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Perineural invasion (PNI) at Auerbach's plexus in colorectal cancer (CRC), known as intramural PNI, is associated with adverse prognostic outcomes. This study aimed to characterize the three-dimensional (3D) architecture of CRC with intramural PNI and to evaluate the morphological features of tumor invasion around nerve tissue. Serial tissue sections from two cases of CRC were stained with cytokeratin AE1/AE3 and an anti-S-100 protein antibody. 3D models were reconstructed by scanning the virtual slides. In one case, intramural PNI was observed at the horizontal invasive front. The 3D reconstruction model showed tumor cells that appeared to infiltrate along the nervous meshwork, the structure of which was preserved. In the other case, intramural PNI was observed both at and behind the horizontal invasive front, and the 3D reconstruction model showed that the tumor cells appeared to be involved with nerve cells at the focal part of the horizontal invasive front. However, the nervous meshwork structure was not well identified in cancer-involved areas. This is the first study to characterize the 3D structure of tumor invasion around nerve tissue in CRC, demonstrating the morphological features of intramural PNI in CRC.

Categorizing desmoplastic reaction (DR) based on the histological findings of cancer-associated fibroblasts is shown to be a promising novel method to predict prognosis of patients with colorectal cancer (CRC). Periostin (POSTN) in cancer-associated stroma is reportedly associated with poor clinical outcomes. Immunohistochemical staining with an anti-POSTN antibody was performed in 73 patients with pStage III CRC (cohort 1). In addition, to evaluate mRNA and protein expression levels of POSTN, we analyzed paired normal and invasive cancer frozen specimens by quantitative real-time polymerase chain reaction and western blot analysis in 41 patients (cohort 2). In cohort 1, according to the DR categorization, 18, 22, and 33 patients were classified as immature, intermediate, and mature, respectively. High immunoreactivity of POSTN was observed 100%, 68.2%, and 27.3%, respectively (p

Supplemental Digital Content is available in the text., Grade 3 (G3, poorly differentiated) is an important treatment-decision factor in stage II colon cancer, but no unified diagnostic criteria are established. According to previous studies, an intratumoural poorly differentiated area with no glandular formation (POR) that fills the microscopic field of a ×40 objective lens was an essential factor that defined G3. We aimed to prospectively validate this in a randomized controlled study of adjuvant chemotherapy (SACURA trial). We enrolled 991 patients with stage II colon cancer. POR was graded according to the ×40 objective lens rule and the intensity of poorly differentiated clusters (GradePOR), and its prognostic power was compared with that of the conventional tumor grade on the basis of predominant histology rule (Gradeconv). According to GradePOR, 313, 526, and 152 tumors were classified as G1POR, G2POR, and G3POR, respectively, and the 5-year relapse-free survival (RFS) rates were 91.1%, 82.9%, and 74.7%, respectively (P

Introduction: Growing evidence indicates the prognostic importance of the crosstalk between cancer cells and stroma through the induction of epithelial-mesenchymal transition (EMT). This study aimed to clarify the prognostic value of evaluating primary tumor histology with the anatomical extent of disease in patients with colorectal liver metastasis (CRLM). Methods: Prognostic analyses were performed in 411 CRLM patients who underwent hepatectomy at two institutions. Tumors were graded into one of three histological categories based on integrated assessment of EMT-associated histology (HistologyEMT) in primary tumors, i.e., poorly differentiated clusters (PDCs) and desmoplastic reaction (DR). Results: A prognostic grouping system for the anatomical extent of disease (N stage, liver metastasis number and size, and extrahepatic disease; Gradeanatomical) stratified patients into three groups with different five-year relapse-free survival (RFS) rates after hepatectomy: A, 31% (191 patients); B, 15% (124 patients); and C, 6% (96 patients; P < 0.0001). HistologyEMT (A, G1 PDC and mature-type DR; C, G3 PDC and immature-type DR; and B, others) identified 49, 120, and 242 patients with 46%, 5%, and 22% five-year RFS, respectively (P < 0.0001). Among prognostic factors, the Akaike information criterion was most favorable in Gradeanatomical, followed by HistologyEMT. Multivariate analysis demonstrated that these two factors independently impacted RFS; two-year RFS after hepatectomy in different patient groups had a wide range (10%-76%). Conclusions: Histological assessment of dedifferentiation and the stromal environment of primary tumors contributed to effective risk stratification of early relapse after hepatectomy, which could be useful to determine clinical management for CRLM patients.

The tumor microenvironment plays a key role in cancer aggressiveness. Desmoplastic reaction (DR), morphologically classified as Mature, Intermediate and Immature types, has previously been shown to be highly prognostic in colorectal cancer (CRC) and it consists to a large extent of cancer-associated fibroblasts (CAFs). The aim of our study was to characterize the molecular background of DR and understand the effects of CAFs in tumor aggressiveness. The prognostic significance of DR was initially examined in 1497 patients. Then CAFs originating from patient tissues with different DR types were isolated and their impact on tumor growth was examined both in vitro and in vivo. DR was shown to be highly prognostic, with patients within the Immature DR group conferring the worst relapse-free survival. The conditioned media of CAFs from tumor with Immature-type DR (CAFs

Highly accurate risk assessment of recurrence may improve adjuvant treatment practice in stage II colorectal cancer (CRC), which lacks definite prognostic factors. Recent studies indicate the importance of stroma in determining cancer behavior, although there are few histopathologic criteria for its evaluation. A pathology review of 679 stage II CRC patients (1980-2005) was conducted at an institution. Desmoplastic reaction (DR) results were classified as mature, intermediate, or immature depending on the presence of hyalinized collagen bundles and myxoid stroma observed at the extramural desmoplastic front on hematoxylin-eosin-stained slides. Pathologically, 430, 180, and 69 tumors were classified into the mature, intermediate, and immature groups, respectively. On the basis of the DR results, 5-year recurrence rate was found to have a wide range of 9.1% to 30.7%; 5-year relapse-free survival (RFS) rates were highest in the mature group (85.2%), followed by the intermediate (77.1%), and immature (60.9%) groups. Multivariate analyses revealed an independent effect of DR pattern on RFS. In addition, 446 patients treated at 4 independent institutions (2007-2008) were examined as a second cohort for result validation, revealing an adverse prognostic impact of unfavorable DR and identifying DR categorization as an independent prognostic factor. In both cohorts, Harrell's concordance index for RFS was higher than the other conventional factors in the DR including T stage. Categorizing DR pattern based on the histologic products of fibroblasts at the desmoplastic front help elucidate their important biological role in cancer development, thus providing clinically useful prognostic information regarding stage II CRC.

We herein present the case of an immunocompetent 63-year-old man who had previously undergone resection of Crohn's disease (CD)-related small intestinal obstruction more than 30 years ago. He had not been receiving any medication for many years, but had recently started to suffer from ileus. A stenosed site of ileo-cecal anastomosis was identified and therefore was surgically resected, which was diagnosed as CD with small intestinal extramedullary plasmacytoma (EMP). The subsequent progression of CD was successfully controlled by anti-TNFα agents without any recurrence of EMP for over 3 years, implying the clinical benefit and safety of the biological therapy. This was the first known case of a patient who received anti-TNFα agents after a resection of small intestinal EMP accompanied with CD.

Background Non-parasitic splenic cysts are associated with elevated serum carbohydrate antigen (CA) 19–9 levels. We report a case in which a 23-year-old female exhibited a large ruptured splenic cyst and an elevated serum CA19–9 level. Case presentation The patient, who experienced postprandial abdominal pain and vomiting, was transferred to our hospital and was found to have a large splenic cyst during an abdominal computed tomography (CT) scan. On physical examination, her vital signs were stable, and she demonstrated rebound tenderness in the epigastric region. An abdominal CT scan revealed abdominal fluid and a low-density region (12 × 12 × 8 cm) with enhanced margins in the spleen. The patient’s serum levels of CA19–9 and CA125 were elevated to 17,580 U/mL and 909 U/mL, respectively. A cytological examination of the ascitic fluid resulted in it being categorized as class II. Finally, we made a diagnosis of a ruptured splenic epidermoid cyst and performed laparoscopic splenic fenestration. The patient’s postoperative course was uneventful, and she was discharged on postoperative day 5. The cystic lesion was histopathologically diagnosed as a true cyst, and the epithelial cells were positive for CA19–9. Follow-up laboratory tests performed at 4 postoperative months showed normal CA19–9 (24.6 U/L) and CA125 (26.8 U/L) levels. No recurrence of the splenic cyst was detected during the 6 months after surgery. Conclusion Laparoscopic fenestration of a ruptured splenic cyst was performed to preserve the spleen, after the results of abdominal fluid cytology and MRI were negative for malignancy.

Spontaneous regression of sarcoma is exceedingly rare. A 62-year-old male presented with myxofibrosarcoma of the thigh which regressed after open biopsy. Treatment strategy for this condition is not well-documented in the literature. In this report, we describe the case of a spontaneously regressed myxofibrosarcoma successfully treated by resection where the extent of the tumor was determined from the initial MRI. This case demonstrates that myxofibrosarcoma has the potential to regress spontaneously, and astute awareness of this phenomenon is necessary for appropriate management of this condition.

Background A few cases of spontaneous regression of germ cell tumors have been reported. Possible mechanisms include steroid medication, surgical intervention, diagnostic radiation exposure, and immune response. None of these hypotheses has been supported by sufficient data. Case Description Two cases of germinoma demonstrated spontaneous regression before antitumor therapy. In the first case, a 19-year-old man presented with acute hydrocephalus due to a pineal mass and underwent emergent endoscopic third ventriculostomy. The pineal tumor started to regress on the 4th postoperative day after endoscopic third ventriculostomy. In the second case, a 22-year-old man presented with acute hydrocephalus and panhypopituitarism due to a suprasellar mass and underwent emergent external ventricular drainage, biopsy, and septostomy on the day of admission. Apparent regression of the tumor was discovered on the 5th day after initial surgery. Pathologic diagnosis was pure germinoma in both cases. Remarkable accumulations of CD4-positive lymphocytes and some apoptotic cells positive for terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick end labeling staining were detected in both cases. Diagnostic radiation exposure is the only common condition in all reported cases. Conclusions This unusual phenomenon of spontaneous regression of germinoma may be caused by a combination of pathognomonic characteristics of anatomic location with paraventricular development and stress induction as a trigger, such as salvage surgery or diagnostic radiation, including at extremely low dosage.

Aims The aim of this study was to clarify the quantitative and qualitative differences in tumour budding identification between haematoxylin and eosin (H&E) staining and immunohistochemical (IHC) staining for cytokeratin, and to estimate the respective clinical impacts in stage II colorectal cancer. Methods and results We retrospectively examined 314 surgically resected cases of stage II colorectal cancer, and assessed tumour budding on serial section slides with H&E staining and IHC staining for cytokeratin. Tumour budding counts based on cytokeratin-stained slides were strongly correlated with those based on H&E-stained slides, and had higher detection and reproducibility. On the basis of receiver operating characteristic analyses, the optimal cut-off values of budding counts for relapse-free survival (RFS) were 7 and 16 in a ×200 microscopic field with H&E and IHC staining, respectively. With these cut-off values, tumour budding based on H&E staining had a significant correlation with RFS (80.3% and 93.2% of 5-year RFS in the high-budding group and the low-budding group, respectively), and similar results were observed for IHC staining (79.9% and 91.7%, respectively). The Akaike Information Criterion value for RFS with H&E staining was favourable as compared with that with IHC staining. Conclusions Tumour budding counts based on cytokeratin-stained slides showed higher detection and better reproducibility, but did not have as satisfactory clinical impacts as those based on H&E staining.

The occurrence of endotracheal/endobronchial metastasis (EEM) after complete resection of a primary lung cancer is rare. Here, we report the case of an 86‐year‐old woman in whom EEM occurred twice over a 20‐year period following complete resection of a primary adenocarcinoma localized to the left main bronchus and trachea. The presence of EEM was confirmed by establishing immunohistochemical homology of the metastases with the primary tumor. To the best of our knowledge, this is the first reported case of repetitive EEM of primary lung adenocarcinoma. Lymphatic invasion in the primary lesion suggested that a possible route for EEM was the peripheral lymphatic tract, explaining the slow recurrence rate. We conclude that observation of the trachea/bronchus over a long period post operation could be important in monitoring for EEM, particularly if lymphatic invasion is confirmed in the primary tumor., This is the first reported case of repetitive localized endotracheal/endobronchial metastasis of primary lung adenocarcinoma with mild lymphatic invasion that occurred twice over a 20‐year period after complete resection. Observation of the trachea/bronchus over a long period post operation could be important in monitoring for endotracheal/endobronchial metastasis, particularly if lymphatic invasion is confirmed in the primary tumor.

Background Trastuzumab (T-mab)-based chemotherapy is a standard regimen for human epithelial growth factor 2 (HER2)-positive gastric cancer. However, some patients have demonstrated a change in HER2 status after T-mab-based treatment of breast cancer. We report a rare case of mixed adenoneuroendocrine carcinoma with loss of HER2 positivity after T-mab-based chemotherapy for HER2-positive gastric cancer. Case presentation A 60-year-old man presented with a mass of the upper abdomen, which was diagnosed as adenocarcinoma with a HER2 score of 3+ by endoscopic biopsy. He received seven cycles of combination chemotherapy with capecitabine, cisplatin, and T-mab. Subsequently, he underwent open total gastrectomy, distal pancreatosplenectomy, and extended left hepatic lobectomy as a conversion surgery. The surgically resected specimen demonstrated both adenocarcinoma and neuroendocrine components; therefore, it was diagnosed as HER2-negative mixed adenoneuroendocrine carcinoma. Although the patient received additional chemotherapy, multiple liver metastases appeared at 3 months postoperatively and he died at 6 months postoperatively because of the rapidly progressing metastatic tumor. Conclusions We encountered a rare case of rapidly progressive mixed adenoneuroendocrine carcinoma that was negative for HER2 expression after T-mab treatment combined with chemotherapy.

Nodular hidradenoma (NH) is a benign adnexal tumor that arises from either eccrine or apocrine sweat glands. NH can originate from any cutaneous site, but the most common sites are the head and anterior surface of the trunk, with very rare cases in the extremities. Long-standing NH has been reported to undergo malignant transformation to malignant NH (MNH); however, its occurrence in the lower leg is extremely rare with only one other case reported to date. In this report, we present a rare case of MNH occurring in the lower leg which was resected with the intent to make a diagnosis. At the final follow-up after 11 months, no local recurrence or metastasis has been observed.

Background Growing evidence suggests the importance of stroma in determining cancer biology and recent studies have identified that genes closely associated with poor prognosis subtypes of colorectal cancer are expressed by the stroma rather than epithelial cancer cells. We aimed to clarify the prognostic value of the novel histologic classification of desmoplastic reaction in stage III colorectal cancer. Methods A pathologic review was conducted for 466 stage III colorectal cancer patients in a single Japanese institution (1999–2006). Desmoplastic reaction was classified as mature, intermediate, or immature according to existence of hyalinized collagen bundles and myxoid stroma, both appear exclusively at the desmoplastic front. An additional 432 patients treated at four independent institutions (2007–2008) were examined as a second cohort to validate the results. Results According to desmoplastic reaction, 164, 133, and 169 patients were classified as mature, intermediate, and immature, respectively. Five-year relapse-free survival rates were highest in the mature group (86.0%), followed by the intermediate (73.7%) and immature (50.9%) groups. An adverse prognostic impact of desmoplastic reaction was invariably observed in stage IIIB, which contained 71% of stage III cases. Harrell's concordance index for relapse-free survival was greater in desmoplastic reaction (0.66) than any conventional tumor-associated prognostic factors including tumor node metastasis substage (0.62) and tumor grade (0.53). Similar results were observed in the second cohort, wherein desmoplastic reaction categorization was the most influential prognostic factor. Conclusion Histologic desmoplastic reaction categorization could be a key to solve the issue of prognostic heterogeneity in stage III colorectal cancer, thereby enhancing the value of tumor node metastasis stage.

Although recent findings of cancer biology research indicate that prognostic power arises from genes expressed by stromal cells rather than epithelial cells, desmoplastic reaction (DR) has not been completely examined as a prognostic marker for colorectal cancer. A pathologic review of 821 stage II and III patients who underwent R0 resection for colorectal cancer at 4 independent institutions was conducted. DR was classified as mature, intermediate, or immature based on the existence of hyalinized keloid-like collagen and myxoid stroma at the extramural desmoplastic front. Totally, 325, 282, and 214 patients were classified as having mature, intermediate, and immature DR, respectively. DR significantly influenced the recurrence rate in the liver, lung, and peritoneum (P≤0.0001 to 0.01). Five-year relapse-free survival (RFS) rate was the highest in the mature group (85.7%), followed by the intermediate (77.3%) and immature (50.4%) groups. A significant adverse impact of immature stroma on RFS was observed in subset analyses of the 4 institutions. Multivariate analysis revealed that DR, along with T and N stages, is an independent prognostic factor. On the basis of Harrell's concordance index, the prognostic power of DR categorization (0.67) in stratifying RFS was greater than any other conventional prognostic factors, including TNM (0.64), N (0.62) and T stages (0.59), venous invasion (0.59), and tumor grade (0.54). Characterizing DR based on the histologic products of activated fibroblasts is valuable for evaluating prognostic outcomes. To our knowledge, this is the first study reporting a greater prognostic power of histology of the fibrotic stroma than that of tumor factors.

Background The aim of this study was to evaluate the association between the expression of programmed death ligand-1 (PD-L1) and clinical outcomes in patients with surgically resected esophageal squamous cell carcinoma (ESCC). Materials and methods We included 76 patients with primary ESCC who underwent surgical resection between January 2009 and December 2014 at National Defense Medical College Hospital. Using the tumor tissues, we evaluated PD-L1 expression in tumor cells and stromal reactive lymphocytes via immunohistochemistry. Furthermore, the relationship between PD-L1 expression and the clinicopathological status of patients with ESCC was investigated. Results PD-L1 expression in tumor cells was detected in 39.5% of the patients. In addition, 51.3% of the patients had PD-L1–positive stromal reactive lymphocytes and exhibited significantly longer overall survival than those with lack of PD-L1 expression in stromal reactive lymphocytes (median survival time, 56.0 versus 27.3 mo; log-rank test, P = 0.04). Patients with lack of PD-L1 expression in both tumor cells and stromal reactive lymphocytes showed worse overall survival than those with the PD-L1–positive expression in tumor cells and/or stromal reactive lymphocytes (P = 0.02). Conclusions PD-L1–positive expression in stromal reactive lymphocytes, rather than in tumor cells, is associated with a longer survival in patients with ESCC.

Background Recently, claudin-4 (CL4) immunocytochemistry was reported to be useful for differential diagnosis in effusion cytology. We wondered whether CL4 might be useful for “single-shot” identification of metastatic carcinoma. The purpose of this study was to evaluate the usefulness of CL4 in effusion cytology. Methods In total, 266 cases (169 metastatic carcinomas, eight malignant mesotheliomas, and 89 reactive mesothelial cells) were selected. Immunocytochemical examinations of cell-block sections were performed for CL4, Ber-EP4, and MOC-31. We used an arbitrary 4-tiered scale based on both staining intensity and positive-cell percentage among all target cells, and calculated a staining index score (sum of the above two scores). Results In a ROC-curve analysis, higher area-under-curve values were found for CL4 than for Ber-EP4 or MOC-31 (0.982, 0.942, and 0.926, respectively). Conclusions Since CL4 exhibited similar or superior usefulness to Ber-EP4 and MOC-31, it could become the first choice for the above differential diagnosis in effusion cytology. Diagn. Cytopathol. 2016. © 2016 Wiley Periodicals, Inc.

Small cell carcinoma (SCC) of the urinary bladder is highly aggressive and portends a poor outcome. Herein, we report a patient with recurrent SCC of the urinary bladder who experienced an unusually long-term disease-free duration after radical cystectomy. The patient was a 60-year-old woman who had undergone transurethral resection followed by radical cystectomy for muscle-invasive bladder cancer (high-grade urothelial carcinoma with adenocarcinomatous differentiation) 6 years prior; the surgical specimen had a negative surgical margin. She was referred to our hospital because of continuous bleeding from her vagina. Magnetic resonance imaging showed a mass located at the anterior wall of her residual vagina, a biopsy of which confirmed a pathological diagnosis of adenocarcinoma. The vaginal tumor and a section of the sigmoid colon were resected en bloc and were pathologically diagnosed as adenocarcinoma and SCC. We reevaluated the initial transurethral resection specimen and found SCC with foci of adenocarcinoma concomitant with high-grade urothelial carcinoma. Local recurrence and metastasis at the pelvic bone occurred 4 months later; although radiation therapy was performed, she died of the progressive disease.

A 76-year-old woman suddenly developed anasarca and a fever, and an examination revealed thrombocytopenia, reticulin fibrosis, and acute kidney injury, yielding the diagnosis of thrombocytopenia, anasarca, fever, reticulin fibrosis, organomegaly (TAFRO) syndrome. Renal replacement therapy and steroid treatment were soon started. Her proteinuria was minor at first; however, once the kidney function improved, nephrotic syndrome occurred. A kidney biopsy showed membranoproliferative glomerulonephritis-like glomerulopathy with massive macrophage infiltration. Although kidney dysfunction is often observed in TAFRO syndrome patients, its detailed mechanism is unclear. This case suggests that TAFRO syndrome involves both acute kidney injury with minor proteinuria and nephrotic syndrome, and these disorders can develop serially in the same patient.

Background Podocyte phospholipase A2 receptor (PLA2R) is a major target antigen in idiopathic adult membranous nephropathy (MN). Histological PLA2R staining in the renal tissue has proven to be useful for the detection of idiopathic MN. However, glomerular PLA2R deposits have also been recently observed in several patients with secondary MN, such as hepatitis B virus-associated, hepatitis C virus-associated, and neoplasm-associated MN. Certain inflammatory environments have been suggested to lead to abnormal expression of PLA2R epitopes, with the resulting production of PLA2R autoantibodies. Case presentation We report two patients diagnosed with anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis with MN-lesions, in whom ANCA titers for myeloperoxidase (MPO) were persistently positive. The first patient was a 52-years-old man who presented with interstitial pneumonitis. Microscopic hematuria and proteinuria were found when the interstitial pneumonitis became more severe. Renal biopsy findings yielded a diagnosis of ANCA-associated glomerulonephritis (mixed class) with MN-lesions. The second patient was a 63-years-old woman who had been treated for relapsing polychondritis. Her renal tissue showed evidence of focal ANCA-associated glomerulonephritis with MN-lesions. Interestingly, both MPO and PLA2R were detected in the glomerular subepithelial deposits of both patients. Immunoglobulin G (IgG) 1 and IgG2 were positive in the glomeruli of patient 2, and all subclasses of IgGs were positive in patient 1. Conclusion The present cases suggest that ANCA-associated glomerulonephritis could expose PLA2R, leading to the development of MN-lesions.

Plasmin has recently been reported to be associated with renal fibrosis in experimental models, but its role in human renal diseases is unclear. Fifty-seven patients with IgA nephropathy (IgAN) were evaluated retrospectively. Plasmin in their renal biopsy tissues was assessed by in situ zymography using a plasmin-sensitive synthetic peptide, and the relationships between patients’ histologic or clinical parameters and their renal plasmin activity [assessed semiquantitatively by calculating the positively stained percentage of the total tubulointerstitial (TI) area] were evaluated. Plasmin activity was observed almost exclusively in the TI space (mainly in the interstitium and partly in the tubular epithelial cells) and was significantly stronger in patients with TI lesion (tubular atrophy/interstitial fibrosis and tubulointerstitial inflammation) than in those without TI lesion. It was significantly and positively correlated with the global glomerulosclerosis rate and significantly and negatively correlated with estimated glomerular filtration rate not only at the time of renal biopsy but also at the end of the follow-up period. Double stainings for plasmin activity and inflammatory cells, cytokeratin, or α-smooth muscle actin (α-SMA) in selected patients revealed TI infiltration of inflammatory cells, attenuated tubular epithelial expression of cytokeratin, and augmented interstitial expression of α-SMA close to upregulated plasmin activity in the TI space. These data suggest that TI plasmin is associated with TI inflammation leading to renal fibrosis, and can cause the decline in renal function seen in patients with IgAN. Reducing plasmin in situ may therefore be a promising therapeutic approach slowing renal fibrogenesis and improving renal function.

This study aimed to determine the prognostic value of a novel grading system based on the histologic assessment of poorly differentiated clusters (PDCs) in the primary lesions in patients with hepatectomy for colorectal liver metastasis (CRLM). Preoperative survival predictors for CRLM are required to determine candidates for perioperative chemotherapy who would otherwise have a poor prognosis.In total, 411 consecutive patients undergoing curative resection of primary colorectal cancers and metastatic liver lesions at 2 institutions were enrolled. Cancer clusters comprising ≥ 5 cancer cells, lacking a gland-like structure, were defined as PDCs and quantifiably graded.According to PDCs, 65, 127, and 219 patients were classified as being grades (G)1, G2, and G3, respectively. PDCs were associated with T and N stages and tumor budding in primary tumor, extrahepatic disease, and serum CEA levels (P ≤ .0001-.045), but not with the number and size of liver metastasis. PDC grade significantly influenced recurrence rate in extrahepatic sites, including the lung and peritoneum (P.0001). The 2-year disease-free survival after hepatectomy was 64.6%, 38.8%, and 22.4% in G1, G2, and G3, respectively. Based on multivariate analysis, PDC grade was selected as an independent prognostic factor together with other conventional factors such as extrahepatic disease and the number of liver metastasis.PDC grade in primary lesions is a novel potent prognostic indicator in CRLM independent of the anatomic extent of disease. Notably, PDC grade can bias survival rates in clinical studies targeting perioperative chemotherapy in CRLM.

We herein report a case involving the systemic presentation of angiolymphoid hyperplasia with eosinophilia (ALHE) in association with membranous nephropathy (MN). A 34-year-old Japanese man presented with leg edema and bilateral temporal nodules. He had a history of Buerger's disease and recurrent coronary stenosis. A renal biopsy performed to assess nephrotic syndrome revealed MN. Furthermore, a temporal nodule was excised, and ALHE was diagnosed. We reevaluated the coronary and posterior tibial artery specimens obtained in his twenties and presumed that these lesions were also vascular tumors arising from ALHE. The association of ALHE and MN is quite rare.

Background: Telomeres are repetitive DNA sequences located at the ends of chromosomes. Chromosomal and genomic instability due to telomere dysfunction has been known to play an important role in the carcinogenesis of some organs. Objectives: The aim of this study was to examine the correlation between smoking and the telomere length of human bronchial epithelial cells in individuals with and without lung cancer. Patients and Methods: We examined 68 non-lung cancer adult autopsy cases and 24 surgically resected cases of lung squamous cell carcinoma. Telomere lengths of the basal cells of bronchial epithelium were measured using the tissue quantitative fluorescence in situ hybridization method and were expressed in normalized telomere-to-centromere ratios (NTCRs). Results: The autopsied individuals included 27 current smokers (CuS), 33 never-smokers (NeS), and 8 ex-smokers (ExS). The NTCRs in the central bronchi of CuS, NeS, and ExS were 1.515, 1.372, and 1.204, respectively. The bronchial epithelial telomeres of CuS were significantly longer than those of non-CuS (NeS + ExS). When the analysis was conducted separately for females and males, a significant difference between CuS and NeS + ExS was recognized only for males. The NTCRs of the bronchial epithelium of lung cancer cases and lung cancer tissue are 1.514 and 1.385, respectively. Conclusions: Our findings suggest that smoking causes telomeric elongation in the bronchial epithelium. Therefore, it appears that the mechanism of carcinogenesis in smoking-related carcinomas may differ from that of many other carcinomas in which genetic instability due to aging-related telomeric shortening is assumed to play a role.

Although the essential roles of stromata in tumor development have been recognized, the morphologic classification of desmoplastic reaction (DR) in colorectal cancer (CRC) is unclear. In this study, DRs were histologically classified into three patterns based on the products of activated fibroblasts (i.e., keloid-like collagen and myxoid stroma). The prognostic impact of DRs was evaluated in two independent cohorts of stages 2 and 3 CRC patients: cohort 1 (880 patients) and cohort 2 (474 patients). The association of DR and the local environment was investigated immunohistochemically. In cohort 1, mature DR was shown by 413 patients, intermediate DR by 275 patients, and immature DR by 192 patients. Categorization of DR was significantly associated with tumor location, pT and pN stages, tumor differentiation, venous invasion, tumor budding, and Crohn’s-like lymphoid reaction (P ≤ 0.0001–0.008). Immature DR was relevant to the high incidence of recurrence in the liver, lung, lymph nodes, peritoneum, and locoregional areas (P ≤ 0.0001–0.002). The 5-year disease-free survival rate was highest in the mature group (87 %), followed by the intermediate group (72 %) and the immature group (49 % (P

Patients with pT1aN0M0 renal cell carcinoma (RCC) generally have good prognosis, and recurrence is rare. However, metastasis develops postoperatively in a small number of patients with pT1aN0M0 RCC. The present study was undertaken to identify predictors for recurrence in patients with pT1aN0M0 RCC. We reviewed the clinicopathological factors of 133 patients with pT1aN0M0 RCC who underwent radical or partial nephrectomy at the Department of Urology, National Defense Medical College (Saitama, Japan). Clinicopathological factors, including age, gender, tumor size, histological subtype, tumor grade, microvascular invasion, histological tumor necrosis, C-reactive protein levels and performance status were reviewed. These factors were compared between patients with and without postoperative recurrence. Recurrence-free survival (RFS) and cause-specific survival (CSS) rates were calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed to determine independent factors predicting recurrence in patients with pT1aN0M0 RCC. The 5-year RFS and CSS rates were 97.2 and 99.1%, respectively. When clinicopathological factors were compared between patients with and without recurrence, tumor size (P=0.0390) and percentage of tumor necrosis (P

Primary nonsecretory plasma cell leukemia (PCL) is an extremely rare type of multiple myeloma. Here, we report a case of nonsecretory PCL with no previous history of multiple myeloma. The case exhibited extremely low levels of serum immunoglobulin and light chain, no detectable serum M-protein or free light chain restriction, no urine BJP, and no cytoplasmic light chain expression in flow cytometry. In fluorescence in situ hybridization, tumor cells exhibited fusion genes for IgH/BCL1 and IgH/cMyc, disappearance of the p53 signal, and a split signal for IgK(2p11), but no split signal for IgL (22q11). Therefore, we diagnosed primary nonsecretory PCL with multiple chromosomal abnormalities.

Although the molecular mechanism of desmoplastic reaction (DR) for providing aggressive tumor characteristics is increasingly recognized, the prognostic role of DR has not been investigated in colorectal liver metastasis (CRLM). A pathologic review of 412 patients who underwent hepatectomy for CRLM at 2 independent institutions was conducted. DR in primary tumors was classified as mature, intermediate, or immature on the basis of the existence of keloid-like collagen and myxoid stroma-distinctive histologic products of extracellular matrix remodeling. With respect to DR, 137, 122, and 153 patients were classified as mature, intermediate, and immature, respectively. Immature DRs were associated with higher T and N stages, higher primary tumor grade, synchronous and larger size of liver metastasis, and extrahepatic disease (P≤0.0001 to 0.002). DR significantly influenced the rate of recurrence in extrahepatic sites, including the lung, peritoneum, and local region in the primary tumor (P≤0.0001 to 0.03), rather than the remnant liver. Five-year overall survival rates after hepatectomy were the highest in the mature group (58.9%), followed by intermediate (42.1%) and immature (26.7%) groups. A significant prognostic impact of DR was observed in subset analyses for institutions, primary tumor location, and timing and number of liver metastases. Multivariate analysis revealed that DR was an independent prognostic factor along with T stage of the primary tumor, size of liver metastasis, and extrahepatic disease. Characterizing DR in the primary tumor on the basis of histologic products of cancer-associated fibroblasts is valuable in evaluating prognostic outcome after hepatectomy in CRLM patients.

Background: The crosstalk between cancer cells and stroma is involved in the acquired capability for metastasis through the induction of epithelial–mesenchymal transition (EMT). We aimed to clarify the prognostic value of the histological category of EMT in colorectal cancer (CRC). Methods: Tumour EMT was graded into one of three histological categories on the basis of integrated assessment of poorly differentiated clusters and pro-EMT desmoplasia at the leading edge of the primary tumour (HistologyEMT). Stage II and III CRC patients (cohort 1, N=500) and stage IV patients (cohort 2, N=196) were retrospectively analysed. Results: In cohort 1, patients were stratified into three groups with widely different disease-free survival rates (95%, 83% and 39%) on the basis of HistologyEMT (P

The study aimed to determine the value of a novel site-specific grading system based on quantifying poorly differentiated clusters (PDC; Grade(PDC)) in colorectal cancer (CRC). A multicenter pathologic review involving 12 institutions was performed on 3243 CRC cases (stage I, 583; II, 1331; III, 1329). Cancer clusters of ≥5 cancer cells and lacking a gland-like structure (PDCs) were counted under a ×20 objective lens in a field containing the maximum clusters. Tumors with

Cancer invasion of the lamina propria is an important pathological finding. However, the clinicopathologic features and diagnostic accuracy of intramucosal carcinoma assessment in colorectal carcinoma (CRC) are unknown. In this study, intramucosal CRCs were reviewed in institutions affiliated with the Japanese Society for Cancer of the Colon and Rectum, and 32 cases with invasion of the lamina propria were identified. Next, a consensus meeting was held to select cases with a high consensus about the presence of invasion, which were reviewed by one Western pathologist for confirmation. In addition to clinicopathologic evaluation, concordance was assessed for diagnosis and histologic findings. During the consensus meeting, 3 cases were found to show ambiguous features such that it was unclear whether there was intramucosal or submucosal invasion, and 7 cases were judged to have invasion of the lamina propria by more than 75% of the pathologists. A poorly differentiated adenocarcinoma and a signet ring cell carcinoma were diagnosed unanimously. Concordance in diagnosis and detection of characteristics of invasion of the lamina propria proved to be only poor to fair. Single or small clusters of cells and atypical or complex glandular arrangements that are beyond normal mucosal architecture were detected more frequently in the 7 high-consensus tumors. Desmoplasia and marked inflammation were detected more often in cases characterized as ambiguous. Intramucosal CRCs with invasion of the lamina propria constituted 5.1% of the surgically resected high-grade intramucosal epithelial dysplastic/neoplastic lesions, and stromal infiltration of single or small clusters of cells is the best objective criterion of invasion.

Background The therapeutic effect of tonsillectomy for immunoglobulin A nephropathy (IgAN) has been widely recognized, but the mechanism by which tonsillar immunity leads to glomerulonephritis has been unclear. We investigated subtypes and localization of dendritic cells (DCs) in tonsils and looked for relationships between the tonsillar DCs and the clinical features and renal histological changes of patients with IgAN. Methods We examined tonsils from 33 IgAN patients, using as control tonsillar specimens from subjects without glomerulonephritis. Five distinct markers of DCs (CD303, CD1c, CD209, CD208 and CD1a) were analyzed by immunohistochemistry and flow cytometry. The mRNA levels of these DC markers were evaluated using real-time polymerase chain reaction. The clinical data and histological results obtained evaluating renal biopsy tissues were statistically compared with immunological data. Results Of the five subtypes of DCs, CD208+ DCs were significantly increased in the tonsils of IgAN patients compared with that of controls. Furthermore, the number of CD208+ DCs in the tonsils was positively and linearly correlated with the proportion of crescentic glomeruli in renal biopsy tissues and with the urinary protein level. Only few CD208+ cells, however, were found in the kidney biopsy specimens of IgAN patients. Conclusions These observations suggest that increased CD208+ DCs in tonsils may play a directive role in the pathogenesis of IgAN. The present results support the therapeutic significance of tonsillectomy for IgAN patients.

The histogenesis of the pattern of cancer spread along Auerbach's plexus (myenteric spread: MS) remains unclear and its prognostic value in colorectal cancer (CRC) has not been thoroughly investigated.Pathology slides of 2845 pT2/pT3/pT4 CRCs stained with hematoxylin-eosin (HE) were reviewed at 10 institutions. MS was classified into 2 groups depending on whether it was accompanied by the finding of perineural invasion (PN) within the lesion. In addition, immunohistochemical staining (D2-40, S100, CD56, synaptophysin) was performed for serially sectioned specimens from 50 CRCs diagnosed as having PN-negative MS.MS was observed in 504 patients (17.7 %); 360 patients were classified as having PN-positive MS and 144 as having PN-negative MS. The 5-year disease-free survival rate of patients with MS was lower than that of patients without MS (63.3 vs 82.7 %, P0.0001); however, there was no significant difference in survival outcome according to the presence or absence of intralesion PN in MS. Multivariate analysis showed that the prognostic impact of MS was independent of conventional prognosticators including T and N stages, vascular invasion and extramural PN. In all the tumors having PN-negative MS, remnants of neural tissue were identified within or around cancer nests located at the leading edge of MS.MS is an important prognostic factor for CRC. This feature is the result of cancer development with replacement of Auerbach's plexus and can be classified as intramural PN. The clinical significance of "Pn1" in the UICC/AJCC TNM classification could be enhanced by individual assessment both intramurally and extramurally.

AimsThe goal of this study is to create an objective pathological diagnostic system for blood and lymphatic vessel invasion (BLI).Methods1450 surgically resected colorectal cancer specimens from eight hospitals were reviewed. Our first step was to compare the current practice of pathology assessment among eight hospitals. Then, H&E stained slides with or without histochemical/immunohistochemical staining were assessed by eight pathologists and concordance of BLI diagnosis was checked. In addition, histological findings associated with BLI having good concordance were reviewed. Based on these results, framework for developing diagnostic criterion was developed, using the Delphi method. The new criterion was evaluated using 40 colorectal cancer specimens.ResultsFrequency of BLI diagnoses, number of blocks obtained and stained for assessment of BLI varied among eight hospitals. Concordance was low for BLI diagnosis and was not any better when histochemical/immunohistochemical staining was provided. All histological findings associated with BLI from H&E staining were poor in agreement. However, observation of elastica-stained internal elastic membrane covering more than half of the circumference surrounding the tumour cluster as well as the presence of D2-40-stained endothelial cells covering more than half of the circumference surrounding the tumour cluster showed high concordance. Based on this observation, we developed a framework for pathological diagnostic criterion, using the Delphi method. This criterion was found to be useful in improving concordance of BLI diagnosis.ConclusionsA framework for pathological diagnostic criterion was developed by reviewing concordance and using the Delphi method. The criterion developed may serve as the basis for creating a standardised procedure for pathological diagnosis.

We herein report a case of IgG4-related autoimmune pancreatitis (AIP). A 72-year-old male with jaundice visited our hospital complaining of epigastralgia. A blood chemistry analysis revealed elevated serum levels of total bilirubin and DUPAN-II. Computed tomography (CT) revealed irregularly shaped pancreatic masses with a stricture of the main pancreatic duct (MPD) in the head and tail that were interposed by marked atrophy with MPD dilation in the body. F-18 fluorodeoxyglucose (FDG)-positron emission tomography/CT revealed abnormally intense FDG uptake only at the masses. During surgery, another small tumor was also found in the atrophied body; therefore, a total pancreatectomy was performed under the diagnosis of multiple pancreatic cancers. The histological analysis revealed fibrosis with dense and diffuse infiltrations of lymphocytes and IgG4-positive plasma cells. The pancreatic parenchyma of the body was firmly replaced by fibrosis. AIP can lead to the formation of multiple pancreatic lesions, and thus the correct diagnosis is occasionally difficult to establish in atypical cases.