Two cases of gastric cancer with elevated serum levels of KL-6.

BACKGROUND: The serum level of Krebs von den Lungen-6 (sKL-6) is a biomarker of interstitial pneumonia and has been reported to be elevated in patients with cancers. However, there have been few cases of gastric cancer (GC) with elevated sKL-6 that were treated by chemotherapy. We herein report two cases of GC with elevated sKL-6 that were treated with oxaliplatin plus S-1 (SOX) chemotherapy and discussed the resulting changes in sKL-6. CASE PRESENTATION: The first patient was a 79-year-old woman complaining of loss of appetite. Esophagogastroduodenoscopy (EGD) showed a type-3 tumor in the gastric antrum and biopsy specimens showed adenocarcinoma. Computed tomography (CT) showed multiple liver metastases. sKL-6 was elevated to 1,292 U/ml, but a CT revealed no obvious lesions of the lungs, including interstitial pneumonia. The tumor was diagnosed as GC with liver metastases and elevated sKL-6. Respiratory function data were normal. SOX therapy using oxaliplatin and S-1 was performed. After 3 courses of SOX therapy, CT showed reductions of the liver metastases as well as the primary tumor, and sKL-6 was decreased to 201 U/ml. After the 44 courses, sKL-6 was slightly elevated. Chest CT showed interstitial pneumonia and chemotherapy was stopped. The patient is still alive without any metastasis 72 months later. The second patient was a 69-year-old woman complaining of upper abdominal pain. EGD revealed a type-3 tumor in the gastric antrum showing adenocarcinoma with HER2-positive pathology. CT showed multiple node metastases around the abdominal aorta. sKL-6 was elevated to 2,239 U/ml, but a respiratory function test showed no abnormalities, and CT of the lungs showed no obvious lesions. The tumor was diagnosed as GC with distant node metastases and elevated sKL-6. The patient received SOX therapy combined with trastuzumab. After 6 courses, the size of the primary tumor and multiple node metastases were reduced, and sKL-6 was decreased to 284 U/ml. CONCLUSIONS: These two cases suggest that sKL-6 may be important not only as an indicator of interstitial pneumonia in chemotherapeutic courses, but also as a tumor marker in GC patients with multiple metastases.

Bystander CD8 + T cells may be involved in the acute phase of diffuse alveolar damage.

Acute respiratory distress syndrome (ARDS) is a serious complication of systemic inflammatory response syndrome, and diffuse alveolar damage (DAD) is a histological manifestation of ARDS. Endothelial cell injury is mainly responsible for ARDS. Many neutrophils and macrophages/monocytes, which are inflammatory cells that play a role in innate immunity, infiltrate the lung tissue in DAD. In recent years, it has become clear that CD8 plays an important role not only in the acquired immune system, but also in the innate immune system. Non-antigen-activated bystander CD8 + T cells express the unique granzyme B (GrB) + /CD25-/programmed cell death-1 (PD-1)-phenotype. The involvement of bystander CD8 + T cells in lung tissue in DAD is an unexplored field. This study aimed to determine whether bystander CD8 is involved in DAD. Twenty-three consecutive autopsy specimens were retrieved from patients with DAD, and the phenotypes of infiltrating lymphocytes in the DAD lesions were evaluated using immunohistochemistry. In most cases, the number of CD8 + T cells was higher than that of CD4 + T cells, and many GrB + cells were also observed. However, the number of CD25 + and PD-1 + cells was low. We conclude that bystander CD8 + T cells may be involved in cell injury during the development of DAD.

A case report of adenosquamous carcinoma of the esophagogastric junction.

BACKGROUND: Many types of tumors can arise in the esophagogastric junction (EGJ). Squamous cell carcinoma (SCC) arising from the esophageal epithelia, adenocarcinoma arising from the gastric mucosa, or Barrett's esophageal mucosa are frequently observed in the EGJ. However, adenosquamous carcinoma (ASC) has been rarely observed in this area. We herein report a rare case of ASC of the EGJ. CASE PRESENTATION: An 81-year-old man visited our hospital complaining of dysphagia. Esophagogastroduodenoscopy detected an elevated tumor in the gastric cardia. Biopsy specimens taken from the tumor showed SCC. Computed tomography revealed a tumor located in the EGJ and node metastases surrounding the EGJ. The tumor was diagnosed as SCC, overhanging in the stomach, of the EGJ. The patient underwent a proximal gastrectomy with a lower esophagectomy and node dissection for the metastases surrounding the EGJ, and esophagogastrostomy in the lower mediastinum. Histopathologic examination showed the tumor consisted of SCC and adenocarcinoma. The adenocarcinoma consisted of nests scattered in the SCC. We observed adenocarcinoma component in 35% of the tumor and epithelial spread of SCC in the lower esophagus. Thus, we diagnosed the tumor as ASC of the EGJ. Eight metastatic nodes were dissected; both SCC and adenocarcinoma were observed in seven. CONCLUSIONS: In the present case, SCC may be originated from the squamous epithelia of the lower esophagus and grew into the stomach, and the adenocarcinoma may have differentiated from SCC through the infiltration.

Histologic and Immunohistochemical Evaluation of Infiltrating Inflammatory Cells in Kawasaki Disease Arteritis Lesions.

Kawasaki disease (KD) is a systemic vasculitis of unknown etiology which predominantly affects medium- and small-sized muscular arteries. Histopathologic studies of KD vasculitis lesions have demonstrated characteristic T cell infiltration and an abundance of CD8 T cells; however, the contribution of cytotoxic lymphocytes to KD vasculitis lesions has not been identified. Here, we histopathologically and immunohistochemically examined infiltrating inflammatory cells, particularly cytotoxic protein-positive cells, such as granzyme B cells and TIA-1 cells, in KD vasculitis lesions. Three autopsy specimens with acute-phase KD were observed and contained 24 vasculitis lesions affecting medium-sized muscular arteries, excluding pulmonary arteries. Infiltrating neutrophils in vasculitis lesions were evaluated by hematoxylin and eosin staining, and monocytes/macrophages and lymphocytes were evaluated by immunohistochemistry. The predominant cells were CD163 monocytes/macrophages and CD3 T cells. CD8 T cells, granzyme B cells, and TIA-1 cells were also observed, but CD56 natural killer cells were rare. To the best of our knowledge, the current study is the first histopathologic report confirming the infiltration of inflammatory cells with cytotoxic proteins in vasculitis lesions in patients with KD. Cytotoxic T cells may play a role in the development of vasculitis lesions in KD patients.

The ratio of CD163-positive macrophages to Iba1-positive macrophages is low in the intima in the early stage of cutaneous arteritis.

The etiology of polyarteritis nodosa (PAN) and localized PAN, including cutaneous arteritis (CA), remains unknown; however, initial endothelial damage has been implicated. The intima of the vasculitis lesions is predominantly infiltrated by innate-like bystander-activated CD8 T cells, in addition to the macrophages. Macrophages are among the major inflammatory cells involved in innate immunity and are classified into M1 and M2 subtypes. M1-type macrophages kill pathogens and cause inflammation, while M2-type macrophages promote the repair of tissues. Macrophage subtypes infiltrating in PAN and localized PAN vasculitis lesions have not yet been investigated. Innate immune response to a triggering factor on the endothelial cell surface may initiate CA pathogenesis. Thus, many M1-type macrophages may infiltrate in the intima during early CA. We assessed this hypothesis by immunohistochemical observation of macrophage phenotypes and polarization. Twenty-seven skin biopsy specimens from patients with CA were retrieved. Based on histology, we classified CA into four phases. The phenotypes of infiltrating macrophages in CA were evaluated by immunohistochemistry using antibodies against Iba-1, a pan-macrophage marker, and CD163, an M2-type macrophage marker. Our results showed that the ratio of CD163-positive M2-type macrophages to Iba1-positive macrophages was lower in the intima in the early stage of CA than in the later stage. In the media to adventitia, there was no significant difference in the ratios between these stages. These findings indicate that innate immunity is involved in the intima in the early stage of CA, suggesting that a trigger for CA might exist in endothelial cells.

An anaplastic pleomorphic xanthoastrocytoma with periventricular extension: An autopsy case report and review of the literature.

Pleomorphic xanthoastrocytomas (PXAs) are rare low-grade astrocytic tumors that typically present as superficial nodular cystic tumors of the cerebrum attached to the leptomeninx. Histologically, they are pleomorphic, hypercellular glial neoplasms. Despite the presence of microscopic pleomorphism, patients' postoperative prognosis is generally good. Anaplastic PXAs (APXAs) have a high mitotic index and patients with APXAs have a worse prognosis than patients with PXAs. Here, we report an autopsy case of APXA initially diagnosed as PXA. After gross total resection, the tumor recurred and was diagnosed as an APXA; thereafter, the patient died. An autopsy revealed that the tumor had relapsed at the primary site and had spread to the leptomeningeal space while concurrently invading the cerebrum including the periventricular area forming multifocal lesions. The histological findings of the autopsy were similar to those for epithelioid glioblastoma (EGBM) and small cell glioblastoma (SCGBM). In particular, the periventricular area with multifocal lesions was composed of SCGBM-like cells. It has been shown that multifocal lesions are frequently identified in patients with SCGBM. This is the first histopathologically confirmed case of APXA-related tumor presenting with periventricular extension and multifocal lesion formation. The periventricular extension might be a feature of PXAs and APXAs. However, suspected periventricular spread on imaging in past cases of PXAs and APXAs might instead represent the malignant transformation of these tumors to glioblastoma-like high-grade tumors, which often show SCGBM-like histological patterns.

Ultrastructure of CIC-DUX4 sarcoma: the first pathological report.

CIC-DUX4 sarcoma (CDS) is a recently identified subtype of small round cell sarcoma. Morphologically, CDS partially resembles Ewing sarcoma (ES) and has been classified as "ES-like sarcoma"; however, detailed clinicopathologic and molecular genetic analyses have indicated that CDS is a new independent disease. Many studies have provided light microscopic, immunohistochemical, and genetic information about CDS. However, ultrastructural findings associated with this sarcoma are lacking. The aim of this study was to investigate the ultrastructure of CDS tumors and to compare their features with those of ES. We examined two cytogenetically confirmed CDS cases. We found that, compared to typical ES, CDS presented heterogeneity: in cell density, from tightly packed to loosely unconnected areas; in cell shape, from polygonal to pleomorphic with small processes; and in nuclear shape including round, oval, polygonal, elongated, invaginated, or wrinkled formations. However, abundant glycogen in the cytoplasm and rare cell adhesion apparatus between cells are major similarities between CDS and typical ES. Neuroendocrine granules, which are seen in rare ES cases, could not be identified in these two CDS cases. Although cytogenetic differences can validate a definite diagnosis, ultrastructural features could also provide important information about the differences between CDS and ES.

Malignant peritoneal mesothelioma diagnosed 50 years post-radiotherapy for ovarian cancer in a patient with a history of multiple malignancies: An autopsy case.

As the number of long-term cancer survivors is increasing, the incidence of post-irradiation malignant mesothelioma may also increase. We herein present the case of an 85-year-old female patient with a history of several surgeries for solid tumors and radiotherapy to the pelvis, who presented with abdominal pain and diarrhea. The patient's general condition gradually worsened and she succumbed to cardiopulmonary arrest triggered by vomiting ~3 months after the onset of the abdominal symptoms. An autopsy revealed malignant intestinal obstruction caused by peritoneal mesothelioma. Irradiation is a known risk factor for malignant mesothelioma, which may develop ~10-30 years after radiotherapy. To the best of our knowledge, this is the first report of a patient with malignant mesothelioma developing ~50 years after radiotherapy. The aim of the present study was to remind physicians that malignant mesothelioma should be considered in the differential diagnosis of patients with a history of radiotherapy who present with gastrointestinal symptoms.

A fulminant case of classical Hodgkin lymphoma: A diagnostic dilemma of Epstein-Barr virus-positive large B-cell neoplasms.

We report a fulminant case of classical Hodgkin lymphoma (CHL). The patient died only approximately 2 months after the onset of subjective symptoms. Autopsy specimens revealed atypical cells resembling Hodgkin and Reed-Sternberg (HRS) cells in a rich inflammatory background in various organs. There were marked, characteristic angiodestructive lesions from infiltrating HRS-like cells and numerous macrophages. The HRS-like cells were infected with Epstein-Barr virus (EBV), immunohistochemically positive for PAX5 and CD30, and negative for CD3, CD20, and ALK. Most B-cell markers other than PAX5 were negative, and the HRS-like cells also expressed cytotoxic molecules. Monoclonal rearrangement of immunoglobulin heavy chain was detected by PCR analysis. According to the 2016 WHO classification, we diagnosed mixed cellularity CHL. However, EBV-positive diffuse large B-cell lymphoma (DLBCL), not otherwise specified and EBV-positive B-cell lymphoma, unclassifiable with features intermediate between DLBCL and CHL were considered as differential diagnoses because both tumors are aggressive EBV-positive large B-cell neoplasms with reactive inflammatory cells and sometimes contains HRS-like cells. The clinical condition of the current case was closer to these two entities than to CHL. A diagnosis of EBV-positive large B-cell neoplasms was difficult because of overlapping morphological and immunohistochemical characteristics, but should be considered for prognosis.

Lower number of 5-hydroxymethylcytosine-expressing cells in plasma cell myeloma than in reactive plasma cell hyperplasia: a useful immunohistochemical approach for identification of neoplastic plasma cells.

Plasma cell myeloma (PCM) is a haematological malignancy defined by aberrant proliferation of plasma cells in the bone marrow. For the diagnosis of PCM, immunostaining of light chains or surface marker analyses by flow cytometry is needed but sometimes difficult. Aberrant methylation at the carbon-5 position of cytosine results in 5-methylcytosine (5-mC), which is a well-known epigenetic hallmark of cancer in mammals. 5-mC is oxidised to 5-hydroxymethylcytosine (5-hmC), and low 5-hmC levels occur in several cancers and haematopoietic malignancies. We compared the expression of 5-hmC by immunohistochemistry (IHC) in neoplastic plasma cells in 31 PCM cases and in non-neoplastic plasma cells in 14 benign reactive lesions. The mean percentage of 5-hmC-positive cells was 7.8% and 81.5% in PCM and plasma cell hyperplasia, respectively. Thus, the frequency of 5-hmC-positive cells in PCM specimens was significantly lower than that in reactive plasma cell hyperplasia (p < 0.001 by Student's t-test). IHC of 5-hmC is a useful method for differentiating neoplastic plasma cells from non-neoplastic plasma cells in reactive lesions even in tiny tissue samples unsuitable for flow cytometric analyses or for immunoglobulin light chain IHC.

Multiple primary chordomas of the lung.

We here report the case of a 40-year-old man with primary pulmonary chordomas. Although an abnormality had been noted on a chest radiograph at age 26 years, the patient had not undergone further examination at that time because he was asymptomatic. Standard chest radiographs and computed tomography showed slow-growing, multiple bilateral pulmonary nodules. Two tumors were resected thoracoscopically to obtain a diagnosis. Pathologic examination resulted in a diagnosis of chordomas. Subsequent systemic examination revealed no additional lesions, not even in the axial skeleton. The patient is alive without any new lesions 38 months after surgery. These clinical and pathological findings suggest that our patient has multiple primary chordomas of the lung, which is an extremely rare condition.