Virchows Archiv

Kurman, Robert; McConnell, Thomas

doi: 10.1007/s00428-009-0824-9pmid: 19859732

This review discusses precursor lesions of endometrial and ovarian carcinoma with an emphasis on the unique molecular alterations that have led to the development of binary classification schemes for tumors of both the endometrium and ovary. While such a system is well established for endometrial carcinoma, only recently has a binary classification scheme been proposed for ovarian carcinoma. For both, the morphologic and molecular genetic-defining characteristics of their respective precursor lesions are described in detail. Furthermore, similarities and differences of the precursor lesions of specific tumors of these two genital tract organs are also addressed with a brief discussion of the clinical implications of their diagnosis.

Feinberg, Andrew

doi: 10.1007/s00428-009-0847-2pmid: 19844740

Traditionally, the pathology of human disease has been focused on microscopic examination of affected tissues, chemical and biochemical analysis of biopsy samples, other available samples of convenience, such as blood, and noninvasive or invasive imaging of varying complexity, in order to classify disease and illuminate its mechanistic basis. The molecular age has complemented this armamentarium with gene expression arrays and selective analysis of individual genes. However, we are entering a new era of epigenomic profiling, i.e., genome-scale analysis of cell-heritable nonsequence genetic change, such as DNA methylation. The epigenome offers access to stable measurements of cellular state and to biobanked material for large-scale epidemiological studies. Some of these genome-scale technologies are beginning to be applied to create the new field of epigenetic epidemiology.

Morawietz, Lars; Floore, Arno; Stork-Sloots, Lisette; Folprecht, Gunnar; Buettner, Reinhard; Rieger, Anja; Dietel, Manfred; Huebner, Gerdt

doi: 10.1007/s00428-009-0867-ypmid: 20012089

For the clinical diagnosis and appropriate therapy of patients with cancer of unknown primary (CUP), biopsies of the tumor metastases are generally examined histopathologically and by immunohistochemistry (IHC). Gene expression profiling (GEP) is a new diagnostic technique that might further contribute to tumor specification. Biopsies of 43 CUP cases underwent a retrospective central histopathological and immunohistochemical review and centrally performed GEP using CupPrintTM. Two samples could not be evaluated by IHC due to small biopsy size or loss of immunoreactivity. One of these and 17 other samples were not suited for GEP due to RNA degradation. In 13 out of the remaining 24 cases (54%), the same primary was proposed by IHC and GEP and was supported by the clinical findings, furthermore leading to the doubtless identification of the primary in four out of these. In seven cases, there was discordance between IHC and GEP, with the clinical picture being more in line with IHC in three and with GEP in four cases. Four cases had to remain undecided because the primary tumors suggested by IHC and GEP were not supported. In conclusion, overlap between IHC and GEP results and the clinical presentation was noted in the majority of those true CUP cases that were evaluable with both techniques. Therefore, GEP can be a complementary diagnostic technique assisting immunohistochemical profiling of cancer biopsies with unknown primary.

Zhao, Jing; Lang, Ronggang; Guo, Xiaojing; Chen, Ling; Gu, Feng; Fan, Yu; Fu, Xilin; Fu, Li

doi: 10.1007/s00428-009-0862-3pmid: 20013346

Pleomorphic carcinoma of the breast is considered a rare variant of high-grade ductal NOS carcinoma (NOS-IDC), and the prognosis is poor. However, its clinicopathologic features are not well-characterized. Using the criteria delineated in the World Health Organization breast tumor classification of 2003, ten cases of pleomorphic carcinoma were identified from 9794 NOS-IDC in our archived materials that were originally diagnosed as high-grade infiltrating ductal carcinoma of breast. To investigate the clinicopathologic characteristics and to elucidate the histologic diagnosis and differential diagnosis of this entity, we reviewed the pathology manifestations and clinical features of these cases and examined the tumor expression of ER, PR, PCNA, AE1/AE3, p53, S-100, C-erbB-2, EMA, p63, and Bcl-2 by immunohistochemistry.

Tarragona, Jordi; Llecha, Nuria; Santacana, Maria; Lopez, Susana; Gatius, Sonia; Llobet, David; Dolcet, Xavier; Palomar-Asenjo, Victor; Gonzalez-Tallada, Francisco; Matias-Guiu, Xavier

doi: 10.1007/s00428-009-0855-2pmid: 19936781

Gupta, Ruchi; Srinivasan, Radhika; Nijhawan, Raje; Suri, Vanita

doi: 10.1007/s00428-009-0860-5pmid: 19937343

Tissue transglutaminase 2 (TG2) is a recently identified molecule with multifunctional physiological roles. This is the first report of the expression of TG2 in cervical intraepithelial neoplasia (CIN) and invasive squamous cell carcinoma (SCC). For comparison, the expression of p16, a known surrogate biomarker of HPV infection, was evaluated. The expression of nuclear factor kappa B (NF-κB), a molecule crucial to inflammation and neoplasia, was also determined to explore its possible linkage with TG2 expression. Twenty cases each with normal cervical histology, CIN1, CIN2, CIN3, and invasive SCC were analyzed for TG2, p16, and NF-κB expression by immunohistochemistry. Intergroup differences were analyzed by Friedman ANOVA. Cytoplasmic as well as nuclear TG2 expression was observed in the epithelial cells. As compared to normal controls, CIN1 showed markedly increased cytoplasmic TG2 expression (p = 0.006). In CIN2/3, additional nuclear TG2 expression was seen (p = 0.009 and 0.031, respectively). Marked extracellular stromal upregulation of TG2 was noted in CIN3/SCC versus normal controls (p = 0.054; p = 0.003). There was no relationship of TG2 with either p16 of NF-κB expression. Combining TG2 immunoreactivity with p16 increased the immunolabeling of dysplasia from 35% to 100% in CIN1, 45% to 60% in CIN2, and 60% to 85% in CIN3. TG2 serves as an additional biomarker for all grades of cervical dysplasia, especially for low-grade dysplasia.

Zheng, Liduan; Weng, Mixia; He, Jun; Yang, Xiuping; Jiang, Guosong; Tong, Qiangsong

doi: 10.1007/s00428-009-0861-4pmid: 19967544

Resistin-like molecule beta (RELMβ), an intestinal goblet cell-specific protein, is a biomarker of intestinal metaplasia in Barrett’s esophagus and over-expressed in colon cancer. Since gastric adenocarcinomas can arise through a process of intestinalization, we hypothesized that RELMβ might be aberrantly expressed in gastric cancer. This study was undertaken to examine the RELMβ expression in gastric cancer and correlate it with clinical outcome. One hundred and thirty-six gastric cancer patients were evaluated for the RELMβ expression by immunohistochemistry. The RELMβ transcripts were measured by real-time quantitative PCR. In normal gastric mucosa, RELMβ expression was absent, whereas areas of intestinal metaplasia revealed RELMβ reactivity. Eighty-nine patients of gastric cancer (65.4%) were positive for RELMβ expression. In a subtotal of 20 patients, RELMβ transcripts were positively correlated with protein levels in gastric cancer tissues, but absent in normal gastric mucosa. The expression rate of RELMβ was higher in intestinal-type carcinomas than in diffuse-type carcinomas (P < 0.001). RELMβ positivity in gastric cancer was positively correlated with tumor differentiation (P = 0.001) and inversely correlated with tumor infiltration (P = 0.007), lymph node metastasis (P = 0.035), and heparanase expression (P < 0.001), without correlation with age, gender, tumor location and size, tumor-node metastasis stages, and Ki-67 expression. Patients showing positive RELMβ expression had a significantly longer overall survival than those with negative expression (P = 0.001). These results provide evidences that the RELMβ expression in gastric cancer is correlated with clinicopathological features and may be a useful prognostic factor for predicting the outcome of gastric cancer patients.

Shi, Huaiyin; Cao, Dengfeng; Wei, Lixin; Sun, Lu; Guo, Aitao

doi: 10.1007/s00428-009-0864-1pmid: 20013345

Primary choriocarcinomas of the liver are rare. Previous reported cases were mostly in infants with only rare adult cases. Here, we presented five adult cases. The patients were all males, with an average age of 41.6 years (from 36 to 48 years). Clinical presentations included right upper abdominal pain or abdominal distension. All patients presented with a large hepatic mass on ultrasonography that measured 11 cm on average in the greatest diameter. Elevated serum human chorionic gonadotropin (HCG) levels were noted in all cases. At presentation, the tumor was confined to the liver in two patients and therefore surgically resected. The other three patients presented with extrahepatic metastases on imaging study and therefore only received chemotherapy. All five patients died from the tumor within 2 to 8 months. Autopsy was performed for all five cases. The autopsy confirmed that the choriocarcinoma was confined to the liver in two surgically resected cases. The other three patients had metastatic choriocarcinoma in the lung (two patients), peritoneum (one patient), adrenal glands (one patient), and brain (one patient). None of the patients had any evidence of a testicular tumor or scar after examination of the entirely submitted testes. No tumor was observed in central nervous system, mediastinum, or other organs other than described above. Grossly, the primary tumors were large, soft, hemorrhagic, and with foci of necrosis. Histologically, the tumors were composed of mononucleated trophoblastic cells with round nuclei, clear cytoplasm, and prominent nucleoli admixed with large, multinucleated syncytiotrophoblastic cells. Immunohistochemically, tumor cells were strongly positive for keratin, HCG, and focally positive for human placental lactogen. Ki-67 proliferation index was high (mean 75%) in the mononucleated trophoblastic cells. Our series is the largest one to document primary hepatic choriocarcinoma in adults. Although these tumors are rare, they behave in a very aggressive fashion.

Magro, Gaetano; Amico, Paolo; Vecchio, Giada; Caltabiano, Rosario; Castaing, Marine; Kacerovska, Denisa; Kazakov, Dmitry; Michal, Michal

doi: 10.1007/s00428-009-0859-ypmid: 19937344

Multinucleated floret-like giant cells (MNFGCs), similar to those commonly observed in pleomorphic lipoma and giant cell fibroblastoma, have been occasionally reported in gynecomastia and neurofibromas from patients affected by neurofibromatosis type 1 (NF1). Accordingly, it has been suggested that their detection, especially in an otherwise typical neurofibroma, could be a morphological clue to diagnosis of NF1. The aim of the present study was the identification of MNFGCs in a large series (94 cases) of sporadic and NF1-associated neurofibromas, to assess if their presence may indeed be a morphological marker of NF1. Numerous MNFGCs, namely, those that were easily apparent at low magnification (×50 and ×100), were identified only in 5.3% of cases. In 18.1% of cases, a low number of these cells could be observed but only after a careful search, especially at higher magnification (×200 and ×400). Immunohistochemically, all MNFGCs were stained with vimentin and CD34, but not with S-100 protein. Interestingly, there was no statistically significant correlation between MNFGCs (presence or absence) and NF1 (p = 0.73), gender (p = 0.59), age (p = 0.43), and site of tumor (cutaneous vs deep-seated soft tissue; p = 0.27). Our clinicopathologic findings suggest that MNFGCs in an otherwise typical neurofibroma are not a reliable marker of NF1, likely representing a morphological reactive change of the indigenous dermal or endoneurial fibroblasts or dendritic cells in response to unknown microenvironmental stimuli.

Mai, Kien; Faraji, Hamidreza; Desantis, Darren; Robertson, Susan; Belanger, Eric; Levac, Joelle

doi: 10.1007/s00428-009-0871-2pmid: 20033232

We performed fluorescent in situ hybridization (FISH) to investigate the numeric change of chromosomes 7, 17, and Y and loss of chromosome 3p in “papillary renal cell carcinomas (RCC) with extensive clear cell changes (CCC).” Consecutive cases of RCC over a 12-year period were reviewed to identify “papillary RCC with extensive CCC.” Immunostaining for cytokeratin 7 and alpha-methylacyl-CoA racemase (AMACR) and FISH for chromosomes 7, 17, Y, and 3p were applied. Of the total of 521 RCC retrieved, there were 49 RCC with papillary architecture and clear cell areas that could be divided into: Group 1 (12 cases), typical clear cell RCC with focal areas of papillary formation; Group 2 (28 cases), focal typical papillary RCC having papillary architecture with extensive CCC; and Group 3 (nine cases), RCC with an admixture of eosinophilic/clear cytoplasm and solid/papillary architecture. Group 1 showed negative immunoreactivity for CK7 and AMACR and absence of numeric chromosomal gain or loss of chromosomes 7/17 and Y. Groups 2 and 3 showed variable reactivity for CK7 and AMACR. Tumors in group 2 and five in group 3 showed trisomies of chromosomes 7 and/or 17 with or without loss of chromosome Y. Loss of small arm 3p was observed in groups 1 and 3 but not in group 2 tumors. In conclusion, papillary RCC may show phenotypical CCC mimicking clear cell RCC. In a small number of cases with mixed histopathological features, FISH is helpful in subtyping RCC.