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Ciliated muconodular papillary tumor( CMPT) is a rare true pulmonary tumor consisting of bronchiolar cellular elements. Although this tumor cannot be classified as benign or malignant, it is mostly believed to be a benign bronchiolar adenoma. Recently, CMPT has been divided into two subtypes: proximal and distal. Herein, we report a case of a proximal type of CMPT containing abundant mucus cells in a 70-year-old woman. Thoracoscopic resection of the tumor in the left lower lobe was successfully performed, and the patient has been well without recurrence or metastasis for more than three years after surgery.

Alveolar mouths (AMs) are very important points for the formation of Masson bodies (MBs) and hyaline membranes (HMs), which are considered serious complications of influenza virus pneumonia. MBs arise by injury, caused by influenza virus infection of AMs, which cover the epithelial and endothelial cells of AMs. Resulting exudates of AMs, mesenchymal cells, fibroblasts, and myofibroblasts proliferate, forming polyp-like MBs which protrude into air spaces. These structures are very sensitive to steroid therapy and are absorbed rapidly after steroid administration. However, if the MBs contain fibrin, as seen in acute fibrinous organizing pneumonia (AFOP), and myofibroblast proliferation, absorbed MBs remain in the septal and luminal spaces as pulmonary fibrosis. Massive MBs cause serious disturbance to respiratory function in peripheral airways. In HM formation, following injury to the epithelial cells of AMs irregular shaped fluffy fragmented substances form at AMs, becoming larger and flat in shape and forming membranous HM structures that disturb peripheral gas exchange. These HMs are immunopositive for cytokeratins, epithelial membrane antigen, KL-6, surfactant protein A, and Factor VIII-related antigens, but never fibrin. Following HM and MB formation, peripheral airways including alveolar orifices, such as respiratory bronchioles, alveolar ducts, alveolar sacs, and alveoli lose their gas-exchange capacity. Moreover, HMs form rapidly at AMs in the structurally retained pulmonary parenchyma, leading to acute respiratory insufficiency and numerous associating MBs in the peripheral airways.

There are various guidelines for the management of a single pulmonary nodule. Although liquid biopsy alone may be able to diagnose lung cancer safely and easily in the future, clinical approaches based on radiological (CT with or without PET) appearance and cancer risk factors are currently common in guidelines.

A 70-year-old Japanese man complained of macrohematuria. He was diagnosed with high grade urothelial carcinoma (UC), G3, and underwent transurethral resection of bladder tumor (TUR-BT) twice. UC containing a chordoid component was found in the TUR-BT tissue samples. Total cystectomy combined with nephroureterectomy was performed because of deep muscular invasion into the bladder, in addition to intensive ureteral and prostatic invasion. Histopathological findings from the bladder tumor revealed an invasive UC with an adenocarcinoma component, combined with peculiar chordoid features associated with abundant myxoid matrix. The chordoid component metastasized to the right kidney, invading the prostate and right ureter. Chordoid component was detected in approximately 50% in total tumor extent Immunohistochemical analysis indicated that, although the chordoid component showed similar staining results to those of chordoma (namely, it was positive for CAM5.2 and cytokeratin 19 and focally positive for epithelial membrane antigen, carcinoembryonic antigen, and S100 protein), the UC and chordoid components were both negative for vimentin. In contrast, both chordoma and extraskeletal myxoid chondrosarcoma demonstrate positivity for vimentin, which is histologically similar to the present case. The patient had come to see us, before 11 months. A follow-up assessment showed no recurrence or distant metastasis 8 months after twice TUR-BT and five months since total cystectomy. But unfortunately, the patient dropped out from our follow-up data, because he did not come to our hospital. Thus, pathologists and clinicians must consider that a chordoid component may represent the malignant characteristic of UC.

Personalised breast cancer therapy requires pathological characterisation of tumours. The proliferative index, based on Ki67, is pivotal, but a standard method has not been established. Here we look for an easy and practical way to evaluate Ki67.Immunohistochemical staining of estrogen receptors, progesterone receptors, HER2 and Ki67 (MIB-1) was performed on resected specimens from 406 primary invasive ductal carcinomas. Ki67 labelling index (LI) from manual counting was compared with visual assessment using a 5-grade scale (Eye-5). Next, 10 pathologists evaluated 100 samples with marked hot spots by using Eye-5. Another 100 samples without marking were also assessed by eight pathologists. One year later, two pathologists reviewed 222 cases with Eye-5. Prognosis was analysed among estrogen receptor-positive cases with postoperative endocrine therapy.Eye-5 showed good correlation to LI. All 136 cases of score 4-5 had LI20% and all 56 cases of score 1 had LI20%, which means that manual counting was not necessary for about half of the cases. Interobserver and intraobserver variability was low even when a hot spot was not fixed. Eye-5 also correlated with histological grade and lymph node metastasis. Combining Eye-5 and histological grade created a new algorism to predict LI, which allows 80% of all cases (74% of luminal cases) without manual counting. Cases of Eye-5 score 1-2 had significantly better survival than score 3-5.Visual assessment of Ki67 by a 5-grade scale (Eye-5) is fast, easy, and reliable with acceptably low interobserver and intraobserver variability. Eye-5 can replace LI in many luminal tumours, and is a strong candidate as a standard method of evaluating Ki67.

KL-6 is known as a useful serum biomarker of the disease activity in interstitial pneumonias. We investigated its usefulness as a biomarker for subtyping intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. IPMNs are generally divided into 4 subtypes, namely pancreatobiliary (PB), intestinal (INT), gastric (GS), and oncocytic (ONC). Aside from the KL-6 antibody, the MUC1, MUC2, MUC5AC, MUC6, and MIB-1 antibodies were also examined. Eighteen IPMN cases were examined, including 12 cases of intraductal papillary mucinous carcinomas (IPMCs) simultaneously associated with dysplasia (IPMDs) and hyperplasia (IPMHs) and 6 IPMD cases with IPMH. KL-6 antibody was positive in the 8 IPMC cases, corresponding to a MUC2-negative PB subtype, but negative in 4 IPMC cases, corresponding to the INT subtype, which is positive for MUC2. IPMD of moderate-to-severe degree positively stained for the KL-6 antibody in the IPMC cases of the PB subtype but not in those of the INT subtype. The IPMH cases were mostly negative for KL-6, similar to the mild IPMD cases. In the 6 cases of mild IPMD and/or IPMH, KL-6 and MUC2 expressions were mostly negative. In conclusion, the KL-6 antibody is immunohistochemically a good biomarker of the PB subtype of IPMC, but not the INT subtype. Identifying IPMN subtypes based on KL-6 stainability would be useful. Clinicopathological studies with more IPMC cases might be needed for further progress in this field of study.

We present a case of multifocal micronodular pneumocyte hyperplasia (MMPH), lymphangiomyomatosis (LAM) and angiomyolipoma (AML) in a 33-year-old woman with tuberous sclerosis complex referred to us during her first pregnancy. Computed tomography of the chest showed diffuse micronodules and cysts in both lungs. Compared to those before pregnancy, the number of micronodules increased evidently. We hypothesized the micronodules in both lungs were either LAM, MMPH, or a combination of the two. Bilateral renal AML also intensified. About one month after childbirth, LAM and renal AML decreased without treatment. Therefore, we observed that LAM and AML were affected by the pregnancy. To the best of our knowledge, this is the first case report regarding the reversible alteration of LAM without treatment.

Reports of a composite paraganglioma (PG) and ganglioneuroma (GN) in the retroperitoneum are rare. In the present case, dynamic computed tomographic (CT) findings showed a 30 × 22 × 20 mm tumor that was located in the retroperitoneum and which was dissociated from pancreatic tissue and the left adrenal gland. The markedly reddish tumor showed a clear margin and central multicystic changes on the cut surface. The tumor was composed of two major components, the PG and the GN. The paraganglionic cells in the PG component, which were arranged in a nested pattern, occupied the main and central part of the tumor. Both ganglionic cells and Schwann cells in the GN were located in a unorganized pattern in the periphery. The paraganglionic cells exhibited a Zellballen pattern, which consisted of an association of edematous vascular-rich stroma and focal hemorrhage, resulting in multicystic changes. These centrally located tumor cells were pleomorphic in part and did not have mitotic figures. In the periphery, Schwann cells, which were arranged in an obscure and fascicular pattern that was intermingled with large ganglionic cells, were located adjacent to the PG component with a mostly sharp margin. With higher magnification, the border was not as sharp, as revealed especially with chromogranin-A immunostain, in which both the PG and GN components were focally intermingled with each other. The histogenesis of the composite PG and GN was thought to be extraadrenal neural crest cells in the retroperitoneum because the tumor was not located in the adrenal gland or the Zuckerkandl organ, according to the CT findings. The immunohistochemical findings of this rare case of a composite PG and GN in the retroperitoneum are reported with a focus on the peculiar arrangement of these two components.

A 24-year-old female presented with fever and dry cough. Influenza A virus infection was suspected and the patient was treated with neuraminidase inhibitors. Five days after diagnosis, the patient developed persistent fever and dyspnea, and was diagnosed with severe pneumonia. Despite intensive treatment, the pneumonia worsened and the patient died 14 days after admission. At autopsy, a diffuse alveolar damage (DAD) pattern was observed. Immunohistochemical evaluation indicated severe epithelial damage, resulting in successive regeneration of alveolar type II cells followed by marked proliferation of smooth muscle cells and an increase of collagen fibers at the tip of alveolar orifices.

Mucoepidermoid carcinoma of the intrahepatic bile duct is a rare variant of cholangiocarcinoma: it is composed of mucus-secreting squamous cells and glandular cells within the same nests. This tumor is very aggressive, with high-grade malignancy, and has a poor prognosis. In the international literature, only 17 cases of mucoepidermoid carcinoma originating in the hepatic bile duct system have been reported until now. We report an autopsy case of mucoepidermoid carcinoma of the intrahepatic bile duct with metastasis to the cranial skin in a Japanese man who was more than 70 years old. This cancer metastasizes to many organs, but skin metastasis is extremely rare.

The role of human papillomavirus (HPV) in the development of lung and esophageal cancer remains inconclusive, which is in contrast to the established role HPV plays in the development of uterine cervical cancer. One of the reasons for this is the difference among reported HPV infection rates in these cancers. An analysis of 485 lung and esophageal cancers (176 lung squamous cell carcinoma, 128 lung adenocarcinoma, 181 esophageal carcinoma) in eight institutions in Asia (Tokyo, Kochi, Kagoshima, and Okinawa, Japan; Seoul and Daegu, Korea; Changhua, Republic of China (Taiwan); Singapore, Singapore) was carried out in order to clarify infection rates with HPV. Samples were examined in one laboratory of the Department of Pathology, the University of Tokyo, Japan in order to avoid inter-laboratory variation using a combination of polymerase chain reaction and in situ hybridization (ISH). HPV was found in 6.3%, 7%, and 9.4% of patients with lung squamous cell carcinoma, lung adenocarcinoma, and esophageal cancer, respectively. Among the geographic areas surveyed, Kagoshima exhibited a significantly higher prevalence of HPV infection in cases of esophageal carcinoma (24.1%). There was no geographical difference in the infection rates of HPV in lung carcinomas. Subtype-specific ISH was also performed, which identified the high-risk HPV types 16/18 in the majority (75.7%) of the patients with lung and esophageal cancer positive for HPV.

Characterization of the signet-ring cell carcinoma (sig) component of a urothelial carcinoma (UC) in the urinary bladder of a 64-year-old man, obtained by transurethral resection of bladder tumor (TUR-BT), is reported. In the present case, a characteristic sig component was detected in approximately 20% of UC, G2 tissues. The sig cells were morphologically similar to those found in gastric cancers and were positively stained with periodic acid-Schiff reaction and Alcian blue and mucicarmine stains. Immunohistochemically, the sig cells were selectively positive for carcinoembryonic antigen (CEA), MUC2, and MUC5AC. These immunohistochemical characteristics were similar to those of sig cells in the stomach, except for the positivity with MUC2. It is interesting to note that CAM5.2-positive sig cells were surrounded by CAM5.2-positive UC cells in a solid nest with no apparent associated adenocarcinoma element. In addition, the ultrastructure of sig cells showed multivacuolar cytoplasmic mucin, which proved to be similar to the ultrastructure of gastric cancers. In the present case of UC, G2 was associated with a sig component. Regarding the origin of the sig component in the bladder, it has been suggested that MUC2-positive sig cells in the bladder might be derived directly from metaplasia of UC, without an associated adenocarcinoma component. From this perspective, it may be noteworthy that sig cells in the bladder were selectively positive for MUC2, exhibiting common antigenicity with mucous cells of the gastric intestinal metaplasia. Because UC associated with a sig component carries a worse prognosis than ordinary UC, the presence of the sig component in any UC should be evaluated even within TUR-BT tissues, as in the present case.

A 50-year-old man was admitted to our hospital for examination of an abnormal shadow on chest radiography. Computed tomography revealed multiple small nodular shadows in bilateral lung fields, with cavitation in a right S3 lesion that was resected by video-assisted thoracoscopic surgery. Histopathological examination revealed marked proliferation of lymphoid tissue, including many plasma cells that were polyclonal in nature. This case was considered to be pulmonary nodular lymphoid hyperplasia (PNLH). Several residual nodules spontaneously disappeared during the 6 years of follow-up. This was a rare case of PNLH with a resected cavity, followed by spontaneous regression of the remaining lesions.

Gangliocytic paraganglioma (GPG) is a rare tumor, occurring almost exclusively in the duodenum. In the present case, a submucosal tumor 2.5 x 2 x 1.5 cm in size was located on the anal side of the papilla of Vater, with clear margins and without capsule on cut-surface examination. Tumor cells included three types of cells: ganglion-like cells (GCs), endocrine cells (ECs), and Schwann cells (SCs). The GCs were large with eccentric nuclei with large nucleoli and clear abundant cytoplasm. ECs were detected in small nests, surrounded by bundles of SCs. Immunohistochemically, GCs were positive for synaptophysin, neuron-specific enolase (NSE), and CD56. ECs were positive for chromogranin A, NSE, somatostatin, pancreatic polypeptide, and CD56, and were associated with S100 protein-positive SCs. On fine structural examination, ECs contained numerous membrane-bounded secretory granules, 250-450 nm in diameter, in their cytoplasm, surrounded by a branched, complex basal lamina. SCs possessed basal lamina along their long interlacing cytoplasmic processes. The histogenesis of GPG most likely involves proliferation and differentiation of pluripotent stem cells in the duodenal crypts in the duodenum as a true tumor, although it is also possible that the retroperitoneal components of both GCs and SCs proliferate, together with ECs, from ventral primordial tissue of the pancreas in the duodenum. The immunohistochemical and ultrastructural findings of a case of GPG are reported, focusing on three major cellular components: GCs, ECs, and SCs.

Hyalinizing trabecular tumor (HTT) of the thyroid gland is rare and benign, and it neither recurs nor metastasizes. In this lesion, tumor cells are arranged in trabeculae, in association with hyalinizing mass in the stroma. The origin and nature of the hyalinizing mass are still controversial. We report here a case of HTT with cytological, immunohistochemical, and ultrastructural findings, focused in particular on the hyalinizing mass. Cytologically, tumor cells exhibiting many intranuclear cytoplasmic inclusions and nuclear grooves were found in association with light green-positive, irregular, fluffy membranous structures on touch smear. Staining with antibody to collagen type IV was positive in these membranous structures. Histopathologically, tumor cells exhibited many intranuclear cytoplasmic inclusions, and were positive for staining with antibodies to S100 protein, neuron-specific enolase, thyroglobulin, and vimentin. The hyalinizing eosinophilic mass, which was positive for PAS reaction, and for staining by antibody to collagen type IV, gradually increased in the areas surrounding tumor cells. This mass then appeared to replace the tumor cells, and exhibited a peculiar filiform pattern. We demonstrated ultrastructurally that this pattern was composed of long, irregular, fine cytoplasmic processes of tumor cells and basal lamina-like substance in the hyalinizing mass. In fact, the homogeneous hyalinizing mass, similar to basal lamina-like substance, contained many degenerated cytoplasmic processes at the ultrastructural level. These results suggested that the key cytological finding in differentiating HTT from papillary carcinoma is the fluffy membranous structure, although nuclear pseudoinclusions are important as well. The filiform pattern noted at light microscopic level consisted of long cytoplasmic processes of tumor cells and hyalinized mass at the ultrastructural level.

To evaluate the peculiar "inside-out" pattern in micropapillary (MP) carcinoma, we investigated the usefulness of KL-6 antibody in the assessment of the MP pattern of cancers, in comparison with antibodies to epithelial membrane antigen (EMA), MUC1 (CD227), and CD 10. Immunohistochemical investigation was performed on specimens exhibiting an MP pattern obtained from 12 persons with cancer: 4 with breast carcinoma, 3 with carcinoma of the urinary bladder, and 5 with colonic carcinoma. Immunohistochemical study with KL-6, EMA, and MUC1 antibodies revealed similar continuous linear positive patterns restricted to the surface of the MP pattern in both breast and urinary bladder cancers, revealing the peculiar "inside-out" morphology. However, EMA also gave cytoplasmic positivity in most of the cases tested, and MUC1 was also present in the cytoplasm of some cases. In sharp contrast, immune reactions of colon carcinomas with these antibodies were negative, except for focal positivity for KL-6 and MUC1 antibodies in some cases. CD10 was only focally positive in an MP pattern in 4 of the 5 cases of colon carcinoma and in 1 case with carcinoma of the urinary bladder. These findings suggest that KL-6 is a useful marker to assess the MP character of breast and urinary bladder carcinomas; that MUC1 was similarly positive, with the addition of cytoplasmic positivity in some cases; and that the MP pattern of colon cancer, positive for CD 10, was different in character from both breast and urinary bladder carcinomas, although all these cancers seemingly exhibit similar MP patterns on histopathology. This heterogeneity of the MP pattern in various cancers needs to be investigated when more cases have been accumulated.

Objective New serum markers (1→3) β-D-glucan (β-D-glucan) and KL-6 are reported to be useful for the clinical diagnosis of Pneumocystis jirovecii pneumonia (PCP). However, the utility of these markers in PCP with HIV infection (HIV PCP) and without HIV (non-HIV PCP) is unknown. This study was aimed to evaluate the utility of β-D-glucan and KL-6 for the diagnosis of PCP in patients with HIV infection (HIV PCP) and non-HIV PCP. Methods Retrospective study Patients We reviewed the medical records of consecutive 35 patients. The serum levels of β-D-glucan and KL-6 in HIV PCP and non-HIV PCP were comparatively evaluated. We evaluated these markers in survivors and non survivors. Results The detection rates of serum β-D-glucan and KL-6 levels in non-HIV PCP were lower than those in HIV PCP (88% vs. 100%, 66% vs. 88%, respectively). The false positive rates of these markers in both groups were similar (12%, 37%, respectively). Oxygenation index, serum albumin, and mechanical ventilation were the variables which were significantly associated with poor outcome in the univariate analysis. Conclusion In conclusion, β-D-glucan was a reliable diagnostic marker for PCP. However, the detection rate of β-D-glucan and KL-6 in non-HIV PCP was lower than in HIV PCP. Neither β-D-glucan nor KL-6 was associated with the outcome of PCP.

Periosteal osteosarcoma is an exceedingly rare type of chondroblastic osteosarcoma, showing rather better prognosis, and secondary bone marrow involvement is unusual. A case of a 22 year old male with periosteal osteosarcoma of the right femur with an associated bone marrow lesion is presented. The juxtacortical tumor, 16 x 11 x 9 cm, was located on the bone cortex of the upper diaphysis and extended into the surrounding soft tissues. A minimal bone marrow lesion was present, although the bone cortex was quite intact. Microscopically, the tumor consisted exclusively of atypical chondroblastic cells with a small osteoblastic area. The bone marrow lesion, interestingly, contained both multiple nodules of well-differentiated chondrosarcomatous components and a few demarcated foci of atypical spindle cells producing a fine osteoid matrix. It was reasonable to conclude, therefore, that this tumor was a periosteal osteosarcoma with an unusual secondary bone marrow lesion rather than a conventional (central) chondroblastic osteosarcoma with soft tissue invasion. The patient's good prognosis with no tumor recurrence or metastasis during more than 7 years follow-up after surgery supports this conclusion.

A case of urothelial carcinoma (UC) containing a micropapillary carcinoma (MPC) component in the urinary bladder of an 83-year-old man is reported. The MPC component of UC has been reported to be a variant featuring poor prognosis and rapid progression. In the present case, a characteristic MPC component with micropapillary growth, in association with a fine meshwork-like stroma, was observed in less than 10% of fragmented cancer tissues of UC, G3, obtained by transurethral resection of a bladder tumor (TUR-BT). Lymphatic invasion was also detected. UC cancer cells had invaded the prostatic glands and replaced the original epithelial cells. The unique "insideout" feature of the MPC component was immunohistochemically obvious on staining with antibody to epithelial membrane antigen (EMA). On immunohistochemical study, cancer cells of both UC and MPC components were positive for pancytokeratin AE1/AE3 and cytokeratins 7 and 20. Carcinoembryonic antigen (CEA) and CAM5.2 were only focally positive in UC cells. MIB-1(Ki-67) labeling index was high, at 80%-90%, in cancer cells of UC. This was a case of UC, G3 with invasion to the muscularis propria layer of the urinary bladder and also to the prostate. MPC and MPC components in cancers should be recognized as a marker of poor prognosis, even when detected in less than 10% of UC within TUR-BT tissues, as in the present case.

Cytokeratin 8 (CK8) is a type II intermediate filament protein that is persistently expressed in most epithelial malignancies. Circulating CK-related polypeptides have commonly been used as tumor markers. While apoptosis is a mechanism of CK release, the molecular nature of circulating CKs is poorly understood. The aim is to clarify the dynamics of CK8 during apoptosis in vitro and the nature of circulating CK8 in patients with lung cancer.Extracellular release of CK8 was examined using A549 human non-small cell lung cancer (NSCLC) cells after apoptosis induction by etoposide. Serum samples from NSCLC patients were examined for circulating CK8 by ELISA (n = 60) and by immunoprecipitation (n = 9).CK8 is released predominantly in full length from A549 cells undergoing apoptosis and is resistant to intracellular cleavage by caspases, unlike type I CK18, which is readily cleaved during apoptosis. Full-length CK8 is shown to constitute a considerable fraction of circulating CK8 in the serum of lung cancer patients.Apoptosis causes extracellular release of full-length CK8 in NSCLC cells. CK8 circulates predominantly in full length in patients with NSCLC, illustrating the fundamental differences in protein processing between type I and type II CKs.

Multiple eccrine spiradenomas are rare. In the present study, a detailed investigation of eccrine spiradenoma was performed, focusing in particular on the presence of Langerhans cells (LCs) in the tumor, and their immunohistochemical and ultrastructural characterization. The patient was a woman in her mid-forties who underwent resection of two tumors of the head that were 2.0 and 0.7 cm in size. They were diagnosed as eccrine spiradenoma and were composed of small and large tumor cells with a dense fibrous capsule in the dermis. Immunohistochemically, staining by antibodies to cytokeratins (AE1/AE3, CAM5.2) and CK 5/6 was diffusely positive in all tumor cells, although not in intermingled LCs, which harbored interdigitated nuclei. The cytoplasm of LCs was positive for S-100 protein and CD1a, and their nuclei were also occasionally positive for S-100 protein. Antibody to epithelial membrane antigen was positive for the surface of both intracytoplasmic and true glandular lumina. Fine structural examination revealed the presence of LCs among the tumor cells, extending fine irregular processes among the tumor cells. Birbeck granules were clearly demonstrated in the cytoplasm of LCs. Other fine structural findings included intracytoplasmic lumina with microvilli on their surfaces in some tumor cells. In these examinations of eccrine spiradenoma, LCs, approximately 15/HPF in the tumor, were distinctly detected even at light microscopic level as negative for various types of cytokeratin stains, although they were positive for S-100 protein and CD1a, whereas on ultrastructural examination Birbeck granules were demonstrated in their cytoplasm. Determination of the significance of these LCs in eccrine spiradenoma requires further investigation of a larger number of cases.

There is increasing acknowledgment of the public health burden of metabolic syndrome. The metabolic syndrome is defined as emerging cardiovascular risk factors, or atherosclerosis, that are related to underlying insulin resistance. One of the adipokines, adiponectin, has antiatherogenic effects and augments the metabolic effects of insulin. To reduce mortality from cardiovascular disease, it is important to understand the pathophysiological properties of adiponectin and receptors in atherosclerotic regions. Recently, T-cadherin, which has been recognized as a unique cadherin molecule, has been characterized as a novel adiponectin receptor on vascular endothelial cells and smooth muscle. Notably, T-cadherin (also known as CDH13, cadherin 13, and H-cadherin) is abundantly expressed in injured vascular endothelial and smooth muscle cells in atherosclerotic regions. In the present review, we describe recent progress in research on adiponectin receptors, with emphasis on the unique vascular adiponectin receptor, T-cadherin, and its role in vascular disease.

Sclerosing lipogranuloma (SLG) is a rare disease that occurs in the male genital region. We report here three cases of SLG, including two of Y-shaped lesions in the penile base forming an intrascrotal mass, as well as a patient with a mass in the epidydimal region. All three lesions histologically exhibited formation of multiple granulomas consisting of multinucleated giant cells and epithelioid cells, in the fibroadipose tissue or around the epidydimis, in association with eosinophil infiltration. Membranocystic changes were found within the cytoplasm of multinucleated cells. In the two patients with scrotal lesions, membranocystic changes were positive for diastase-PAS reaction and on Sudan black B staining in dewaxed sections. CD68 staining was strongly positive in multinucleated giant cells and epithelioid cells. Most of the lymphocytes infiltrating the lesions were T cells associated with some S-100-positive dendritic cells. T-cell mediated immune reaction appears to be important in the histogenesis of SLG. The histogenesis is generally considered to be a foreign-body reaction to degenerated or damaged fatty tissue or lipids, but no apparent causative factors can be identified in some reported cases. All three patients in the present study had a good clinical course after biopsy or surgical excision. We thus report three cases of SLG including an unusual case in the epidydimal region, with some considerations regarding the histogenesis of SLG.

We analysed the biologic properties of a small cell lung carcinoma cell line (designated KK0206) established from a patient with SCLC who had cancer-associated retinopathy (CAR). Morphological and immunohistochemical studies showed that KK0206 cells have features of the classic type of SCLC. KK0206 cells grew in suspension, forming relatively small clumps of cells with a doubling time of 72 h. On light microscopy, the cells were relatively small with little cytoplasm. On immunohistochemistry using anti-bovine recoverin rabbit antibody, the cells were intensely positive for recoverin. In addition, they were positive for NSE, Ki-67, and TP53. They also expressed human recoverin, a photoreceptor protein, whose presence was confirmed by RT-PCR analysis with cDNA sequencing and Western blot analysis. The point mutation of their TP53 gene (exon 156) was detected as well. The present study demonstrates that human recoverin is expressed in SCLC cells cultured from an anti-recoverin antibody-negative patient with CAR. KK0206 might be important for further research on SCLC related retinopathy.

Little is known about the role of chemokines and their receptors interaction, which are essential for recruitment of selective lymphocyte subsets during inflammation, in the pathogenesis of idiopathic nonspecific interstitial pneumonia (NSIP). Recent studies have revealed Th1 and Th2 cells preferentially employ the chemokine receptors, CXCR3 and CCR4, respectively, in the process of accumulation into inflammatory sites. We evaluated the CXCR3 and CCR4 expression on infiltrated lymphocytes in lung tissues of 12 NSIP cases and 10 idiopathic pulmonary fibrosis (IPF) cases in our previous study. The number of CXCR3 positive lymphocytes of NSIP patients was significantly greater than that of IPF patients (261.1+/-145.1 vs. 64.9+/-27.0, P0.01). The number of CCR4 positive lymphocytes of NSIP patients was significantly lower than that of IPF (9.5+/-8.3 vs.62.6+/-26.9, P0.01). The CXCR3 to CCR4 ratio of NSIP patients was significantly greater than that of IPF patients (47.9+/-45.9 vs. 1.11+/-0.40, P0.01). The differences of CXCR3 positive, CCR4 positive lymphocyte counts, and of CXCR3/CCR4 ratio between cellular and fibrosing NSIP were not significant. These results suggest that a Th1 pattern of chemokine receptor expression predominates in the lung interstitium of patients with NSIP but, in IPF patients, CCR4 might be relatively predominant, in contrast to the finding in NSIP patients, and that Th1/Th2 balance might be an important factor in the pathogenesis of NSIP.

Tumor-specific immunotherapy with a Wilms' tumor 1 (WT1) peptide has been on clinical trial for leukemia, myelodysplastic syndrome, breast and lung cancers and is producing promising results. In this study, we treated three patients with renal cell carcinoma with an anchor modified, HLA-A*2402 binding WT1 peptide which was emulsified in Freund's incomplete adjuvant. In two patients tumor growth was suppressed and clinical response was evaluated as stable disease by the RECIST criteria after 3 months of weekly immunizations. Notably, development of new metastases has stopped in these patients for a prolonged period. No deleterious side effects were observed. Peptide-specific T cells were expanded in PBMCs of the patients and a substantial fraction of them bore the surface phenotype consistent with a CD8+ cytotoxic effector population. Although established tumors did not regress further, considering the component of the vaccine, i.e. peptide alone, the stabilization effect suggested the potential of WT1 peptide to develop into a more effective vaccine. To our knowledge, this is the first report of WT1 immunotherapy for renal cell carcinoma. Hopefully, the results will stimulate more extensive clinical studies.

Post-transurethral resection (TUR) status in the prostate and urinary bladder has been infrequently documented. Furthermore, sequential changes in eosinophil count in peripheral blood (PB) after TUR have not been investigated in detail. In the present study, eosinophil counts and changes in eosinophils in PB were examined before to after TUR of the prostate (P) in 20 patients with benign prostatic hyperplasia. Among them, 14 patients exhibited increased numbers of eosinophils, the greatest increase being 17%. After TUR to treat bladder tumor (BT), massive infiltration of eosinophils into the resected areas, peaking 1 month later, was also detected in 8 of 15 cases of post-TUR cystitis. The PB eosinophil counts increased by more than 5% in two of five cases of post-TUR cystitis in which eosinophil counts were obtained before and after surgery. Most infiltrating eosinophils reacted positively to antibodies to eosinophil cationic proteins. These results indicated that, in patients with post-TUR prostatitis, the number of eosinophils in PB increased, and peaked 1 month later, with infiltration by eosinophils observed. Pathologists and urologists should be aware of the potential for increase in eosinophils not only in regions of TUR but also in PB.

PURPOSE The objective of this study was to optimize least invasive techniques, like microwave tissue coagulation (MCT), radiofrequency ablation (RFA) or ultrasonically-activated scalpel (USS) for the electric and thermal conduction in kidney. MATERIALS AND METHODS Needle electrode of MCT, RFA or USS were inserted into pig's kidney, under general anesthesia. We examined if the interruption of renal artery or cooling of renal parenchyma by irrigation in the renal pelvis had an effect on the tissue temperature distribution and area of tissue degeneration. The tissue parenchyma temperatures were measured at regular intervals of area (each 2.5-5.0 mm) from needle electrode or hook probe and of time (each 10 sec) using by needle temperature sensor, and pathological investigations on the tissue degeneration of the renal parenchyma were done. RESULTS By MCT, interruption of renal artery had no effect on the distribution of tissue temperature and the area of tissue degeneration. Cooling of renal parenchyma by irrigation in the renal pelvis did not affect the area of tissue degeneration but the tissue temperature was elevated significantly. By RFA, particular interest, interruption of renal artery and cooling of renal parenchyma enhanced to increase both the tissue temperature and the area of tissue degeneration. By USS, interruption of renal artery enhanced to increase both the tissue temperature and the area of tissue degeneration. Cooling of renal parenchyma by irrigation in the renal pelvis had no effect on the distribution of temperature and the area of tissue degeneration. We also examined weather cooling of renal parenchyma by several irrigation solutions which have different electric conductivity (EC) such as normal saline solution (EC: 15,800 microS/cm), tap water (EC: 133 microS/cm) and glucose solution (EC: 8.6 microS/cm) in the renal pelvis using ureteral catheter would effect on the distribution of temperature and the area of tissue degeneration. In MCT and USS, these solutions did not have any effect, but in RFA the degree of tissue temperature elevation by normal saline, tap water and glucose solution were high, intermediate and low, respectively. CONCLUSION As RFA and USS tend to be affected by the surrounding environment, electric and thermal conductivity should be applied with caution, while using these techniques.

Increased expression of carbonic anhydrase-related protein (CA-RP) VIII has previously been shown in colorectal carcinoma. Since CA-RP has no catalytic carbonic anhydrase (CA) activity, the present study attempted to elucidate its biological significance in colon cancer cells. From a colon cancer cell line (LoVo), we established clones that overexpressed CA-RP VIII (LoVo-CA8) and a control transfectant with a vector alone (LoVo-pCIneo) and studied alterations in the biological behaviors of the tumor cells both in vitro and in vivo. LoVo-CA8 cells showed significantly increased mRNA and protein expressions of CA-RP VIII as compared to LoVo-pCIneo cells. Cell proliferation, colony formation, and cell invasion assays showed that LoVo-CA8 cells had significantly higher cell proliferative and invasive abilities as compared to parental LoVo and LoVo-pCIneo cells in vitro. In an in vivo xenograft assay, LoVo-CA8 cells showed a higher tumor growth rate than parental LoVo cells. Further, small interfering RNA (siRNA)-mediated knockdown of CA-RP VIII revealed significant inhibition in cell proliferation and colony formation of a colon cancer cell line HCT116, which showed high endogenous expression of CA-RP VIII. These findings indicated that CA-RP VIII plays a role in the growth of colon cancer cells. © 2007 Wiley-Liss, Inc.

To study the early stages of hyaline membrane (HM) formation, diffuse alveolar damage (DAD) was thoroughly investigated using immunohistochemical methods in 15 autopsy cases, which consisted of various types of interstitial pneumonias and pulmonary diseases derived from nonmalignant or malignant diseases. Alveolar mouths (AMs) that were presumed to be normal were ultrastructurally examined in detail, by using pulmonary tissues in the pneumothorax. It is interesting to note that during the initial stages of HM formation in AMs, fragmented eosinophilic masses were closely attached to AMs as irregular fragments or by a cap-like structure. The ultrastructure revealed some distance between the capillary spaces and surface epithelium of the AMs, indicating that the epithelial cells at the AMs might be often easily damaged even by minor stimuli; they can be considered as “locus minoris resistentiae.” HMs were found to be formed initially at the site of AMs derived from fragmented eosinophilic masses in not only pulmonary but also extrapulmonary diseases, including both nonmalignant and malignant diseases. These irregular eosinophilic masses, representing the early shape of HMs, were immunohistochemically positive for the epithelial membrane antigens, namely, surfactant protein A and factor VIII antigen, and occasionally for KL-6 and cytokeratins. These results suggested that fragmented irregular masses represent the initial phase of HM formation. Five of 15 cases were focally negative for KL-6 at the initial irregular mass of HMs. Because KL-6 is one of the fundamental components of pulmonary surface elements, it needs to be studied further by detailed clinicopathological examination.

Elongin A is a transcription elongation factor that increases the overall rate of mRNA chain elongation by RNA polymerase II. To gain more insight into the physiological functions of Elongin A, we generated Elongin A-deficient mice. Elongin A homozygous mutant (Elongin A(-/-)) embryos demonstrated a severely retarded development and died at between days 10.5 and 12.5 of gestation, most likely due to extensive apoptosis. Moreover, mouse embryonic fibroblasts (MEFs) derived from Elongin A(-/-) embryos exhibited not only increased apoptosis but also senescence-like growth defects accompanied by the activation of p38 MAPK and p53. Knockdown of Elongin A in MEFs by RNA interference also dramatically induced the senescent phenotype. A study using inhibitors of p38 MAPK and p53 and the generation of Elongin A-deficient mice with p53-null background suggests that both the p38 MAPK and p53 pathways are responsible for the induction of senescence-like phenotypes, whereas additional signaling pathways appear to be involved in the mediation of apoptosis in Elongin A(-/-) cells. Taken together, our results suggest that Elongin A is required for the transcription of genes essential for early embryonic development and downregulation of its activity is tightly associated with cellular senescence.

Carbonic anhydrase-related protein VIII (CA-RP VIII) is believed to be an oncofetal antigen and is overexpressed in colorectal and non-small cell lung cancer. However, the pathobiological properties of CA-RP VIII in lung cancer remain unclear. In the present study, we examined ultrastructural changes caused by exogenous CA-RP VIII expression in a well-differentiated lung adenocarcinoma cell line, PC-9. Many vacuoles lined by cilia, sometimes large vacuoles pushing the nuclei to one side, were found in the cytoplasm of CA-RP VIII-expressing PC-9 cells, but not in control PC-9 cells. Moreover, signet-ring cells containing abundant intracytoplasmic mucin were often found among CA-RP VIII-expressing PC-9 cells, but rarely among control PC-9 cells. We subsequently examined CA-RP VIII expression in atypical adenomatous hyperplasia and early-stage lung adenocarcinoma (Stage Ia). Significant expression of CA-RP VIII was observed in invasive lung adenocarcinoma but not in noninvasive adenocarcinoma. Interestingly, CA-RP VIII was strongly expressed in signet-ring cell cancer and invasive mucinous adenocarcinoma components. CA-RP VIII also appeared to enhance the invasiveness of PC-9 cells in Matrigel invasion assay. The present findings suggest that CA-RP VIII expression in lung adenocarcinoma is related to cancer cell invasion.

We herein describe splenic lymphoma with villous lymphocytes (SLVL) carrying t(9;14)(p13;q32). The t(9;14)(p13;q32) is a rare reciprocal chromosome translocation found in a subset of B-cell malignancies, mainly in low-grade non-Hodgkin's lymphomas. In t(9;14)(p13;q32), PAX-5 gene on 9p13 is involved with the immunoglobulin heavy-chain gene on 14q32. It has been thought that the deregulated expression of PAX-5 as a result of t(9;14)(p13;q32) may contribute to abnormal cell proliferation. Although continuous cell lines are invaluable tools for studying lymphomagenesis in the t(9;14)(p13;q32)-bearing lymphomas, establishment of such cell lines is extremely difficult since they are usually mature B-cell malignancies. In an attempt to transform the SLVL cells into a proliferating cell line, we examined the responses of the cells to infection by Epstein-Barr virus (EBV). SLVL cells were found to be susceptible to immortalization by EBV, resulting in a permanent cell line. The cell line, designated SL-15, possessed the t(9;14)(p13;q32). Genotype analysis and immunophenotype profiles confirmed that the cell line arose from the primary lymphoma cells. The cells had characteristic cytoplasmic villi. SL-15 cells has been growing over 2 years equivalent to 350-400 population doubling levels without proliferative crisis that is often observed in EBV-positive lymphoblastoid cell lines. Furthermore, SL-15 cells, when inoculated into nude mice, formed t(9;14)(p13;q32)-bearing tumors with cytoplasmic villi. The validated SLVL-derived cell line provide a useful model system to study molecular biology of t(9;14)(p13;q32)-bearing B-cell malignancies as well as lymphomagenesis of SLVL in vitro and in vivo.

Purpose: Transitional cell carcinoma (TCC) of the urinary tract is a chemosensitive tumor. Most deaths from TCC of the urinary tract are caused by metastasis, which is resistant to conventional chemotherapy. Frequent sites of metastases from TCC of the urinary tract are regional lymph nodes, liver, lung, and bone. Of these distant metastases, bone metastasis is consistently resistant to cisplatin-based conventional chemotherapy. Therefore, in this study, we investigated whether or not a newly developed minodronate, YM529, could prevent osteolytic bone metastasis of human TCC and also enhance the effect of docetaxel in a bone tumor model of athymic nude mice. Experimental Design: In the present study, we evaluated the effect of in vitro treatment with minodronate and/or docetaxel on the proliferation by cell count, the induction of apoptosis by terminal deoxynucleotidyl transferase–mediated nick end labeling (TUNEL) assay, and the biological activity of osteoclast by pit formation assay in human bladder cancer cell line, UMUC-14, and mouse osteoclast cells. In vivo, we examined the effect of minodronate in a bone tumor model of athymic nude mice, in which the percutaneous intraosseal injection in the tibia of UMUC-14, leads to osteolytic bone tumor, as a bone metastasis model. To examine whether or not minodronate could inhibit tumorigenicity and enhance the effect of the chemotherapeutic agent, docetaxel, we gave minodronate i.p. and/or docetaxel i.p. to nude mice 3 days after an intraosseal tumor implantation. Moreover, proliferation and the induction of apoptosis of cancer cells and osteoclasts in bone tumors were determined by immunohistochemistry and the TUNEL assay. Results: In vitro: In vitro treatment with docetaxel inhibited proliferation and resorption pit-forming activity and induced apoptosis of mouse osteoclast cells and UMUC-14 cells. In vitro treatment with minodronate inhibited proliferation and activity and induced apoptosis of mouse osteoclast cells but not UMUC-14 cells. The treatment with minodronate enhanced the inhibition of proliferation and activity by docetaxel in osteoclasts. In vivo: In vivo combination therapy with docetaxel and minodronate significantly reduced the tumor incidence compared with the control (P < 0.05) and also growth of intraossal TCC in athymic nude mice compared with the control (P < 0.001), single therapy with docetaxel (P < 0.01), and minodronate (P < 0.05). Drug-induced body weight loss was not significantly different in any treatment group. Therapy with minodronate significantly enhanced inhibition of proliferation by docetaxel in osteoclasts of bone tumors compared with the control (P < 0.01), single therapy with docetaxel (P < 0.01), and minodronate (P < 0.05). Conclusions: These studies indicate that combination therapy with minodronate and docetaxel may be beneficial in patients with bone metastasis of human TCC in the urinary tract.

This study found that the HIV-1 protease inhibitor nelfinavir (NFV) induced growth arrest and apoptosis of human prostate cancer cells (LNCaP, DU145 and PC-3 cells), as measured by MTT and terminal deoxyribonucleotide transferase-mediated dUTP nick end labeling (TUNEL) assays, respectively, on the third day of culture. In addition, NFV blocked androgen receptor (AR) signaling in association with downregulation of nuclear levels of AR in LNCaP cells as measured by reporter assay and western blot analysis. As expected, NFV downregulated the level of the AR target molecule prostate specific antigen in these cells. Moreover, NFV disrupted STAT3 signaling; protease inhibitors blocked interleukin-6-induced phosphorylation of STAT3 and inhibited STAT3 DNA binding activity in LNCaP and DU145 cells, as measured by western blot analysis and enzyme-linked immunosorbent assay (ELISA), respectively. Furthermore, NFV blocked AKT signaling in prostate cancer cells as measured by kinase assay with glycogen synthase kinase-3α/β as a substrate. Importantly, NFV inhibited the proliferation of LNCaP cells presented as tumor xenografts in BALB/c nude mice without side-effects. Taken together, NFV inhibited the proliferation of prostate cancer cells in conjunction with blockade of signaling by AR, STAT3, and AKT, suggesting that this family of compounds might be useful for the treatment of individuals with prostate cancer. (Cancer Sci 2005; 96: 425 – 433)

Recent experiments have revealed that aberrant functionality of the chromatin remodeling complex is related to tumorigenicity in various malignant tumors. Skeletrophin is an actin-binding cytoskeleton-related molecule, which is induced by the overexpression of truncated human SWI1 (SMARCF1). Human SWI1 is a sub-unit of the chromatin remodeling complex and binds chromatin through its ARID (AT-rich interactive domain). Truncated SWI1 lacks one of the two glucocorticoid-receptor binding domains and inhibits the intact human SWI1 in a dominant negative manner. Skeletrophin, was therefore identified as a candidate molecule for the indication of change to a malignant phenotype due to the aberrant function of the chromatin remodeling complex. Surprisingly, the skeletrophin gene is located in 1p36.32, where the putative tumor suppressor gene of cutaneous malignant melanoma has long been postulated to be on. Cutaneous malignant melanoma is a highly aggressive tumor. To overcome the clinical problem of malignant melanoma and highly invasive and metastatic activity, it is important to unravel the molecular mechanism responsible for melanoma progression. Recent studies including those from our laboratories have elucidated that skeletrophin is a novel RING-HC type ubiquitin ligase and that the ubiquitin ligase pathway mediated by skeletrophin acts to oppose melanoma cell invasion. Here, we summarize the characterization of skeletrophin, with emphasis on its biological activity, the disruption of which is linked with melanoma progression.

BACKGROUND To identify organ-specific, metastasis-related factors that can be used to predict the development and location of metastasis of clear cell renal cell carcinoma (CRCC), the authors assessed the angiogenesis and the expression of angiogenesis-related genes in primary and metastatic tumors. METHODS They evaluated intratumoral microvessel density (MVD) by immunohistochemical staining, assessed the expression of angiogenesis-related genes by mRNA in situ hybridization, and determined the clinicopathologic characteristics of 92 archival specimens of primary and metastatic CRCCs from 54 patients. All 38 metastatic tumor specimens were resected from 24 patients. RESULTS The pathologic stage (P = 0.026) of the primary tumor specimen was an important predictor for metastasis, as were MVD (P = 0.000025) and the ratio of matrix metalloproteinases (MMPs) to E-cadherin (M/E ratio; P = 0.000041). In addition, primary tumor specimens resected from patients with metastatic CRCCs had high MVD, high levels of MMP-2 expression, and a high M/E ratio (P < 0.05). Relative to the primary tumors, the metastatic tumors also had high MVD, overexpression of basic fibroblast growth factor, vascular endothelial growth factor, interleukin-8, MMPs, and a high M/E ratio (P < 0.05). Multivariate analysis revealed that MVD and the M/E ratio in the primary tumor were independent prognostic factors for metastasis (P = 0.049 and P = 0.001, respectively). Furthermore, the M/E ratio in metastatic tumor specimens resected from the lung and lymph node was an independent prognostic factor for metastasis (P = 0.01823 and P = 0.03950, respectively). CONCLUSIONS The current study indicated that angiogenesis and M/E ratio were specific predictors for metastases of RCC, especially to the lung or lymph node. Therefore, MMPs and E-cadherin could be relevant targets for novel therapeutic strategies to control or prevent the metastasis of RCC. Cancer 2005. © 2005 American Cancer Society.

The pathologic patterns of lung involvement were evaluated in 16 patients with rheumatoid arthritis (RA). They consisted of six females and ten males, with a median age of 67.5 years and diagnosed according to the American Rheumatism Association revised criteria. High-resolution computed tomography (HRCT) of the lungs was performed in all patients, and honeycomb formation was apparent in seven. Histopathologically, seven patients were diagnosed with usual interstitial pneumonia (UIP) pattern, seven with nonspecific interstitial pneumonia/fibrosis (NSIP) pattern, and two with UIP/NSIP hybrid pattern. There were no apparent honeycomb formations on HRCT in patients diagnosed with NSIP pattern. In conclusion, the present study demonstrates that NSIP pattern is also a significant histologic classification of interstitial pneumonia associated with RA.

We previously showed that HIV-1 protease inhibitors (PIs) slowed the proliferation of human myeloid leukemia cells and enhanced their differentiation in the presence of all–trans-retinoic acid. In this study, we found that PIs, including ritonavir, saquinavir, and indinavir, inhibited the growth of DU145 and PC-3 androgen-independent prostate cancer cells as measured by a clonal proliferation assay. Recent studies showed that ritonavir inhibited cytochrome P450 3A4 enzyme (CYP3A4) in liver microsomes. The CYP3A4 is involved in drug metabolism and acquisition of drug resistance. To clarify the drug interaction between ritonavir and other anticancer drugs, we cultured DU145 cells with docetaxel either alone or in combination with ritonavir. Ritonavir enhanced the antiproliferative and proapoptotic effects of docetaxel in the hormonally independent DU145 prostate cancer cells in vitro as measured by the clonogenic soft agar assay and detection of the activated form of caspase-3 and cleavage of poly(ADP-ribose) polymerase using Western blot analysis. Real-time PCR showed that docetaxel induced the expression of CYP3A4 at the transcriptional level, and ritonavir (10−5 mol/L) completely blocked this induction. An ELISA-based assay also showed that ritonavir inhibited DNA binding activity of nuclear factor κB (NFκB) in DU145 cells, which is a contributor to drug resistance in cancer cells. Furthermore, combination treatment of docetaxel and ritonavir dramatically inhibited the growth of DU145 cells present as tumor xenografts in BNX nude mice compared with either drug alone. Importantly, docetaxel induced expression of CYP3A4 in DU145 xenografts, and ritonavir completely blocked this induction. Ritonavir also inhibited NFκB DNA binding activity in DU145 xenografts. Extensive histologic analyses of the liver, spleen, kidneys, bone marrow, skin, and subcutaneous fat pads from these mice showed no abnormalities. In summary, combination therapy of ritonavir and anticancer drugs holds promise for the treatment of individuals with advanced, drug resistant cancers.

Patients with primary Sjogren's syndrome (SS) occasionally develop interstitial pneumonia (SS-IP), the prognosis of which is less grave compared with that of idiopathic pulmonary fibrosis (IPF). We examined distribution of helper T-cell subsets in open lung biopsy specimens from seven patients with SS-IP and, for comparison, ten patients with IPF. The expression of CXCR3 and CCR4, chemokine receptors associated in vitro with Th1 and Th2 cells, respectively, was analyzed in the mononuclear infiltrate using immunohistochemistry. The expression of CD4, CD8, and CD20 in the infiltrate was similarly examined. The positive cells were semiquantified in fibrosing areas and lymphoid clusters of both SS-IP and IPF. In fibrosing areas, CXCR3-positive cells were dominant over CCR4-positive cells in all cases of SS-IP, whereas the two types of cells showed no such difference in cases of IPF. Each of the CXCR3/CD4 and CXCR3/CCR4 ratios was significantly higher in SS-IP than in IPF ( P