Anatomic Abstracts
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February 2009 Editors:
Microscopic tumor burden in SLNs as a predictor of synchronous
It has been demonstrated that additional positive lymph nodes are identified in eight percent to 33 percent of patients with melanoma who have positive sentinel lymph nodes and who undergo complete therapeutic lymph node dissection (cTLND). The authors conducted a study to determine what predicts additional regional lymph node involvement in patients with positive sentinel lymph nodes (SLNs). They identified patients with clinically node-negative melanoma who underwent SLN biopsy between 1991 and 2003 and who had positive SLNs. Clinicopathologic factors, including extent of microscopic disease within SLNs, were evaluated as potential predictors of positive non-SLNs. The authors found that, overall, 359 of the 2,203 patients (16.3 percent) identified had a positive SLN. They identified positive non-SLNs in 48 of the 343 patients (14 percent) with positive SLNs who underwent cTLND. The following predicted positive non-SLNs on univariate analysis: several measures of SLN microscopic tumor burden, one versus three or more SLNs harvested, tumor thickness of more than 2 mm, age older than 50 years, and Clark level higher than III. Primary tumor ulceration and number of positive SLNs had no apparent impact. On multivariable logistic regression analysis, measures of SLN microscopic tumor burden were the most significant independent predictors of positive non-SLNs. Tumor thickness of more than 2 mm and number of SLNs harvested also predicted additional disease. A model was developed that stratified patients according to their risk for non-SLN involvement. The authors concluded that in melanoma patients with positive SLNs, SLN tumor burden, primary tumor thickness, and number of SLNs harvested may be useful in identifying a group of patients at low risk for positive non-SLNs and who may be spared the potential morbidity of a cTLND. Gershenwald JE, Andtbacka RH, Prieto VG, et al. Microscopic tumor burden in sentinel lymph nodes predicts synchronous nonsentinel lymph node involvement in patients with melanoma. J Clin Oncol. 2008;26:4296–4303. Correspondence: Dr. Jeffrey E. Gershenwald at jgershen@mdanderson.org
The authors conducted a study to evaluate whether human papillomavirus genotyping for select oncogenic HPV types can improve the efficacy of HPV DNA testing in predicting cervical intraepithelial neoplasia (CIN 2/3) in women with mildly abnormal Pap results. They compared HPV DNA testing and HPV genotyping for eight oncogenic types (16, 18, 31, 33, 35, 45, 52, and 58) in Pap specimens with abnormal results (high-grade squamous intraepithelial lesion [HSIL], 20 cases; low-grade squamous intraepithelial lesion [LSIL], 42 cases; atypical squamous cells of undetermined significance [ASCUS], 94 cases) and in follow-up biopsies. Using consensus primer-mediated polymerase chain-reaction assays, HPV DNA was detected in 90 percent (18/20) of HSIL, 95 percent (40/42) of LSIL, and 64 percent (60/94) of ASCUS cases. HPV DNA positivity was significantly associated with CIN 2/3/carcinoma (P<.001) in women with ASCUS but not in women with LSIL (P=.52). Of HPV DNA-positive specimens, the eight oncogenic HPV types were detected in 83 percent of HSIL cases (15/18), 53 percent of LSIL cases (21/40), and 47 percent of ASCUS cases (28/60). The eight oncogenic HPV types were significantly associated with CIN 2/3/carcinoma (odds ratio, 10.6; 95 percent confidence interval [CI], 3.98–28.10; P<.001), whereas no significant association was observed between the other oncogenic HPV types and CIN 2/3/carcinoma (odds ratio, 2.20; 95 percent CI, 0.80–6.03; P=.125). For women with ASCUS, HPV genotyping for the eight oncogenic types showed higher specificity (81 percent versus 46 percent) and positive predictive value (PPV) (44 percent versus 26 percent) for predicting CIN 2/3/carcinoma than did HPV DNA testing. Similarly, for women with LSIL, the HPV genotyping test for the eight oncogenic types showed higher specificity (69 percent versus eight percent) and PPV (62 percent versus 39 percent) for predicting CIN 2/3/carcinoma than did HPV DNA testing. The authors’ findings suggest that HPV genotyping for the eight oncogenic types might help improve the efficacy of HPV DNA testing for predicting CIN 2/3/carcinoma in women with mildly abnormal Pap results, which may lead to personalized clinical management with improved patient compliance for followup. Guo M, Lin CY, Gong Y, et al. Human papillomavirus genotyping for the eight oncogenic types can improve specificity of HPV testing in women with mildly abnormal Pap results. Mod Pathol. 2008;21:1037–1043. Correspondence: Dr. M. Guo at mguo@mdanderson.org
Studies analyzing the concordance of biopsy and radical prostatectomy Gleason scores have limitations. Some included two or more centers, used historical controls from the early prostate-specific antigen era, or lacked a clear definition of the biopsy schemes. Furthermore, most did not control the results for prostate volume. The authors conducted a study to confirm whether the ability to predict radical prostatectomy (RP) Gleason score can be optimized by taking more biopsy cores in a contemporary series of patients, with pathologic samples analyzed by the same pathologist, and controlling these results for prostate volume. The authors divided 393 patients with prostate cancer treated with RP into three groups for their retrospective case-control analysis. Those in group one underwent a six-core biopsy; group two, an eight-core biopsy; and group three, a 10 or more core biopsy. Concordance rates between biopsy and RP Gleason scores, as well as the rates of undergrading and overgrading, were determined for each biopsy scheme. Concordance rates were 60.9 percent, 58.3 percent, and 64.6 percent for patients from groups one, two, and three, respectively (P=.18). When the authors analyzed patients with prostate volumes of less than 50 cm3, concordance rates were 58.3 percent, 58.3 percent, and 65.1 percent for each group, respectively (P=.03). Among patients with prostate volumes of 50 cm3 or more, concordance rates were 70 percent, 58.1 percent, and 63.6 percent, respectively (P=.66). The authors concluded that taking 10 or more cores can improve the prediction of RP Gleason score in patients with prostate volumes of less than 50 cm3. For patients with prostate volumes of 50 cm3 or more, increasing the biopsy cores to 10 or more did not improve prediction of RP Gleason score. Antunes AA, Leite KR, Dall’Oglio MF, et al. The effect of the number of biopsy cores on the concordance between prostate biopsy and prostatectomy Gleason score: a prostate volume-controlled study. Arch Pathol Lab Med. 2008;132:989–992. Correspondence: Dr. Alberto Azoubel Antunes at antunesuro@uol.com.br
Histology is used as the endpoint to define success with photodynamic therapy in patients with high-grade dysplasia (HGD). Recurrences despite successful ablation are common. The role of biomarkers in assessing response to photodynamic therapy (PDT) remains undefined. The authors conducted a study to assess biomarkers in a prospective cohort of patients with HGD/mucosal cancer before and after PDT and to correlate biomarker status after PDT with histology. Thirty-one patients were studied. The median patient age was 66 years (interquartile range [IQR], 56–73 years), and 28 patients (88 percent) were men. All patients underwent esophagogastroduodenoscopy, four-quadrant biopsies every centimeter, endoscopic mucosal resection of visible nodules, and endoscopic ultrasound. Cytology samples were obtained using standard cytology brushes. Biomarkers were assessed using fluorescence in situ hybridization (FISH). The biomarkers assessed included loss of 9p21 (site of the p16 gene) and 17p13.1 (site of the p53 gene) loci; gains of the 8q24 (c-myc), 17q (HER2/neu), and 20q13 loci; and multiple gains. Patients received PDT 48 hours after porfimer sodium was administered. Demographic and clinical variables were collected prospectively. Patients were followed with endoscopy and repeat cytology for biomarkers. The McNemar test was used to compare biomarker proportions before and after PDT. The mean Barrett segment length was 5 cm (standard error of the mean, 0.5 cm). Post-PDT biomarkers were obtained after a median duration of nine months (IQR, 3–12 months). There was a statistically significant decrease in the proportion of several biomarkers assessed after PDT. Six patients without HGD after PDT still had positive FISH results for one or more biomarkers. Of these, two patients (33 percent) developed recurrent HGD. In this initial study, histologic downgrading of dysplasia after PDT was associated with loss of biomarkers that have been associated with progression of neoplasia in Barrett esophagus. Patients with persistently positive biomarkers appeared to be at higher risk of recurrent HGD. The authors recommended that these findings be confirmed in a larger study. Prasad GA, Wang KK, Halling KC, et al. Correlation of histology with biomarker status after photodynamic therapy in Barrett esophagus. Cancer. 2008;113:470–476. Correspondence: Dr. Kenneth K. Wang at wang.kenneth@mayo.edu
Primary invasive squamous cell carcinoma of the vagina is rare, and the role of human papillomavirus in its pathogenesis remains unclear. The authors conducted a study to determine the distribution of human papillomavirus genotypes in 21 cases of primary invasive squamous cell carcinoma of the vagina and to correlate human papillomavirus genotype with histological subtypes. Patients’ clinical records were reviewed for demographic data and stage of disease. Tumors (n=21) were classified according to World Health Organization criteria. Human papillomavirus genotyping (Inno-Lipa HPV Genotyping) was performed in the whole series, and statistical analysis was performed with Fisher’s Exact Test and Student’s t-test. The patients ranged in age from 36 to 88 years (mean, 65). Six cases were keratinizing squamous cell carcinoma, and 15 cases were non-keratinizing squamous cell carcinoma (seven non-keratinizing not otherwise specified, three basaloid, and five warty types). The median age of patients with keratinizing squamous cell carcinoma was 73.8 years and that of non-keratinizing squamous cell carcinoma patients was 61.5 years (P=.08). Human papillomavirus DNA was detected in 17 cases (81 percent): 13 non-keratinizing squamous cell carcinoma (87 percent) and four keratinizing squamous cell carcinoma (67 percent) (P=.31). The human papillomavirus genotypes identified were 6, 11, 16, 18, 31, 33, 35, 40, and 58. Human papillomavirus 16 DNA was the most prevalent (33 percent). Invasive squamous cell carcinoma of the vagina is frequently associated with human papillomavirus infection, and human papillomavirus 16 is the most common genotype. Although without statistical significance, keratinizing squamous cell carcinoma is more frequent in older patients, whereas nonkeratinizing squamous cell carcinoma more frequently affects younger women. All studied histological subtypes are strongly associated with human papillomavirus infection. Ferreira M, Crespo M, Martins L, et al. HPV DNA detection and genotyping in 21 cases of primary invasive squamous cell carcinoma of the vagina. Mod Pathol. 2008;21:968–972. Correspondence: Dr. M. Ferreira at marco_franco@sapo.pt
There are conflicting data about chemoresistance and prognosis in ovarian clear cell carcinoma. This could be due to significant interobserver variation in the diagnosis of the carcinoma and other ovarian surface epithelial tumors containing clear cells. Thirty-two cases previously diagnosed as clear cell carcinoma (CCC), high-grade ovarian serous carcinoma (SC), and mixed surface epithelial carcinoma (SEC) with clear cell and serous components were reviewed by four gynecologic pathologists blinded to the original diagnoses. They evaluated interobserver reproducibility and assessed each case using the immunohistochemical markers Wilms tumor 1, estrogen receptor, and p53. The interobserver reproducibility was greatest for pure CCC (κ, 0.82) and lowest for mixed SEC (κ, 0.32). Moderate agreement was seen in the pure SC category (κ, 0.59). All pure SC and most mixed SEC presented as stage III or IV disease. Most pure CCC presented as stage I or II disease. Immunoreactivities of the mixed SECs were similar to those of pure SC but significantly different from those of pure CCC for Wilms tumor 1 (P=.0011 for both components), estrogen receptor (P=.0003 for clear cell component; P=.0001 for serous component), and p53 (P=.0062 for both components). The serous and clear cell components of mixed SEC showed higher mitotic rates than did pure CCC (P=.004 and P=.023, respectively), but the mitotic rate of pure SC was similar to that for mixed SEC. The authors concluded that pure CCC is reproducibly diagnosed; the diagnosis of mixed ovarian SEC with clear cell component is not reproducible; and mixed SEC with clear cell and serous components shows similar stage, mitotic activities, and immunoreactivities to those of pure SC, and likely represents SC with clear cell changes. Han G, Gilks CB, Leung S, et al. Mixed ovarian epithelial carcinomas with clear cell and serous components are variants of high-grade serous carcinoma: an interobserver correlative and immunohistochemical study of 32 cases. Am J Surg Pathol. 2008;32:955–964. Correspondence: Dr. C. Blake Gilks at blake.gilks@vch.ca 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. |
