Granulomatosis with Polyangiitis following COVID-19 in an Adolescent.

Granulomatosis with polyangiitis (GPA) is a systemic disease that causes vasculitis in various organs. Although the mechanism of pathogenesis remains unclear, infection has been reported to be a causative factor. We herein report a case of GPA that developed following coronavirus disease 2019 (COVID-19) in an adolescent girl. One month after contracting mild COVID-19, the patient had facial allodynia, a fever, and weight loss and was admitted for multiple nodular shadows on a chest roentgenogram. GPA was diagnosed based on pathological findings of the lung and nasal mucosal biopsies. She received methylprednisolone and rituximab, and her symptoms and radiological findings improved.

Sex-dependent expression of prostatic markers and hormone receptors in cystic tumor of the atrioventricular node: A histopathological study of three cases.

We pathologically investigated three autopsy cases of cystic tumor of the atrioventricular node (CTAVN) with sudden death. Case 1 was a 36-year-old woman without any clinical history. Case 2 was a 76-year-old man with an implanted pacemaker for complete atrioventricular block. Case 3 was a 45-year-old man with a history of first-degree AV block and sinus bradycardia. Microscopically, all three cases showed the bilayered structure of tumor glands and corpora amylacea in the glandular lumens. Immunohistochemically, the inner cells of the tumor glands were positive for cytokeratin CAM5.2, CEA, EMA, olfactomedin-4 and alpha-methylacyl-coenzyme A racemase; the outer cells were positive for p63 and cytokeratin high molecular weight. In Case 1, androgen receptor and estrogen receptor were negative; progesterone receptor was focally positive in both the inner and outer cells. In Case 2, androgen receptor showed intermediate positivity in the inner cells; estrogen receptor and progesterone receptor were positive in the outer cells. Positive expression of both prostate-specific antigen and prostate-specific acid phosphate were found in the inner cells of both male cases. Because CTAVN cells exhibit different degrees of the prostatic phenotype depending on the patient's sex, we believe that CTAVN may originate from urogenital sinus tissue in some cases.

Immune microenvironment in Barrett's esophagus adjacent to esophageal adenocarcinoma: possible influence of adjacent mucosa on cancer development and progression.

The immune microenvironment plays a pivotal role in cancer development and progression. Therefore, we studied the status of immune cells in esophageal adenocarcinoma (EAC) and adjacent Barrett's esophagus (BE) and their association with the clinical course of patients. We included 87 patients with EAC who underwent surgical resection or endoscopic submucosal dissection. CD3, CD8, Foxp3, p53, and Ki-67 were immunolocalized in EAC and adjacent BE (N = 87) and BE without EAC (N = 13). BE adjacent to EAC exhibited higher CD3+ lamina propria lymphocyte (LPL) numbers than BE without EAC. Abundant Foxp3+ LPLs in BE were associated with dysplasia and increased Ki-67 labeling index (LI) in BE glandular cells and tended to link to aberrant p53 expression. Abundant CD8+ LPLs in adjacent BE were associated with worse prognosis of EAC patients (P = 0.019). Results of our present study firstly revealed the potential influence of the tissue immune microenvironment of BE adjacent to EAC on cancer development and eventual clinical outcome of EAC patients. T cell infiltration could play pivotal roles in facilitating the dysplasia-adenocarcinoma sequence in BE. The number of Foxp3+ T cells is increased at the early stage of carcinogenesis and could help identify patients harboring dysplastic and highly proliferating cells. CD8+ T cells could reflect unfavorable inflammatory response in adjacent tissue microenvironment and help predict worse prognosis of EAC patients.

Glucocorticoid receptor and serum- and glucocorticoid-induced kinase-1 in esophageal adenocarcinoma and adjacent Barrett's esophagus.

Barrett's esophagus (BE) is a consequence of gastroesophageal reflux disease and is predisposed to esophageal adenocarcinoma (EAC). EAC is an exemplar model of inflammation-associated cancer. Glucocorticoids suppress inflammation through glucocorticoid receptor (GR) and serum- and glucocorticoid-induced kinase-1 (Sgk1) expressions. Therefore, we immunolocalized GR and Sgk1 in EAC and the adjacent BE tissues and studied their association with clinical disease course in 87 patients with EAC who underwent surgical resection (N = 58) or endoscopic submucosal dissection (N = 29). Low GR and Sgk1 expressions in adjacent BE tissues were associated with adverse clinical outcomes (P = 0.0008 and 0.034, respectively). Patients with low Sgk1 expression in EAC cells exhibited worse overall survival (P = 0.0018). In multivariate Cox regression analysis, low GR expression in the adjacent nonmalignant BE tissues was significantly associated with worse overall survival (P = 0.023). The present study indicated that evaluation of GR and Sgk1 expressions in both the EAC cells and adjacent nonmalignant BE tissues could help to predict clinical outcomes following endoscopic and surgical treatments. In particular, the GR status in BE tissues adjacent to EAC was an independent prognostic factor.

Gastric Arteriovenous Malformation with Characteristic Endoscopic Findings.

Gastric arteriovenous malformation (AVM) is an uncommon cause of upper gastrointestinal bleeding, and the endoscopic findings are unclear. We herein describe a case of gastric AVM in a 28-year-old man. Esophagogastroduodenoscopy showed a Dieulafoy lesion surrounded by a red mucosa with a sharp margin, which implied blood vessel malformation. Computed tomography angiography and conventional angiography revealed aggregated vessels on the greater curvature. Partial gastrectomy was performed, with no recurrent bleeding postoperatively. The histopathological diagnosis was AVM. We conclude that gastric AVM should be considered in the differential diagnosis of patients who present with a Dieulafoy lesion surrounded by a red mucosa.

[A Case of Hypertrophic Pachymeningitis with Symptomatic Venous Congestion due to Sinus Stenosis].

We report a patient with hypertrophic pachymeningitis and symptomatic stenosis of the superior sagittal sinus. A 71-year-old man presented with right hemiparesis, sensory-dominant aphasia, and right hemispatial neglect that had been worsening over 2 weeks. Computed tomography showed isodense crescent-shaped lesions deforming the surface of the left cerebral hemisphere, mimicking a subdural hematoma with atypical perifocal edema in the left parietal lobe. Magnetic resonance imaging showed diffuse thickening of the dura mater with contrast enhancement of his left cerebral hemisphere. Histopathological examination of the dural specimen obtained by burr-hole surgery revealed mononuclear inflammatory cell infiltration, and he was diagnosed with hypertrophic pachymeningitis. Dynamic cerebral angiography showed superior sagittal sinus stenosis with reduced venous flow through the left parietal lobe. Administration of high-dose steroid therapy led to neurological improvement. In the case of a subdural mass with atypical parenchymal edema such as a chronic subdural hematoma, other etiology should be taken into consideration.

Adventitial Cystic Disease Communicating with the Knee Joint: A Case Report with Histopathological Study of the Connection.

Adventitial cystic disease is a rare nonatheromatous cause of popliteal artery disease. Here, we present a case of a 51-year-old male patient who presented with right calf claudication caused by adventitial cystic disease. Preoperative magnetic resonance imaging and intraoperative findings revealed the presence of a connection between the cyst and adjacent knee joint. In addition, histopathological examination revealed that the tissue structure of the connection was similar to that of adventitial cysts. The tissue composed of 2 types of cells, namely macrophages and fibroblast-like cells, and lesional cells expressed D2-40. These findings supported the ganglion theory as the underlying physiopathology of this disease and were helpful in deciding the management of this case.

[Successful Treatment of Malignant Lymphoma Arising from the Left Atrial Myxoma with Acute Myocardial Infarction;Report of a Case].

Primary cardiac malignant lymphoma within a cardiac myxoma is extremely rare. Here we report a case of a previously healthy 71-year-old woman who developed acute myocardial infarction. Transthoracic echocardiography showed a 69×45-mm solid tumor in the left atrium that was moving in a circular manner in the left atrial and ventricular cavities. Coronary angiography revealed an occlusion due to a coronary emboli in the distal part of the right coronary artery. Thrombectomy with an aspiration catheter was successfully performed to remove large red thrombi from the arterial lumen. Emergent surgical removal of the left atrial tumor along with tricuspid valve annuloplasty was performed under cardiopulmonary bypass. The postoperative course was uneventful. Histological examination demonstrated presence of malignant lymphoma within the myxoma. The patient was treated with rituximab, tetrahydropyranyl adriamycin, cyclophosphamide, vincristine, and predonisone (R-THP-COP) and is doing well without recurrence of lymphoma at 18-month follow-up. We emphasise that all surgical cardiac specimens should be sent for histological analysis aiming at the best treatment.

DNA damage response and its clinicopathological relationship in appendiceal tumors.

BACKGROUND: Appendiceal tumors are rare, and their pathogenesis is not well known. DNA damage response (DDR) is a sequence from the detection of damaged DNA to the repair, and its impairment is implicated in the progression of cancers. The aim of the current study is to explore the expression and phosphorylation of checkpoint kinase 2 (Chk2) and TP53, which are key molecules in DDR, and their clinicopathological correlation in the appendiceal tumors. METHODS: Chk2, phosphorylated Chk2 (pChk2), and TP53 were immunostained in 4 cases of adenoma (AD), 5 non-mucinous adenocarcinomas (AC), 29 low-grade appendiceal mucinous neoplasms (LAMN), and 7 mucinous adenocarcinomas (MAC). Ki-67 labeling index was also evaluated by immunostaining. RESULTS: Chk2 was highly expressed in the nuclei of all the appendiceal tumors. While pChk2 was high in AD, LAMN, and MAC, it was reduced in AC. Nuclear positive reaction of TP53 was lower in LAMN compared with those of other tumors. The Ki-67 labeling index was slightly lower in LAMN than those in other tumors. The recurrence and death in LAMN is infrequent compared with those in AC and MAC. CONCLUSIONS: The current study suggested the impairment of DDR in AC and MAC. DDR appeared to be preserved in LAMN, and it may account for low proliferating activity and a favorable clinical course in LAMN.

Tumor microenvironment and RIG-I signaling molecules in Epstein Barr virus-positive and -negative classical Hodgkin lymphoma of the elderly.

Classical Hodgkin lymphoma (CHL) is a B-cell neoplasm characterized by Hodgkin and Reed-Sternberg (HRS) cells. Its prevalence exhibits a bimodal pattern of peaking in young adults and the elderly. There is an association with Epstein-Barr virus (EBV) infection in about 50% of cases of CHL of the elderly, and the outcome of these patients is unfavorable. It is not well known how the latent infection of EBV is involved in the pathophysiology of CHL of the elderly. To address this issue, we examined the tumor microenvironment (TME) and the expression of molecules related to EBV infection in HRS cells in 10 EBV-positive CHL and 7 EBV-negative CHL patients older than 50 years. In EBV-positive CHL, we found an increased population of FOXP3(+) cells, while that of granzyme B(+) cells was reduced, compared with those in EBV-negative CHL. The expression of inhibitory chemokine CCL20 was increased in EBV-positive HRS cells compared with that in EBV-negative HRS cells. In addition, despite increased expression of a pattern recognition receptor, RIG-I, in intracellular innate immunity, there was no evidence of interferon regulatory factor 3 activation or interferon-ß induction in EBV-positive HRS cells in CHL of the elderly. The disease recurred frequently (50%) in EBV-positive CHL. The current study thus suggests the possibility that the latent infection of EBV alters the expression of chemokines and the innate immunity response in HRS cells and modulates TME to an immunosuppressive state, which may account for the unfavorable disease course in CHL of the elderly.

Disseminated infection and pulmonary embolization of Cunninghamella bertholletiae complicated with hemophagocytic lymphohistiocytosis.

A 22-year-old Japanese woman was diagnosed with hemophagocytic lymphohistiocytosis and subsequently was treated with etoposide and cyclophosphamide. On Day 22, multiple nodular lesions appeared in the bilateral lungs. Neither the administered antibiotics nor the antifungal agent were effective, and she died suddenly of respiratory failure on Day 35. An autopsy revealed disseminated zygomycosis and a pulmonary infarction due to the embolization of an angioinvasive fungus, which was later identified as Cunninghamella bertholletiae using in situ hybridization of 18S rRNA. C. bertholletiae is aggressive as well as resistant to antifungal agents. This rare species should therefore be taken into consideration as a potential causative agent of zygomycosis.

Whipple disease diagnosed with PCR using formalin-fixed paraffin-embedded specimens of the intestinal mucosa.

We herein present the case of a 54-year-old Japanese woman with Whipple disease diagnosed with polymerase chain reaction (PCR) using formalin-fixed paraffin-embedded (FFPE) specimens. The patient complained of weight loss, diarrhea and arthralgia. An endoscopic examination revealed swollen villi in the duodenum and ileum. Pathology demonstrated the presence of numerous macrophages filled with diastase-resistant PAS-positive particles. PCR using FFPE specimens amplified a fragment of 16S rDNA from Tropheryma whipplei. After the administration of ceftriaxone followed by trimethoprim/sulfamethoxazole, no signs of recurrence were observed for two years. The use of FFPE specimens for PCR should be considered for the prompt diagnosis and prevention of disease progression.

Primary gastric synovial sarcoma: molecular diagnosis and prediction of prognosis.

A 42-year-old Japanese woman complained of upper abdominal pain. Endoscopic examination demonstrated an elevated lesion in the body of the stomach, and a biopsy specimen demonstrated proliferation of atypical spindle cells. She underwent partial gastrectomy; the resected tumor measured 3.5 × 2.8 × 1.2 cm in size. Histological examination disclosed the haphazard proliferation of spindle cells in the mucosa mixed with less prominent epithelioglandular component. The spindle cells were positive for cytokeratin, vimentin, EMA and CD99, but not for KIT, DOG1, desmin or S100. Reverse transcription-polymerase chain reaction using paraffin sections amplified a SYT-SSX1 chimera transcript. A diagnosis of synovial sarcoma was made. There has been no sign of recurrence or metastasis for 6 years after the operation. Synovial sarcoma in the stomach is very rare. Since differential diagnosis of synovial sarcoma from carcinosarcoma and mesenchymal tumors is critical for the treatment and prediction of prognosis, accurate diagnosis with molecular analysis is essential.

Profiling of somatostatin receptor subtype expression by quantitative PCR and correlation with clinicopathological features in pancreatic endocrine tumors.

OBJECTIVES: Pancreatic endocrine tumor (PET) presents variable clinical features. Five subtypes of somatostatin receptor (SSTR) are involved in hormone secretion and cell proliferation. In this paper, we explore the correlation between the SSTR subtype messenger RNA (mRNA) expression and clinicopathological features of PET. METHODS: Twenty-one cases of PET and 5 cases of pancreatic adenocarcinomas (AC) were studied. Using total RNA extracted from paraffin sections and fresh tissues, SSTR subtype mRNA was quantified by real-time polymerase chain reaction. The hormones and MIB1 index were examined using immunohistochemical techniques. RESULTS: The mRNA levels of SSTR1, SSTR2, SSTR3, and SSTR5 were high in PET compared with AC, whereas the expression of SSTR4 was low in PET and AC. Levels of each subtype did not vary with histological grades. Somatostatin receptor 2 levels in functioning tumors were slightly low compared with nonfunctioning tumors. Four distinct groups of PET were identified by hierarchical cluster analysis, and two of these groups showed reduced SSTR5 with elevation of MIB1 index. CONCLUSIONS: The study showed a heterogeneous expression profile of SSTR subtype mRNA and the association of reduction in SSTR5 with high proliferative activity. Such profiling of SSTR subtypes may provide useful information on tumor biology and treatment of PET.

Mycobacterial infection of the musculoskeletal tissues: the use of pathological specimens for identification of causative species by PCR-direct sequencing of 16S rDNA.

Mycobacterial infection of musculoskeletal tissue is a rare disease that may cause destruction of the tissues. Both Mycobacterium tuberculosis and non-tuberculous mycobacteria affect the tissues. Although surgical debridement and antibiotic therapy are required for the treatment, it is necessary to identify the causative species before selecting the antibiotics. However, it is difficult to identify the species in clinical samples from musculoskeletal tissue. In the current study, using pathological specimens, the causative species was identified by PCR amplification and direct sequencing of mycobacterial 16S rDNA containing a hypervariable region. Twelve cases of chronic granulomatous inflammation of musculoskeletal tissues were used for the study. DNA was extracted from paraffin sections, and mycobacterial 16S rDNA was amplified by PCR. The amplicons were obtained in 5 of 12 cases (41%), even in specimens in which the microorganism was only scarcely detected by using special stains. Direct sequencing of the amplified products presented high homology with M. tuberculosis in four cases and M. avium in one. Therefore, PCR-direct sequencing of 16S rDNA containing hypervariable region using pathological specimens is useful for the diagnosis and identification of causative species in mycobacterial infection of musculoskeletal tissues.

Localized amyloidosis at the site of repeated insulin injection in a diabetic patient.

A 60-year-old woman diabetic patient presented with a subcutaneous mass in right lower abdominal quadrant where recombinant human insulin or insulin analogue had been injected for 16 years. Her diabetes has been insulin resistant with insufficient blood glucose control. The mass was extirpated under the suspicion of neoplasm but it was found to consist of diffuse deposition of eosinophilic amorphous materials mixed with inflammatory change. Congo-red staining demonstrated positive red color and yielded green birefringence by polarized microscopy. Pre-digestion with potassium permanganate was incomplete to quench positive Congo-red stains. Immunostains with insulin antibody were positive for this deposition but not so with amylin or AA or AL amyloid. Thus, the mass was considered to be localized amyloidosis composed of iatrogenic A-Ins type amyloid. Thus, the case suggested that her insulin resistance, i.e. refractoriness of insulin treatment, may be ascribed to poor penetration of injected insulin and human insulin itself or its analogue is amyloidogenic to form a local mass.

Sporadic amyotrophic lateral sclerosis with pallido-nigro-luysian degeneration: a TDP-43 immunohistochemical study.

Recently, Nishihira et al. demonstrated the presence of two types of TDP-43 pathology in sporadic amyotrophic lateral sclerosis (ALS) (Acta Neuropathol 2008; 116: 169-182). Type 1 represents the TDP-43 distribution pattern observed in classic ALS, whereas type 2 shows the presence of TDP-43 inclusions in the frontotemporal cortex, hippocampal formation, neostriatum and substantia nigra and is significantly associated with dementia. However, ALS with pallido-nigro-luysian degeneration (PNLD) is very rare. We recently encountered a case of ALS with PNLD of 9 years duration, in which the patient received artificial respiratory support for 6 years. In our case, neuronal loss and TDP-43-positive neuronal cytoplasmic inclusions were found in the globus pallidus, substantia nigra and subthalamic nucleus. Neither neuronal loss nor TDP-43-immunoreactive inclusions were found in the frontotemporal cortex and hippocampus. These findings suggest that the pallido-nigro-luysian system is also involved in the disease process of ALS and that ALS with PNLD is different from ALS with dementia based on the distribution pattern of neuronal loss and TDP-43 accumulation.

Small cell carcinoma with skeletal muscle differentiation of urinary bladder.

Reported herein is a case of small cell carcinoma (SCC) with skeletal muscle differentiation of urinary bladder in a 76-year-old woman presenting macrohematuria. Ultrasonography and CT detected a mass at the anterior wall of the urinary bladder, and total cystectomy followed. The tumor consisted of solid growth of small round cells with high nucleocytoplasmic ratio admixed with rhabdoid cells with eosinophilic cytoplasmic inclusions, invading the perivesical tissue. On immunohistochemistry the tumor cells were diffusely positive for neural markers and CD99, and sporadically for skeletal muscle markers. Fluorescence in situ hybridization showed no translocation of EWS. The patient died from massive recurrence in the pelvis 4 months after operation. This rare tumor indicates a potential of myoid differentiation in SCC of the urinary bladder and differential diagnosis from primitive neuroectodermal tumor is important because the treatment is different.

Correction of protein kinase C activity and macrophage migration in peripheral nerve by pioglitazone, peroxisome proliferator activated-gamma-ligand, in insulin-deficient diabetic rats.

Pioglitazone, one of thiazolidinediones, a peroxisome proliferator-activated receptor (PPAR)-gamma ligand, is known to have beneficial effects on macrovascular complications in diabetes, but the effect on diabetic neuropathy is not well addressed. We demonstrated the expression of PPAR-gamma in Schwann cells and vascular walls in peripheral nerve and then evaluated the effect of pioglitazone treatment for 12 weeks (10 mg/kg/day, orally) on neuropathy in streptozotocin-diabetic rats. At end, pioglitazone treatment improved nerve conduction delay in diabetic rats without affecting the expression of PPAR-gamma. Diabetic rats showed suppressed protein kinase C (PKC) activity of endoneurial membrane fraction with decreased expression of PKC-alpha. These alterations were normalized in the treated group. Enhanced expression of phosphorylated extracellular signal-regulated kinase detected in diabetic rats was inhibited by the treatment. Increased numbers of macrophages positive for ED-1 and 8-hydroxydeoxyguanosine-positive Schwann cells in diabetic rats were also corrected by the treatment. Pioglitazone lowered blood lipid levels of diabetic rats, but blood glucose and nerve sorbitol levels were not affected by the treatment. In conclusion, our study showed that pioglitazone was beneficial for experimental diabetic neuropathy via correction of impaired PKC pathway and proinflammatory process, independent of polyol pathway.