Tubulopapillary Growth Pattern Research Articles

Histopathological features of epithelioid malignant pleural mesotheliomas in patients with extended survival

Diffuse malignant mesothelioma (DMM) of the pleura is a rare and aggressive disease, wherein the long-term survival (LTS) rate is low. The epithelioid subtype is the most prevalent form of DMM with the best prognosis. To study prognostic histopathologic factors associated with extended survival in epithelioid DMM, we examined 43 tumors from patients with survival more than five years (LTSs) and compared the findings with 84 tumors from a reference group (RG) with average survival. We analyzed the tumors considering previously published histopathological prognostic features and attempted to identify additional morphological features predictive of extended survival. Most of the LTS tumors presented with nuclear grade I (n=34, 90%) and a tubulopapillary growth pattern (n=30, 70%). One LTS tumor had necrosis. In contrast, nuclear grade II (n=49, 61%) and solid growth pattern (n=59, 70%) were more frequent in the RG, and necrosis was present in 16 (19%) tumors. We also evaluated the association of asbestos lung tissue fiber burden quantified from autopsy samples with histopathological features and found that elevated asbestos fiber was associated with higher nuclear grade (P<0.001) and the presence of necrosis (P=0.021). In univariate survival analysis, we identified the following three novel morphological features associated with survival: exophytic polypoid growth pattern, tumor density, and single mesothelium layered tubular structures. After adjustments, low nuclear grade (P<0.001) and presence of exophytic polypoid growth (P=0.024) were associated with prolonged survival. These results may aid in estimating DMM prognosis.

Gastric adenocarcinoma with enteroblastic differentiation should be differentiated from hepatoid adenocarcinoma: A study with emphasis on clear cells and clinicopathologic spectrum

BackgroundIn gastric cancer, clear cells are preferentially found in gastric adenocarcinoma with enteroblastic differentiation (GAED) and hepatoid adenocarcinoma (HAC). The distinction between GAED and HAC is difficult because of their rarity and histologic overlap. MethodsTo elucidate identification of gastric adenocarcinoma with clear cells as GAED or HAC, survival analyses were performed in 28 GAED, 26 HAC, and 1107 conventional adenocarcinoma cases. Cells of origin were assessed by investigating the expression of oncofetal proteins (α-FP, glypican-3, SALL4), in addition to gastric (MUC5AC, MUC6), and intestinal (MUC2, CD10, CDX-2) cell markers. ResultsClinically, HAC showed frequent (57.5%) distant metastasis (mostly in the liver) at the time of diagnosis compared to GAED (P < 0.001). On pathology, all 28 GAED had a predominantly tubulopapillary growth pattern while 24 HAC displayed a predominantly hepatoid growth pattern. In survival analyses, patients with HAC had significantly shorter overall and recurrence-free survival (mean: 25 months, and 53 months, respectively) compared to those with GAED (mean: 107 months, and 118 months, respectively) (P < 0.001).HAC with clear cells showed diffuse and strong expression of all oncofetal proteins (α-FP, glypican-3, and SALL4), were highly positive for CDX-2, and were negative for CD10, MUC6, MUC5AC, and MUC2, suggesting an intestinal mucin phenotype and hepatoid features. In contrast, GAED showed focal expression of one or two oncofetal proteins and commonly expressed CD10, CDX-2, and MUC6 but not MUC2 and MUC5AC, suggesting both gastric antral/intestinal mucin phenotype and focal enteroblastic differentiation. SALL4 was diffusely and strongly positive in HAC, while it was heterogeneously expressed in GAED. ConclusionsIn conclusion, although rare, HAC with clear cells should be differentiated from GAED based on the poor prognosis, diffuse and strong oncofetal protein expression, and intestinal mucin phenotype.

Intrapancreatic recurrence of intraductal tubulopapillary neoplasm (ITPN) 16\xa0years after the initial surgery for noninvasive ITPN: a case report

BackgroundIntraductal tubulopapillary neoplasm (ITPN) is a rare pancreatic intraductal neoplasm. It is characterized by a tubulopapillary growth pattern, entirely high-grade atypical cells, minimal cytoplasmic mucin, and no obvious luminal mucin secretion. Most of its biological nature remains unclear.Case presentationWe herein report a case of intrapancreatic recurrence of ITPN in the remnant pancreas of a patient who underwent pancreatoduodenectomy 16 years previously for a noninvasive intraductal pancreatic head tumor. We reexamined the primary tumor and compared it with the most recently resected specimen. Histologically, the primary tumor showed a tubulopapillary growth of high-grade atypical cells with scanty cytoplasmic mucin, which was similar to the recently resected specimen except for the invasive area. Immunohistochemically, the neoplastic cells in both specimens showed focal staining of MUC1 and positivity for MUC6 but negativity for MUC2, MUC5AC, CDX2, and trypsin. Molecular analysis revealed no KRAS/GNAS/BRAF/PIK3CA mutations in either of the specimens.ConclusionsThese findings of the original tumor and recently resected tumor were compatible with the features of ITPN. Thus, recurrence is possible even for a primary noninvasive ITPN, and long-term surveillance is recommended.

Pancreatic intraductal tubulopapillary neoplasm with associated invasive cancer successfully treated by total pancreatectomy: A case report.

A 74-year-old male was admitted to Departments of Surgery, Toyonaka Municipal Hospital (Osaka, Japan) for treatment of a pancreatic tumor. Contrast enhanced computed tomography (CT) revealed a mass with small cystic lesions in the pancreatic head and body. Fluorodeoxyglucose-positron emission tomography/CT revealed an abnormal uptake of fluorodeoxyglucose, corresponding to the mass lesions. Upper gastrointestinal endoscopy revealed rough mucosa near the opening of the accessory pancreatic duct, and the mucosa biopsy exhibited adenocarcinoma with no mucin observed. The preoperative diagnosis was pancreatic intraductal tubulopapillary neoplasm (ITPN) with cancerous lesions, and a total pancreatectomy with splenectomy was performed. The resected tissue specimen revealed a solid tumor occupying the entire pancreas with intraductal growth into the main pancreatic duct. Histological examination revealed high-grade dysplastic cells in a tubulopapillary growth pattern without overt mucin production beyond the pancreatic duct. Immunohistochemical staining analysis of the tumor was positive for cytokeratin (CK)7, CK19 and mucin (MUC)1, and negative for MUC2, MUC5AC, MUC6 and caudal type homeobox 2. The tumor was finally diagnosed as pancreatic ITPN with associated invasive cancer. The patient remains well without evident recurrence nine months post-surgery. ITPN is a rare type of epithelial neoplasm of the pancreas, and is characterized by intraductal tubulo-papillary growth, ductal differentiation, limited intracellular mucin production, and cellular dysplasia. The present case report may contribute to improved understanding of how to effectively treat patients with ITPN.

Oncocytic Renal Cell Carcinoma with Tubulopapillary Growth Having a Fat Component.

We report a rare case of oncocytic renal cell carcinoma (RCC) with tubulopapillary growth in the background of tuberculous end-stage kidney disease. Histology of the renal mass consisted of oncocytic cells forming solid, thin tubules and rare papillae. The tumor had abundant eosinophilic oncocytic cells containing occasional cytoplasmic Mallory body–like hyaline globules and a tiny focus of clear cells with intervening mature fat. Both the oncocytic cells and clear cells were immunoreactive for a-methylacyl-CoA racemase, vimentin, pancytokeratin, and CD10, and negative for transcription factor E3, CD15, human melanoma black 45, and c-kit. Mallory body–like hyaline globules were positive for CAM 5.2 and periodic acid–Schiff with or without diastase. Ultrastructurally, the tumor cells had abundant cytoplasmic mitochondria. The present case is a rare case of oncocytic RCC with tubulopapillary growth pattern. The case is unique in that the tumor was mixed with fat component, which is not common in RCC and thus can lead to misdiagnosis.

A Rare Case of Mesothelioma Showing Micropapillary and Small Cell Differentiation with Aggressive Behavior

Pleural mesothelioma is a rare neoplasm and roughly 70% are the epithelioid type, which is characterized by proliferation of epithelioid tumor cells with a tubulopapillary growth pattern [1]. There have been few reports of mesothelioma having a micropapillary pattern [2] and a small cell component [3]. To the best of our knowledge, there has been no previously reported case containing both micropapillary and small cell components. Herein, we report a rare case of mesothelioma with micropapillary component and small cell differentiation exhibiting aggressive behavior in a 59-year-old woman.

Is intraductal tubulopapillary neoplasia a new entity in the spectrum of familial pancreatic cancer syndrome?

We report on a 78-year old male with a positive family history for pancreatic cancer, who underwent total pancreatectomy for a suspected intraductal papillary mucinous neoplasm with extensive involvement of the main pancreatic duct and multiple branch ducts. The post operative course was uneventful. Macroscopic examination of the specimen revealed multiple solid non-mucinous tumour nodules throughout the main pancreatic duct and within multiple branch ducts. The microscopic appearance of the tumour, in particular its tubulopapillary growth pattern and immunohistochemical mucin profile (MUC1, MUC6 positive; MUC2, MUC5AC negative) were consistent with intraductal tubulopapillary neoplasia (ITPN) showing high-grade dysplasia. No evidence of stromal invasion was identified. To the best of our knowledge, this is the first report on ITPN in a high-risk patient based on a history of familial pancreatic cancer (FPC). The potential association between this entity and the spectrum of neoplastic lesions in FPC should be investigated with particular consideration of the lower biological aggressiveness of ITPN.

Intraductal tubulopapillary neoplasm of the pancreas: a clinicopathologic study of 6 cases

To study the pathologic features, diagnosis, differential diagnosis and molecular characteristics of intraductal tubulopapillary neoplasm of the pancreas (ITPN). The clinical findings, morphologic features, immunophenotype (by EnVision method) and KRAS gene alterations (by reverse transcriptase-polymerase chain reaction) of 6 cases of ITPN encountered during the period from January, 2001 to June, 2010 were analyzed. There were altogether 2 males and 4 females. The mean age of the patients was 64 years. Gross examination showed that the tumors were located in large pancreatic ducts and appeared as polypoid nodules with ductal obstruction. Solid tumor nodules associated with adjoining dilated ducts were identified in one case. Histologically, the tumors were characterized by tubulopapillary growth pattern without luminal mucin. The tumor cells showed high-grade nuclear atypia with scanty intracytoplasmic mucin. Intraductal necrotic foci were frequently observed. Immunohistochemical study showed that the tumor cells expressed CK7 and CK19. Focal positivity for MUC5AC was demonstrated. Two cases expressed MUC1. The staining for MUC2 was negative. KRAS gene mutations were identified in 2 cases, with a single-amino-acid substitution in codon 12 (35G > A and 35G > T/34G > A). ITPN is a newly described pancreatic intraductal neoplasm and different from intraductal papillary mucinous neoplasm. ITPN is characterized by intraductal tubulopapillary growth pattern, severe cytologic atypia and scanty mucin secretion.

Intraductal Tubulopapillary Neoplasms of the Pancreas Distinct From Pancreatic Intraepithelial Neoplasia and Intraductal Papillary Mucinous Neoplasms

We have encountered cases of unusual intraductal pancreatic neoplasms with predominant tubulopapillary growth. We collected data on 10 similar cases of "intraductal tubulopapillary neoplasms (ITPNs)" and analyzed their clinicopathologic and molecular features. Tumor specimens were obtained from 5 men and 5 women with a mean age of 58 years. ITPNs were solid and nodular tumors obstructing dilated pancreatic ducts and did not contain any visible mucin. The tumor cells formed tubulopapillae and contained little cytoplasmic mucin. The tumors exhibited uniform high-grade atypia. Necrotic foci were frequently observed, and invasion was observed in some cases. The ITPNs were immunohistochemically positive for cytokeratin 7 and/or cytokeratin 19 and negative for trypsin, MUC2, MUC5AC, and fascin. Molecular studies revealed abnormal expressions of TP53 and SMAD4 in 1 case, but aberrant expression of beta-catenin was not observed. No mutations in KRAS and BRAF were observed in the 8 cases that were examined. Eight patients are alive without recurrence, 1 patient died of liver metastases, and 1 patient is alive but had a recurrence and underwent additional pancreatectomy. The mitotic count and Ki-67 labeling index were significantly associated with invasion. All the features of ITPN were distinct from those of other known intraductal pancreatic neoplasms, including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and the intraductal variant of acinar cell carcinoma. Intraductal tubular carcinomas showed several features that were similar to those of ITPN, except for the tubulopapillary growth pattern. In conclusion, ITPNs can be considered to represent a new disease entity encompassing intraductal tubular carcinoma as a morphologic variant.

Unusual Multifocal Glomeruloid Pattern in a Well-Differentiated Papillary Mesothelioma of the Peritoneum

by clefted spaces. The mesothelial origin of the tumor was confirmed by immunoreactivity showing positive immunolabeling for calretinin (1:300; Dako, Carpinteria, California), CK 5/6 (1:30; Bio Sb, Santa Barbara, California), thrombomodulin (1:50; Dako), WT-1 (1:50; Cell Marque, Austin, Texas), and CK7 (1:100; Cell Marque). CK20 (1:50; Cell Marque) was negative (Figure 2). Well-differentiated papillary mesothelioma is an uncommon distinct subtype of mesothelioma that occurs principally in the peritoneum of women in the third and fourth decades. It is often discovered incidentally during abdominal or pelvic surgery, and it is generally regarded as a tumor of low malignant potential. In the English literature, less than 100 cases have been reported affecting both men and women, including cases arising in the pleura and tunica vaginalis. Histologically, WDPM is A46-year-old woman presented to the ABC Medical Center in Mexico City with the clinical picture of acute cholecystitis and underwent cholecystectomy. The patient had no history with regard of asbestos exposure. During surgery, incidental multifocal small firm, white to tan peritoneal nodules were found, ranging from 5 mm to 1 cm, and on frozen section, a diagnosis of papillary epithelial neoplasm consistent with well-differentiated papillary mesothelioma (WDPM) was rendered (Figure 1A). The patient underwent total hysterectomy, along with omentectomy and resection of multiple peritoneal and diaphragmatic implants. The serosal membranes of the uterus and ovary were unremarkable, although a microscopic focus (1 mm) of parenchymal infiltration was found in the left ovary. The histological study disclosed a well-developed tubulopapillary growth pattern with solid areas. The papillae were lined by a single layer of uniform cuboidal to flattened cells with minimal cytological atypia, covering thin fibrovascular cores. Mitosis was absent. The stroma showed focal myxoid change. Focal psammoma bodies were present. Throughout the tumor, constituting approximately 20% of the neoplasm and mainly localized to the periphery of the nodules, the fibrovascular papillae were arranged forming a distinct glomeruloid pattern of growth characterized by round to oval neoplastic mesothelial cell tufts supported by a fibrovascular core (Figures 1B and 1C). The mesothelial cells were sometimes arranged in semicircular concentric rows separated

Mucinous tubular and spindle cell carcinoma of kidney is probably a variant of papillary renal cell carcinoma with spindle cell features

Mucinous tubular and spindle cell carcinoma is a rare and newly described type of renal cell carcinoma (RCC) with a relatively indolent behavior. However, its histogenetic origin or line of differentiation remains unclear. Twelve cases of mucinous tubular and spindle cell carcinoma were identified and retrieved from the files of 3 institutions. Detailed morphological features, as well as their immunohistochemical profile established with markers of proximal renal tubules (RCC marker antigen, CD15, and alpha-methylacyl-CoA racemase) and of distal renal tubules (kidney-specific cadherin and cytokeratin 7), were studied. The age range of the patients was 35 to 73 years with a median of 56 years. The male to female ratio was 1:3. All of the patients were alive with follow-up between 4 and 38 months. All the tumors were confined to the kidney with a mean tumor size of 6.9 cm (range, 1.8-17 cm). The tumors were composed of variable proportions of tubular and spindle cell areas with focal to prominent mucinous or myxoid stroma. Foamy macrophages were seen in 10 cases and were prominent in 4 cases. A focal compressed tubulopapillary growth pattern was seen in 10 cases. The tumor cells were uniformly cuboidal with ovoid to round nuclei and inconspicuous nucleoli (Furhman nuclear grade 3 in 6 cases). Focal necrosis was seen in 3 cases. Immunostains showed that tumors were positive for RCC marker antigen (11/12), alpha-methylacyl-CoA racemase (11/12), CD15 (8/12), CD10 (2/12), kidney-specific cadherin (1/12), and cytokeratin 7 (11/12). Its morphological features as well as a strong preferential expression of proximal tubule markers suggest that this tumor is a type of RCC with proximal tubular differentiation, which appears closely related to or represents a morphological variant of papillary RCC.

Collecting duct carcinoma of the kidney

The collecting duct carcinoma that we reported 1 showed tubulopapillary growth pattern and low-grade nuclear atypia (Fuhrman’s grade 2), 2 clearly bordered by fibrous capsule. It was unusual in typical collecting duct carcinoma. Even though it was not mentioned in our paper, the immunohistochemical study showed positive reaction against UEA-1, CAM 5.2, BerEP4 and Progen19. Alcian blue was positive in the aliquot area. More importantly, this small neoplasm (1.5 cm in diameter) existed clearly in the renal medulla. We believed that the tumor color was influenced by the preoperative needle biopsy; therefore, we synthetically diagnosed it as collecting duct carcinoma. In Japan, regular health check-ups among middleaged and elderly people are popular. Therefore, the detection rate of incidental carcinoma may be higher than that in other countries. Subsequently, there is the possibility that the tumors are diagnosed at an early stage, and we may find the clinical and pathological features such as those in our previous paper. Srigley and Eble 3 have proposed major and minor diagnostic criteria for collecting duct carcinoma, and have presented a scheme of the spectrum of collecting duct carcinoma. Papillary carcinomas also show positive reaction for distal nephron markers, which may make it difficult to distinguish between low-grade collecting duct carcinoma and papillary carcinoma. Additional pathologic series should help to elucidate the morphologic and biological spectrum of collecting duct neoplasia. Furthermore, cytogenetic and molecular genetic studies 4–7 may help sort out the morphologic diversity of putative collecting duct carcinomas, very much like the way that molecular studies have assisted in the classification of other renal epithelial neoplasms including clear cell, papillary and chromophobe renal cell carcinomas.

Malignant vascular tumors of the serous membranes mimicking mesothelioma. A report of 14 cases.

Malignant endothelial neoplasms involving the serous membranes are rare, and only a few cases have been documented. We report 14 patients with epithelioid hemangioendothelioma (EHE) or epithelioid angiosarcoma (EA) diffusely involving the pleural, peritoneal, or pericardial cavities, resulting in a picture closely resembling mesothelioma. The mean age at diagnosis was 52 (range, 34-85). The patients included two women and one man with peritoneal tumors, eight men with pleural tumors, and three men with pericardial tumors. A shared histological appearance was a diffuse sheet-like and clustered pattern of tumor growth with variable degrees of vascular differentiation. A tubulopapillary growth pattern, often seen in mesothelioma, was prominent in four cases. Nine cases showed a variable number of spindle cells, some neoplastic, others reactive, focally producing a biphasic growth pattern, further suggesting mesothelioma. Initial interpretations included mesothelioma, adenocarcinoma, and, in one case with prominent spindle-cell components, leiomyosarcoma. Immunohistochemically, strong vimentin staining and negative or weak to moderate cytokeratin staining were observed in all 14 cases. The tumor cells coexpressed at least two of the four endothelial markers used in the study (CD31, CD34, von Willebrand factor, and Ulex europaeus agglutinin-I [UEA-I)]. Detection of abortive vessel formation was facilitated by staining for collagen type IV. Markers of mesothelial, epithelial, muscular, and neuronal differentiation were all negative in the subset of cases studied. As a control group, 39 mesotheliomas and more than 60 adenocarcinomas of various origins were studied using the same antibody panel. This group revealed strong keratin staining, moderate or negative vimentin staining, and no expression of any of the endothelial-lineage markers, with the exception of positive staining for UEA-I in occasional adenocarcinomas. Clinically, these endothelial tumors were highly aggressive; 12 patients presented with disseminated disease, and most died within months of the initial presentation. These findings indicate that, although uncommon, EHE/EA should be included in the differential diagnosis of serous membrane neoplasms with histological and clinical features of malignant mesothelioma. The diagnosis of an endothelial neoplasm can be suspected by the presence of abortive vessel formation and by the strong expression of vimentin, with absent or low-level expression of cytokeratin. The demonstration of immunoreactivity for two or more endothelial-associated markers is essential in confirming the diagnosis.

Cytogenetic studies in renal cell carcinoma patients receiving low-dose recombinant interleukin-2-based immunotherapy.

A variety of cytogenetic aberrations have been reported in sporadic and familial renal cell carcinoma. Rearrangements of the short arm of chromosome 3 (3p), trisomy 17, and nuclear hyperdiploidy have been reported to be common clonal chromosome changes. We analyzed a total of ten tumor-derived cell lines from patients who underwent nephrectomy for renal cell carcinoma employing conventional cytogenetics. All patients received an immunomodulatory therapy based on recombinant interleukin-2 (rIL-2). Tumor stage and grade, histo- and cytopathology, and patients' response to immunotherapy were assessed and correlated statistically to rearrangement of 3p, trisomy 17, and nuclear hyperdiploidy. Trisomy 17 as clonal aberration could be revealed only in papillary renal cell carcinoma, whereas tumors with compact or tubulopapillary growth pattern lacked this abnormality (p < 0.002). One of 3 patients with diploid or near-diploid karyotype (< or = 49 chromosomes) achieved a partial remission while two presented with stable disease after immunotherapy. In contrast, all 6 patients with tumor progression upon rIL-2-based immunotherapy revealed hyperdiploid (> 49 chromosomes) karyotypes. The correlation between hyperdiploidy and tumor progression was found to be statistically significant (p < 0.029). Interestingly, the only patient achieving an objective tumor remission after immunotherapy presented with a normal diploid karyotype. Our findings suggest tumor hyperdiploidy as an adverse prognostic factor in renal cell carcinoma patients receiving rIL-2-based immunotherapy.

Renal cell carcinoma in children: Histology, immunohistochemistry, and follow‐up of 10 cases

Ten renal cell carcinomas in children under 15 years were investigated. The average age was 122.5 months and the girls predominated in our cases (7 girls, 3 boys). By using the classification of Thoenes et al., Pathol Res Pract 181: 125-143, 1986 a predominance of clear cell-eosinophilic tumor cell type and of the tubulopapillary growth pattern was found. Immunohistochemistry revealed a heterogeneity of cytokeratin expression. By using the monoclonal antibodies Cam 5.2 and KL 1, cytokeratins were found in 7 cases each. The other 4 cytokeratin antibodies used were less sensitive. The expression of cytokeratin 13 in 3 cases suggested a more complex histogenesis than assumed. Vimentin was found in 3 tumors, but an association to a higher grade (G) of malignancy was not found in these cases. One tumor expressed the Tamm-Horsfall-protein, which is predominantly found in the distal tubule of the normal kidney. In summary the results of immunohistochemistry characterized the great heterogeneity of these tumors. Follow-up information was available in 9 cases. All patients with G I- and G II-tumors were free of disease after an average time of 39.6 months (mean 27 months). Two of the 3 cases with G III-tumors died after 9 and 15 months, despite additional chemo- or radiotherapy. Therefore tumors of grade I and II of the Thoenes classification seem to have a good prognosis.