Matthias Choschzick

Clinical management of primary vulvar cancer

AIMS Vulvar cancer is a rare disease with increasing incidence over the last decades. Treatment includes surgical, radio- and chemotherapeutical options; however, due to the low incidence of the disease and the lack of randomised trials many questions regarding indication of different treatment approaches remain unanswered. This article discusses the current literature to elaborate recommendations for the management of primary vulvar cancer in clinical routine. METHODS We reviewed the available literature on treatment of invasive vulvar cancer with emphasis on therapeutic strategies such as surgery and radio/chemotherapy. RESULTS Surgery of the primary tumour and the groins remain the cornerstone of treatment in vulvar cancer with a strong trend towards a less radical approach in early stage disease. Complete vulvectomy was replaced by radical local excision with plastic reconstruction and the sentinel node technique was implemented to avoid the morbidity of complete groin dissection in node negative patients. In patients with advanced primary disease, treatment decisions are still a challenge. Criteria for the indication and performance of chemo/radiotherapy of the vulva/groins/pelvis are still not fully established and vary between different countries and institutions due to the low level of evidence. Often an individualised therapeutic approach aside from guidelines is necessary to treat these patients adequately. CONCLUSIONS To enable reasonable treatment decisions and avoid unnecessary morbidity, treatment in specialised centres should be intended at any time. Clinical studies performed by several study groups on an international level are urgently needed to further improve therapy.

Heterogenous high-level HER-2 amplification in a small subset of colorectal cancers

HER-2 is the molecular target for antibody-based treatment of breast cancer (trastuzumab). The potential benefit of anti-HER-2 therapy is currently investigated in several other HER-2 amplified cancers. For example, trastuzumab was recently shown to be effective in HER-2 positive gastric cancer. To address the potential applicability of anti-HER-2 therapy in colorectal cancer, tissue microarray sections and colorectal resection specimens of 1851 colorectal cancers were analyzed for HER-2 overexpression and amplification using FDA approved reagents for immunohistochemistry and fluorescence in situ hybridization. HER-2 amplification was seen in 2.5% and HER-2 overexpression in 2.7% of 1439 interpretable colorectal cancers. Amplification was often high level with HER-2 copies ranging from 4 to 60 per tumor cell and was strongly related to protein overexpression. HER-2 amplification and overexpression were unrelated to histological tumor type, tumor localization, grading, pT, pN, pM or survival. As heterogeneity of drug target expression could represent a major drawback for targeted cancer therapy we next studied HER-2 heterogeneity in selected cases. Extensive evaluation of all available large sections from patients with HER-2 positive colorectal cancer revealed heterogenous findings in 3 of 4 cases. In summary, high-level HER-2 amplification occurs in a small fraction of colorectal cancers. Heterogeneity of amplification may limit the utility of anti- HER-2 therapy in some of these tumors and therefore, adequate clinical trials are needed to further evaluate this approach.

Prognostic Role of Lymph Node Metastases in Vulvar Cancer and Implications for Adjuvant Treatment

Objective Lymph node metastases are the most important prognostic factor for recurrence and survival in vulvar cancer. However, information regarding the impact of the number of positive nodes in vulvar cancer is inconsistent, and so are recommendations when to apply adjuvant radiotherapy. Methods One hundred fifty-seven consecutive patients with primary squamous cell cancer of the vulva treated at our center were analyzed. All patients underwent primary surgery by triple incision resulting in complete tumor resection. Results Median age was 61 years; 49 patients (31%) had lymph node metastases; 21 patients had 1, 13 had 2, and 15 had more than 2 positive lymph nodes. Thirty-two percent of the patients received adjuvant radiotherapy. The risk of lymph node metastases increased with age, greater tumor size, deeper invasion, and higher tumor grade. Median follow-up was 36 months; 23 patients (14.6%) developed disease recurrence (61% vulva, 35% groins, and 4% both). Compared with node-negative patients, survival in all node-positive patients was significantly impaired (P < 0.001; disease-free patients after 2 years: 88% in node-negative patients; 60%, 43%, and 29% in patients with 1, 2, and >2 affected nodes, respectively), whereas no significant difference between the node-positive subgroups could be demonstrated regarding disease-free survival. In multivariate analysis, lymph node status remained the most important prognostic factor regarding disease-free survival, but the effect of positive nodes differed significantly dependent on adjuvant treatment (P = 0.001). In patients without adjuvant radiotherapy to the groins/pelvis, the number of metastatic nodes was highly relevant for prognosis (hazard ratio, 1.752; P < 0.001), whereas this effect disappeared in patients who were treated with adjuvant radiotherapy (hazard ratio, 0.972; P = 0.828). Conclusions The negative impact of lymph node metastases is already evident in patients with only 1 affected lymph node. In patients receiving adjuvant radiotherapy, the negative effect of additional lymph node metastases is reduced; adjuvant treatment might therefore be beneficial in patients with only 1 positive node.

Overexpression of carbonic anhydrase IX (CAIX) is an independent unfavorable prognostic marker in endometrioid ovarian cancer

Carbonic anhydrase IX (CAIX) is a strictly membranous expressed metalloenzyme involved in cell adhesion, pH homeostasis, and cancer progression. This study was designed to assess the role of CAIX in primary ovarian cancer. Two hundred five well-characterized primary ovarian carcinomas were analyzed on a tissue microarray. CAIX expression was determined by immunohistochemistry using a four-step scoring system. Moderate and strong membranous CAIX expression was found in 37 out of 205 (18%) of all assessable ovarian cancer specimens. High levels of CAIX expression were related to mucinous and endometrioid phenotype of ovarian carcinomas (p < 0.05). There was no association between CAIX overexpression and tumor stage, grading, and mitotic count of ovarian carcinomas (p > 0.05). In univariate Cox regression analysis, advanced tumor stage (p < 0.01), high tumor grade (p = 0.017), high mitotic count (p = 0.025), and high CAIX expression levels (p = 0.031) were correlated to shorter overall patient survival. High pT stage (p = 0.036) and CAIX overexpression were connected to poor clinical outcome in endometrioid ovarian carcinomas. Multivariate Cox regression hazard analysis comprising tumor stage, tumor grade, mitotic count, and CAIX expression revealed pT2/3 stage and CAIX overexpression (scores 2 and 3) as independent prognostic markers in ovarian cancer (p < 0.01, each) as well as in the subgroup of endometrioid carcinomas (p < 0.05, each). In conclusion, CAIX is overexpressed in a substantial proportion of mucinous and endometrioid ovarian carcinomas and connected to poor patient outcome. Our data support the potential therapeutic benefit of newly developed targeting antibodies in advanced ovarian cancer.

Carbonic anhydrase IX in tumor tissue and sera of patients with primary cervical cancer

BackgroundCarbonic anhydrase IX (CAIX) is a membranous expressed metalloenzyme involved in pH homeostasis and cell adhesion. The protein is overexpressed in a variety of tumors and potentially associated with negative outcome. This study was designed to investigate the prognostic role of CAIX in serum and tumor tissue of patients with primary cervical cancer.MethodsTumor samples of 221 consecutive patients with primary cervical cancer who underwent surgery between 1993 and 2008 were analyzed for CAIX expression by immunohistochemistry. Additionally, preoperative serum CAIX concentrations were determined by ELISA in a subset of patients. Correlation with intratumoral CAIX expression as well as clinicopathological factors and outcome was analyzed.ResultsCAIX expression was observed in 81.9% of the tumor specimens; 62.0% showed a moderate or strong staining intensity. Moderate/strong expression was associated with squamous histology (p = 0.024), advanced tumor stage (p = 0.001), greater invasion depth (p = 0.025), undifferentiated tumor grade (p < 0.001) and high preoperative SCC-Ag values (p = 0.042). Furthermore patients with moderate/strong intratumoral CAIX expression had a higher number of metastatic lymph nodes compared to those with none/weak intratumoral expression levels (p = 0.047) and there was a non-significant association between high intratumoral CAIX expression and shorter survival (p = 0.118). Preoperative serum concentrations of CAIX ranged between 23 and 499 pg/mL and did not correlate with intratumoral expression or other clinicopathological variables.ConclusionCAIX is associated with advanced tumor stages and lymph node metastases in cervical cancer, potentially representing a new target in this disease. In contrast to other epithelial cancers we could not observe a correlation between serum CAIX and its intratumoral expression.

Homogeneous EGFR amplification defines a subset of aggressive Barrett's adenocarcinomas with poor prognosis.

Marx A H, Zielinski M, Kowitz C‐M, Dancau A‐M, Thieltges S, Simon R, Choschzick M, Yekebas E, Kaifi J T, Mirlacher M, Atanackovic D, Brümmendorf T H, Fiedler W, Bokemeyer C, Izbicki J R & Sauter G
(2010) Histopathology 57, 418–426
Homogeneous EGFR amplification defines a subset of aggressive Barrett’s adenocarcinomas with poor prognosis

Role of TP53 mutations in vulvar carcinomas.

Human papillomavirus (HPV)-independent development of vulvar carcinomas is common and the disruption of the TP53 pathway seems to play a key role in these tumors. Overexpression of TP53 in precursor lesions (differentiated VIN) and associated invasive carcinomas is regarded as an important diagnostic feature of this subtype of vulvar cancer. To determine the relationship of TP53 mutation status with clinicopathologic parameters, HPV status, and patient outcome, 18 squamous cell carcinomas of the vulva with TP53 overexpression along with 21 immunohistochemically TP53-negative tumors were analyzed. TP53 mutations were found in 17 (43.6%) of vulvar cancers, 18 (46.2%) tumors were HPV associated, and 8 (20.5%) carcinomas showed no relation to HPV infection or TP53 mutations. The presence of TP53 mutations was significantly linked to TP53 overexpression (P=0.002) and negative HPV status (P=0.012). The specificity of TP53 protein overexpression for the occurrence of TP53 mutations was 68.2%, with a positive predictive value of 66.7%. The most frequent mutation types were C:G →T:A transitions (57.9%). This mutation pattern strongly indicates the important role of oxidative stress in vulvar carcinogenesis. There were no relationships between TP53 mutation status and tumor stage, grading, nodal status, depth of invasion, or patient prognosis. In summary, TP53 mutations play a crucial role in a substantial proportion of vulvar carcinomas and are probably associated to cellular oxidative stress in chronically degenerative diseases of the vulva, such as lichen sclerosus. These data support the potential utility of restoring TP53 function as a therapeutic alternative in vulvar cancer. Further studies are necessary to clarify the prognostic implications of TP53 mutations in vulvar carcinomas.

Management of patients with vulvar cancer: a perspective review according to tumour stage

Treatment of patients with vulvar cancer is challenging for gynaecologic oncologists. Owing to the localization in a sensitive area, surgical radicality and the indication for adjuvant treatment have to be balanced with psychosocial aspects to treat patients adequately. Clinical management is therefore highly dependent on the tumour stage. For patients with early-stage disease (FIGO I–II) therapy mainly concentrates on surgery with resection of the primary tumour and staging of the groin lymph nodes. In intermediate-stage vulvar cancer (FIGO III), advanced disease is expressed by affected inguinofemoral lymph nodes bringing radical lymphadenectomy and adjuvant therapy as well as radiation or chemoradiation into the focus of treatment. For locally advanced or metastatic vulvar cancer (FIGO IV) neoadjuvant or definitive chemoradiation has to be considered besides surgery. Owing to the low incidence of the disease, the level of evidence for different treatment modalities is poor. This review therefore puts different recommendations of clinical management in context and highlights the need for future trials.

Oestrogen receptor gene (ESR1) amplification is frequent in endometrial carcinoma and its precursor lesions.

Oestrogen receptor alpha (ER) plays a critical, diverse and not fully understood role in endometrial carcinoma. Most endometrial carcinomas express ER and some of these tumours respond favourably to anti‐oestrogen therapy. On the other hand, tamoxifen therapy constitutes a major risk factor for endometrial carcinoma development. Amplification of the ESR1 gene encoding ER was recently shown to constitute a mechanism for ER over‐expression in breast carcinoma. This study was designed to determine the potential role of ESR1 amplifications in endometrial carcinoma. Tissue microarrays of 368 endometrial carcinomas and large sections of 43 cases of endometrial hyperplasia were analysed for ESR1 gene amplification and ER protein expression by means of fluorescence in situ hybridization (FISH) and immunohistochemistry. FISH revealed ESR1 amplification in 40/176 (23%) cancers, 6/19 (32%) atypical complex hyperplasias, 3/10 (30%) complex hyperplasias without atypia and 2/14 (14%) simple hyperplasias without atypia. Strong ER protein expression was significantly linked to ESR1 amplification in endometrial carcinoma (p = 0.0036). These data indicate that ESR1 amplification might be one mechanism for ER over‐expression in endometrial carcinoma, and suggest an early role for ESR1 amplification in the development of a significant fraction of endometrial carcinoma. Given the predictive role of ESR1 amplification for tamoxifen response in breast carcinoma, it will be interesting to investigate the response of ESR1‐amplified endometrial cancers to anti‐oestrogenic drugs. Copyright

Amplification of 8q21 in breast cancer is independent of MYC and associated with poor patient outcome

Copy number gains involving the long arm of chromosome 8, including high-level amplifications at 8q21 and 8q24, have been frequently reported in breast cancer. Although the role of the MYC gene as the driver of the 8q24 amplicon is well established, the significance of the 8q21 amplicon is less clear. The breast cancer cell line SK-BR-3 contains three separate 8q21 amplicons, the distal two of which correspond to putative target genes TPD52 and WWP1. To understand the effect of proximal 8q21 amplification on breast cancer phenotype and patient prognosis, we analyzed 8q21 copy number changes using fluorescence in situ hybridization (FISH) in a tissue microarray containing more than 2000 breast cancers. Amplification at 8q21 was found in 3% of tumors, and was associated with medullary type (P<0.03), high tumor grade (P<0.0001), high Ki67 labeling index (P<0.05), amplification of MYC (P<0.0001), HER2, MDM2, and CCND1 (P<0.05 each), as well as the total number of gene amplifications (P<0.0001). 8q21 copy number gains were significantly related to unfavorable patient outcome in univariate analysis. However, multivariate Cox regression analysis did not reveal an independent prognostic value of 8q21 amplification. The position of our FISH probe and data of a previously performed high-resolution CGH study in the breast cancer cell line SK-BR-3 involve TCEB1 and TMEM70 as new possible candidate oncogenes at 8q21 in breast cancer.