Csaba Gajdos

Lumpectomy margins, reexcision, and local recurrence of breast cancer

BACKGROUND The diagnosis of breast cancer is often made by excisional biopsy without margin assessment for mammographic findings or palpable masses. Many patients treated with breast conservation undergo reexcision to obtain clear margins although the relationship between clear margins and local recurrence remains controversial. METHODS Patients undergoing breast conservation and adjuvant radiation therapy with complete follow-up over 5 years were studied. Factors associated with obtaining clear histopathologic margins and undergoing reexcision to obtain clear margins were studied in relation to the risk of local recurrence. RESULTS Clear biopsy margins were associated with diagnosis by fine-needle aspiration cytology (fine-needle aspiration 42%, spot localization 11%, excisional biopsy 10%; P <0.001). Reexcision was significantly related to diagnostic method (spot localization 63%, excisional biopsy 36%, fine-needle aspiration 10%; P <0.001), first margin status (clear 0%, close 11%, positive 46%, unknown 48%; P <0.001), patient age (54 years for reexcised patients and 58 for non-reexcised patients; P <0.001), and tumor size (mean tumor size 1. 4 cm for reexcised patients and 1.7 cm for non-reexcised patients; P = 0.003). Patients undergoing reexcision were significantly more likely to be diagnosed by spot localization, have nonnegative excisional biopsy margins, be younger, and have smaller tumors than patients not undergoing reexcision. Local recurrence was not significantly related to margin status (8% with clear margins, 7% with positive margins, 19% with close margins, and 11% with unknown margins) or reexcision (10% local recurrence rate for patients with negative final margins after reexcision and 12% with positive, close or unknown first margin without reexcision). Estrogen receptor status was the only variable related to local recurrence in Cox proportional hazards model (P = 0.009). Estrogen receptor negative patients with nonnegative margins experienced a 20% rate of local recurrence compared with 10% for estrogen receptor negative patients with negative margins and 7% for estrogen receptor positive patients regardless of margin status (P = 0.021). CONCLUSIONS Clear excision margins are facilitated by preoperative diagnosis by fine-needle cytology. For patients with nonnegative margins, reexcision was more commonly performed in young patients with small tumors diagnosed by spot localization biopsy. The relationship of local recurrence to margins and reexcision was not statistically significant. Estrogen receptor negative tumors with nonnegative margins had a significantly higher rate of local recurrence than estrogen receptor negative tumors with clear margins and estrogen receptor positive tumors regardless of margin status.

Lymphatic Invasion, Tumor Size, and Age Are Independent Predictors of Axillary Lymph Node Metastases in Women With T1 Breast Cancers

OBJECTIVE To identify characteristics of the primary tumor highly associated with lymph node metastases. SUMMARY BACKGROUND DATA Recent enthusiasm for limiting axillary lymph node dissection (ALND) in women with breast cancer may increase the likelihood that nodal metastases will be missed. Identification of characteristics of primary tumors predictive of lymph node metastases may prompt a more extensive surgical and pathologic search for metastases in patients with negative sentinel lymph nodes or limited ALND. METHODS The authors studied 850 consecutive patients who underwent ALND for T1 breast cancer. Age, tumor size, histopathologic diagnosis, tumor differentiation, presence of lymphatic invasion, and estrogen and progesterone receptor results were studied prospectively. Stepwise logistic regression was used to identify variables independently associated with axillary lymph node metastases. RESULTS Lymphatic invasion, tumor size, and age were independently associated with lymph node metastases. Fifty-one percent of the 181 patients with lymphatic invasion had axillary lymph node metastases, compared with 19% of the 669 patients without lymphatic invasion. Thirty-five percent of the 470 patients with tumors >1 cm had nodal involvement compared with 13% of the 380 patients with smaller cancers. Thirty-seven percent of the 63 women younger than age 40 had lymph node involvement compared with 25% of the 787 women older than age 40. Significant correlations were noted between lymphatic invasion and patient age and between lymphatic invasion and tumor size. The proportion of tumors with lymphatic invasion decreased progressively with increasing age and increased with increasing tumor size. CONCLUSIONS Axillary lymph node metastases are most significantly related to lymphatic invasion in the primary tumor, followed, in order of significance, by tumor size and patient age. Axillary nodal metastases should be suspected in the presence of lymphatic invasion of large tumors in young patients.

Mammographic Appearance of Nonpalpable Breast Cancer Reflects Pathologic Characteristics

ObjectiveTo study the relationship of mammographic appearance of nonpalpable breast cancer to the pathologic characteristics. Summary Background DataThe mammographic appearance of nonpalpable breast cancer may be associated with pathologic variables having prognostic significance, which could influence clinical management. MethodsThe authors correlated the mammographic appearance and pathologic characteristics of 543 nonpalpable malignancies diagnosed in a single institution between July 1993 and July 1999. Cancers were divided into four groups based on mammographic presentation: mass, calcification, mass with calcification, and architectural distortion. ResultsThe majority of masses (95%), masses with calcifications (68%), and architectural distortions (79%) were due to invasive cancers, whereas the majority of calcifications (68%) were due to ductal carcinoma in situ (DCIS). Among invasive cancers, calcifications were associated with more extensive intraductal carcinoma, more Her2/neu immunoreactivity, and more necrosis of DCIS. Lymphatic invasion was more common in cancers presenting as a mass with calcifications. Sixty-nine percent of DCIS associated with invasive cancers presenting as calcifications were of high grade according to the European Organization for Research and Treatment of Cancer. Calcifications in noninvasive tumors were associated with necrosis in DCIS. Two thirds of cancers presenting as architectural distortion had positive margins (65%) compared with 35% to 37% of other mammographic presentations. Mammographic presentation was not significantly related to tumor differentiation or estrogen or progesterone receptor status. The ratio of invasive to noninvasive malignancies increased progressively with increasing age from 1:1 in patients younger than 50 years of age to 3:1 in patients older than 70 years, whereas the proportion presenting as calcifications declined from 63% in patients younger than 50 years to 26% in patients older than 70 years. ConclusionsMalignancies presenting as calcifications on mammography are most commonly DCIS. When invasive malignancies presented as calcifications, the calcifications were associated with accompanying high-grade DCIS, and the invasive cancers were often Her2/Neu positive. Mammographic masses with calcifications were associated with lymphatic invasion. Excisional biopsy margins were most commonly positive with architectural distortions. The mammographic appearance of nonpalpable malignancies is related to pathologic characteristics with prognostic value, which varies with patient age and influences clinical management.

The consequence of undertreating breast cancer in the elderly.

BACKGROUND: Recent studies have noted that a large fraction of elderly patients do not receive conventional treatment for breast cancer. The consequences of undertreatment of the elderly have not been adequately assessed. STUDY DESIGN: The senior author’s database (PIT) was used to identify women undergoing potentially curative operations for breast cancer between 1978 and 1998. Risk factors, presentation, pathologic findings, treatment, and outcomes of 206 women aged over 70 years were compared with those of 920 younger patients. In addition, conventionally treated and “undertreated” elderly patients were identified, and their characteristics and outcomes were compared. RESULTS: Older patients’ cancers were more often visible on mammography, usually as a mass; younger patients’ mammograms were less frequently positive, presenting more often with calcifications (p = 0.002). Cancers of the elderly were better differentiated (p < 0.001) and more likely to be estrogen- and progesterone-receptor positive (p < 0.001; p = 0.007). Patients over 70 had fewer mastectomies (19% versus 33%; p < 0.001) and were also less likely to undergo axillary node dissection (71% versus 81%, p = 0.006), postoperative radiation (69% versus 92%, p < 0.001), and chemotherapy (18% versus 48%, p < 0.001). Fifty-seven percent of older patients were treated with tamoxifen compared with 36% of younger patients (p < 0.001). Elderly patients’ rates of local and distant recurrence were comparable to those of younger patients after both mastectomy and breast conservation. Ninety-eight patients (54%) over 70 were undertreated by conventional criteria. Undertreated elderly patients were significantly older (78 versus 76 years, p = 0.003), were diagnosed with excisional biopsy more often (69% versus 57%, p = 0.069) and with fine-needle aspiration less frequently (22% versus 38%, p = 0.069), and were more likely to have breast conservation (90% versus 73%, p = 0.004). Local and distant disease-free survival rates of both groups were comparable. Tamoxifen treatment significantly reduced the chance of developing distant metastasis in node-negative elderly patients with invasive tumors (p = 0.028). Omission of chemotherapy had no impact on disease control in the elderly. Axillary node status and estrogen-receptor status were significantly related to local disease-free survival, and axillary node status was significantly related to distant disease-free survival in multivariate analysis in the elderly. CONCLUSIONS: Elderly breast cancer patients are frequently treated with breast conservation, omitting axillary dissection, radiation therapy, and chemotherapy. Despite undertreatment by conventional criteria, the rates of local recurrence and distant metastasis are not increased in comparison with conventionally treated elderly patients. Tamoxifen should be administered to elderly breast cancer patients with invasive tumors because it significantly improves distant control.

Slower walking speed forecasts increased postoperative morbidity and 1-year mortality across surgical specialties.

Objective: The purpose of this study was to determine the relationship between the Timed Up and Go test and postoperative morbidity and 1-year mortality, and to compare the Timed Up and Go to the standard-of-care surgical risk calculators for prediction of postoperative complications. Methods: In this prospective cohort study, patients 65 years and older undergoing elective colorectal and cardiac operations with a minimum of 1-year follow-up were included. The Timed Up and Go test was performed preoperatively. This timed test starts with the subject standing from a chair, walking 10 feet, returning to the chair, and ends after the subject sits. Timed Up and Go results were grouped as fast ⩽ 10 seconds, intermediate = 11–14 seconds, and slow ≥ 15 seconds. Receiver operating characteristic curves were used to compare the 3 Timed Up and Go groups to current standard-of-care surgical risk calculators at forecasting postoperative complications. Results: This study included 272 subjects (mean age of 74 ± 6 years). Slower Timed Up and Go was associated with increased postoperative complications after colorectal (fast 13%, intermediate 29%, and slow 77%; P < 0.001) and cardiac (fast 11%, intermediate 26%, and slow 52%; P < 0.001) operations. Slower Timed Up and Go was associated with increased 1-year mortality following both colorectal (fast 3%, intermediate 10%, and slow 31%; P = 0.006) and cardiac (fast 2%, intermediate 3%, and slow 12%; P = 0.039) operations. Receiver operating characteristic area under curve of the Timed Up and Go and the risk calculators for the colorectal group was 0.775 (95% CI: 0.670–0.880) and 0.554 (95% CI: 0.499–0.609), and for the cardiac group was 0.684 (95% CI: 0.603–0.766) and 0.552 (95% CI: 0.477–0.626). Conclusions: Slower Timed Up and Go forecasted increased postoperative complications and 1-year mortality across surgical specialties. Regardless of operation performed, the Timed Up and Go compared favorably to the more complex risk calculators at forecasting postoperative complications.

Is There a Benefit to Sentinel Lymph Node Biopsy in Patients With T4 Melanoma

Controversy exists as to whether patients with thick (Breslow depth >4 mm), clinically lymph node‐negative melanoma require sentinel lymph node (SLN) biopsy. The authors examined the impact of SLN biopsy on prognosis and outcome in this patient population.

Long-term Follow-up and Survival of Patients Following a Recurrence of Melanoma After a Negative Sentinel Lymph Node Biopsy Result

OBJECTIVE To analyze the predictors and patterns of recurrence of melanoma in patients with a negative sentinel lymph node biopsy result. DESIGN Retrospective chart review of a prospectively created database of patients with cutaneous melanoma. SETTING Tertiary university hospital. PATIENTS A total of 515 patients with melanoma underwent a sentinel lymph node biopsy without evidence of metastatic disease between 1996 and 2008. MAIN OUTCOME MEASURES Time to recurrence and overall survival. RESULTS Of 515 patients, 83 (16%) had a recurrence of melanoma at a median of 23 months during a median follow-up of 61 months (range, 1-154 months). Of these 83 patients, 21 had melanoma that metastasized in the studied nodal basin for an in-basin false-negative rate of 4.0%. Patients with recurrence had deeper primary lesions (mean thickness, 2.7 vs 1.8 mm; P < .01) that were more likely to be ulcerated (32.5% vs 13.5%; P < .001) than those without recurrence. The primary melanoma of patients with recurrence was more likely to be located in the head and neck region compared with all other locations combined (31.8% vs 11.7%; P < .001). Median survival following a recurrence was 21 months (range, 1-106 months). Favorable characteristics associated with lower risk of recurrence included younger age at diagnosis (mean, 49 vs 57 years) and female sex (9% vs 21% for males; P < .001). CONCLUSION Overall, recurrence of melanoma (16%) after a negative sentinel lymph node biopsy result was similar to that in previously reported studies with an in-basin false-negative rate of 4.0%. Lesions of the head and neck, the presence of ulceration, increasing Breslow thickness, older age, and male sex are associated with increased risk of recurrence, despite a negative sentinel lymph node biopsy result.

Reversal of tamoxifen resistant breast cancer by low dose estrogen therapy

Currently, the standard of care for estrogen receptor (ER)-positive breast cancer is 5 years of tamoxifen (TAM) or an aromatase inhibitor (AI) such as anastrozole. New studies indicate that extending antiestrogen therapy beyond 5 years with sequential regimens will improve disease-free survival. Based on the emerging concept that longer therapies are better, we have developed sequential models of tamoxifen-resistant breast cancer in vivo to mimic the clinical scenario of long-term antiestrogen therapy. The goal of the current study was to investigate the consequences of long-term treatment with tamoxifen on the growth of breast tumors in athymic mice. The results demonstrate that there are distinct phases of resistance to tamoxifen that correlate with time of treatment and expression of HER2/neu mRNA. In the treatment phase, 17beta-estradiol (E2) stimulated growth, while TAM inhibited growth of MCF-7 tumors (MCF-7E2). The withdrawal of treatment, mimicking the use of an AI, completely prevented growth. In Phase I resistance, the tumors (MCF-7TAMST) were growth-stimulated by either E2 or TAM, but inhibited by no treatment, fulvestrant, or E2 + fulvestrant. Phase II-resistant tumors (MCF-7TAMLT) were treated for more than 5 years and growth-stimulated by TAM. However, no treatment, fulvestrant, or E2 completely inhibited growth. Interestingly, the few tumors (MCF-7TAMLT) that survived in response to E2 were robustly re-stimulated by E2 after transplantation into new generations of athymic mice. These E2-stimulated tumors (MCF-7TAME) were inhibited by TAM in a dose-dependent similar to their parental tumors (MCF-7E2). In addition, the MCF-7TAME tumors were inhibited by either no treatment or fulvestrant. HER2/neu and HER3 mRNAs were over-expressed in TAM-stimulated MCF-7TAMLT tumors and remained high in E2-stimulated MCF-7TAME tumors. The data indicate that complete reversal of resistance to TAM can be achieved with the use of low dose E2 therapy. Also, these data suggest that over-expression of HER2/neu alone is insufficient to predict resistance to TAM. Based on the results, we suggest using an alternating treatment regimen, cycling antiestrogen with estrogen therapy to avoid drug-resistance.

Characteristics of 10-Year Survivors of Pancreatic Ductal Adenocarcinoma

IMPORTANCE To our knowledge, this study reports on the largest cohort of long-term survivors (LTSs) (≥10 years) following a diagnosis of pancreatic ductal adenocarcinoma (PADC) and identifies the characteristics associated with LTS. OBJECTIVE To determine patient, tumor, surgical, and sociodemographic characteristics associated with LTS. DESIGN, SETTING, AND PARTICIPANTS A nationwide retrospective cohort study of patients with invasive PADC (International Classification of Diseases for Oncology, Third Edition codes 8140/3, 8500/3, 8021/3, and 8035/3) was conducted using data collected in the National Cancer Database (NCDB). A multivariable logistic regression model of factors significantly associated with LTS was developed and used to generate a nomogram predicting the likelihood of surviving at least 10 years from initial diagnosis. Data collected from more than 1500 academic centers and community hospitals in the United States and Puerto Rico were assessed. Patients included were those with histologically proven PADC who underwent pancreatic surgical resection aimed at removal of the primary tumor between January 1, 1998, and December 31, 2002 (n = 11,917). The initial cohort (n = 70,915) excluded noninvasive tumors or tumors with unknown histology (n = 11,696) and was limited to patients who underwent surgical resection (n = 47,302 excluded). Analysis was conducted from January 1, 1998, to December 31, 2011. EXPOSURES Pancreatic ductal adenocarcinoma. MAIN OUTCOMES AND MEASURES Long-term survival, defined as surviving at least 10 years from initial diagnosis. RESULTS Of the 11,081 patients with complete survival information, 431 individuals (3.9%) were LTSs. Significant predictors of LTS included (determined using odds ratio [OR]; 95% CI), in order of importance, lymph node positivity ratio (0%: 4.6; 3.4-6.4), adjuvant chemotherapy (2.4; 2.0-3.0), pathologic T stage (T1: 3.1; 1.8-5.6), patient age (50-60 years: 3.4; 1.8-6.7), tumor grade (well differentiated: 2.2; 1.5-3.0), surgical margin (negative: 1.9; 1.4-2.6), pathologic M stage (M = X: 5.6; 2.1-22.8), tumor size (<2 cm: 1.7; 1.2-2.5), educational level (>86% high school graduates: 1.7; 1.2-2.4), and insurance status according to the patients zip code (private: 2.0; 95% CI, 0.9-5.1). The model C index was 0.768. Based on our nomogram, patients with the most favorable characteristics had an 18.1% chance of LTS. Furthermore, survival curves demonstrated that the probability of dying following initial diagnosis of PADC reached a plateau of approximately 10% per year after 7 years of survival. CONCLUSIONS AND RELEVANCE Although PADC remains a deadly disease, long-term survival is possible, even beyond the 10-year mark. Our adjusted analysis identified lymph node ratio, administration of adjuvant chemotherapy, and pathologic T stage as being the top 3 variables associated with LTS of PADC. In addition, our easy-to-use nomogram may be able to identify potential LTS among patients with resected PADC.

Subareolar breast cancers

BACKGROUND Despite the high rate of pathologic involvement of the nipple-areola complex (NAC) with subareolar cancers and the suboptimal cosmetic results when lumpectomy removes the NAC, breast conservation surgery has been extended to include these patients. METHODS Ninety-five patients with subareolar cancers operated on between 1979 and 1998 were identified and the relationships between the pathologic findings, treatment, and outcome were studied. RESULTS Clinical involvement of the NAC (P = 0.001), clinical presentation (P <0.001, mammographic calcium or Pagets disease), and pathologic tumor size (P = 0.019) were significantly related to pathologic involvement of the NAC in univariate analysis. After consideration for clinical NAC involvement, no other variable was significantly related to pathologic NAC involvement in multivariate analysis. Thirty-three patients underwent mastectomy, and 62 were treated with breast conservation. Radiation therapy (P = 0.005), clinical (P = 0.031), and pathologic (P = 0.037) involvement of the NAC were significantly related to local disease-free survival in breast conservation patients in univariate analysis. After consideration for radiation therapy in multivariate analysis, clinical involvement of the NAC was the only additional variable significantly related to local recurrence in breast conservation patients. Clinical or pathologic involvement of the NAC was not significantly associated with local and distant recurrence after mastectomy. No other variable was significantly related to local outcome in univariate analysis in patients treated with mastectomy. CONCLUSIONS Subareolar cancers can be successfully treated with breast conservation surgery provided adjuvant radiation therapy is always given. Clinical involvement of the nipple-areola complex is associated with high risk of local failure when treated with breast conservation without radiation therapy.