Mahmoud A. Khalifa

Sentinel lymph node biopsy vs. pelvic lymphadenectomy in early stage cervical cancer: Is it time to change the gold standard?

OBJECTIVE To compare the incidence of pelvic lymph node metastases in early stage cervical cancer patients undergoing sentinel lymph node biopsy (SLN) to a matched cohort undergoing pelvic lymphadenectomy. METHODS All patient data were entered prospectively into an ongoing cervical cancer database. Since April 2004, 87 patients with FIGO stage IA/B1 cervical cancer underwent SLN detection with identification of bilateral SLN. This cohort (cases) was compared to a matched group of patients who underwent complete pelvic lymphadenectomy (controls). The groups were matched 3:1 for tumour size (+/-5 mm), histology, depth of invasion (+/-2 mm), and presence of capillary lymphatic space invasion (CLS). Descriptive statistics were calculated for all variables of interest. The association between cases and controls and lymph node metastases was carried out using a conditional logistic regression analysis. RESULTS 81 women in the SLN cohort were matched with 1 control, 72 cases with 2 controls, and 65 cases with 3 controls. Among cases, 14 (17%) had pelvic lymph nodes metastases vs. 15 (7%) in the controls (p=0.0059, odds ratio= 2.8, 95% CI=1.3-5.9). Among the 14 cases of SLN metastases, 11 were detected by frozen section and 3 were detected on final paraffin sectioning. All were detected by H and E stains. The size of the SLN metastases ranged from less than 1 mm to 8 mm. CONCLUSIONS Sentinel lymph node biopsy in early cervical cancer is a more sensitive procedure in detecting pelvic lymph node metastases compared to complete lymphadenectomy.

Radical vaginal trachelectomy vs. radical hysterectomy for small early stage cervical cancer: A matched case-control study

OBJECTIVE To determine the efficacy and outcome from radical vaginal trachelectomy (RVT) compared to a matched group of patients undergoing radical hysterectomy for small early stage cervical cancer. METHODS All patient data were entered prospectively. Patients wishing preservation of fertility with cervical cancer, tumor <2 cm, and not meeting the definition of microinvasive cancer were offered RVT. The outcomes were compared to a matched group of patients who underwent radical hysterectomy for stage IA/IB cervical cancer. Groups were matched 1:1 for age (+/-5 years), tumor size (+/-1 mm), histology, grade, depth of invasion (+/-1 mm), presence of capillary lymphatic space invasion, pelvic lymph node metastasis, and adjuvant radiotherapy. RESULTS A total of 137 patients underwent RVT between 1994 and 2007. Of them, 90 patients were successfully matched. Median tumor size was microscopic. Moreover, 43% and 49% were squamous and had adeno/adenosquamous histology. Median depth of invasion was 3.1 mm. Capillary lymphatic space invasion was present in 68% of cases. Of the tumors, 60% were grade 1, 29% were grade 2, and 11% were grade 3. After a median follow-up of 51 and 58 months, 5 and 1 recurrences were diagnosed in the RVT and radical hysterectomy groups, respectively. Five-year recurrence-free survival rates were present in 95% and 100% of the groups, respectively (p=0.17). In addition, 3 and 1 deaths occurred in the RVT and radical hysterectomy groups, resulting in 5-year survival rates of 99% and 100%, respectively (p=0.55). CONCLUSIONS RVT seems to be the procedure of choice for women with small early stage cervical cancers wishing to preserve fertility.

Adenomyosis is associated with myometrial invasion by FIGO 1 endometrial adenocarcinoma

Summary: Adenomyosis is commonly seen in hysterectomy specimens for endometrial adenocarcinoma where it could be involved with the tumor. When adenocarcinoma involves adenomyosis, the tumor may remain limited to the adenomyosis or proceeds to invade the adjacent myometrium. The purpose of this study was to investigate whether the risk of myometrial invasion by grade 1 endometrioid adenocarcinoma in cases with cancer-positive adenomyosis is different from that of cases where cancer occurs in the absence of adenomyosis. Forty-six consecutive hysterectomy specimens with International Federation of Gynecology and Obstetrics (FIGO) grade 1 endometrial endometrioid adenocarcinoma involving adenomyosis and 49 consecutive specimens with the same tumor occurring in the absence of adenomyosis were retrospectively studied by 4 experienced gynecologic pathologists. In cases with adenomyosis, myometrial invasion was confirmed by CD10-negative staining around glands with irregular outline surrounded by inflamed desmoplastic stroma. Myometrial invasion was found in significantly more adenomyosis cases (n = 42, 91.3%) than in cases without adenomyosis (n = 38, 77.5%) (&khgr;2 = 4.79, P = 0.03). In 16 cases of the former group, the invasion only occurred from the foci of adenomyosis. Although myometrial invasion in the outer half was more common in the adenomyosis group (n = 16, 34.8%) than in cases without adenomyosis (n = 9, 18.4%), the difference was not statistically significant (&khgr;2 = 3.29, P = 0.07). By involving coexistent adenomyosis, FIGO grade 1 endometrial endometrioid adenocarcinoma is associated with myometrial invasion, probably through increasing the surface area of its interface with the adjacent myometrium. When compared with their counterparts that occur in the absence of adenomyosis, these tumors are significantly more likely to invade the myometrium.

Immunophenotyping of serous carcinoma of the female genital tract

To update the data on the expression of ‘mesothelioma markers’ by serous carcinomas of various sites we have studied cases from ovary (n=56), endometrium (n=37), fallopian tube (n=6), primary peritoneum (n=5) and cervix (n=3) using a panel of antibodies (WT1, P53, estrogen receptors, HER2/neu, D2-40, cytokeratin 5/6 and E-cadherin). Ovarian carcinomas demonstrated D2-40 and cytokeratin 5/6 immunoreactivity in 23.2 and 55.4% of cases, respectively. Endometrial carcinomas demonstrated D2-40 and cytokeratin 5/6 immunoreactivity in 43.2 and 37.8% of cases, respectively. D2-40 staining pattern was predominantly focal; however, strong reactivity was identified in 16.2% of endometrial and 10.7% of ovarian carcinomas. HER2/neu oncoprotein overexpression was demonstrated in 7 of 37 (18.9%) uterine serous carcinomas. In contrast, all the serous carcinomas of the other sites were HER2/neu negative. The proportion of positive cases was significantly different in ovarian vs endometrial carcinomas regarding WT1 (P=0.0458), estrogen receptors (P<0.001) reactivity and HER2/neu overexpression (P=0.0025). D2-40 and cytokeratin 5/6 are expressed in a considerable proportion of serous carcinomas and should be used cautiously in a ‘mesothelioma panel’ in situations where serous carcinoma is in the differential diagnosis. HER2/neu was exclusively overexpressed in serous carcinomas of endometrial origin.

Multimodal CME for surgeons and pathologists improves colon cancer staging.

BACKGROUND Optimal treatment of localized colorectal cancer (CRC) depends on accurate retrieval and assessment of lymph nodes (LN) in the resected specimen. METHODS Formal CE, informal opinion leadership and reinforcing strategies aimed at pathologists and surgeons to improve LN assessment were implemented. RESULTS In the pre-intervention period a median of 8 lymph nodes were assessed in making a designation of Stage II CRC (n = 115). Thirty months later (post-intervention period) the median number of LN reported in Stage II CRC increased to 18 (n = 41), p < 0.001. CONCLUSION A durable improvement in staging was realized through a multipronged change initiative aimed at both surgeons and pathologists.

CDX2, cytokeratins 7 and 20 immunoreactivity in rectal adenocarcinoma.

There are limited data regarding CDX2 expression in rectal carcinoma. The CK20/CK7 immunoprofile of colorectal adenocarcinoma has been described in studies, which have mostly lumped colonic and rectal tumors together. In this study, we investigated the diagnostic utility of immunohistochemical stains for CK7, CK20, and CDX2 in a series of rectal adenocarcinoma. Fifty-five specimens of rectal adenocarcinomas were retrieved and immunostained for CK7 (Dako-M7018), CK20 (NovoCastra NCL-L-CK20), and CDX2 (NovoCastra NCL-CDX2). Thirty cases of pancreatic adenocarcinoma and 15 cholangiocarcinomas were also studied as a comparison group. CK7 was expressed in 12/55 (22%) and CK20 in 48/55 (87%) cases of rectal adenocarcinoma. The CK7−/CK20+ immunophenotype was identified in 36/55 (65%), CK7+/CK20+ in 12/55 (22%), and CK7−/CK20− in 7/55 (13%) rectal adenocarcinoma. CDX2 showed moderate-strong positivity in all cases and was not related to tumor differentiation. Benign rectal mucosa was available in 37 cases and showed the following results: CK7−/CK20+ in 25/37 (67%), CK7+/CK20+ in 8/37 (22%) and CK7−/CK20− in 4/37 (11%) cases. In pancreatic adenocarcinomas and cholangiocarcinomas, 29/45 (64%) were CK7+/CK20+ and 16/45 (36%) were CK7+/CK20−. CDX2 was positive in only 3/45 (7%) of these cases; all were pancreatic adenocarcinomas. In conclusion, CK7 can be expressed in rectal adenocarcinoma, and should not be used as the sole basis for excluding a rectal primary. CDX2 is a sensitive marker for rectal origin of adenocarcinoma. It can be helpful in cases with metastatic rectal carcinoma, especially those with CK7+/CK20+ or CK20−/CK7− immunophenotype. In this study, CDX2 expression was not influenced by the grade (differentiation) of rectal adenocarcinoma.

Assessment of endometrial sampling as a predictor of final surgical pathology in endometrial cancer

Background:The histology and grade of endometrial cancer are important predictors of disease outcome and of the likelihood of nodal involvement. In most centres, however, surgical staging decisions are based on a preoperative biopsy. The objective of this study was to assess the concordance between the preoperative histology and that of the hysterectomy specimen in endometrial cancer.Methods:Patients treated for endometrial cancer during a 10-year period at a tertiary cancer centre were identified from a prospectively collected pathological database. All pathology reports were reviewed to confirm centralised reporting of the original sampling or biopsy specimens; patients whose biopsies were not reviewed by a dedicated gynaecological pathologist at the treating centre were excluded. Surgical pathology data including histology, grade, depth of myometrial invasion, cervical stromal involvement and lymphovascular space invasion (LVSI) as well as preoperative histology and grade were collected. Preoperative and final tumour cell type and grade were compared and the distribution of other high-risk features was analysed.Results:A total of 1329 consecutive patients were identified; 653 patients had a centrally reviewed epithelial endometrial cancer on their original biopsy, and are included in this study. Of 255 patients whose biopsies were read as grade 1 (G1) adenocarcinoma, 45 (18%) were upgraded to grade 2 (G2) on final pathology, 6 (2%) were upgraded to grade 3 (G3) and 5 (2%) were read as a non-endometrioid high-grade histology. Overall, of 255 tumours classified as G1 endometrioid cancers on biopsy, 74 (29%) were either found to be low-grade (G1–2) tumours with deep myometrial invasion, or were reclassified as high-grade cancers (G3 or non-endometrioid histologies) on final surgical pathology. Despite these shifts, we calculate that omitting surgical staging in preoperatively diagnosed G1 endometrioid cancers without deep myometrial invasion would result in missing nodal involvement in only 1% of cases.Conclusions:Preoperative endometrial sampling is only a modest predictor of surgical pathology features in endometrial cancer and may underestimate the risk of disease spread and recurrence. In spite of frequent shifts in postoperative vs preoperative histological assessment, the predicted rate of missed nodal metastases with a selective staging policy remains low.

CDX2 as a marker for intestinal differentiation: Its utility and limitations

CDX2 is a nuclear homeobox transcription factor that belongs to the caudal-related family of CDX homeobox genes. The gene encoding CDX2 is a nonclustered hexapeptide located on chromosome 13q12-13. Homeobox genes play an essential role in the control of normal embryonic development. CDX2 is crucial for axial patterning of the alimentary tract during embryonic development and is involved in the processes of intestinal cell proliferation, differentiation, adhesion, and apoptosis. It is considered specific for enterocytes and has been used for the diagnosis of primary and metastatic colorectal adenocarcinoma. CDX2 expression has been reported to be organ specific and is normally expressed throughout embryonic and postnatal life within the nuclei of epithelial cells of the alimentary tract from the proximal duodenum to the distal rectum. In this review, the authors elaborate on the diagnostic utility of CDX2 in gastrointestinal tumors and other neoplasms with intestinal differentiation. Limitations with its use as the sole predictor of a gastrointestinal origin of metastatic carcinomas are also discussed.

BAG-1 Expression Correlates with Bcl-2, p53, Differentiation, Estrogen and Progesterone Receptors in Invasive Breast Carcinoma

BAG-1, a recently identified anti-apoptotic protein, is overexpressed in the majority of invasive breast carcinomas. Overexpression of BAG-1 is important for both multi-step oncogenesis and resistance of cancer cells to apoptosis induced by DNA-damaging alkylating agents. BAG-1 protein species are localized differentially; nuclear expression may be associated with a shorter disease-free and overall survival in early stage breast cancer, while cytoplasmic expression has been associated with longer survival in non-small cell lung cancer. Growing evidence suggests that Bcl-2 and p53 are also involved in the oncogenesis of breast cancer. Since BAG-1 interacts with Bcl-2 and is upregulated by mutant p53 in vitro, it would be interesting to determine if their expressions are correlated with each other and with other clinical prognostic factors in invasive breast cancer. To address this question we conducted a large scale retrospective study of BAG-1, Bcl-2 and p53 in 185 breast cancer patients. Our study again showed that BAG-1 is overexpressed in the majority of breast cancer patients. In addition, it demonstrated that the expression of BAG-1 correlates with that of Bcl-2, p53, differentiation, estrogen and progesterone receptors. Our clinical study supports the preclinical finding of the interaction between BAG-1 and Bcl-2, p53 and estrogen and progesterone receptors. Further experiments to explore the prognostic and therapeutic role of BAG-1 in breast cancer are warranted.

Retroperitoneal margin of the pancreaticoduodenectomy specimen: anatomic mapping for the surgical pathologist

Surgical margin status of the pancreaticoduodenectomy specimen is an independent predictor of survival in patients with pancreatic head cancer. Although most surgical pathologists are familiar with the protocols for grossing and evaluation of the various margins of the specimen, the currently prevailing definitions of the retroperitoneal surgical margin minimize the fact that this margin is actually a combination of surfaces of different anatomical structures. The unfamiliarity with its detailed anatomy often creates communication gaps when the pathologic findings are presented to other members of the multidisciplinary team. The following discussion is the collective opinion of hepato-pancreato-biliary pathologists in two tertiary care Canadian medical centers in this field. It describes the authors’ proposed nomenclature and landmarks for anatomic mapping of the retroperitoneal margin of the pancreaticoduodenectomy resected specimen. Increasing familiarity with the subtleties of the retroperitoneal margin is expected to improve communication and sets the stage for future quality improvement initiatives and translational research in the multidisciplinary setting.