Anatomic Abstracts
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October 2011 Editors:
Lymph node status is one of the most important predictors of survival in pancreatic ductal adenocarcinoma. Surgically resected pancreatic adenocarcinoma is often locally invasive and may invade peripancreatic lymph nodes. The significance of direct invasion into lymph nodes in the absence of true lymphatic metastases is unclear. The authors conducted a study to retrospectively compare clinical outcomes in patients with pancreatic ductal adenocarcinoma who had direct invasion into peripancreatic lymph nodes against patients with node-negative adenocarcinomas and patients with true lymphatic lymph node metastasis. They evaluated 380 patients with invasive pancreatic ductal adenocarcinoma classified as pT3: ductal adenocarcinoma with true lymphatic metastasis to regional lymph nodes (248 cases), ductal adenocarcinoma without lymph node involvement (97 cases), and ductal adenocarcinoma with regional lymph nodes involved only by direct invasion from the main tumor mass (35 cases). Isolated lymph node involvement by direct invasion occurred in 35 of 380 (nine percent) patients. Overall survival for patients with direct invasion of lymph nodes (median survival, 21 months; five-year overall survival, 36 percent) was not statistically different from that for patients with node-negative adenocarcinomas (median survival, 30 months; five-year overall survival, 31 percent; P=0.609). Patients with node-negative adenocarcinomas had an improved survival rate compared with patients with lymph node involvement by true lymphatic metastasis (median survival, 15 months; five-year overall survival, eight percent; P<0.001), regardless of the number of lymph nodes involved by adenocarcinoma. The authors noted a trend toward decreased overall survival for patients with one or two lymph nodes involved by true lymphatic metastasis compared with patients with direct invasion of tumor into lymph nodes (P=0.056). However, this did not reach statistical significance. The authors concluded that the overall survival rate for patients with isolated direct lymph node invasion is comparable to that for patients with node-negative adenocarcinomas and not with the overall survival rate for those with true lymphatic lymph node metastasis. Pai PK, Beck AH, Mitchem J, et al. Pattern of lymph node involvement and prognosis in pancreatic adenocarcinoma: direct lymph node invasion has similar survival to node-negative disease. Am J Surg Pathol. 2011;35(2):228–234. Correspondence: Dr. Reetesh K. Pai at reeteshp@stanford.edu
Calreticulin is a chaperone protein located in the lumen of the endoplasmic reticulum. Calreticulin has been associated with pathological conditions such as autoimmune disorders and certain types of cancer. However, little is known about its role in the pathogenesis of breast cancer. The authors conducted a study to determine the expression of calreticulin in vitro and correlate its expression levels in breast cancer tissue samples with clinicopathological parameters. Calreticulin expression was evaluated in MCF-7 and MDA-MB-231 breast cancer cells by real-time reverse transcriptase polymerase chain reaction, Western blot, immunohistochemistry, and immunofluorescence staining. Patient tissue microarrays were constructed from 228 breast cancer specimens for the purpose of immunohistochemical analysis. The in vitro study showed a higher calreticulin expression in more aggressive MDA-MB-231 cells as compared with MCF-7 cells at mRNA and protein levels. The authors found that 227 of 228 breast cancer specimens exhibited calreticulin staining in at least five percent of cancer cells. Calreticulin immunostaining was observed to be localized to the cytoplasm of the cancer cells. Regression analysis of calreticulin immunostaining in the tissue microarrays revealed that its expression was positively correlated to logarithm of tumor size (P=0.046) and development of distant metastasis (P=0.017). Multivariate analysis confirmed calreticulin expression as an independent predictor of log tumor size and occurrence of distant metastasis. The data suggest that calreticulin expression is associated with more advanced tumors and is a potential prognostic biomarker. Lwin ZM, Guo C, Salim A, et al. Clinicopathological significance of calreticulin in breast invasive ductal carcinoma. Mod Pathol. 2010;23:1559–1566. Correspondence: Dr. P. H. Tan at tan.puay.hoon@sgh.com.sg or Dr. B. H. Bay at antbaybh@nus.edu.sg
The prognosis for patients with colorectal cancer can be uncertain. Therefore, the authors compared the prognostic significance of immune criteria with that for tumor extension criteria using the American Joint Committee on Cancer/International Union Against Cancer-TNM (AJCC/UICC-TNM) staging system. The authors studied the intratumoral immune infiltrates in the center of the tumor and in the invasive margin of 599 specimens of stage I to IV colorectal cancers from two independent cohorts. They analyzed these findings in relation to degree of tumor extension and frequency of recurrence. The authors found that growth of the primary tumor and metastatic spread were associated with decreased intratumoral immune T-cell densities. Sixty percent of patients with high densities of CD8+ cytotoxic T-lymphocyte infiltrate presented with stage Tis/T1 tumor, whereas no patients with low densities presented with such early stage tumor. In patients who did not relapse, the density of CD8 infiltrates was inversely correlated with T stage. In contrast, in patients whose tumor recurred, the number of CD8 cells was low regardless of the T stage of the tumor. Univariate analysis showed that immune score was significantly associated with differences in disease-free, disease-specific, and overall survival (hazard ratio [HR], 0.64, 0.60, and 0.70, respectively; P<0.005). Time-dependent receiver operating characteristic curve analysis illustrated the predictive accuracy of the immune parameters (c-index, 65.3 percent; time-dependent c-index, 66.5 percent). A final stepwise model for Cox multivariate analysis supports the advantage of immune score (HR, 0.64; P<0.001; time-dependent c-index, 67.9 percent) over histopathologic features in predicting recurrence and survival. The authors concluded that assessing CD8+ cytotoxic T lymphocytes in combined tumor regions provides an indicator of tumor recurrence beyond that predicted by AJCC/UICC-TNM staging. Mlecnik B, Tosolini M, Kirilovsky A, et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol. 2011;29(6):610–618. Correspondence: Dr. Jérôme Galon at jerome.galon@crc.jussie.fr
Cervical carcinoma is the second most frequent type of cancer in women worldwide. Inflammatory cells and stromal cells are important for tumor progression. Stromal cells produce growth factors and extracellular matrix and provide an adequate environment for angiogenesis. Versican, a member of the extracellular matrix, has been shown to play a role in tumor progression. The authors conducted a study to investigate versican expression and its association with tumor-infiltrating inflammatory cell subsets and clinicopathological parameters in cervical cancers. The authors studied the expression of versican in 149 cervical cancers using immunohistochemistry and mRNA in situ hybridization. Versican was predominantly expressed in the stroma (myofibroblasts). Using quantitative real-time-PCR, V0 was found to be the most prominent isoform. High stromal versican expression was significantly associated with a low number of tumor-infiltrating T cells (P=0.018) and, particularly, a low number of CD8-positive T cells (cytotoxic T cells; P=0.002). Stromal versican expression was significantly higher in patients with an infiltration depth of greater than 14 mm (P=0.004) and patients with parametrial invasion (P=0.044). Stromal versican expression was not associated with survival. The authors’ results suggest that versican expression in the stromal compartment of cervical cancers results in reduced numbers of intraepithelial CD8-positive T cells and enhanced local invasion. Gorter A, Zijlmans HJ, van Gent H, et al. Versican expression is associated with tumor-infiltrating CD8-positive T cells and infiltration depth in cervical cancer. Mod Pathol. 2010;23:1605–1615. Correspondence: Dr. A. Gorter at a.gorter@lumc.nl
The authors conducted a study to address the controversy surrounding whether the estrogen receptor status of a primary tumor remains stable during progression to metastasis and to evaluate the influence of disease course and prior systemic therapy on estrogen receptor status. For the study, breast carcinomas from 227 women with known estrogen receptor status in primary tumor and paired metastasis were reviewed retrospectively. Estrogen receptor status was compared between primary and metastatic tumors with respect to metastatic site, interval between two estrogen receptor assays, and intervening chemotherapy and endocrine therapy. Semiquantitative comparison of estrogen receptor values was performed for 92 tumor pairs. The authors found that estrogen receptor status agreed in 210 (92.5 percent) patients, including 147 that were positive and 63 that were negative. For the 17 patients (7.5 percent) with discordant estrogen receptor status, negative-to-positive conversion (n=7) and positive-to-negative conversion (n=10) were observed. Estrogen receptor discordance was not significantly associated with metastatic site (locoregional versus distant), time interval between assays (less than five years versus five years or more), or intervening chemotherapy and endocrine therapy. Semiquantitative levels of estrogen receptor expression were similar between primary and metastatic tumors. In discordant cases, variations in testing methods and marginal scores were common. The authors concluded that estrogen receptor status in breast carcinoma is generally stable during progression to metastasis. Preanalytical and analytical variability may contribute to discordance in some cases. Given the importance of estrogen receptor status to clinical management, estrogen receptor testing in metastatic breast carcinoma should be repeated, especially for patients whose clinical courses are not compatible with stated estrogen receptor status. Gong Y, Han EY, Guo M, et al. Stability of estrogen receptor status in breast carcinoma: a comparison between primary and metastatic tumors with regard to disease course and intervening systemic therapy. Cancer. 2011;117(4):705–713. Correspondence: Dr. Yun Gong at yungong@mdanderson.org
Intraoperative pathologic examination of sentinel lymph nodes is an important tool that can reduce the need for re-operations in patients with sentinel lymph node-positive breast cancer. The authors conducted a study to determine the accuracy of intraoperative frozen section of sentinel lymph nodes (SLNs) during breast cancer surgery. They retrospectively reviewed the records of 326 patients with breast cancer who underwent intraoperative frozen section analysis of SLNs at a single institution. They then conducted a meta-analysis that included 47 published studies of intraoperative frozen sections of SLNs in patients with breast cancer. The authors found that hematoxylin-and-eosin staining revealed metastasis in the SLNs of 99 patients (30.4 percent), including 61 patients with macrometastasis greater than 2 mm (the MAM group) and 38 patients with micrometastasis or isolated tumor cell deposits (the Mi/ITC group). The overall sensitivity of the institutional series was 60.6 percent (60 of 99 patients) and overall specificity was 100 percent (227 of 227 true negatives). The sensitivity of intraoperative frozen sections was significantly lower in the Mi/ITC group (28.9 percent) than in the MAM group (80.3 percent; P<0.0001). According to a meta-analysis of published studies and data from the authors’ institution (47 studies, for a total of 13,062 patients who underwent SLN dissection with intraoperative frozen sections of SLNs), the mean sensitivity was 73 percent and mean specificity was 100 percent. The mean sensitivity was 94 percent for the MAM group and 40 percent for the Mi/ITC group. The authors concluded that intraoperative frozen section of SLNs was more reliable for detecting MAM than for detecting Mi/ITC deposits. It was not accurate enough to rule out Mi/ITC deposits. Liu LC, Lang JE, Lu Y, et al. Intraoperative frozen section analysis of sentinel lymph nodes in breast cancer patients: a meta-analysis and single-institution experience. Cancer. 2011;117:250–258. Correspondence: Dr. Stanley P. Leong at leongsx@cpmcri.org Anatomic pathology abstracts editors: Michael Cibull, MD, professor and vice chair, Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington; Melissa Kesler, MD, and Rouzan Karabakhtsian, MD, assistant professors of pathology and laboratory medicine, University of Kentucky College of Medicine; and Megan Zhang, MD, visiting fellow, Division of Dermatopathology, University of California, San Francisco. |
