Sharon Nofech-Mozes

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.

HER2/neu and Ki-67 expression predict non-invasive recurrence following breast-conserving therapy for ductal carcinoma in situ.

Background:Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer that may progress to invasive cancer. Identification of factors that predict recurrence and distinguish DCIS from invasive recurrence would facilitate treatment recommendations. We examined the prognostic value of nine molecular markers on the risks of local recurrence (DCIS and invasive) among women treated with breast-conserving therapy.Methods:A total of 213 women who were treated with breast-conserving therapy between 1982 and 2000 were included; 141 received breast-conserving surgery alone and 72 cases received radiotherapy. We performed immunohistochemical staining on the DCIS specimen for nine markers: oestrogen receptor, progesterone receptor, Ki-67, p53, p21, cyclinD1, HER2/neu, calgranulin and psoriasin. We performed univariable and multivariable survival analyses to identify markers associated with the recurrence.Results:The rate of recurrence at 10 years was 36% for patients treated with breast-conserving surgery alone and 18% for women who received breast-conserving surgery and radiotherapy. HER2/neu+/Ki-67+ expression was associated with an increased risk of DCIS recurrence, independent of grade and age (HR=3.22; 95% CI: 1.47–7.03; P=0.003). None of the nine markers were predictive of invasive recurrence.Conclusion:Women with a HER2/neu/neu+/Ki67+ DCIS have a higher risk of developing DCIS local recurrence after breast-conserving surgery.

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.

Patterns of recurrence in the basal and non-basal subtypes of triple-negative breast cancers

Traditional prognostic markers for breast cancer include estrogen receptor (ER), progesterone receptor (ER) and HER2/neu. Negative staining for these three markers defines the ‘triple-negative’ phenotype. By adding markers for cytokeratin 5/6 and EGFR, triple-negative breast cancers can be divided into ‘basal-like’ and ‘normal-like’ subgroups. We conducted immuno-staining on a panel of 958 patients with breast cancer, using all five markers and we followed the patients for distal recurrence and death. We compared rates of distal recurrence in the basal-like and normal-like subgroups with that of women with ER-positive breast cancer. Only 16 of 958 women had normal-like breast cancers. These cancers resembled basal-like cancers in that they had a high proliferative index, but the women with normal-like breast cancers resembled ER-positive women in terms of distant recurrence. The addition of CK5/6 and EGFR to the standard panel (ER/PR/HER2/neu) defines a small subgroup of women with normal-like breast cancer. The prognosis of these women may be superior to that of basal-like breast cancers but firm conclusions cannot be made.

Identification of a Low-Risk Luminal A Breast Cancer Cohort That May Not Benefit From Breast Radiotherapy

PURPOSE To determine the prognostic and predictive value of intrinsic subtyping by using immunohistochemical (IHC) biomarkers for ipsilateral breast relapse (IBR) in participants in an early breast cancer randomized trial of tamoxifen with or without breast radiotherapy (RT). PATIENTS AND METHODS IHC analysis of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), cytokeratin 5/6, epidermal growth factor receptor, and Ki-67 was conducted on 501 of 769 available blocks. Patients were classified as luminal A (n = 265), luminal B (n = 165), or high-risk subtype (luminal HER2, n = 22; HER2 enriched, n = 13; basal like, n = 30; or triple-negative nonbasal, n = 6). Median follow-up was 10 years. RESULTS Classification by subtype was prognostic for IBR (10-year estimates: luminal A, 5.2%; luminal B, 10.5%; high-risk subtypes, 21.3%; P < .001). Luminal subtypes seemed to derive less benefit from RT (luminal A hazard ratio [HR], 0.40; luminal B HR, 0.51) than high-risk subtypes (HR, 0.13); however, the overall subtype-treatment interaction term was not significant (P = .26). In an exploratory analysis of women with clinical low-risk (age older than 60 years, T1, grade 1 or 2) luminal A tumors (n = 151), 10-year IBR was 3.1% versus 11.8% for the high-risk cohort (n = 341; P = .0063). Clinical low-risk luminal A patients had a 10-year IBR of 1.3% with tamoxifen versus 5.0% with tamoxifen plus RT (P = .42). Multivariable analysis showed that RT (HR, 0.31; P < .001), clinical risk group (HR, 2.2; P = .025), and luminal A subtype (HR, 0.25; P < .001) were significantly associated with IBR. CONCLUSION IHC subtyping was prognostic for IBR but was not predictive of benefit from RT. Further studies may validate the exploratory finding of a low-risk luminal A group who may be spared breast RT.

Intratumoral heterogeneity of HER2/neu in breast cancer--a rare event.

Abstract:  HER2/neu is overexpressed in about 20% of invasive breast carcinomas. Numerous studies have shown that there is high level of concordance between the HER2/neu status of the primary breast cancer and the metastases of a given patient. Recently, changes in HER2/neu status with tumor progression have been reported, suggesting the possibility of an emerging different tumor clone. Little is known about intratumoral heterogeneity with regard to HER2/neu oncoprotein overexpression. We identified nine cases of invasive ductal carcinoma that showed intratumoral variation in HER2/neu oncoprotein expression by immunohistochemistry. This was confirmed by the intratumoral variation in the amplification status of the HER2/neu gene by fluorescence in situ hybridization and by chromogenic in situ hybridization. The results of this study suggest that some cases of primary breast carcinoma are heterogeneous in regard to HER2/neu gene amplification or protein overexpression. Heterogeneity of HER2/neu status in a tumor may be a rare event or underestimated. This phenomenon should be examined as it may contribute to a better understanding of the variation in therapeutic responses and the conflicting data in studies about the prognostic and predictive role of HER2/neu status in subsets of breast cancer patients.

Prognostic and predictive molecular markers in DCIS: a review.

Eighteen percent of all new breast cancers detected on screening mammography are ductal carcinoma in situ (DCIS), a preinvasive lesion that is highly curable. However, some women with DCIS will develop life-threatening invasive breast cancer. Because the determinants of invasive recurrence are unknown, all women with DCIS require the same treatment (usually with surgery and radiation). Therefore, there is a need to identify biologic markers and create a profile that will provide prognostic information that is more accurate than the currently used van Nuys Index to predict invasive recurrence. In the present review, we examined the many biologic markers studied in breast cancer, describe their main biologic role and their expression in DCIS, and review the various studies regarding their ability to serve as prognostic factors in breast cancer with an emphasis on predicting invasive recurrence in patients with DCIS. This review covers established markers, namely, ER, PR and HER2/neu, that are used routinely to make treatment decisions as well as investigative biologic factors involved in cell proliferation, cell cycle regulation, extracellular molecules, factors involved in extracellular matrix degradation, and angiogenesis. However, controversies exist regarding the value of these prognostic factors, their interrelationship, and their advantages over morphologic evaluation.

Significance of Multifocality in Ductal Carcinoma In Situ: Outcomes of Women Treated With Breast-Conserving Therapy

PURPOSE There is concern that women with multifocal ductal carcinoma in situ (DCIS; confined to one quadrant) who are treated with breast-conserving surgery face a high risk of local recurrence; therefore, many are treated with mastectomy. The objective of this study is to evaluate the significance of multifocality and the outcomes of women with multifocal DCIS treated with breast-conserving therapy. METHODS The records of patients treated with breast-conserving surgery for DCIS between 1982 and 2000 were reviewed. Multivariate analyses were performed to evaluate the effects of multifocality and other prognostic factors on the rate of local recurrence. RESULTS Of 615 cases of DCIS reviewed, 310 (41%) received breast-conserving surgery and 305 (40%) received breast-conserving surgery plus radiation (n = 260 with multifocality, n = 314 without multifocality, and n = 31 focality unreported). On multivariate analysis, multifocality (hazard ratio [HR] = 1.80; 95% CI, 1.15 to 2.80; P = .01), radiation treatment (HR = 0.46; 95% CI, 0.29 to 0.74; P = .001), margin width 4 mm or smaller (HR = 1.74; 95% CI, 1.03 to 2.92; P = .04), and high nuclear grade (HR = 1.65; 95% CI, 1.02 to 2.65; P = .04) were associated with risk of local recurrence. The detrimental effect of multifocality was limited to women who did not receive radiotherapy; the local recurrence-free survival rate at 10 years was 59% for women with multifocal disease and 80% for women without multifocality (P = .02). Among women treated with breast-conserving surgery plus radiation, there was no difference in 10-year local recurrence-free survival (80% v 87%; P = .35). There was no association between multifocality and the development of invasive recurrence. CONCLUSION Multifocality is a significant predictor of local recurrence in women who receive breast-conserving surgery for DCIS without radiotherapy; however, low recurrence rates can be achieved if adjuvant radiation is administered.

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.