May 2010

Editors:
Michael Cibull, MD
Melissa Kesler, MD
Rouzan Karabakhtsian, MD
Megan Zhang, MD

• Micrometastases or isolated tumor cells and outcome of breast cancer
• Venous invasion by Elastica van Gieson stain and tumor budding to predict metastases in T1 stage colorectal cancer
• Florid reactive lymphoid hyperplasia of the lower female genital tract
• Clinical validation of an array CGH test for HER2 status in breast cancer relative to polysomy 17
• Expression of PAX8 in normal and neoplastic renal tissues
• Histologic assessment to differentiate multiple lung primary nonsmall cell carcinomas from metastases

Micrometastases or isolated tumor cells and outcome of breast cancer

The association of isolated tumor cells and micrometastases in regional lymph nodes with the clinical out-come of breast cancer is unclear. The authors identified all patients in the Netherlands who underwent a sentinel-node biopsy for breast cancer before 2006 and had breast cancer with favorable primary-tumor characteristics and isolated tumor cells or micrometastases in regional lymph nodes. Patients with node-negative disease were randomly selected during 2000 and 2001. The primary end point was disease-free survival. The study included 856 patients with node-negative disease who had not received systemic adjuvant therapy (node-negative, no-adjuvant-therapy cohort), 856 patients with isolated tumor cells or micrometastases who had not received systemic adjuvant therapy (node-positive, no-adjuvant-therapy cohort), and 995 patients with isolated tumor cells or micrometastases who had received such treatment (node-positive, adjuvant-therapy cohort). Median followup was 51 years. The adjusted hazard ratio for disease events among patients with isolated tumor cells who did not receive systemic therapy, as compared with women with node-negative disease, was 1.50 (95 percent confidence interval [CI], 1.15–1.94). Among patients with micrometas-tases, the adjusted hazard ratio was 1.56 (95 percent CI, 1.15–2.13). Among patients with isolated tumor cells or micrometastases, the adjusted hazard ratio was 0.57 (95 percent CI, 0.45–0.73) in the node-positive, adjuvant-therapy cohort as compared with the node-positive, no-adjuvant-therapy cohort. The authors concluded that isolated tumor cells or micrometastases in regional lymph nodes were associated with a reduced five-year rate of disease-free survival among women with favorable early stage breast cancer who did not receive adjuvant therapy. Disease-free survival was improved in patients with isolated tumor cells or micrometastases who received adjuvant therapy.

DeBoer M, van Deurzen CH, van Dijck JA, et al. Micrometastases or isolated tumor cells and the outcome of breast cancer. N Engl J Med. 2009;361:653–663.

Correspondence: Dr. V. C. Tjan-Heijnen at vcg.tjan.heijnen@mumc.nl
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Venous invasion by Elastica van Gieson stain and tumor budding to predict metastases in T1 stage colorectal cancer

It may be difficult to evaluate pathologic predictors of metastases in T1 stage colorectal can-cer using only hematoxylin-and-eosin staining. The authors conducted a study to clarify the role of pathologic predictors using immunohistochemical staining and Elastica van Gieson (EVG) staining. They studied 124 patients who underwent bowel resection for single T1 stage colorectal cancer from 1990 to 2004 in one institution. D2-40, EVG staining, and CAM5.2 were used to detect lymphatic invasion, venous invasion, and tumor budding, respectively. The authors evaluated these three factors separately based on hematoxylin-and-eosin (H&E) staining. One pathologist reviewed histology. Lymph node metastases in the surgical specimen were the standard reference. Distant metastases were identified by periodic computed tomography for two years or more after surgery. A logistic regression model was applied to analyze risk factors for lymph node metastases. A Cox regression model was used for distant metastases. In predicting lymph node metastases, univariate analysis demonstrated significance for all predictors, except venous invasion by H&E staining. Multivariate analysis found that venous invasion by EVG and tumor budding by H&E showed significance as predictors. In predicting distant metastases, univariate analysis demonstrated significance for lymphatic in-vasion shown by D2-40, tumor budding shown by CAM5.2 and H&E, and lymph node metastases. Multivariate analysis showed only venous invasion by EVG stain as being significantly associated with distant metastases (P=.001). The authors concluded that evaluation of venous invasion by EVG staining is a useful pathologic predictor for metastases in T1 stage colorectal cancer.

Suzuki A, Togashi K, Nokubi M, et al. Evaluation of venous invasion by Elastica van Gieson stain and tumor budding predicts local and distant metastases in patients with T1 stage colorectal cancer. Am J Surg Pathol. 2009;33(11): 1601–1607.

Correspondence: Dr. Kazutomo Togashi at ktogashi@jichi.ac.jp
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Florid reactive lymphoid hyperplasia of the lower female genital tract

Lymphoma-like lesions of the lower female genital tract are florid reactive inflammatory processes that primarily occur in women during their reproductive years. They are characterized by a dense lymphoid infiltrate with admixed large cells that is often suspicious for lymphoma. However, in contrast to lymphoma, they are superficial lesions that typically show surface erosion and a mixed lymphoid infiltrate and do not have evidence of a mass, deep invasion, or prominent sclerosis. In some cases, clonal rearrangement of the immunoglobulin heavy chain (IgH) gene potentially may lead to misdiagnosis. The authors conducted a study that examined the clinicopathologic features and outcomes of 12 patients with lymphoma-like lesions (nine in the cervix and three in the endometrium). The patients, who ranged in age from 18 to 54 years (median, 37 years), came to medical attention because of squamous dysplasia (eight patients), vaginal bleeding (three), or adnexal mass (one). One patient had an endocervical polyp, but otherwise none had a discrete mass. The specimens contained a dense, polymorphous inflammatory infiltrate commonly associated with mucosal erosion. Immunohistochemical studies showed a mixture of B and T cells without immunoglobulin light chain restriction. Four cases (all cervical) had a clonal IgH gene rearrangement by polymerase chain reaction. There was no evidence of lymphoma on staging or followup in any patient, including the four patients with clonal IgH rearrangement, after a mean followup of 3.5 years (range, four months to 13 years). The authors concluded that a clonal IgH rearrangement in this setting does not warrant a diagnosis of lymphoma. They recommended a search for infectious organisms with followup and rebiopsy at a later date. Careful correlation of clinical, histologic, immunophenotypic, and genetic features is required to avoid misdiagnosis and inappropriate treatment. Routine microscopic findings and detailed clinical information are paramount in establishing the correct diagnosis.

Geyer JT, Ferry JA, Harris NL, et al. Florid reactive lymphoid hyperplasia of the lower female genital tract (lymphoma-like lesion): a benign condition that frequently harbors clonal immunoglobulin heavy chain gene rearrangements. Am J Surg Pathol. 2010;34(2):161–168.

Correspondence: Dr. Lawrence R. Zukerberg at lzukerberg@partners.org
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Clinical validation of an array CGH test for HER2 status in breast cancer relative to polysomy 17

The HER2 gene is an important prognostic and therapeutic marker in newly diagnosed breast cancer. HER2 status is most frequently determined by immunohistochemical detection of HER2 protein expression on the cellular membrane surface or by fluorescence in situ hybridization (FISH) analysis of HER2 gene copy number in fixed tissue using locus-specific probes for the HER2 gene and chromosome 17 centromere. How-ever, these methods are problematic because of issues with intra- and inter-laboratory reproducibility and preanalytic variables, such as fixation time. In addition, the commonly used HER2/chromosome 17 ratio presumes that chromosome 17 polysomy is present when the centromere is amplified, even though analysis of the remainder of the chromosome is not included in the assay. The authors conducted a study in which 97 frozen samples of invasive lobular and invasive ductal carcinoma with known immunohistochemistry and FISH results for HER2 were analyzed by comparative genomic hybridization to a commercially available bacterial artificial chromosome whole-genome array. The latter contained 99 probes targeted to chromosome 17 and the HER2/TOP2 amplicon. Results were 97 percent concordant for HER2 status, meeting the validation requirements for HER2 testing set by the College of American Pathologists and American Society of Clinical Oncology. Surprisingly, not a single case of complete polysomy 17 was detected even though multiple breast cancer cases showed clear polysomies of other chromosomes. The authors concluded that array comparative genome hybridization is an accurate and objective DNA-based alternative for evaluating HER2 gene copy number and that polysomy 17 is a rare event in breast cancer.

Yeh IT, Martin MA, Robetorye RE, et al. Clinical validation of an array CGH test for HER2 status in breast cancer reveals that polysomy 17 is a rare event. Mod Pathol. 2009;22(9):1169–1175.

Correspondence: Dr. I. Tien Yeh at yehi@uthscsa.edu
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Expression of PAX8 in normal and neoplastic renal tissues

Cell-lineage-specific transcription factors are a group of regulatory proteins expressed in embryonic, dif-ferentiated, and neoplastic cells of the same lineage and represent a valuable repertoire of tissue-specific markers for diagnosing human tumors. Together with PAX2, PAX8 is a nephric-lineage transcription factor and is required to establish renal-lineage cells and form the kidney. Unlike with PAX2, little is known about the expression of PAX8 in adult kidney and renal tumors. The authors conducted a study in which they used immunohistochemistry to investigate the expression of PAX8 in adult human kidney and renal epithelial tumors. They reported that PAX8 was detected in renal epithelial cells in all segments of renal tubules, from the proximal tubules to the renal papillae, and in the parietal cells of Bowman’s capsule in the adult kidney. PAX8 was also present in 98 percent of clear cell renal cell carcinomas (RCCs), 90 percent of papillary RCCs, and 95 percent of oncocytomas, similar to PAX2. In addition, PAX8 was found in 82 percent of chromophobe RCCs, 71 percent of sarcomatoid components of RCCs, and 100 percent of renal medullary carcinomas. Overall, PAX8 was detected in 85 percent of metastatic renal tumors. The authors found it interesting that expression of PAX8 was noted in some urothelial cells in the renal pelvis and ureters and approximately 23 percent of urothelial carcinomas of the renal pelvis but not in the urothelium or urothelial carcinomas of the urinary bladder. This probably emphasizes the varying embryonic origins of urothelial cells in the upper and lower urinary tracts. The study showed that PAX8 is widely expressed in normal and neoplastic renal tissues. It may be a useful additional marker for renal epithelial tumors; however, its specificity and sensitivity need further investigation.

Tong GX, Yu WM, Beaubier NT, et al. Expression of PAX8 in normal and neoplastic renal tissues: an immunohistochemical study. Mod Pathol. 2009;22(9):1218–1227.

Correspondence: Dr. G. X. Tong at gt2125@columbia.edu
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Histologic assessment to differentiate multiple lung primary nonsmall cell carcinomas from metastases

Lung adenocarcinoma is morphologically heterogeneous, with mixtures of acinar, papillary, bronchioloalveolar, and solid patterns in more than 80 percent of cases. In the case of synchronous or metachronous multiple nonsmall cell lung cancer (NSCLC), distinguishing intrapulmonary metastases from independent primary tumors is of great clinical importance as it influences staging and, potentially, therapeutic strategy. The authors undertook a study involving a cohort of 20 patients with 42 multiple NSCLC tumors (24 potential pair comparisons) that were annotated molecularly using genomic and mutational profiling to evaluate the value of comprehensive histologic assessment in this setting. Using the Martini-Melamed criteria, paired tumors were characterized as multiple primary NSCLCs in 21 cases and intrapulmonary metastases in three cases. Genomic and mutational data led to a diagnosis of multiple primaries in 14 cases and metastases in eight cases; two cases could not be assessed. This molecular characterization contradicted the Martini-Melamed diagnosis in seven of the 22 (32 percent) assessable comparisons. Adenocarcinoma was found in 32 of the 42 (76 percent) tumors. After review in a blinded fashion, semiquantitative comprehensive histologic assessment of paired tumors was different in 16 and similar in eight paired tumors. The authors found that comparing adenocarcinomas is a complex process that requires assessing not only percentages of the histologic subtypes, but also the recording of additional histologic details, such as cytologic features, patterns of stroma, necrosis, discrete nodularity versus miliary growth, and variants such as clear cell, signet ring, mucinous, and fetal patterns. The authors found too that paired squamous cell carcinomas could be compared based on histologic subtyping, as well as cytologic and stromal characteristics. Considering histologically different tumors as multiple primaries and similar tumors as metastases, comprehensive histologic sub-typing was consistent with the molecular characterization in 20 of the 22 (91 percent) pairs comparisons. The authors concluded that comprehensive histologic assessment is a powerful tool that shows promise in determining whether multiple lung adenocarcinomas or squamous cell carcinomas are metastatic or multiple primaries. This has great clinical implications for staging and therapeutic management of lung cancer patients with multiple tumors.

Girard N, Deshpande C, Lau C, et al. Comprehensive histologic assessment helps to differentiate multiple lung primary non-small cell carcinomas from metastases. Am J Surg Pathol. 2009;33(12):1752–1764.

E-mail correspondence information not provided.
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