Performance of HER2 DAKO HercepTest and Ventana 4B5 immunohistochemical assays on detecting HER2 gene-amplification in uterine serous carcinomas.

We compared the performance of two commonly-used HER2 immunohistochemistry (IHC) assays in uterine serous carcinomas (USC), correlating with HER2 gene amplification by fluorescence in-situ hybridization (FISH). Sixty-five USCs were stained by both HercepTest™ and PATHWAY 4B5 assays. FISH was performed by HER2 IQFISH pharmDx. Consensus HER2 IHC scoring was performed, and HER2 testing results were evaluated using USC-specific criteria. Complete concordance between HercepTest and 4B5 assays was achieved in 44/65 tumors (68%). The overall HER2 IHC/FISH concordance was 94% (45/48) by HercepTest and 91% (42/46) by 4B5. All HER2 IHC 3+ cases with HercepTest (n = 6) and 4B5 (n = 4) were gene-amplified, corresponding to specificities of 100%. For cases with IHC 2+, 41% (7/17) by HercepTest and 42% (8/19) by 4B5 had HER2 gene amplification. The sensitivity for HercepTest and 4B5 were 38% and 25%, respectively, at a cut-off of IHC 3+ (P = 0.50), and were 81% and 75%, respectively, at a cut-off of IHC 2+ (P > 0.99). Among HER2 IHC 0-1+ cases, 3/42 cases by HercepTest and 4/42 cases by 4B5 showed amplified FISH results, corresponding to overall false negative rates of 19% for HercepTest and 25% for 4B5. By using USC-specific IHC scoring criteria, both HercepTest and 4B5 assays showed high specificities (100%) for HER2 gene amplification in IHC 3+ cases, high IHC/FISH concordance, and comparable sensitivity for detecting HER2 gene amplification. The notable false negative rates using IHC 2+ as a cut-off for reflexing FISH analysis may warrant consideration for performing FISH in IHC 1+ cases until more data become available.

HER2 in uterine serous carcinoma: Current state and clinical perspectives.

OBJECTIVES: Uterine cancer has the highest incidence and the second-highest mortality rate among gynecologic malignancies in the United States. Although uterine serous carcinoma (USC) represents less than 10% of endometrial carcinomas, it accounts for a disproportionate 50% of tumor relapses and 40% of endometrial cancer deaths. Over the past decade, clinical trials have focused on finding better treatments for this aggressive subtype of endometrial cancer, especially HER2-targeted therapy. METHODS: We conducted a literature search in PubMed to expand the understanding of HER2 in USC. RESULTS: HER2 has been established as an important biomarker with prognostic and therapeutic implications in USC. Intratumoral heterogeneity and lateral/basolateral membranous staining of HER2 as well as high discordance between HER2 immunohistochemistry and in situ hybridization are more common in USC than in breast carcinoma. Therefore, a universal HER2 testing and scoring system more suitable to endometrial cancer is needed and currently under investigation. CONCLUSIONS: This review discusses the clinical perspective of HER2 overexpression/gene amplification in USC, the distinct HER2 staining pattern and the evaluation of HER2 in USC, the resistance mechanisms of HER2-targeted therapy in HER2-positive cancers, and likely areas of future investigation.

Invariant NKT cell-augmented GM-CSF-secreting tumor vaccine is effective in advanced prostate cancer model.

Invariant natural killer T cells (iNKT cells) express a semi-invariant T cell receptor that recognizes certain glycolipids (including α-galactosylceramide, αGC) bound to CD1d, and can induce potent antitumor responses. Here, we assessed whether αGC could enhance the efficacy of a GM-CSF-producing tumor cell vaccine in the transgenic SV40 T antigen-driven TRAMP prostate cancer model. In healthy mice, we initially found that optimal T cell responses were obtained with αGC-pulsed TRAMP-C2 cells secreting GM-CSF and milk fat globule epidermal growth factor protein-8 (MFG-E8) with an RGD to RGE mutation (GM-CSF/RGE TRAMP-C2), combined with systemic low dose IL-12. In a therapeutic model, transgenic TRAMP mice were then castrated at ~ 20 weeks, followed by treatment with the combination vaccine. Untreated mice succumbed to tumor by ~ 40 weeks, but survival was markedly prolonged by vaccine treatment, with most mice surviving past 80 weeks. Prostates in the treated mice were heavily infiltrated with T cells and iNKT cells, which both secreted IFNγ in response to tumor cells. The vaccine was not effective if the αGC, IL-12, or GM-CSF secretion was eliminated. Finally, immunized mice were fully resistant to challenge with TRAMP-C2 cells. Together these findings support further development of therapeutic vaccines that exploit iNKT cell activation.

Acantholytic Squamous Cell Carcinoma Arising From Lichen Sclerosus: A Rare Case Affecting Vulvar Skin.

We present the case of an 82-year-old female with acantholytic squamous cell carcinoma affecting vulvar skin. The patient had a history of perineal lichen sclerosus for 5 years before presentation. She was referred to a dermatologist for intractable severe pain associated with the lesions. Biopsies showed an infiltrative squamous cell carcinoma with histology consistent with the acantholytic subtype. Acantholytic squamous cell carcinoma is a rare histologic variant characterized by dyscohesive keratinocytes with pseudoglandular formation and dyskeratosis. It is associated with sun-damaged skin and most commonly occurs in the head and neck of elderly men. Few cases have been reported at nondermal sites and non-sun-exposed dermis. The patient underwent a radical vulvectomy and bilateral inguinal node dissection. The 1.6 cm tumor was diffusely acantholytic and pseudoglands were present. The tumor cells were diffusely positive for p63 immunohistochemical stain. As expected at this site, there was no solar elastosis identified histologically. However, vulvar intraepithelial neoplasia and chronic lichen sclerosus were apparent. This case represents a rare histologic subtype of squamous cell carcinoma in an unusual site associated with lichen sclerosus instead of solar elastosis.

Interobserver agreement in the diagnosis of anal dysplasia: comparison between gastrointestinal and gynaecological pathologists and utility of consensus conferences.

AIMS: Management of anal dysplasia relies upon the accurate diagnosis of anal biopsy specimens. As institutions move towards subspecialty signout (SSSO), decisions must be made regarding whether to assign anal biopsies to the gastrointestinal (GI) or gynaecological (GYN) pathology service. MATERIALS AND RESULTS: We identified 200 archival tissue biopsies of anal mucosa and circulated them among three GI pathologists and three GYN pathologists. Each pathologist separately scored each biopsy as normal, atypical, low-grade squamous intra-epithelial lesion (LSIL) or high-grade squamous intra-epithelial lesion (HSIL). Every case that was called HSIL by at least one pathologist was stained with p16 immunostain and a 'gold standard' interpretation of whether or not a case represented HSIL was made. The GI pathologists agreed on 97 (49%) cases prior to consensus; the GYN pathologists agreed on 33 (17%). The sensitivities of the three GI pathologists in detecting HSIL against the 'gold standard' were 47, 100 and 21% and for the GYN pathologists the sensitivities were 74, 89 and 84%; the sensitivities of the GI and GYN consensus diagnoses were 74% each. The specificities of the three GI pathologists in detecting HSIL were 99, 90 and 100% and for the GYN pathologists the specificities were 99, 92 and 91%; the specificities of both the GI and GYN consensus diagnoses were 100%. CONCLUSIONS: A mild to moderate degree of interobserver variability exists in the diagnosis of anal dysplasia among pathologists. Our study indicates the utility of some form of consensus conference, as overall agreement among GI pathologists and among GYN pathologists improved following in-person consensus.

Effect of Thin Prep(®) imaging system on laboratory rate and relative sensitivity of atypical squamous cells, high-grade squamous intraepithelial lesion not excluded and high-grade squamous intraepithelial lesion interpretations.

INTRODUCTION: Automated screening of Thin Prep(®) Papanicolaou Tests has become increasingly common in clinical practice. Increased productivity has initiated laboratory use of the Thin Prep(®) Imaging System (TIS). Increased sensitivity is a potential additional benefit of TIS. Published studies have shown an increase in discovery of dysplastic cells. This study evaluates the effect of TIS on the incidence of atypical squamous cells high-grade squamous intraepithelial lesion not excluded (ASC-H) and high-grade squamous intraepithelial lesion (HGSIL) results on Thin Prep(®) Pap Tests by comparing TIS-assisted and manual screening findings and the diagnoses on subsequent follow-up in a screening population over a 1-year time period. MATERIALS AND METHODS: A compilation of all ASC-H and HGSIL cases was prepared by conducting a computerized search over a 1-year period (7/06-6/07). The accumulated cases include Thin Prep Pap tests that were both TIS and manually screened. Follow-up results of cytologic and histologic cervical specimens were obtained for a time period extending to 2010. Interpretation utilizing TIS was in place 10 months prior to the study's initiation. RESULTS: During the study period 70,522 Pap tests were performed in our laboratory. One third (33%) of Pap tests were screened with assistance of TIS. Manual screening was performed on 47,380 Pap tests of which 153 (0.32%) were interpreted as ASC-H and 164 (0.35%) were interpreted as HGSIL. During the same time period automated screening (TIS) was performed on 23,111 Pap tests. Interpretation of 62 (0.27%) cases provided an ASC-H result, while 71 (0.31%) were HGSIL. Follow-up cervical dysplasia by colposcopic biopsy and cone biopsy was distributed proportionally between TIS and manual screening for both ASC-H and HGSIL categories. Cervical intraepithelial neoplasia (CIN II/III) was identified on follow-up biopsy of 41% TIS cases and 45% manually screened cases for ASC-H. In the HGSIL subset 71% of TIS cases and 69% manually screened cases showed CIN II/III on follow-up. TIS was 26% less sensitive relative to manual screening for ASC-H cases and 3% less sensitive for HGSIL. CONCLUSION: The similar rate of detection using TIS with an equal percentage of histologic correlation for ASC-H and HGSIL lesions on follow-up histology suggests patients screened by the TIS method are being sent for appropriate follow-up surveillance and treatment. A high-grade or possible high-grade lesion is as likely to be detected by TIS as by a manual screen. The similarities in relative sensitivity and specificity in a direct comparison between manual and TIS screening methodologies indicate that TIS compared to manual screening does not affect detection in patients with high-grade cervical lesions.