since positive PWC was shown to be a potential risk factor for recurrence.

Clinicopathological study of three cases of infantile fibromatosis of the orbit.

We report the clinical and pathological findings in three infants with infantile fibromatosis that involved several extraocular muscles which led to disorders of ocular motility. We also describe their clinical features before and after surgery. This was a retrospective interventional case study with clinicopathological correlations. We present three cases of infantile fibromatosis that were diagnosed by clinical features and histopathlogical examination of biopsy specimens. The three patients were all female children aged 1, 3, and 3 years at their initial visit. The orbital tumor was unilateral in all patients. All three patients had disorders of ocular motility because the tumors involved ≥2 extraocular muscles. The margins between the tumor and the involved extraocular muscles were not distinct. We performed partial resection of the tumors to preserve the extraocular muscles. In all cases, the tumors partially remained, but periodic postoperative magnetic resonance imaging showed no enlargement of the tumors during the follow-up period. All three patients had residual limitations of eye movements. We should consider the postoperative binocular function when we treat infantile benign fibrous tumors involving the extraocular muscles.

A solitary pulmonary nodule in a former glass blower mimicking a primary lung adenocarcinoma.

INTRODUCTION: Inhalation of silicon dioxide causes silicosis, a condition that may occur in various industries and work settings. Radiologic findings typically show numerous nodular opacities, while solitary pulmonary nodules are atypical for silicosis. PRESENTATION OF CASE: A 68-year-old woman, a former glassblower, presented with a left solitary pulmonary nodule (13 mm) on chest computed tomography. The nodule enlarged to 23 mm over 6 months, exhibiting an irregular shape, spiculated margin, and rapid growth with a doubling time of 186.4 days. She underwent a left upper lobectomy with a suspicion of lung cancer. The histopathological findings revealed peribronchial lymphocytic infiltration and granulomatous-like structures containing multinucleated giant cells and phagocytic crystalline foreign bodies. These findings were consistent with a foreign body reaction to the glass fragments. DISCUSSION: Inhaled glass fragments may present as a solitary pulmonary nodule after the retirement of a glass blower. Its behavior and radiological features mimicked a primary lung adenocarcinoma. CONCLUSION: Solitary pulmonary nodules due to inhaled glass fragments may mimic a primary lung adenocarcinoma. A definitive diagnosis requires a histological examination in this rare condition.

A morphological and immunohistochemical study of ductal carcinoma in situ, invasive breast carcinoma of no special type, and mucinous carcinoma of the breast in comparison with solid papillary carcinoma regarding neuroendocrine marker expression.

The exact relationship between solid papillary carcinoma (SPC) and invasive breast carcinoma of no special type (IBC-NST) with neuroendocrine differentiation and SPC and mucinous carcinoma (MC) of the breast remains unclear. To clarify the relationship, we conducted a comparative study of morphological and neuroendocrine features between ductal carcinoma in situ (DCIS, 72 cases) and SPC in situ (35 cases), and IBC-NST (103 cases) and invasive SPC (92 cases). We also conducted the study between MC associated with and without SPC. Synaptophysin, chromogranin A, and INSM1 were employed for the immunohistochemical study. IBC-NST had occasionally a morphological similarity with invasive SPC. While 123 of 127 cases with SPC demonstrated diffuse staining with one or more of the neuroendocrine markers, the only one case of DCIS and none of IBC-NST showed it. Type B was observed in 16 of 18 cases of MC associated with SPC and in 13 of 33 cases of MC without it. All the cases of MC with SPC and 6 of 33 cases without it showed diffuse staining for at least one of the neuroendocrine markers. In conclusion, a careful distinction between invasive SPC and IBC-NST with neuroendocrine differentiation is required. We assume that SPC in situ is a potential candidate for precursor of IBC-NST with neuroendocrine differentiation. MC of the breast is suggested to have two pathogenetic pathways through SPC in situ or non-SPC in situ. SPC in situ is thought to be less common as a precursor of MC than non-SPC in situ.

Localized nodular pulmonary amyloidosis mimicking primary lung cancer associated with cystic airspaces: A case report.

Localized nodular pulmonary amyloidosis can form pulmonary nodules associated with cystic air spaces, but due to its rarity, it cannot be included in the differential diagnosis without appropriate knowledge. Among the differential diagnoses of nodules with cysts in the lungs is primary lung cancer, however, diagnosis based solely on imaging findings is challenging. A 59-year-old Japanese female was referred to our hospital for an abnormality noted on the chest radiograph of an annual health check. She had no history of smoking or medical issues. Chest computed tomography revealed a 1.2 cm pulmonary nodule with surrounding multilocular cystic air spaces in the superior lingular segment. We suspected it was a nodule of primary lung cancer arising in the pulmonary cyst and performed video-assisted thoracic surgery. As the intraoperative frozen examination after a wedge resection revealed fibrotic tissue without malignancy, we did not do any further resection. The histopathological examination of the permanent section revealed unstructured eosinophilic deposits positive for direct fast scarlet staining, which were consistent with amyloidosis. The surrounding pulmonary cysts contained the check valve made by amyloid deposition. Localized nodular pulmonary amyloidosis can give rise to pulmonary cysts and mimic primary lung cancer associated with cystic air spaces. It should be raised as a potential differential diagnosis for pulmonary nodules with cystic air space formation, particularly in patients without a smoking history.