Neal S. Goldstein

Lymph node recoveries from 2427 pT3 colorectal resection specimens spanning 45 years: Recommendations for a minimum number of recovered lymph nodes based on predictive probabilities

This study investigates the relationship between the number of recovered lymph nodes and lymph node metastases in colorectal resection specimens. All of the slides from 2427 pT3 colorectal resection specimens from patients operated on at William Beaumont Hospital during the 45 years from 1955 through 2000 were reviewed. Lymph node metastases were present in 333 of 1499 (22.2%) specimens with fewer than 15 recovered lymph nodes, compared with 789 of 928 (85.0%) specimens with 15 or greater recovered lymph nodes (p <0.01). The proportion of lymph node metastases increased as a function of the number of recovered lymph nodes (p <0.01). Similarly, in patients without lymph node metastases, survival increased as a function of the number of recovered lymph nodes. Among these patients, the 5-year overall survival rate was 62.2% among patients with seven or fewer recovered lymph nodes and 75.8% among patients with 18 or more recovered lymph nodes (p = 0.018). Statistical analysis found the predictive probability of identifying the single lymph node metastasis in a theoretical specimen with a single lymph node metastasis is 0.25 if 12 lymph nodes are recovered and 0.46 if 18 lymph nodes are recovered. The predictive probability increased as the number of recovered lymph nodes increased, suggesting there is no minimum number that reliably or accurately stages all patients. Thus, all palpable lymph nodes should be recovered, including those that are 1 or 2 mm.

Hyperplastic-like colon polyps that preceded microsatellite-unstable adenocarcinomas.

We compared hyperplastic-like polyps that preceded microsatellite-unstable adenocarcinomas to incidental hyperplastic polyps to identify distinguishing morphologic criteria. The study group included 106 hyperplastic-like, nonadenomatous, serrated polyps, most from the ascending colon in 91 patients; the control group included 106 rectosigmoid hyperplastic polyps from 106 patients in whom adenocarcinoma did not develop. Study group polyps had an expanded crypt proliferative zone, a serrated architectural outline that became apparent in the basilar crypt regions, basilar crypt dilation, inverted crypts, and a predominance of dysmaturational crypts (crypts with minimal cell maturation). In contrast, control group polyps had a proliferative zone confined to the basal crypt region, serrated architecture that became apparent in the superficial crypt region, rare to no basilar crypt dilation, and rare or no dysmaturational crypts. Hyperplastic-like polyps that preceded microsatellite-unstable adenocarcinomas had a distinctive constellation of morphologic features related to altered and decreased cell function and control that resulted in dysmaturational crypts. Dysmaturation constitutes a range of morphologic alterations, some of which overlap with incidental-type innocuous hyperplastic polyps. The morphologic features described herein provide initial guidelines to identify this potentially important subset of premalignant serrated-like polyps.

Accelerated Treatment of Breast Cancer

PURPOSE Radiation therapy (RT) restricted to the tumor bed, by means of an interstitial implant, and lasting 4 to 5 days after lumpectomy was prospectively evaluated in early-stage breast cancer patients treated with breast-conserving therapy (BCT). The goals of the study were to determine whether treatment time can be reduced and whether elective treatment of the entire breast is necessary. MATERIALS AND METHODS Between January 1993 and January 2000, 174 cases of early-stage breast cancer were managed with lumpectomy followed by RT restricted to the tumor bed using an interstitial implant. Each brachytherapy patient was matched with one external-beam RT (ERT) patient derived from a reference group of 1,388 patients treated with standard BCT. Patients were matched for age, tumor size, histology, margins of excision, absence of an extensive intraductal component, nodal status, estrogen receptor status, and tamoxifen use. Median follow-up for both the ERT and brachytherapy groups was 36 months. RESULTS No statistically significant differences were noted in the 5-year actuarial rates of ipsilateral breast treatment failure or locoregional failure between ERT and brachytherapy patients (1% v 0%, P =.31 and 2% v 1%, P =.63, respectively). In addition, there were no statistically significant differences noted in rates of distant metastasis (6% v 3%, P =.24), disease-free survival (87% v 91%, P =.55), overall survival (90% v 93%, P =.66), or cause-specific survival (97% v 99%, P =.28). CONCLUSION Accelerated treatment of breast cancer using an interstitial implant to deliver radiation to the tumor bed alone over 4 to 5 days seems to produce 5-year results equivalent to those achieved with conventional ERT. Extended follow-up will be required to determine the long-term efficacy of this treatment approach.

Ongoing clinical experience utilizing 3D conformal external beam radiotherapy to deliver partial-breast irradiation in patients with early-stage breast cancer treated with breast-conserving therapy ☆

PURPOSE We present our ongoing clinical experience utilizing 3D conformal radiation therapy (3D-CRT) to deliver partial-breast irradiation (PBI) in patients with early-stage breast cancer treated with breast-conserving therapy. MATERIALS AND METHODS Thirty-one patients referred for postoperative radiation therapy after lumpectomy were treated with PBI using our previously reported 3D-CRT technique. Ninety-four percent of patients had surgical clips outlining the lumpectomy cavity (mean: 6 clips). The clinical target volume (CTV) consisted of the lumpectomy cavity plus a 10-mm margin in 9 patients and 15-mm margin in 22 (median: 15 mm). The planning target volume consisted of the CTV plus a 10-mm margin for breathing motion and treatment setup uncertainties. The prescribed dose (PD) was 34 or 38.5 Gy (6 patients and 25 patients, respectively) in 10 fractions b.i.d. separated by 6 h and delivered in 5 consecutive days. Patients were treated in the supine position with 3-5 beams (mean: 4) designed to irradiate the CTV with <10% inhomogeneity and a comparable or lower dose to the heart, lung, and contralateral breast compared with standard whole-breast tangents. The median follow-up duration is 10 months (range: 1-30 months). Four patients have been followed >2 years, 6 >1.5 years, and 5 >1 year. The remaining 16 patients have been followed <12 months. RESULTS No skin changes greater than Grade 1 erythema were noted during treatment. At the initial 4-8-week follow-up visit, 19 patients (61%) experienced Grade 1 toxicity and 3 patients (10%) Grade 2 toxicity. No Grade 3 toxicities were observed. The remaining 9 patients (29%) had no observable radiation effects. Cosmetic results were rated as good/excellent in all evaluable patients at 6 months (n = 3), 12 months (n = 5), 18 months (n = 6), and in the 4 evaluable patients at >2 years after treatment. The mean coverage of the CTV by the 100% isodose line (IDL) was 98% (range: 54-100%, median: 100%) and by the 95% IDL, 100% (range: 99-100%). The mean coverage of the planning target volume by the 95% IDL was 100% (range: 97-100%). The mean percentage of the breast receiving 100% of the PD was 23% (range: 14-39%). The mean percentage of the breast receiving 50% of the PD was 47% (range: 34-60%). CONCLUSIONS Utilizing 3D-CRT to deliver PBI is technically feasible, and acute toxicity to date has been minimal. Additional follow-up will be needed to assess the long-term effects of these larger fraction sizes on normal-tissue sequelae and the impact of this fractionation schedule on treatment efficacy.

Minimum Formalin Fixation Time for Consistent Estrogen Receptor Immunohistochemical Staining of Invasive Breast Carcinoma

To identify the minimum time necessary for consistent immunohistochemical estrogen receptor (ER) results in our laboratory, we evaluated results in timed fixation blocks and cases with disparate and similar needle core biopsy and partial mastectomy specimens. Tissue sections of 24 ER-positive, invasive breast carcinomas were fixed for 3, 6, 8, and 12 hours and 1, 2, and 7 days. ER values were quantified using the Q score (0-7). In timed fixation blocks, the mean Q score per block was 2.46 for blocks fixed for 3 hours, 5.75 for blocks fixed for 6 hours, and 6.70 for blocks fixed for 8 hours (P < .001). The difference between the case maximum and mean block Q scores was a plateau of almost 0 at 6 to 8 hours of formalin fixation. For needle core biopsy specimen fixation times, the means for specimens with ER-disparate and ER-similar results were 1.2 and 6.3 hours, respectively (P = .01). The minimum formalin fixation time for reliable immunohistochemical ER results is 6 to 8 hours in our laboratory, regardless of the type or size of specimen.

Impact of Young Age on Outcome in Patients With Ductal Carcinoma-In-Situ Treated With Breast-Conserving Therapy

PURPOSE We reviewed our institutions experience treating patients with ductal carcinoma-in-situ (DCIS) with breast-conserving therapy (BCT) to determine the impact of patient age on outcome. PATIENTS AND METHODS From 1980 to 1993, 146 patients were treated with BCT for DCIS. All patients underwent excisional biopsy, and 64% underwent re-excision. All patients received whole-breast irradiation to a median dose of 45 Gy. Ninety-four percent of patients received a boost to the tumor bed, for a median total dose of 60.4 Gy. All slides on every patient were reviewed by one pathologist. The median follow-up period was 7.2 years. RESULTS Seventeen patients developed an ipsilateral local recurrence, for 5- and 10-year actuarial rates of 10.2% and 12.4%, respectively. The 10-year rate of ipsilateral failure was 26.1% in patients younger than 45 years of age versus 8.6% in older patients (P =.03). On multivariate analysis, young age was independently associated with recurrence of the index lesion (true recurrence/marginal miss ¿TR/MM failures), regardless of how it was analyzed (eg, < 45 years of age or as a continuous variable). In addition, young patients had a dramatically higher 10-year rate of invasive TR/MM failures (19.9% v 3.2%). In a separate multivariate analysis for the development of invasive TR/MM failures, only patient age and predominant nuclear grade were independently associated with recurrence. The relationship between excision volume and outcome was analyzed in the 95 patients who underwent re-excision. The 5-year actuarial rate of TR/MM failure was significantly worse only in young patients with smaller (< 40 mL) re-excision volumes (33.3% v 9.1%; P =.02). In a separate multivariate analysis of only these 95 patients (25 of whom were < 45 years of age), the volume of re-excision had the strongest association with outcome (P =.05). Patient age was no longer associated with local recurrence. CONCLUSION These findings suggest that young patients with DCIS have a significantly greater risk of local recurrence after BCT that is independent of other previously defined risk factors. Our data also suggest that the extent of resection may in part be related to the less optimal results that are observed in these patients.

Recommendations for improved standardization of immunohistochemistry.

Immunohistochemistry (IHC) continues to suffer from variable consistency, poor reproducibility, quality assurance disparities, and the lack of standardization resulting in poor concordance, validation, and verification. This document lists the recommendations made by the Ad-Hoc Committee on Immunohistochemistry Standardization to address these deficiencies. Contributing factors were established to be underfixation and irregular fixation, use of nonformalin fixatives and ancillary fixation procedures divested from a deep and full understanding of the IHC assay parameters, minimal or absent IHC assay optimization and validation procedures, and lack of a standard system of interpretation and reporting. Definitions and detailed guidelines pertaining to these areas are provided.

Small colonic microsatellite unstable adenocarcinomas and high-grade epithelial dysplasias in sessile serrated adenoma polypectomy specimens: a study of eight cases.

Eight sessile serrated adenoma (SSA), right colon polypectomies with focal invasive adenocarcinoma or high-grade dysplasia were studied to identify features indicating a high risk of transformation and characterize the morphologic features of serrated dysplasia; 6 cases had invasive adenocarcinoma; 2 were high-grade dysplasia. All 8 were microsatellite unstable-high and had absent hMLH1 nuclear immunoreactivity. The mean patient age at polypectomy was 69.5 years (range, 57.1-83.9 years). Mean polyp maximum dimension was 8.5 mm (range, 6-12 mm). The majority of each polyp was nonmalignant SSA. All 8 cases had an abrupt transition from benign to highgrade in situ or invasive malignancy. In the 6 invasive adenocarcinomas, the neoplasm extended directly down into the submucosa without lateral intramucosal spread. The mean maximum dimension of the invasive adenocarcinoma was 2.9 mm (range, 2-4 mm). All 8 cases had high-grade serrated-type dysplasia. The nonmalignant SSAs had marked expansion of the proliferative zone. Crypts adjacent to malignancy had moderately enlarged nuclei, irregular nuclear membranes, and overly prominent nucleoli. SSA crypts were lined by a variety of gastric-type cells; no cell type predominated. Foci of adjacent crypts had similar cytologic features. Small proximal SSAs can transform into adenocarcinoma without a component of adenomatous dysplasia. The serrated neoplasia pathway has its underpinnings in a recently characterized molecular mechanism that eventuates in microsatellite unstable-high (MSI-high) colorectal adenocarcinomas. Kambara et al 1 suggested that some serrated polyps were the precursors in this pathway. Early and late serrated neoplasia pathway lesions have been the focus of studies, and knowledge about these lesions has started to accrue. Midpathway lesions with noninvasive malignancy or small volumes of invasive adenocarcinoma are rare lesions and have not been studied thoroughly. These lesions may provide insight into several current issues that are the subject of active debate. It has been suggested that transformation from serrated pathway precursor to invasive adenocarcinoma can be rapid and occur when the lesions are small; however, evidence supporting these events is scant. 2-4 Morphologic features that portend an increased risk of neoplastic transformation are unknown. This study evaluated 8 serrated neoplasia pathway polyps with incidental high-grade dysplasia or invasive adenocarcinoma to address these issues.

WT1 immunoreactivity in uterine papillary serous carcinomas is different from ovarian serous carcinomas.

WT1 diffusely stains most ovarian serous carcinomas; reactivity of uterine papillary serous carcinomas has not been evaluated. We studied WT1 expression in 13 International Federation of Gynecology and Obstetrics stage 1 and 5 stage 3 or 4 uterine papillary serous carcinomas without ovarian metastases and compared their reactivity with the WT1 staining of 30 ovarian serous carcinomas. WT1 reactivity was evaluated with the C19 and 6F-H2 antibody clones. All 18 uterine papillary serous carcinomas were nonreactive for WT1. The nonovarian metastases of the 5 high-stage uterine papillary serous carcinomas also were nonreactive for WT1. In contrast, 29 (97%) of 30 ovarian serous carcinomas were reactive for WT1. WT1 reactivity in an unknown primary serous carcinoma would suggest it is from a nonuterine site. The mechanisms underlying these findings are unknown. They raise the possibility of genetic differences between the 2 morphologically similar neoplasms.

Mucinous and Nonmucinous Bronchioloalveolar Adenocarcinomas Have Distinct Staining Patterns With Thyroid Transcription Factor and Cytokeratin 20 Antibodies

We studied 14 mucinous and 26 nonmucinous bronchioloalveolar adenocarcinomas (BACs) with thyroid transcription factor (TTF), cytokeratin (CK) 7, CK20, and villin to characterize their staining patterns with these antibodies and identify staining differences between the neoplasms. We also stained 11 mucinous colon adenocarcinomas with the same antibodies to compare their reaction patterns with mucinous BACs. All pulmonary neoplasms were confirmed pulmonary primary BACs. Three (21%) of 14 mucinous neoplasms had weak TTF reactivity in fewer than 25% of neoplastic cell nuclei, and the other 11 (79%) were nonreactive. In contrast, 24 (92%) of 26 nonmucinonus BACs were strongly TTF reactive. Eleven mucinous BACs (79%) had CK20 reactivity in more than 25% of neoplastic cells, whereas only 1 nonmucinous BAC (4%) had reactivity in fewer than 50% of the cells. One mucinous BAC (7%) had villin reactivity in approximately 10% of the neoplastic cells. All mucinous colon adenocarcinomas were diffusely reactive with CK20 and villin. Mucinous and nonmucinous BACs have disparate staining patterns with TTF and CK20. Mucinous BACs are usually TTF nonreactive and CK20 reactive, but nonreactive with villin, which distinguishes them from mucinous colon adenocarcinomas.