TP63, a member of the TP53gene family, is a nuclear marker of myoepithelial cells. Antibody against p63 is frequently used in diagnosing prostate carcinoma and identifying myoepithelial cells in other tissues, including the breast. P63 is also a marker for squamous cell carcinoma. It was recently found that all p53 family members are involved in regulating the process of muscle differentiation through the retinoblastoma protein. Ablation of these p53 family functions blocks the differentiation process and promotes malignant transformation by enabling cooperating oncogenes to transform myoblasts. The authors studied p63 expression in a number of neoplasms with myogenic differentiation. Immunohistochemical staining for p63 was performed on paraffin sections from 38 rhabdomyosarcomas, five leiomyomas, five leiomyosarcomas, five rhabdomyomas, five rhabdomyomatous Wilms tumors, three normal cardiac muscles, one medullomyoblastoma, one pleuropulmonary blastoma with rhabdomyomatous differentiation, and one teratoma with prominent rhabdomyoblasts. Each case was also stained with desmin. Unlike with the nuclear staining scored in myoepithelial cells, only cytoplasmic staining for p63 was considered positive. The authors found that of 38 cases of rhabdomyosarcoma, 36 showed cytoplasmic p63 staining, and 24 of those showed highlighting of cross-striations superior to that generated with desmin. In addition, cytoplasmic p63 staining was exhibited in five of five rhabdomyomas, five of five rhabdomyomatous Wilms tumors, one of one pleuropulmonary blastoma with rhabdomyomatous differentiation, one of one teratoma with atypical rhabdoblasts, and one of one medullomyoblastoma. Normal cardiac muscle samples (three of three) also demonstrated positive cytoplasmic staining and distinct cross-striations. Smooth muscle tumors exhibited only very focal and faint cytoplasmic staining in five of five leiomyomas and four of five leiomyosarcomas. Immunoelectron microscopic study of skeletal muscle showed p63 localization to the Z bands of sarcomeres. The authors concluded that p63 immunostain is a sensitive marker for skeletal muscle differentiation and highlights the cross-striations of strap cells with exceptional definition.
Martin SE, Temm CJ, Goheen MP, et al. Cytoplasmic p63 immunohistochemistry is a useful marker for muscle differentiation: an immunohistochemical and immunoelectron microscopic study. Mod Pathol. 2011:24;1320–1326.
Correspondence: Dr. E. M. Hattab at firstname.lastname@example.org
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Tubal metaplasia of the endometrium may display cytologic atypia (atypical tubal metaplasia) resembling serous carcinoma or endometrial intraepithelial carcinoma. Although atypical tubal metaplasia is presumed to be reactive or degenerative in etiology, its clinical significance is unknown. The authors conducted a study in which they investigated atypical tubal metaplasia with regard to its immunoexpression of p53, Ki-67, and human telomerase reverse transcriptase (TERT), and its long-term clinical outcome. They followed 63 cases of atypical tubal metaplasia and 200 cases of endometrial samples with typical tubal metaplasia for a mean of 64 and 61 months, respectively. Of the 63 atypical tubal metaplasia cases, formalin-fixed, paraffin-embedded tissue sections from 16 cases were immunostained with antibodies to p53, Ki-67, and TERT. Sections from 13 cases of uterine serous carcinoma were also stained for TERT as controls. After long-term followup, five percent of patients in the atypical tubal metaplasia group developed hyperplasia without atypia compared with four percent of patients in the control group (P=.44), whereas three percent in the atypical tubal metaplasia group developed atypical hyperplasia or carcinoma compared with two percent in the control group (P=.44). P53 immunoreactivity was focal and weak or negative in all cases of atypical and typical tubal metaplasia (P>.05). Ki-67 immunoreactivity was present in zero to five percent of cells in 94 percent of atypical and typical tubal metaplasia cases (P>.05). TERT immunoexpression was absent in all 16 cases of atypical tubal metaplasia but present in all 13 cases of uterine serous carcinoma (P<.0001). The authors concluded that their study indicates that atypical tubal metaplasia displays an immunostaining pattern similar to otherwise typical tubal metaplasia of the endometrium and distinct from uterine serous neoplasms. The presence of atypical tubal metaplasia in endometrial samplings does not increase the risk of developing endometrial hyperplasia or malignancy.
Simon RA, Peng SL, Liu F, et al. Tubal metaplasia of the endometrium with cytologic atypia: analysis of p53, Ki-67, TERT, and long-term follow-up. Mod Pathol. 2011;24:1254–1261.
Correspondence: Dr. R. A. Simon at email@example.com
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Mutation of the FOXL2 gene recently has been consistently identified in adult granulosa cell tumors of the ovary. The authors conducted a study to investigate whether the FOXL2 mutation and mRNA expression play a role in the pathogenesis of juvenile and adult granulosa cell tumors and influence tumor progression. For the study, 34 granulosa cell tumors from adults and 20 granulosa cell tumors from juveniles were examined for the FOXL2 (C402G) mutation. Expression levels were studied by quantitative polymerase chain reaction and immunohistochemistry. The authors found that the FOXL2 mutation was present in 19 of 27 (70 percent) of the adult-type tumors but in none of the 18 juvenile-type granulosa cell tumors. No correlation was found between the presence of the FOXL2 mutation and various clinicopathologic parameters, except for the presence of a different sex-cord component, which was more frequently found in the subgroup of wild-type adult granulosa cell tumors than in the mutated tumors. Patients with tumors harboring the FOXL2 mutation had a worse disease-free survival rate than those with the wild-type gene. Expression levels of FOXL2 mRNA had an impact on disease-free survival in adult and juvenile granulosa cell tumors. The authors also found that the mutated tumors had a higher immunohistochemical expression of the FOXL2 protein. They noted a linear correlation between mRNA and immunohistochemical FOXL2 expression in adult and juvenile granulosa cell tumors. Patients with juvenile granulosa cell tumors and higher FOXL2 protein expression had worse overall and disease-free survival rates than those with negative or weakly immunoreactive tumors. The authors concluded that their data suggest that the FOXL2 mutation and mRNA expression are of prognostic importance in adult and juvenile granulosa cell tumors.
D’Angelo E, Mozos A, Nakayama D, et al. Prognostic significance of FOXL2mutation and mRNA expression in adult and juvenile granulosa cell tumors of the ovary. Mod Pathol. 2011; 24:1360–1367.
Correspondence: Dr. J. Prat at firstname.lastname@example.org
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The authors conducted a study to evaluate whether so-called cardiac adenocarcinomas (adenocarcinomas of the esophagogastric junction type II and III [AEG II and III]) are better staged as cancers of the esophagus or cancers of the stomach. For the study, a single-center cohort of 1,141 patients undergoing surgery for AEG II and III was staged according to the seventh edition of the tumor-node-metastasis classification for cancers of the esophagus and stomach. Kaplan-Meier and Cox regression analyses were used to evaluate the prognostic performance of the two staging schemes. The authors found that for so-called cardiac adenocarcinomas, the esophageal T classification was monotone—that is, it defined subgroups with continuous decreasing survival with increasing T stage. It was also distinct, meaning survival of these monotonic subgroups differed significantly. The gastric T classification was monotone but not distinct for pT2 versus pT3 (P=.641) and pT4a versus pT4b tumors (P=.130). The type of infiltrated adjacent structure mattered, with significant differences in prognosis between the esophageal subgroups T4a and T4b (P<.001). For the N classification, the esophageal and gastric schemes were monotone and distinct, with decreasing prognosis with increasing number of lymph node metastases. The subclassification of N3a and N3b disease according to the gastric scheme defined two subgroups with significant differences in prognosis (P<.01). Both the gastric and esophageal schemes included heterogeneous stage groups (two and one, respectively) and were not distinctive between several stage groups (four and three, respectively). The authors concluded that neither the esophageal nor the gastric scheme proves to be clearly superior over the other and neither is perfect for AEG II and III. They stated that their analysis includes further hints that so-called cardiac adenocarcinomas have different biological properties than genuine gastric and genuine esophageal cancers.
Gertler R, Stein HJ, Loos M, et al. How to classify adenocarcinomas of the esophagogastric junction: as esophageal or gastric cancer? Am J Surg Pathol. 2011;35(10):1512–1522.
Correspondence: Dr. Marcus Feith at email@example.com
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There is a need to develop novel therapies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and to identify biomarkers predictive for therapeutic response. Lenalidomide was previously shown to induce an overall response rate of 28 percent in patients with relapsed/refractory DLBCL. It is unknown if response rates differ between patients with different DLBCL subtypes. The authors retrospectively evaluated the clinical outcomes of patients with germinal center B-cell–like versus nongerminal center B-cell–like DLBCL who were treated with salvage lenalidomide at four academic institutions. The evaluation included 40 patients with relapsed/refractory DLBCL (24 men; 16 women; median age, 66 years; median of four prior treatments, including rituximab chemotherapy). Patients were classified as germinal center B-cell–like (n=23) or nongerminal center B-cell–like (n=17) DLBCL according to the Hans algorithm. The subgroups were similar in terms of stage, international prognostic index score, prior number of treatments, and rituximab resistance. A significant difference in clinical response to lenalidomide was observed in nongerminal center B-cell–like versus germinal center B-cell–like patients. The overall response rate was 52.9 percent versus 8.7 percent, and the complete response rate was 23.5 percent versus 4.3 percent. The median progression-free survival rate was 6.2 versus 1.7 months, although no difference in overall survival was observed between nongerminal center B-cell–like and germinal center B-cell–like DLBCL patients. The authors concluded that the data suggest that the two major subgroups of patients with DLBCL differ in their anti-tumor responsiveness to lenalidomide in the relapsed/refractory setting. A large international trial has been opened to enrollment in an attempt to prospectively validate these retrospective observations.
Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL, et al. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell–like than in germinal center B-cell–like phenotype. Cancer. 2011;117(22):5058–5066.
Correspondence: Dr. Francisco J. Hernandez-Ilizaliturri at firstname.lastname@example.org
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It is hypothesized that BRAF mutant cancers represent a discrete subset of metastatic colorectal cancer defined by poorer survival. The authors conducted a study to investigate whether BRAF mutant colorectal cancer (CRC) is further defined by a distinct pattern of metastatic spread and to explore the impact of BRAF mutation and microsatellite instability (MSI) on prognosis in metastatic CRC. Using prospective clinical data and molecular analyses from the Royal Melbourne Hospital and the University of Texas MD Anderson Cancer Center, patients with known BRAF mutation status were analyzed for clinical characteristics, survival rates, and metastatic sites. The authors identified 524 metastatic CRC patients where BRAF mutation status was known; 57 (11 percent) were BRAF mutant tumors. BRAF mutant tumors were significantly associated with right-sided primary tumor, MSI, and poorer survival (median, 10.4 months versus 34.7 months; P<.001). A distinct pattern of metastatic spread was observed in BRAF mutant tumors, namely higher rates of peritoneal metastases (46 percent versus 24 percent; P=.001), distant lymph node metastases (53 percent versus 38 percent; P=.008), and lower rates of lung metastases (35 percent versus 49 percent; P=.049). In additional survival analyses, patients with MSI tumors had significantly poorer survival rates compared with patients who had microsatellite stable tumors (22.1 months versus 11.1 months; P=.017), but this difference was not evident in the BRAF mutant population. The authors concluded that the pattern of metastatic spread observed in this study further defines BRAF mutant CRC as a discrete disease subset. The authors demonstrated that, unlike with early stage disease, MSI is associated with poorer survival rates in metastatic CRC, although this is driven by its association with BRAF mutation.
Tran B, Kopetz S, Tie J, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 2011;117:4623–4632.
Correspondence: Ben Tran at email@example.com
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Number of positive lymph nodes has been proposed as a prognostic indicator in N1 nonsmall cell lung cancer (NSCLC). However, the number of positive lymph nodes is confounded by the number of nodes resected during surgery. The lymph node ratio (ratio of the number of positive nodes divided by the number of nodes resected) can circumvent this limitation. The prognostic significance of the lymph node ratio (LNR) has been demonstrated in elderly patients with NSCLC. The authors conducted a study to evaluate whether a higher LNR is a marker of worse survival in patients with NSCLC aged 65 or older who have N1 disease. The Surveillance, Epidemiology, and End Results database was used to identify 4,004 patients who underwent resection for N1 NSCLC. Patients were classified into three groups according to LNR: 0.15 or less, 0.16 to 0.5, and more than 0.5. Associations of the LNR with lung cancer-specific and overall mortality were evaluated using the Kaplan-Meier method. Stratified and Cox regression analyses were used to assess correlations between LNR and survival rates after adjusting for other prognostic factors. Unadjusted analysis indicated that a higher LNR was associated with worse lung cancer-specific survival (P<.0001) rates and overall survival (P<.0001) rates. Stratified and multivariate analyses also indicated that the LNR was an independent predictor of survival after controlling for potential confounders. The authors concluded that the current results confirm that the LNR is an independent prognostic factor for survival for patients with N1 NSCLC. This information may be used to identify patients who are at greater risk for cancer recurrence.
Jonnalagadda S, Arcinega J, Smith C, et al. Validation of the lymph node ratio as a prognostic factor in patients with N1 nonsmall cell lung cancer. Cancer. 2011;117:4724–4731
Correspondence: Dr. Juan P. Wisnivesky at firstname.lastname@example.org
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Immunohistochemistry is increasingly used to differentiate lung adenocarcinoma and squamous cell carcinoma. However, detailed analysis of co-expression profiles of commonly used markers in large series of whole-tissue sections is lacking. Furthermore, the optimal diagnostic algorithm, particularly the minimal-marker combination, is not firmly established. Therefore, the authors studied whole-tissue sections of resected adenocarcinoma and squamous cell carcinoma (n=315) with markers commonly used to identify adenocarcinoma (TIF-1) and squamous cell carcinoma (p63, CK5/6, 34bE12). They prospectively validated the devised algorithm in morphologically unclassifiable small biopsy/cytology specimens (n=38). Analysis of whole-tissue sections showed squamous cell carcinoma had a highly consistent immunoprofile (TTF-1 negative and p63, CK5/6, 34bE12 diffuse). In contrast, adenocarcinoma showed significant immunoheterogenetity for all “squamous markers” (p63 [32 percent], CK5/6 [18 percent], 34bE12 [82 percent]) and TTF-1 (89 percent). As a marker, only diffuse TTF-1 was specific for adenocarcinoma, whereas none of the squamous markers, even if diffuse, were entirely specific for squamous cell carcinoma. In contrast, co-expression profiles of TTF-1/p63 had only minimal overlap between adenocarcinoma and squamous cell carcinoma, and there was no overlap if CK5/6 was added as a third marker. An algorithm was devised in which TTF-1/p63 was used as the first-line panel and CK5/6 added for rare indeterminate cases. Prospective validation of this algorithm in small specimens showed 100 percent accuracy of adenocarcinoma versus squamous cell carcinoma prediction as determined by subsequent resection. The authors concluded that although reactivity for squamous markers is common in lung adenocarcinoma, a two-marker panel of TTF-1/p63 is sufficient for subtyping the majority of tumors as adenocarcinomas versus squamous cell carcinoma, and addition of CK5/6 is needed in only a small subset of cases. This simple algorithm achieves excellent accuracy in small specimens while conserving tissue for potential predictive marker testing.
Rekhtman N, Ang DC, Sima CS, et al. Immunohistochemical algorithm for differentiation of lung adenocarcinoma and squamous cell carcinoma based on large series of whole-tissue sections with validation in small specimens. Mod Pathol. 2011;24:1348–1359.
Correspondence: Dr. N. Rekhtman at email@example.com
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The authors conducted a study that demonstrated that, among ovarian carcinomas, amplification of the MET gene and overexpression of MET specifically and commonly occur in clear-cell adenocarcinoma histology. In a more recent study, detailed here, the authors addressed how these alterations contribute to development and progression of this highly chemoresistant form of ovarian cancer. The authors histologically reviewed 21 previously described MET amplification-positive clear-cell adenocarcinoma cases and selected 11 tumors with synchronous endometriosis and two tumors with adjacent clear-cell adenofibroma (CCAF) components. Using double in situ hybridization and immunohistochemistry, copy number alterations of the MET gene and levels of MET protein expression were analyzed in these putative precursor lesions and the corresponding invasive carcinoma components in this selected cohort. All of the non-atypical precursor lesions analyzed—that is, non-atypical endometrioses and benign CCAFs—were negative for MET gain. However, low-level gain of MET (three or more MET copies in 10 percent or more of tumor cells and four or more MET copies in 10 percent to 40 percent of tumor cells) was detected in four of the 10 atypical endometrioses and one of the two borderline CCAFs. Moreover, high-level gain of MET (four or more MET copies in 40 percent or more of tumor cells) was detected in five (50 percent) of the atypical endometrioses. In four of the 13 (31 percent) cases enrolled, intratumoral heterogeneity for MET gain was documented in invasive carcinoma components wherein all the relatively differentiated carcinoma components showed low-level gain of MET and all the corresponding poorly differentiated carcinomas showed high-level gain. The overall incidence of MET overexpression gradually increased from the precursors of non-atypical form (none), through those of atypical form (67 percent) and the relatively differentiated carcinoma components (92 percent), to the poorly differentiated carcinoma components (100 percent). The authors concluded that these results suggest that accumulative MET gene copy number alterations causing MET overexpression are associated with higher tumor grade and might drive development and progression of MET amplification-positive ovarian clear-cell adenocarcinoma.
Yamamoto S, Tsuda H, Miyai K, et al. Accumulative copy number increase of METdrives tumor development and histological progression in a subset of ovarian clear-cell adenocarcinomas. Mod Pathol. 2012;25:122–130.
Correspondence: Dr. H. Tsuda at firstname.lastname@example.org
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Anatomic pathology abstracts editors: Michael Cibull, MD, professor and vice chair, Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington; Rouzan Karabakhtsian, MD, assistant professor of pathology and laboratory medicine, University of Kentucky College of Medicine; and Thomas Cibull, MD, dermatopathologist, Evanston Hospital, NorthShore University HealthSystem, Evanston, Ill.