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  Anatomic Abstracts

 

 

 

 

 

August 2007

Editor:
Michael Cibull, MD
Melissa Kesler, MD

Overexpression of p16 identifies HPV-positive vulvar squamous cell carcinoma
Replication protein A as a prognostic indicator in colon cancer
Ductal phenotypic expression of E-cadherin/catenin complex in tubulolobular carcinoma
Low-grade dysplasia as a risk factor for progression to esophageal adenocarcinoma
Role of EGFR in esophageal and esophagogastric junction adenocarcinomas
Prognostic ability of simplified nuclear grading of renal cell carcinoma

bullet Overexpression of p16 identifies HPV-positive vulvar squamous cell carcinoma

Invasive vulvar squamous cell carcinoma accounts for more than 90 percent of malignant vulvar neoplasms. The carcinoma has been divided into two groups based on its clinical and pathologic features. These two types of vulvar squamous cell carcinomas (VSCCs) are recognized according to their relationship to human papillomavirus (HPV). Basaloid or warty carcinomas are considered HPV-associated tumors, whereas differentiated keratinizing neoplasms are not considered to be associated with HPV. Immunohistochemical detection of p16 and p53 recently has been proposed to differentiate these two types of VSCCs. The authors conducted a histologic study to evaluate the usefulness of immunohistochemistry in classifying VSCCs and to describe the clinicopathologic characteristics of both types of VSCCs. The study involved immunohistochemical evaluation of p16 and p53 and HPV detection and typing by polymerase chain reaction using two different sets of primers in 92 cases of VSCCs. The authors detected HPV in 16 of 92 (17.4%) specimens and identified HPV16 in 75 percent of positive cases. They observed a significant number of discrepancies between histology and HPV detection, with 37.5 percent of HPV-positive tumors considered keratinizing and 9.2 percent of HPV-negative carcinomas showing basaloid or warty features. Diffuse positivity for p16 and p53 was observed in 100 percent and 6.2 percent of HPV-positive tumors and 2.3 percent and 64.5 percent of HPV-negative neoplasms, respectively. The sensitivity and specificity of p16 immunostaining to detect HPV-associated carcinomas (100% and 98.7%, respectively) were better than those of histologic criteria (93.8% and 35.5%) and p53 negative stain (62.5% and 93.4%). Vulvar intraepithelial neoplasia grade 3 of basaloid/warty type was identified in 53.8 percent of HPV-positive tumors, including three keratinizing tumors. All cases were p16 positive and p53 negative. Vulvar intraepithelial neoplasia grade 3 of differentiated type was observed in 45.6 percent of HPV-negative cases; 90.8 percent of them were positive for p53 and all were negative for p16. No differences in age, stage, or development of recurrence were observed between HPV-positive and -negative tumors. In summary, the morphologic criteria to discriminate HPV-positive from -negative VSCCs have significant overlap. Immunostaining for p16 is a reliable marker for HPV-positive VSCCs and improves the results of histologic classification.

Santos M, Landolfi S, Olivella A. P16 overexpression identifies HPV-positive vulvar squamous cell carcinomas. Am J Surg Pathol. 2006;30:1347–1356.

Reprints: Dr. Jaume Ordi, Dept. of Pathology, Hospital Clinic, C/Villarroel 170, 08036, Barcelona, Spain; jordi@clinic.ub.es

bullet Replication protein A as a prognostic indicator in colon cancer

Replication protein A, a component of the origin recognition complex, is required to stabilize single-stranded DNA at early and later stages of DNA replication and is, therefore, critical for eukaryotic DNA replication. Experimental studies in colon cancer cell lines have shown that replication protein A (RPA) protein may be the target of cytotoxins designed to inhibit cellular proliferation. This study investigated the expression of RPA1 and RPA2 subunits of RPA protein and assessed their prognostic value in colon cancer patients. The authors analyzed immunohistochemically the expression of RPA1 and RPA2 proteins in 130 colon cancer resection specimens in relation to conventional clinicopathological parameters and patient survival. Their results showed positive associations between RPA1 and RPA2 protein expressions (P=0.0001), RPA1 and RPA2 labeling indices and advanced stage of the disease (P=0.001 and 0.003, respectively), RPA1 and RPA2 labeling indices and the presence of lymph node metastasis (P=0.002 and 0.004, respectively), RPA1 labeling indices and the number of infiltrated lymph nodes (P=0.021), and RPA2 labeling indices and histological grade of carcinomas (P=0.05). Moreover, a statistically significantly higher RPA1 labeling index was observed in the metastatic sites compared to the original sites (P=0.012). RPA1 and RPA2 protein expression was associated with adverse patient outcome in univariate (log rank test, P<0.00001 and 0.00001, respectively) and multivariate (Cox model, P=0.092 and 0.0001, respectively) statistical analyses. Statistically significant differences according to the expression of RPA1 and RPA2 proteins were also noted in the survival of stage II (P<0.00001 and 0.0016, respectively) and stage III (P=0.0029 and 0.0079, respectively) patients. The authors concluded that RPA1 and RPA2 proteins appear to be useful prognostic indicators in colon cancer patients and attractive therapeutic targets for regulation by tumor suppressors or other proteins involved in controlling cell proliferation.

Givalos N, Gakiopoulou H, Skliri M, et al. Replication protein A is an independent prognostic indicator with potential therapeutic implications in colon cancer. Mod Pathol. 2007;20:159–166.

Reprints: Dr. N. Givalos, Dept. of Surgery, Medical School, National Kapodistrian University of Athens, 5 Iras str., P Psyhiko, GR-154 52 Athens, Greece; givalos@teledomenet.gr

bullet Ductal phenotypic expression of E-cadherin/catenin complex in tubulolobular carcinoma

Tubulolobular carcinoma is a type of mammary carcinoma that displays an admixture of invasive tubules and lobular-like cells. Previous reports have shown that it shares clinical similarities with lobular carcinoma, whereas more recent studies have shown it to be E-cadherin positive. The authors conducted a study to further explore the immunophenotype of tubulolobular carcinoma and to document its natural behavior. The authors retrieved 19 cases of tubulolobular carcinoma and 10 cases each of tubular and lobular carcinoma for comparison analysis. Immunohistochemistry was performed with antibodies against estrogen receptor, progesterone receptor, HER2/neu, 34βE12, E-cadherin, and the catenins. Twenty-five percent of patients with tubulolobular carcinoma presented with greater than stage I disease, compared to zero and 60 percent of patients with tubular and lobular carcinoma, respectively. Two patients with tubulolobular carcinoma had tumor recurrence, one of whom also developed metastasis. The majority of all carcinomas were estrogen- and progesterone-receptor positive. E-cadherin displayed membranous staining in all tubular and tubulolobular carcinomas and was negative in all lobular carcinomas. Half of each carcinoma subtype displayed granular cytoplasmic 34βE12 immunoreactivity. Alpha-catenin exhibited partial or complete membranous staining in all tubulolobular and tubular carcinomas and was negative in all lobular carcinomas. Beta-catenin displayed membranous staining in tubulolobular and tubular carcinomas, whereas all lobular carcinomas had coarse cytoplasmic immunoreactivity. P120 and γ-catenin displayed membranous staining in 100 percent of tubulolobular and tubular carcinomas and cytoplasmic staining in 100 percent of lobular carcinomas. Tubulolobular carcinoma of the breast is thus a distinct type of mammary carcinoma that displays tubular and lobular patterns histologically but displays the membranous E-cadherin/catenin complex characteristic of the ductal immunophenotype. Tubulolobular carcinoma appears to be more aggressive than tubular carcinoma, as 16 percent of patients had lymph node metastases, although all were alive at mean followup of 40 months.

Esposito NN, Chivukula M, Dabbs DJ. The ductal phenotypic expression of the E-cadherin/catenin complex in tubulolobular carcinoma of the breast: an immunohistochemical and clinicopathologic study. Mod Pathol. 2007;20:130–138.

Correspondence: Dr. N.N. Esposito, Dept. of Pathology, University of Pittsburgh Medical Center, A711.1 Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261; espositonc@upmc.edu

bullet Low-grade dysplasia as a risk factor for progression to esophageal adenocarcinoma

The authors conducted a study to evaluate the hypothesis that extent of low- and high-grade dysplasia are risk factors for progression to esophageal adenocarcinoma. The authors evaluated baseline biopsies from 77 Barrett’s esophagus patients with dysplasia, including 44 who progressed to esophageal adenocarcinoma and 33 who did not progress during followup. The total numbers of low-grade dysplasia (LGD) and high-grade dysplasia (HGD) crypts were determined separately by counting all crypts, and the extent of LGD, HGD, and total dysplasia were correlated with outcome for esophageal adenocarcinoma. Thirty-one and 46 patients had a maximum diagnosis of LGD and HGD, respectively. When the crypts were stratified by dysplasia grade, the mean number of LGD crypts per patient was borderline higher in progressors (93.9) compared with nonprogressors (41.2; P=0.07), and the mean proportion of LGD crypts per patient was significantly higher in progressors (46.4% versus 26%; P=0.037). Neither mean number of HGD crypts per patient (P=0.14) nor mean proportion of HGD crypts per patient (P=0.20) was significantly associated with outcome for esophageal adenocarcinoma. The authors concluded that extent of LGD is a significant risk factor for developing esophageal adenocarcinoma in Barrett’s esophagus. Although presence of HGD is significantly associated with a greater relative risk for developing esophageal adenocarcinoma, extent of HGD was not an independent risk factor for progression.

Srivastava A, Hornick JL, Li X, et al. Extent of low-grade dysplasia is a risk factor for the development of esophageal adenocarcinoma in Barrett’s esophagus. Am J Gastroenterol. 2007;102(3):483–493.

Reprints: Dr. Robert D. Odze, GI Pathology Service, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115

bullet Role of EGFR in esophageal and esophagogastric junction adenocarcinomas

The prognosis for patients with esophageal and esophagogastric junction adenocarcinoma remains poor, even after surgical resection. Pathologic assessment of depth of invasion and lymph node status are the primary prognostic factors in these patients. In patients with esophageal squamous cell carcinoma, increased epidermal growth factor receptor (EGFR) expression has been associated with a worse prognosis. It is not known whether EGFR plays a similar role in esophageal and esophagogastric junction (EGJ) adenocarcinomas. To address this issue, the authors studied tumor specimens from 103 patients with surgically resected esophageal and EGJ adenocarcinomas (nine patients with stage I disease, 23 patients with stage II disease, 57 patients with stage III disease, and 14 patients with stage IV disease). They assessed the expression of EGFR by immunohistochemical analysis of tissue microarrays. Tumors were considered positive for EGFR expression when more than five percent of tumor cells were stained and negative when five percent or fewer tumor cells were stained. The authors found that EGFR was expressed in 33 of 103 adenocarcinomas (32%) and was correlated with higher pathologic tumor (T) classification (P=0.02); presence of lymph node metastasis (P=0.01); and higher pathologic tumor, lymph node, metastasis classification (P=0.02). EGFR expression also was correlated with shorter disease-free and overall survival in univariate analyses (P=0.001 and P=0.004, respectively), and there was a trend toward correlation between EGFR expression and shorter disease-free survival in multivariate analyses (P=0.07 and P=0.08). The results demonstrated that EGFR expression in esophageal adenocarcinomas was correlated with advanced pathologic tumor classification and lymph node metastasis. EGFR expression also was correlated with poor disease-free and overall survival, but the correlation was not independent of T classification. The authors concluded that EGFR expression correlates with poor prognostic factors and may be used to predict patient outcomes.

Wang KL, Wu TT, Choi IS, et al. Expression of epidermal growth factor receptor in esophageal and esophagogastric junction adenocarcinomas: association with poor outcome. Cancer. 2007;109:658–667.

Reprints: Dr. Tsung-Teh Wu, Dept. of Pathology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905; wu.tsungteh@mayo.edu

bullet Prognostic ability of simplified nuclear grading of renal cell carcinoma

The Fuhrman grading system is an established predictor of survival in patients with renal cell carcinoma. The authors tested the predictive accuracy of various Fuhrman grading schemes with the intent of improving the prediction of renal cell carcinoma-C-specific survival (RCC-SS). Their analyses targeted 5,453 patients from 14 institutions. Univariable, multivariable, and predictive accuracy analyses addressed RCC-SS. The authors quantified the statistical significance of the gain in predictive accuracy using the Mantel-Haenszel test. The median followup time was 4.5 years. The authors found that in univariable and multivariable analyses, Fuhrman grade achieved independent predictor status regardless of the coding scheme (I–IV, I and II versus III, I and II versus IV, and I and II versus III and IV). When Fuhrman grade was not considered in multivariable analyses, the predictive accuracy was 83.8 percent. Adding Fuhrman grade to the multivariable model resulted in predictive accuracy gains of 0.8 percent for all three grading schemes tested. The authors concluded that Fuhrman grade must be considered when assessing RCC-SS. However, modified or conventional Fuhrman grading schemes perform just as well as the conventional grading system.

Rioux-Leclercq N, Karakiewicz PI, Trinh QD, et al. Prognostic ability of simplified nuclear grading of renal cell carcinoma. Cancer. 2007;109:868–874.

Reprints: Dr. Nathalie Rioux-Leclercq, Department d’Anatomie et de Cytologie Pathologiques, CHU Pontchaillou, 2 rue Henri Le Guilloux, 35033 Rennes Cedex 9, France; nathalie.rioux@chu-rennes.fr


Dr. Cibull is professor of pathology and laboratory medicine and direct of surgical pathology, University of Kentucky Medical Center, Lexington. Dr. Kesler is hematopathology fellow, University of Texas Southwestern Medical Center at Dallas.