Takuma Tajiri

Intraductal Tubular Neoplasms of the Pancreas : Histogenesis and Differentiation

Objectives: Intraductal neoplasms of the pancreas are generally referred to as intraductal papillary mucin-producing neoplasms (IPMNs), according to the WHO classification system. Herein, we report that morphologic and immunohistochemical features of intraductal tubular carcinoma (ITC) are quite different from those of intraductal papillary mucinous carcinoma (IPMC). Methods: We analyzed histogenesis and differentiation of ITC by light microscopy and immunohistochemistry. Results: Histologically, ITC was characterized as an intraductal nodular appearances with a monotonous tubular growth pattern without papillary projection. ITC showed de novo-like appearance without sequential progression usually observed in IPMC, suggesting that ITC is a homogeneous neoplasm. Cuboidal tumor cells in ITC resembled normal pancreatic duct epithelia, and the characteristic growth pattern of ITC replaced that of normal pancreatic duct epithelium. Immunohistochemically, ITC cells were positive for MUC-1 on the apical side of the cell membrane. In contrast to ITC cells, IPMC cells were negative for MUC-1, and ductal adenocarcinoma cells were strongly positive for MUC-1, as was the stroma around the cancer. The immunohistochemical staining pattern of DUPAN-2 resembled that of MUC-1. Interestingly, localization of MUC-1 and DUPAN-2 staining in ITC cells was similar to that in normal pancreatic ductules. ITC cells were negative for MUC-2 and MUC-5AC. In contrast, most IPMC cells were positive for MUC-2 and MUC-5AC. Conclusion: Based on our histologic and immunohistochemical findings, the intraductal pancreatic neoplasm (IPN) can be classified into 2 groups: IPN with gastrointestinal differentiation and IPN with pancreatic duct differentiation. Our present data indicated that ITC cells may arise directly from duct epithelia without progression and possessed pancreatic duct differentiation. On the basis of our data, we suggest that classification of pancreatic neoplasms in the WHO and The Armed Forces Institute of Pathology (AFIP) systems should be reconsidered.

Ampullary Region Carcinomas: Definition and Site Specific Classification With Delineation of Four Clinicopathologically and Prognostically Distinct Subsets in an Analysis of 249 Cases

Ampullary (AMP) carcinomas comprise a heterogenous group of cancers lacking adequate subcategorization. In the present study, 249 strictly defined primary AMP carcinomas (ACs) identified in 1469 malignant pancreatoduodenectomy specimens were analyzed for defining features. Gross and microscopic findings were used to determine tumor epicenter and extent of preinvasive component. ACs were classified into 4 distinct subtypes based on location: (1) Intra-AMP (25%): Invasive carcinomas arising in intra-ampullary papillary-tubular neoplasms with zero to minimal, duodenal surface involvement (<25% of the tumor). These tumors were more commonly found in men, they had a relatively large overall size (mean, 2.9 cm) but had smaller invasive component (mean, 1.5 cm), and were predominantly of a lower TNM stage (85%, T1/2; and 72% N0). They carried the best prognosis among the 4 groups (3-y survival, 73%). (2) AMP-ductal (15%): These were tumors forming constrictive, sclerotic, plaque-like thickening of the walls of the common bile duct and/or pancreatic duct resulting in mucosa-covered, button-like elevations of the papilla into the duodenal lumen. There was no significant exophytic (preinvasive) growth. These were the smallest tumors (mean overall size, 1.9 cm; mean invasion size 1.7 cm), but carried the worst prognosis (3-y survival, 41%), presumably due to the pancreatobiliary histology/origin (in 86%); however, even this group had significantly better prognosis when compared with 113 ordinary pancreatic ductal adenocarcinomas (3 y, 11%; P<0.0001). (3) Peri-AMP-duodenal (5%): Massive exophytic, ulcero-fungating tumors growing into the duodenal lumen and eccentrically encasing the ampullary orifice with only minimal intra-ampullary luminal involvement. These were mostly of intestinal phenotype (75%) and some had mucinous features. Although these tumors were the largest (mean overall size 4.7 cm; and mean invasion size 3.4 cm), and had the highest incidence of lymph node metastasis (50%), they carried an intermediate prognosis (3-y survival, 69%) to that seen among a group of 55 nonampullary duodenal carcinoma controls. (4) AC—not otherwise specified (“papilla of Vater”; 55%): Ulcero-nodular tumors located at the papilla of Vater, which do not show the specific characteristics identified among the other 3 subtypes. In conclusion, ACs comprise 4 clinicopathologic subtypes that are prognostically distinct.

Histologic and Immunohistochemical Comparison of Intraductal Tubular Carcinoma, Intraductal Papillary-Mucinous Carcinoma, and Ductal Adenocarcinoma of the Pancreas

Objective: To analyze the differences between intraductal tubular carcinoma (ITC) and intraductal papillary-mucinous carcinoma (IPMC), we performed light microscopic and immunohistochemical analysis of 4 cases of ITC, 6 cases of IPMC, and 9 cases of ductal adenocarcinoma of the pancreas. Methods and Results: Light microscopic examination showed no hyperplasia or adenoma around the carcinoma in ITC, and immunohistochemical analysis showed that the apical side of the cell membrane was positive for MUC-1 in almost all ITC cells. In contrast to ITC cells, all IPMC cells were negative for MUC-1 and ductal adenocarcinoma cells were strongly positive for MUC-1 in the cytoplasm and cell membrane. Immunohistochemical staining patterns of DUPAN-2 in ITC resembled those of MUC-1 in these cancers. ITC and IPMC cells were negative for carcinoembryonic antigen, but ductal adenocarcinoma cells were positive. There were no apparent differences in proliferative activity between ITC and IPMC, but ductal adenocarcinoma showed significantly greater activity than either ITC or IPMC. Conclusion: The PCNA-L.I of IPMC and ITC was lower and the cell atypia of them was more mild compared with those of ductal carcinoma, indicating that IPMC possess low-grade malignant potentials. However, we observed differences of growth patterns and mucous secretion between ITC and IPMC of the pancreas.

Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a comparative analysis of four counting methodologies

Ki67 index is now an essential part of classification of pancreatic neuroendocrine tumors. However, its adaptation into daily practice has been fraught with challenges related to counting methodology. In this study, three reviewers used four counting methodologies to calculate Ki67 index in 68 well-differentiated pancreatic neuroendocrine tumors: (1) ‘eye-ball’ estimation, which has been advocated as reliable and is widely used; (2) automated counting by image analyzer; (3) manual eye-counting (eye under a microscope without a grid); and (4) manual count of camera-captured/printed image. Pearson’s correlation (R) was used to measure pair-wise correlation among three reviewers using all four methodologies. Average level of agreement was calculated using mean of R values. The results showed that: (1) ‘eye-balling’ was least expensive and fastest (average time <1 min) but had poor reliability and reproducibility. (2) Automated count was the most expensive and least practical with major impact on turnaround time (limited by machine and personnel accessibility), and, more importantly, had inaccuracies in overcounting unwanted material. (3) Manual eye count had no additional cost, averaged 6 min, but proved impractical and poorly reproducible. (4) Camera-captured/printed image was most reliable, had highest reproducibility, but took longer than ‘eye-balling’. In conclusion, based on its comparatively low cost/benefit ratio and reproducibility, camera-captured/printed image appears to be the most practical for calculating Ki67 index. Although automated counting is generally advertised as the gold standard for index calculation, in this study it was not as accurate or cost-effective as camera-captured/printed image and was highly operator-dependent. ‘Eye-balling’ produces highly inaccurate and unreliable results, and is not recommended for routine use.

Intra-ampullary Papillary-Tubular Neoplasm (IAPN): Characterization of Tumoral Intraepithelial Neoplasia Occurring Within the Ampulla: A Clinicopathologic Analysis of 82 Cases

BackgroundThere has been no uniform terminology for systematic analysis of mass-forming preinvasive neoplasms (which we term tumoral intraepithelial neoplasia) that occur specifically within the ampulla. Here, we provide a detailed analysis of these neoplasms, which we propose to refer to as intra-ampullary papillary-tubular neoplasm (IAPN). Materials and MethodsThree hundred and seventeen glandular neoplasms involving the ampulla were identified through a review of 1469 pancreatoduodenectomies and 11 ampullectomies. Eighty-two neoplasms characterized by substantial preinvasive exophytic component that grew almost exclusively (>75%) within the ampulla (in the ampullary channel or intra-ampullary portions of the very distal segments of the common bile duct or pancreatic duct) were analyzed. Results(1) Clinical: The mean age was 64 years, male/female ratio was 2.4, and mean tumor size was 2.7 cm. (2) Pathology: The tumors had a mixture of both papillary and tubular growth (each constituting at least 25% of the lesion) in 57%; predominantly (>75%) papillary in 23%, and predominantly (>75%) tubular in 20%. High-grade dysplasia was present in 94% of cases, of which 39% showed focal (<25% of the lesion), 28% showed substantial (25% to 75%), and 27% showed extensive (>75%) high-grade dysplasia. In terms of cell-lineage morphology, 45% had a mixture of patterns. However, when evaluated with a forced-binary approach as intestinal (INT) versus gastric/pancreatobiliary (GPB) based on the predominant pattern, 74% were classified as INT and 26% as GPB. (3) Immunohistochemistry: Percent sensitivity/specificity of cell-lineage markers were, for INT phenotype: MUC2 85/78 and CDX2 94/61; and for GBP: MUC1 89/79, MUC5AC 95/69, and MUC6 83/76, respectively. Cytokeratin 7 and 20 were coexpressed in more than half. (4) Invasive carcinoma: In 64 cases (78%), there was an associated invasive carcinoma. Size of the tumor and amount of dysplasia correlated with the incidence of invasion. Invasive carcinoma was of INT-type in 58% and of pancreatobiliary-type in 42%. Cell lineage in the invasive component was the same as that of the preinvasive component in 84%. All discrepant cases were pancreatobiliary-type invasions, which occurred in INT-type preinvasive lesions. (5) Outcome: The overall survival of invasive cases were significantly worse than that of noninvasive ones (57% vs. 93%; P=0.01); and 3 years, 69% versus 100% (P=0.08); and 5 years, 45% versus 100% (P=0.07), respectively. When compared with 166 conventional invasive carcinomas of the ampullary region, invasive IAPNs had significantly better prognosis with a mean survival of 51 versus 31 months (P<0.001) and the 3-year survival of 69% versus 44% (P<0.01). ConclusionsTumoral intraepithelial neoplasia occurring within the ampulla are highly analogous to pancreatic or biliary intraductal papillary and tubular neoplasms as evidenced by their papillary and/or tubular growth, variable cell lineage, and spectrum of dysplastic change (adenoma-carcinoma sequence), and thus we propose to refer to these as IAPN. IAPNs are biologically indolent; noninvasive examples show an excellent prognosis, whereas those with invasion exhibit a malignant but nevertheless significantly better prognosis than typical invasive ampullary carcinomas unaccompanied by IAPNs. Twenty eight percent (64 of 230) of invasive carcinomas within the ampulla arise in association with IAPNs.

Tumor Budding as a Strong Prognostic Indicator in Invasive Ampullary Adenocarcinomas

Prognostication of invasive ampullary adenocarcinomas (AACs) and their stratification into appropriate management categories have been highly challenging owing to a lack of well-established predictive parameters. In colorectal cancers, recent studies have shown that tumor budding confers a worse prognosis and correlates significantly with nodal metastasis and recurrence; however, this has not been evaluated in AAC.To investigate the prevalence, significance, and clinical correlations of tumor budding in AAC, 244 surgically resected, stringently defined, invasive AAC were analyzed for tumor budding---defined as the presence of more than or equal to 5 isolated single cancer cells or clusters composed of fewer than 5 cancer cells per field measuring 0.785 mm2 using a 20× objective lens in the stroma of the invasive front. The extent of the budding was then further classified as “high” if there were greater than or equal to 3 budding foci and as “low” if there were <3 budding foci or no budding focus.One hundred ninety-four AACs (80%) were found to be high-budding and 50 (20%) were low-budding. When the clinicopathologic features and survival of the 2 groups were compared, the AACs with high-budding had larger invasion size (19 mm vs. 13 mm; P<0.001), an unrecognizable/absent preinvasive component (57% vs. 82%; P<0.005), infiltrative growth (51% vs. 2%; P<0.001), nonintestinal-type histology (72% vs. 46%; P<0.001), worse differentiation (58% vs. 10%; P<0.001), more lymphatic (74% vs. 10%; P<0.001), and perineural invasion (28% vs. 2%; P<0.001); more lymph node metastasis (44% vs. 17%; P<0.001), higher T-stage (T3 and T4) (42% vs. 10%; P<0.001), and more aggressive behavior (mean survival: 50 mo vs. 32 mo; 3-year and 5-year survival rates: 93% vs. 41% and 68% vs. 24%, respectively; P<0.001). Furthermore, using a multivariable Cox regression model, tumor budding was found to be an independent predictor of survival (P=0.01), which impacts prognosis (hazard ratio: 2.6) even more than T-stage and lymph node metastasis (hazard ratio: 1.9 and 1.8, respectively).In conclusion, tumor budding is frequently encountered in AAC. High-budding is a strong independent predictor of overall survival, with a prognostic correlation stronger than the 2 established parameters: T-stage and lymph node metastasis. Therefore, budding should be incorporated into surgical pathology reports for AAC.

Immunohistochemical analysis of nestin and c-kit and their significance in pancreatic tumors.

The purpose of the present study was to clarify the difference of expression of two stem cell markers, nestin and c‐kit, among various pancreatic epithelial tumors and evaluate their utility. Immunohistochemistry was done for 99 surgically resected pancreatic tumor specimens, including 20 ductal adenocarcinoma (DAC), two undifferentiated carcinomas (UC), 31 intraductal papillary‐mucinous neoplasms (IPMN), six mucinous cystic neoplasms (MCN), five serous cystadenomas (SCA), six acinar cell carcinomas, two pancreatoblastoma (PB), eight solid‐pseudopapillary neoplasms (SPN), and 19 endocrine neoplasms (EN). Nestin was widely expressed in four SPN, one PB, one SCA, sarcoma areas in two UC, one MCN, and one DAC, and an area of oncocytic component in one IPMN. Some of these SPN, SCA and sarcomatous or oncocytic components in which nestin was expressed, also coexpressed c‐kit. Additionally, partial (scattered) expression of c‐kit was observed in ductal elements of 16 DAC, eight IPMN, five MCN, and one UC, one SCA, and three EN. The eight c‐kit‐positive IPMN included four of 23 adenoma‐to‐border lesions and four of eight non‐invasive‐to‐invasive carcinomas. The three EN were all carcinomas. These indicate that expression of two stem cell markers is different by tumor type, but the utility of judging direction or degree of differentiation and malignant grade on the basis of their expression status is suggested.

Manually controlled targeted prostate biopsy with real‐time fusion imaging of multiparametric magnetic resonance imaging and transrectal ultrasound: An early experience

To report our early experience with manually controlled targeted biopsy with real‐time multiparametric magnetic resonance imaging and transrectal ultrasound fusion images for the diagnosis of prostate cancer.

Autopsy cases of fulminant bacterial infection in adults: clinical onset depends on the virulence of bacteria and patient immune status

To assist physicians in recognizing the potentially fatal onset of symptoms in cases of fulminant bacterial infection, we analyzed 11 autopsy cases of such infection (four caused by Streptococcus pneumoniae, four by S. pyogenes, one by S. dysgalactiae subsp. equisimilis, one by Staphylococcus aureus, and one by Vibrio vulnificus). Clinicohistopathologic features were evaluated. All patients experienced sudden onset of hypotension and multiple organ failure, leading to unexpected death. Blood culture confirmed bacteremia. The main chief complaints were gastrointestinal symptoms (45%) and limb pain (36%). All had an underlying chronic illness (82%), e.g., a hematologic disorder (36.3%) or liver cirrhosis (27.2%). Necrotizing fasciitis occurred in only 55% of cases, with none involving pneumococcal infection. Laboratory tests typically showed C-reactive protein elevation but without leukocytosis, indicating a high-level inflammatory state. In ten cases, death was attributed to circulatory collapse due to sepsis; severe pulmonary congestion and hemorrhage were present in these cases. The onset of fulminant bacterial infection depends on both virulence of the bacterium and status of the host defense system.

Diagnostic challenge: intraductal neoplasms of the pancreatobiliary system.

To help pathologists avoid misdiagnosis of intraductal neoplasms arising from the pancreatobiliary system, we report two cases that illustrate diagnostic pitfalls. The first is of a 66-year-old man who complained of appetite loss. An early examination led to a diagnosis of intraductal papillary mucinous neoplasm. Macroscopically, a multilocular cyst without visible mucin was identified. Histologically, the compartments consisted of complex fusion of tubular glands surrounded by dilated pancreatic duct. The neoplasm resembled an acinar cell cystadenocarcinoma. However, the neoplastic cells were negative for trypsin. Thus, the final histopathologic diagnosis was an unusual cystic variant of intraductal tubulopapillary neoplasm (ITPN) of the pancreas. The second case is of a 71-year-old man who complained of right upper quadrant pain. Although bile duct stone was suspected, a polypoid nodule was extracted. Histologically, the nodule was composed of tubular glands, with some complex fusion and focal dysplasia, consistent with carcinoma. In addition, lack of MUC-5AC expression led to an initial impression of ITPN of the bile duct. However, the neoplasm showed dysplastic cells based on the columnar cells resembling pyloric glands, indicating the sequential progression. Thus, the final histopathological diagnosis was intraductal papillary neoplasm of the bile duct with high-grade intraepithelial neoplasia. Because phenotypic variants of intraductal neoplasms of the pancreatobiliary system exist, ITPN and ITPN-mimicking tumor must be carefully differentiated from other intraductal neoplasms.