Invariant p53 immunostaining in primary and recurrent breast cancer.

In animal models, acquired mutations of the p53 gene that result in increased p53 protein expression are associated with tumour recurrence following chemotherapy. The aim of this study was to test the hypothesis that breast cancer recurrences following adjuvant therapy exhibit aberrant p53 expression. We therefore evaluated p53 expression in paired primary and recurrent breast tumours: 48% of primary and 32% of recurrent tumours had abnormally increased p53 expression. Of the paired samples, 84% showed no change in p53 expression between the primary tumour and the metastasis. In fact, in no case was low (normal) p53 expression in the primary tumour followed by the development of high (aberrant) p53 expression in the recurrence. These results show that increased p53 expression is not selected for in the malignant cells emerging following adjuvant therapy, suggesting that p53 expression is unlikely to play a central role in breast cancer recurrences.

Differential expression of mucin genes in mammary and extramammary Paget's disease.

Paget's disease (PD) of the skin is characterized by intraepidermal adenocarcinoma cells, which contain clear cytoplasm and abundant mucin. Nearly all cases of mammary PD (MPD) are associated with underlying ductal carcinoma of the breast, whereas in the majority of cases of extramammary PD (EMPD) no underlying regional malignancy is identified. Mucins are high molecular weight glycoproteins produced by epithelial cells. Different mucin genes are expressed in various types of tissues such as mammary glands, intestinal mucosa, and adnexal structures of the skin. We studied the immunohistochemical expression of apomucin MUC1, MUC2, MUC5AC in MPD, and EMPD. MUC1 is commonly expressed in most cases of PD. MUC5AC is a unique mucin that is exhibited in the majority of cases of EMPD, but not in any MPD. Of the 13 patients with MPD who all had associated breast ductal carcinoma, both Paget cells and underlying ductal carcinoma exhibited the phenotype (MUC1+MUC2-MUC5AC-). This mucin phenotype is also expressed by Toker cells, which have been identified in the epidermis of five of 50 nipples in mastectomies without MPD. Of the three patients with perianal PD who all had associated rectal adenocarcinoma, Paget's cells expressed MUC2 constantly but expressed MUC1 and MUC5AC variably. Seven patients with intraepidermal vulvar PD and two patients with scrotal-penile PD had no identifiable underlying malignancy. Paget cells from all of these nine cases of EMPD expressed a uniform phenotype of mucin (MUC1+MUC2-MUC5AC+). One case of vulvar PD associated with underlying apocrine carcinoma had a phenotype (MUC1+MUC2-MUC5AC-) identical to that of normal apocrine glands. The skin appendage and Bartholin's glands from 20 normal-appearing vulvar skin samples and anal glands from 10 hemorrhoidectomies were also studied. Only Bartholin's gland expressed a mucin phenotype identical to that of intraepidermal EMPD. The results of the present study indicate that 1) MPD may arise from either mammary glands or epidermal Toker cells, 2) intraepidermal EMPD in the anogenital areas may arise from ectopic MUC5AC+ cells originating from Bartholin's or some other unidentified glands, and 3) unique expression of MUC2 in perianal PD indicates its origin from colorectal mucosa. We conclude that the study of mucin gene expression is useful in identifying the histogenesis of PD.

Human breast cancer susceptibility to paclitaxel therapy is independent of Bcl-2 expression.

In laboratory studies, ectopic overexpression of the antiapoptotic protein Bcl-2 has been shown to result in resistance to the cytotoxic effects of many chemotherapeutic drugs. Furthermore, posttranslational modification of moderately expressed endogenous Bcl-2 has been correlated with susceptibility to paclitaxel treatment in vitro. To determine whether tumor expression of Bcl-2 protein correlates with response and ultimate outcome in vivo, we quantified Bcl-2 expression by immunohistochemical analysis of archived biopsy specimens from metastatic breast cancer patients treated with single-agent paclitaxel. The statistical association between the degree of Bcl-2 expression, objective tumor response, and clinical outcome was then determined. In patients (n = 39) whose tumors had low (< or = 10% cells positive) Bcl-2 levels by immunohistochemical analysis, the overall response (complete response + partial response) rate was 21% versus an overall response rate of 22% in patients (n = 36) with high (>10% cells positive) Bcl-2 expression (P = 0.92). In patients with low Bcl-2 expression, the median time to progression was 126 days [95% confidence interval (CI), 63-160 days]. This was not significantly different than the 105 days for patients with high tumor Bcl-2 expression (95% CI, 84-214 days). The median survival time from initiation of paclitaxel therapy for patients with low Bcl-2 expression was 663 days (95% CI, 456-1119 days) and was not significantly different than the 450 days (95% CI, 239-1058 days) observed for patients with high Bcl-2 expression. In conclusion, we found that in metastatic breast cancer, there is no significant association between tumor Bcl-2 expression and response to paclitaxel, median time to progression, or survival, suggesting that the main mechanism of paclitaxelinduced cytotoxicity in breast tumors is independent of Bcl-2 expression.

The role of cervical lymphadenectomy after aggressive concomitant chemoradiotherapy: the feasibility of selective neck dissection.

OBJECTIVES: To evaluate the necessity, technical feasibility, and complication rate of neck dissection performed on patients with head and neck cancer after 5 cycles of concomitant chemoradiotherapy (CRT) and to justify a selective neck dissection (SND) approach and define the optimal timing of post-CRT neck dissection. DESIGN AND SETTING: Retrospective analysis in an academic university medical center. PATIENTS: Sixty-nine eligible patients with advanced (stage III and IV) head and neck cancer who have undergone 1 of 4 CRT protocols. Patients ranged in age from 36 to 75 years, and surgical procedures were performed over a 4-year period. Follow-up ranged from 6 to 64 months. INTERVENTION: Neck dissection (most commonly unilateral SND) performed within 5 to 17 weeks after CRT completion. MAIN OUTCOME MEASURES: Complication rate and incidence of positive pathology (viable cancer) in pathologic neck dissection specimens. RESULTS: Seven (10%) of 69 patients developed wound healing complications, 4 (6%) of whom required surgical intervention for ultimate closure. There were no wound infections. Other complications occurred in 11 (16%) of 69 patients and included need for tracheotomy, nerve transection and paresis, and permanent hypocalcemia. Twenty-four (35%) of 69 patients revealed microscopic residual disease. Ten (50%) of 20 patients with N3 neck disease had positive pathology, whereas 14 (36%) of 39 patients with N2 disease had viable carcinoma in the dissection specimen (P =.09 by chi(2) analysis). There was no significant relation between radiologic complete response or partial response and residual microscopic cancer. In 1 patient, disease recurred in the neck after dissection. Mean follow-up time was 30.3 months. CONCLUSIONS: (1) Neck dissection for patients with N2 or greater neck disease after CRT is necessary to eradicate residual disease. (2) The complication rate of SND after CRT with hyperfractionated radiotherapy is low. (3) SNDs are technically feasible when performed within the "window" between the acute and chronic CRT injury (4-12 weeks). (4) SNDs, rather than more radical procedures, appear to be therapeutically appropriate in this group of patients because of the low incidence of disease recurrence in the neck.

Fine-needle aspiration of thyroid nodules in radiation-exposed patients.

External radiation used to treat benign conditions in the head and neck area results in an increased risk of thyroid cancer in exposed individuals. Fine-needle aspiration (FNA) biopsy is the standard procedure used to evaluate suspicious thyroid nodules. Its accuracy has been extensively studied, but little is known about FNA in irradiated patients. We analyzed the FNA experience of 136 irradiated subjects. Fifty-two had surgery enabling a comparison of the histologic diagnosis with the FNA results. In these 52 patients with a total of 53 FNAs, 20 were reported as benign, 14 as follicular neoplasms, 6 as papillary cancer, and 13 as inadequate samples. Seven malignant nodules were aspirated; 4 were reported as papillary cancer, 1 was reported as benign and 2 had inadequate specimens. An additional 11 patients had thyroid cancer in foci that were not subjected to FNA. For the nodules that were aspirated, and considering an FNA report of follicular neoplasm as a false-positive when a follicular adenoma or a colloid nodule was found at surgery, the calculated sensitivity was 80%, specificity 54%, positive predictive value 20%, and negative predictive value 95%. Of the 14 follicular neoplasm FNA diagnoses, 10 were colloid nodules (71%), and 4 only were follicular adenomas. We conclude that the sensitivity of FNA in irradiated patients is similar to what is reported for the general population. However, smaller malignant nodules are common and are not diagnosed by the FNA. Also, the FNA diagnosis of follicular neoplasm is often inaccurate and inadequate aspirations are frequent in this patient group.

Bcl-xL and Bcl-2 expression in squamous cell carcinoma of the head and neck.

BACKGROUND: Inhibition of apoptosis, or programmed cell death, may be critical both in the development of cancer and in determining response to therapy. The authors examined the expression of two related apoptotic inhibitors, Bcl-2 and Bcl-xL, in pretreatment biopsies from a series of 42 patients with squamous cell carcinoma of the head and neck. The observed pattern of apoptotic inhibitor expression was compared with that of the p53 gene product, another factor implicated in carcinogenesis and therapeutic responsiveness. METHODS: Formalin fixed, paraffin embedded tumor biopsies from 42 patients with locally advanced squamous cell carcinoma of the head and neck were analyzed by immunohistochemistry using antibodies specific for Bcl-xL, Bcl-2, and p53. Measures of clinical outcome, including disease specific survival and overall survival, were compared among the groups. RESULTS: The majority of the tumors demonstrated enhanced expression of either Bcl-2 or Bcl-xL compared with surrounding normal epithelium. Fifty-two percent of the tumors had up-regulated Bcl-xL, and 17% had up-regulated Bcl-2. There was no overlap between these groups. Expression of Bcl-2, but not Bcl-xL, was correlated with improved disease specific survival. Immunohistochemically detectable p53 expression (48% of tumors) was not found to correlate with expression of either Bcl-xL or Bcl-2 and, in this series, was not a predictor of clinical outcome. CONCLUSIONS: These results suggest that disruption of apoptotic control pathways is an important event in the evolution of squamous cell carcinoma of the head and neck. A common mechanism for this disruption involves overexpression of Bcl-xL, Patients whose tumors demonstrate Bcl-2 positivity, even with locoregionally advanced disease, appear to have a high likelihood of cure with aggressive combined modality therapy and may be treated successfully with less toxic therapy.

Role of CD44 in nonpalpable T1a and T1b breast cancer.

Primary infiltrating ductal carcinomas (IDCs) of the breast which measure less than 0.5 cm (T1a lesions) and between 0.5 and 1.0 cm (T1b lesions) are associated with a small risk of nodal metastasis. The role of axillary dissection in T1a and T1b breast cancer is controversial. In the absence of axillary dissection, comparable prognostic information might be obtained by examination of the primary cancer. The adhesion molecule CD44 represents a family of transmembrane proteins that mediate cell-cell and cell-matrix interactions. Previous investigators have correlated expression of CD44 and its isoforms with prognosis in breast cancer. We investigated the value of CD44 isoform expression as a predictor of nodal metastases in nonpalpable T1a and T1b IDC. Monoclonal antibody against the standard form of CD44 (CD44s) and polyclonal antibody directed against the variant isoform (CD44v6) was tested on 34 cases of nonpalpable node-negative infiltrating ductal carcinoma (IDC) less than 1.0 cm and 9 cases of nonpalpable node-positive IDC less than 1.0 cm. The expression of CD44s was significantly decreased in node-positive T1a and T1b IDC versus node-negative T1a and T1b IDC (11% vs 65%). In contrast, 97% of the node-negative IDC and 100% of the node-positive IDC expressed the CD44v6 isoform. We conclude that CD44s expression is significantly altered in T1a and T1b IDC with nodal metastases but that the CD44v6 isoform does not correlate with nodal metastases in nonpalpable stage T1a and T1b IDC.

Breast cancer metastatic phenotype as predicted by histologic tumor markers.

PURPOSE: Two clinical characteristics of the metastatic cancer phenotype are virulence-which reflects the pace of disease growth, clinical manifestation, and dissemination-and metastagenicity, the ultimate likelihood of distant metastasis. Molecular markers may allow distinguishing between these two cancer phenotypes. The purpose of this study is to determine whether proliferating cell nuclear antigen (PCNA) and tumor nuclear grade are markers of virulence or metastagenicity. PATIENTS AND METHODS: PCNA and tumor nuclear grade were determined in patients with extensive follow-up, treated only with mastectomy, for whom archival paraffin-embedded tissue was available. RESULTS: There is no significant difference in long-term disease-free survival (DFS) as a function of PCNA, but after only 5 years of analysis there are significant differences that gradually disappear with further follow-up, reflecting differences in virulence. While the likelihood of recurrence is the same, in patients with high PCNA 80% of disease recurrences become evident in the first 2 to 3 years, whereas in patients with low PCNA it takes more than 10 years for 80% of metastases to become clinically detectable. There was a significant difference in 20-year DFS for nuclear grade 1 compared with nuclear grade 2 and 3 tumors, indicating a difference in metastagenicity. The differences in DFS between nuclear grade 2 and 3 tumors decrease as the length of follow-up increases; thus, like PCNA, these grade differences are also a marker of virulence. Eighty percent of the metastasis became evident within 4 years in grade 3 tumors and within 12 years in grade 2 tumors. DISCUSSION: PCNA and nuclear grade (2 vs 3) are markers of virulence. We have previously shown angiogenesis to be a marker of metastagenicity as is, in this study, the difference between nuclear grade 1 and nuclear grades 2 and 3. Both phenotypic characteristics, virulence and metastagenicity, are important to understanding the natural history of the tumors and may influence the nature of the therapy.

Overexpression of BCL-x protein in primary breast cancer is associated with high tumor grade and nodal metastases.

PURPOSE: Dysregulation of genes that control apoptosis can contribute to tumor progression and increased drug resistance. The BCL2 gene and its family member BCL-x as well as the TP53 genes regulate apoptosis and have been shown to have a direct effect on the sensitivity of cancer cells to radiation and chemotherapeutic agents. METHODS: The expression of BCL-x, a BCL2-related protein that is a potent inhibitor of apoptosis, was investigated by immunohistochemical and immunoblot methods in 43 primary untreated breast carcinomas, in conjunction with BCL2 and TP53. RESULTS: BCL-x protein was overexpressed in 18 of 42 (43%) invasive breast cancers when compared with adjacent normal breast epithelium. Western blot analysis of eight primary breast cancers and five breast cancer cell lines indicated that BCL-xL was the predominant BCL-x protein expressed. Overexpression of BCL-x protein in these tumors was associated with higher tumor grade and increased number of positive nodes. In contrast, BCL2 protein was overexpressed in 19 of 42 tumors (45%) and was strongly correlated with estrogen receptor positivity, lower tumor grade, smaller tumor size, and lower stage. TP53 protein immunostaining was detected in 12 of 40 tumors (29%) and was inversely correlated with BCL2 expression and ER positivity. There was no correlation between the level of BCL-x protein expression and age, tumor size, ER status, and TP53 status. At a median follow-up time of 216 weeks, there was a trend toward decreased overall survival in patients with tumors overexpressing BCL-x. CONCLUSIONS: These findings suggest that expression of BCL-x protein is increased in a significant fraction of invasive breast cancers. In contrast to BCL2 expression, up-regulation of BCL-x protein may be a marker of tumor progression. Additional data including larger numbers of patients, more uniform treatments, and longer follow-up are needed to define the prognostic significance of overexpression of BCL-x during breast cancer progression.

Thymidylate synthase expression and response to neoadjuvant chemotherapy in patients with advanced head and neck cancer.

BACKGROUND: Thymidylate synthase (TS), an essential enzyme in DNA synthesis, is a target for the fluoropyrimidines, an important group of antineoplastic agents used widely in the treatment of head and neck cancer. PURPOSE: We evaluated relationships between the level and/or pattern of tumor TS expression and response to fluorouracil (5-FU)-based neoadjuvant chemotherapy in patients with advanced head and neck cancer. METHODS: Tumor specimens from 86 patients were available for this retrospective analysis. The patients were enrolled in four consecutive phase II studies that tested combinations of 5-FU, leucovorin, and cisplatin with or without added methotrexate plus piritrexim or interferon alfa-2b (IFN alpha-2b). TS protein expression in the tumors was assessed by use of the TS 106 monoclonal antibody and standard immunohistochemical staining techniques. TS immunostaining was classified according to its level of intensity (TS 0-1 = low, TS 2 = intermediate, and TS 3 = high) and according to its extent (focal pattern = less than 25% of tumor cells positive; diffuse pattern = greater than or equal to 25% of tumor cells positive). Data from 79 patients were available for an analysis of tumor TS expression and patient/tumor characteristics; 70 patients were assessable for their response to neoadjuvant chemotherapy. RESULTS: There was a statistically significant association between the level of tumor TS expression and the degree of tumor differentiation; a higher proportion of patients whose tumors exhibited TS 0-1 immunostaining had undifferentiated or poorly differentiated tumors than patients whose tumors exhibited TS 2 or TS 3 immunostaining (P = .04, Jonckheere-Terpstra trend test). Among the 70 patients who were assessable for response to neoadjuvant chemotherapy, TS 3 tumor immunostaining was associated with a lower rate of complete response (i.e., complete disappearance of clinically detectable disease for a minimum of 4 weeks from time of initial determination) than was TS 2 or TS 0-1 immunostaining, but this association was not statistically significant (P = .09, exact trend test); among the 39 patients who were treated with regimens that included 5-FU, leucovorin, cisplatin, and IFN alpha-2b, this inverse association between TS immunostaining intensity and response was statistically significant (P = .02, exact trend test). Tumor TS immunostaining intensity and overall survival were not found to be associated. Patients with tumors exhibiting a focal pattern of TS immunostaining have experienced significantly longer survival than patients with tumors exhibiting a diffuse pattern; for the 53 patients with diffuse tumor TS immunostaining, the median survival was 24.7 months, whereas the median survival has not yet been reached for the 22 patients with focal tumor TS immunostaining (P = .04, two-tailed logrank test). However, the survival advantage for the focal versus diffuse TS immunostaining pattern was limited to patients whose tumors also exhibited a TS 3 level of immunostaining intensity. CONCLUSIONS AND IMPLICATIONS: Characterization of tumor TS expression may be of value in identifying patients with advanced head and neck cancer who would benefit from fluoropyrimidine-based neoadjuvant chemotherapy.

Angiogenesis as a predictor of long-term survival for patients with node-negative breast cancer.

BACKGROUND: Angiogenesis (the formation of new blood vessels) is necessary for tumor growth and metastasis. PURPOSE: We investigated whether angiogenesis as measured by microvessel count (MVC) predicts clinical outcome in a series of patients with axillary lymph node-negative breast cancer who received no adjuvant therapy and who were followed for a long period of time. Our long-term goal is to identify those patients who may or may not need adjuvant chemotherapy. METHODS: Pathologic archival material and clinical information were analyzed for 167 patients treated with mastectomy from 1941 through 1987; none received adjuvant treatment. The median follow-up time among living patients was 15.4 years (range, 2.6-35.8 years). Ninety-six (58%) patients had a tumor size of 2 cm or less, 52 (31%) had tumors of 2.1-3 cm, and 19 (11%) had tumors of larger than 3 cm. Paraffin-embedded tissue sections were stained for expression of CD34 antigen on microvessel-associated endothelial cells by use of a monoclonal anti-CD34 antibody. Vascularity was defined as the number of microvessels (average of the three highest counts) per high-power microscopic field (400 x magnification) in the area of highest vascular density. A high vascular count was defined as 15 or more microvessels per field. Actuarial survival curves were calculated according to the Kaplan-Meier method and comparisons were made with the logrank test. The Cox proportional hazards model was used for multivariate analysis. All P values were based on two-sided testing. RESULTS: The 20-year disease-free survival (DFS) for the 167 node-negative patients treated with mastectomy and no adjuvant therapy was 74.8% (95% confidence interval [CI] = 64.7%-82.0%). The 20-year DFS was 93.1% (95% CI = 79.9%-97.7%) if the MVC was low versus 68.9% (95% CI = 56.8%-78.0%) if the MVC was high (P = .018). This difference was maintained irrespective of tumor size: for tumor size of 2 cm or less (93.3% [95% CI = 75.3%-98.3%] versus versus 67.8% [95% CI = 50.1%-80.3%]) and for tumor size of larger than 2 cm (92.3% [95% CI = 56.6%-98.9%] versus 70.9% [95% CI = 54.6%-81.6%]). However, the likelihood of a high MVC was greater with large tumors (P = .05). The proportions of tumors with low and high MVC were 33% and 67%, respectively, if the tumor size was 2 cm or less, and 20% and 80%, respectively, if tumor size was larger than 2 cm. There was no significant difference in the 20-year DFS as a function of tumor grade (P = .2). After combining patients with tumors of nuclear grades 2 and 3 compared with those of nuclear grade 1, the 20-year DFS was 93.9% (95% CI = 77.2%-98.4%) for low MVC versus 66.9% (95% CI = 52.2%-78.0%) for high MVC (P = .02). In a multivariate analysis that included the variables tumor size, age, nuclear grade, estrogen receptor status, and MVC, only MVC appeared to be an independent prognostic indicator (P = .04). CONCLUSIONS: Angiogenesis as measured by MVC is a reliable independent prognostic marker of long-term survival in patients with node-negative breast cancer. The prognostic usefulness of this marker is maintained after more than 15 years of follow-up. A low MVC identifies a subgroup of patients with DFS of 92% or more, independent of tumor size or grade.

Breast preservation in stage I and II carcinoma of the breast. The University of Chicago experience.

BACKGROUND: Although breast conservation has received increased acceptance, there are still unresolved issues regarding local treatment techniques, such as the extent of surgery, in relation to the final margins of excision and the use of tumor bed boost radiation. The goal of this study was to determine the local control and breast preservation with particular emphasis on the importance of the final microscopic margins in patients receiving tumor bed boost therapy. METHODS: The authors analyzed 869 cases of Stage I and II breast carcinoma in 852 women who were treated with breast-conserving surgery and radiation therapy between 1984 and 1994. The median follow-up was 43 months. Final microscopic margins were negative in 762 (88%), microscopically positive in 82 (9%), and unknown in 25 (3%) of the patients. Negative margins were defined as no tumor cells at the surgical margin. The patients were treated with external beam radiation therapy to the entire breast to a median dose of 46 Gray (Gy). A boost to the tumor bed was delivered to 863 (99%) of the patients. The median tumor bed dose was 60 Gy. A multivariate analysis of factors impacting on the local control and overall survival was performed. Variables introduced into the model included size, age, lymph node status, microscopic margins, nuclear grade, histologic grade, and estrogen and progesterone receptor status. RESULTS: The actuarial 5-year local control rate was 97%. The median time to local failure was 32 months (range, 14-69 months). In multivariate analysis, the only significant factor affecting local control was the status of margins. In patients receiving boost radiation to the excision site, the local control rate at 5 years was 98% and 89%, respectively, if the margins were negative or positive (P < 0.01). This resulted in 5-year actuarial breast preservation rates of 98% and 92% (P = 0.03). In the patients in whom the margins of excision were microscopically positive, the local control rate was 91% if the total dose to the tumor bed was > 60 Gy compared with 76% for a dose < or = 60 Gy (P = 0.05). The 5-year actuarial overall survival rate was 89%. Approximately 94% of the women considered their cosmetic outcome good to excellent. CONCLUSIONS: By obtaining microscopically negative margins and using tumor bed boost therapy, excellent local control, breast preservation, and cosmesis can be achieved. In patients with microscopically positive margins, an acceptable local control rate can be achieved if a tumor bed boost is given.

Loss of heterozygosity from the short arm of chromosome 8 is associated with invasive behavior in breast cancer.

Loss of heterozygosity (LOH) from the short arm of chromosome 8 (8p) is frequent in many human cancers, including breast, colon, prostate, and bladder cancers. LOH occurs in two regions of 8p, 8p21 and 8p22, and suggests the presence of two separate tumor suppressor genes. In breast cancers, 8p LOH occurs in both early and late clinical stage tumors, while in colon, prostate, and bladder cancers, there is an association between 8p LOH and advanced clinical stage. We investigated this discrepancy by comparing 8p LOH in infiltrating ductal carcinomas (IDC) to breast cancers of earlier clinical stage, i.e., tumors with no invasion [ductal carcinoma in situ (DCIS)-only tumors]. We used three markers which sample several reported loci of 8p LOH. We microdissected tumor from paraffin blocks of 39 IDC and 23 DCIS-only breast cancers and amplified tumor/normal DNA pairs for the microsatellite markers D8S254 (8p22), D8S133 (8p21.3), and NEFL (8p21). All cases of IDC were informative with at least one marker, with a combined rate of LOH of 46%. The results for each marker were [no. LOH/no. informative (%)]: D8S254, 8/26 (31%); D8S133 12/31 (39%), and NEFL, 9/25 (36%). In the DCIS-only group, all 23 were informative for at least one marker, but 8p LOH was absent. We conclude that 8p LOH from 8p21-22 is frequent in IDC of the breast, but absent in DCIS-only cases, and may play a role in breast cancer progression by conferring invasive ability.

Loss of heterozygosity from the short arm of chromosome 8 is an early event in breast cancers.

Loss of heterozygosity (LOH) from the short arm of chromosome 8 (8p) is common to many human carcinomas, including those of the colon and prostate. It localizes to two discrete regions, 8p21 and 8p22. This suggests the presence of at least two tumor suppressor genes (TSGs) on this chromosome arm. Human breast cancers show consistent 8p deletions in cytogenetic studies, chromosome 8 aneusomy and isochromosome 8q, indicating that the relevant gene(s) may play a role, but the results of molecular analyses of chromosome 8 in breast cancer have been variable. We present here data for 8p LOH in an unselected series of human breast cancers with the use of three CA-repeat markers that showed high rates of LOH in other tumors. All cases were informative for at least one marker, and LOH was seen in 11 of 20 cases (55%). LOH was more frequent for the 8p22 markers D8S254 and D8S133 than for NEFL in 8p21. Regional metastases of the tumors showed allele profiles identical to those of their primaries regardless of whether there was LOH or retention of alleles. One case of microsatellite instability (RER+) was seen. LOH did not correlate with receptor status, ploidy, percentage of cells in S phase, or tumor size: We observed LOH at equal rates in small (< 2 cm) and in larger (> 2 cm) tumors. The data suggest that LOH from 8p is frequent in human breast cancers and that loss of the putative 8p TSG may be an important event in early stage breast cancer.

Staging procedures, clinical management, and survival outcome for ovarian carcinoma.

OBJECTIVE: To evaluate the relationship between survival and patterns of clinical management for ovarian carcinoma. DESIGN: Retrospective analysis of cancer registry data including follow-up, operative reports, and pathology reports. SETTING: Seventy-seven Illinois hospitals with active cancer registries. PATIENTS: A total of 2669 women with newly diagnosed ovarian carcinoma from 1983 through 1988. MAIN OUTCOME MEASURES: Frequency of use of specific staging procedures and treatment options. Survival was estimated using the Kaplan-Meier product-limit method. RESULTS: Thirty percent of 632 stage I patients, 31% of 233 stage II patients, and 45% of 516 stage III patients underwent hysterectomy, bilateral salpingo-oophorectomy, omentectomy, sampled peritoneal washings, and node biopsy. Five-year survival for those receiving this extensive surgery (who were therefore pathologically staged) was as follows: stage I, 80%; stage II, 63%; and stage III, 28%. For those not receiving this extensive surgery (who were therefore clinically staged), the 5-year survival at these stages was 76%, 62%, and 21%, respectively. The overall survival curves were not significantly different between those who were pathologically staged and those who were clinically staged for stage I patients (P = .27) or stage II patients (P = .47), but were for stage III patients (P = .01). Platinum-based combination chemotherapy was given to 76% of 221 patients with pathological stage III disease. Their 5-year survival--50% for the group with no residual disease and 20% for the group with residual disease--was better than for those receiving regimens without platinum--37% and 5%, respectively, for the two groups--and the overall survival curves were significantly better for those receiving platinum (P < .0005 for both groups). The groups receiving platinum had younger patients. CONCLUSIONS: Extensive surgery for pathological staging was not usually done for management of ovarian cancer, while platinum-based chemotherapy was commonly used. Failure to undergo extensive surgery had little impact on survival for stage I and II patients. However, use of extensive surgery and platinum-based chemotherapy improved survival for stage III patients. The improved survival for this group receiving platinum-based chemotherapy may be explained in part by selection of younger patients for this treatment.

Treatment and prognosis of orbital non-Hodgkin's lymphomas.

Twenty patients with orbital lymphomas were treated and followed over a 14-year period. Ten of these patients had well-differentiated lymphocytic lymphoma (WDL), and all of them were clinical stage IE. Five patients had nodular poorly differentiated lymphocytic lymphomas (NPDL), three patients had diffuse histiocytic lymphomas (DHL), one had nodular mixed-cell lymphoma, and one had diffused mixed-cell lymphoma. The patients with WDL received local radiation therapy, and all of them entered completed remissions. The projected survival at 10 years was 100% for these patients. The patients with low-grade lymphomas with advanced disease were treated with chlorambucil and prednisone or cytoxan and vincristine. The patients with high-grade lymphomas received treatment with methotrexate, cyclophosphamide, doxorubicin, vincristine, bleomycin, dexamethasone (mBACOD) or cyclophosphamide, vincristine, methotrexate, cytosine arabinoside, leucovorin (COMLA). The overall survival estimate for all patients was 63% at 10 years. The disease-free survival was 49% at 10 years. The patients with high-grade lymphomas had a poor prognosis, with no survivors after 4 years. This study suggests that patients with WDL usually present with localized disease to the involved orbit, and have an excellent prognosis with radiation therapy alone. Patients with high-grade orbital non-Hodgkin's lymphomas have a poor outcome despite use of aggressive combination chemotherapy regimens.