Harmen Hollema

Sentinel Lymph Node Procedure Is Highly Accurate in Squamous Cell Carcinoma of the Vulva

PURPOSEnTo determine the diagnostic accuracy of the sentinel lymph node procedure in patients with squamous cell carcinoma of the vulva and to investigate whether step sectioning and immunohistochemistry of sentinel lymph nodes increase the sensitivity for detection of metastases.nnnPATIENTS AND METHODSnBetween July 1996 and July 1999, 59 patients with primary vulvar cancer were entered onto a two-center prospective study. All patients underwent sentinel lymph node procedure with the combined technique (preoperative lymphoscintigraphy with technetium-99m-labeled nanocolloid and intraoperative blue dye). Radical excision of the primary tumor with uni- or bilateral inguinofemoral lymphadenectomy was performed subsequently. Sentinel lymph nodes and lymphadenectomy specimens were sent for histopathologic examination separately. Sentinel lymph nodes, negative at the time of routine pathologic examination, were re-examined with step sectioning and immunohistochemistry.nnnRESULTSnIn 59 patients, 107 inguinofemoral lymphadenectomies were performed (11 unilateral and 48 bilateral). All sentinel lymph nodes, as observed on preoperative lymphoscintigram, were identified successfully intraoperatively. Routine histopathologic examination showed lymph node metastases in 27 groins, all of which were detected by the sentinel lymph node procedure. The negative predictive value for a negative sentinel lymph node was 100% (97.5% confidence interval [CI], 95% to 100%). Step sectioning and immunohistochemistry showed four additional metastases in 102 sentinel lymph nodes (4%; 95% CI, 1% to 9%) that were negative at the time of routine histopathologic examination.nnnCONCLUSIONnSentinel lymph node procedure with the combined technique is highly accurate in predicting the inguinofemoral lymph node status in patients with early-stage vulvar cancer. Future trials should focus on the safe clinical implementation of the sentinel lymph node procedure in these patients. Step sectioning and immunohistochemistry slightly increase the sensitivity of detecting metastases in sentinel lymph nodes and should be included in these trials.

Proximal adenomas in hereditary non-polyposis colorectal cancer are prone to rapid malignant transformation

Background: Hereditary non-polyposis colorectal cancer (HNPCC) is thought to arise from adenomas. HNPCC mostly occurs in the proximal colon. We investigated whether this proximal preponderance is due to a proximal preponderance of adenomas or (also) differences in transformation rates from adenomas to cancer between the distal and proximal colon. Methods: A total of 100 HNPCC adenomas were evaluated and compared with 152 sporadic adenomas for location, size, and dysplasia. Twenty five adenomas from patients with a known mismatch repair (MMR) gene mutation were stained for expression of MLH1 and MSH2. Results: HNPCC adenomas were more often located proximally (50% v 26%; p=0.018) and were smaller in comparison with sporadic adenomas. They were similarly dysplastic. However, all proximal HNPCC adenomas ≥5 mm were highly dysplastic compared with 17% of the larger proximal sporadic polyps (p<0.001). They were also more often highly dysplastic than larger distal HNPCC adenomas (p<0.001). Small HNPCC adenomas were, except for their location, not different from sporadic adenomas. Fifteen of the 25 “known mutation” adenomas showed loss of expression of either MLH1 or MSH2. The 10 adenomas with expression were all small with low grade dysplasia. Conclusion: HNPCC adenomas are located mainly in the proximal colon. The progression to high grade dysplasia is more common in proximal than distal HNPCC adenomas, indicating a faster transformation rate from early adenoma to cancer in the proximal colon. MMR gene malfunction probably does not initiate adenoma development but is present at a very early stage of tumorigenesis and heralds the development of high grade dysplasia.

Changes in apoptosis during the development of colorectal cancer: a systematic review of the literature

The development of colorectal cancer is characterised by an accumulation of molecular genetic alterations causing disorders in cell growth, differentiation and apoptosis. Although changes in apoptosis with colorectal cancer development have been studied extensively, a clear consensus of opinion has not yet emerged. In this review, the literature about changes in the frequency and distribution of apoptosis in tissue sections of normal and neoplastic colorectal tissues was reviewed systematically. Using a PUBMED search, 53 relevant articles were identified. Data from these studies are discussed with respect to the following aspects: methods used to detect apoptotic cell death; frequency and locoregional distribution of apoptosis in normal mucosa, adenomas and carcinomas; the correlation between levels of apoptosis and proliferation and the prognostic significance of the degree of apoptosis in colorectal cancer. Possible underlying mechanisms of dysregulation of apoptosis are discussed briefly. Finally, possible therapeutic implications of knowledge of the molecular regulation of apoptosis are discussed and potential options for further research are suggested.

Interobserver variability and the effect of education in the histopathological diagnosis of differentiated vulvar intraepithelial neoplasia

No published data concerning intraobserver and interobserver variability in the histopathological diagnosis of differentiated vulvar intraepithelial neoplasia (DVIN) are available, although it is widely accepted to be a subtle and difficult histopathological diagnosis. In this study, the reproducibility of the histopathological diagnosis of DVIN is evaluated. Furthermore, we investigated the possible improvement of the reproducibility after providing guidelines with histological characteristics and tried to identify histological characteristics that are most important in the recognition of DVIN. A total number of 34 hematoxylin and eosin-stained slides were included in this study and were analyzed by six pathologists each with a different level of education. Slides were reviewed before and after studying a guideline with histological characteristics of DVIN. Kappa statistics were used to compare the interobserver variability. Pathologists with a substantial agreement were asked to rank items by usefulness in the recognition of DVIN. The interobserver agreement during the first session varied between 0.08 and 0.54, which slightly increased during the second session toward an agreement between −0.01 and 0.75. Pathologists specialized in gynecopathology reached a substantial agreement (kappa 0.75). The top five of criteria indicated to be the most useful in the diagnosis of DVIN included: atypical mitosis in the basal layer, basal cellular atypia, dyskeratosis, prominent nucleoli and elongation and anastomosis of rete ridges. In conclusion, the histopathological diagnosis of DVIN is difficult, which is expressed by low interobserver agreement. Only in experienced pathologists with training in gynecopathology, kappa values reached a substantial agreement after providing strict guidelines. Therefore, it should be considered that specimens with an unclear diagnosis and/or clinical suspicion for DVIN should be revised by a pathologist specialized in gynecopathology. When adhering to suggested criteria the diagnosis of DVIN can be made easier.

IMMUNOPHENOTYPES OF MALIGNANT-LYMPHOMA CENTROBLASTIC-CENTROCYTIC AND MALIGNANT-LYMPHOMA CENTROCYTIC - AN IMMUNOHISTOLOGIC STUDY INDICATING A DERIVATION FROM DIFFERENT STAGES OF B-CELL DIFFERENTIATION

Five cases of intermediate lymphocytic lymphoma (ILL), 13 cases of malignant lymphoma centrocytic (MLCC), and 27 cases of malignant lymphoma centroblastic centrocytic (MLCBCC) were studied morphologically and with the aid of a panel of monoclonal antibodies. The immunophenotypes of ILL and MLCC (IgM+/IgD+, MT1+, CALLA-) indicate a mantle zone or very early follicle center derivation. The immunophenotypes of MLCBCC (IgM+ or IgG/IgA+, MT1-, CALLA+) indicate a true follicle center derivation. The morphologic diversity of MLCBCC could not be related to specific immunophenotypes.

Potential Target Antigens for a Universal Vaccine in Epithelial Ovarian Cancer

The prognosis of epithelial ovarian cancer (EOC), the primary cause of death from gynaecological malignancies, has only modestly improved over the last decades. Immunotherapeutic treatment using a cocktail of antigens has been proposed as a “universal” vaccine strategy. We determined the expression of tumor antigens in the context of MHC class I expression in 270 primary tumor samples using tissue microarray. Expression of tumor antigens p53, SP17, survivin, WT1, and NY-ESO-1 was observed in 120 (48.0%), 173 (68.9%), 208 (90.0%), 129 (56.3%), and 27 (11.0%) of 270 tumor specimens, respectively. In 93.2% of EOC, at least one of the investigated tumor antigens was (over)expressed. Expression of MHC class I was observed in 78.1% of EOC. In 3 out 4 primary tumors, (over)expression of a tumor antigen combined with MHC class I was observed. These results indicate that a multiepitope vaccine, comprising these antigens, could serve as a universal therapeutic vaccine for the vast majority of ovarian cancer patients.

Letter Commenting on "Risk-Reducing Salpingo-Oophorectomy (RRSO) in BRCA Mutation Carriers

To the Editor: W great interest, we read the recent article of Powell et al on occult malignancy in risk-reducing salpingooophorectomy (RRSO) specimens in 111 BRCA1/2 mutation carriers. The authors describe an overall detection rate of 9.1% (10/111) for occult ovarian/tubal carcinoma in prophylactically removed adnexa in BRCA1/2 mutation carriers. Table 1 displays the pathological findings in 10 patients with occult carcinoma. Our attention was drawn to one of the patients in Table 1, no. 6. In this patient, an ovarian intraepithelial carcinoma was diagnosed. We would like to comment on this finding and on the detected prevalence of occult malignancy. In prophylactically removed adnexa in BRCA1/2 carriers, tubal carcinoma in situ (TCIS) has previously been described and is located in the fimbrial end of the fallopian tube. Other than atypia and moderate dysplasia, the presence of TCIS is an officially recognized (International Federation of Gynecology and Obstetrics classification) precursor of tubal cancer. Furthermore, TCIS has been recognized as a precursor of ovarian and peritoneal cancer. However, to the best of our knowledge, an ovarian in situ carcinoma has never been reported, until now. Either this case no. 6 would be groundbreaking news in the field of adnexal carcinogenesis, which we doubt, or the diagnosis is incorrect. Moreover, the reported prevalence of occult malignancy in this retrospective study is remarkably high (9.1%) compared with that in literature (2.2%).5 Powell et al included a ‘‘clean’’ selection of screen-negative (106/111) women with a proven BRCA1 or BRCA2 germline mutation and used a surgical-pathological protocol to increase the ability of detecting occult cancer at RRSO. The median ages at time of RRSO were 46 years (range, 32Y69 years) for the entire group and 51 years for women with carcinoma found at RRSO, both corresponding to previous studies. However, although the authors report ‘‘occult carcinoma,’’ they included both premalignant lesions (n = 5) as well as invasive carcinoma (n = 5), resulting in a twice as high rate of occult carcinoma as is really present. In conclusion, we believe that the finding of ovarian intraepithelial carcinoma should not go unnoticed, because it would be the first reported case to date. In addition, we suggest that the authors should only include invasive cancers in the prevalence of occult malignancies.