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Needle tract displacement is a recognized mimicker of invasive ductal carcinoma (IDC). Artifactual displacement of ductal carcinoma in situ (ADDCIS) unassociated with needle tracts may occur secondary to mechanical compression of breast specimens but has not been systematically studied. We identified 16 cases of ADDCIS unassociated with needle tract changes; the majority (75%) were internal referrals to the breast pathology service to rule out IDC, 19% were received as external diagnostic consultations to rule out IDC, and 6% were routine second review cases originally diagnosed as IDC at an outside hospital. The majority (62.5%) of ADDCIS occurred in lumpectomies, whereas 25% occurred in mastectomies and 12.5% in core biopsies. ADDCIS foci ranged from1 to 5 mm; however, all ADDCIS spanning4 mm demonstrated a linear pattern of displacement. In all cases, ADDCIS involved mammary stroma in a nonlobular distribution; in half, ADDCIS extended between benign lobules. Immunohistochemistry revealed no myoepithelial cells around the ADDCIS (n=7), adding to the concern for IDC. However, in contrast to most IDC, ADDCIS lacked stromal reaction and showed degenerative, smudged chromatin. None of the 9 patients with significant follow-up (mean, 7 y) developed metastasis. All received further local therapy for DCIS (5 radiation, 4 completion mastectomy); 1 received adjuvant systemic therapy (hormone therapy for contralateral IDC). In conclusion, ADDCIS mimics IDC, particularly given its permeative pattern and absence of myoepithelial cells. ADDCIS is most common in lumpectomies but can occur in mastectomies or core biopsies. Diagnostic clues include smudged nuclear chromatin, lack of stromal response, and linear pattern of displacement in larger lesions. The benign follow-up without systemic therapy supports our view that ADDCIS does not represent true IDC.

Aims Breast sarcomas are rare, usually occurring in the setting of malignant phyllodes tumour (MPT). Heterologous differentiation commonly resembles well-differentiated or pleomorphic liposarcoma. In extramammary sites, these subtypes have different biological behaviours and distinct genetic alterations: MDM2 and CDK4 amplification in well-differentiated liposarcoma, and polyploidy with complex structural rearrangements in pleomorphic liposarcoma. The aim of this study was to investigate foci resembling well-differentiated liposarcoma in MPT for MDM2 and CDK4 amplification. Methods and results We evaluated the clinicopathological characteristics of MPTs received by the Vanderbilt Breast Consultation Service containing components resembling well-differentiated or pleomorphic liposarcoma. Cases with available tissue blocks were subjected to fluorescence in-situ hybridization with MDM2 and CDK4 probes. Thirty-eight MPTs with liposarcomatous components were available for review. The mean patient age was 49.8 years (range 26–84 years). In addition to well-differentiated liposarcoma, the following components were also present: high-grade undifferentiated sarcoma (n = 9; 23.7%), pleomorphic liposarcoma (n = 4; 10.5%), non-high-grade sarcoma not otherwise specified (n = 22; 57.9%), and malignant peripheral nerve sheath tumour-like (n = 2; 5.2%). Among 10 cases tested, none showed amplification of MDM2 or CDK4. Conclusions This study examined molecular changes in the well-differentiated liposarcomatous components of MPT. Despite histological similarity to well-differentiated liposarcoma of soft tissues, liposarcomatous differentiation in MPT lacks the molecular phenotype characteristic of extramammary well-differentiated liposarcoma.

Aiming to minimize overtreatment of high-risk breast lesions (HRLs), including atypical ductal hyperplasia, and small breast cancers, including ductal carcinoma in situ (DCIS), we investigated a minimally invasive (MI) approach to definitive diagnosis and management of these conditions. In the prospective Intact Percutaneous Excision registry study, women aged 31–86 years had removal of small invasive cancers, DCIS, or HRLs using image-guided 12–20 mm radiofrequency basket capture (MI excision). Second-pass 20 mm basket capture obtained shaved margins in cancer patients. Standard imaging (specimen, breast) and histologic criteria were applied. Patient data were registered in an Institutional Review Board approved, Health Insurance Portability and Accountability Act-compliant registry. Of 282 registered patients, 124 had DCIS (n = 52) or invasive cancer (n = 72) and 160 had HRLs. Among cancer patients, 101 (81%) had clear histologic margins [average lesion size was 11 mm for both invasive cancers (4–20 mm) and DCIS (1.5–20 mm)]; 29 patients had re-excision (six despite clear margins). Among 160 HRLs, two were upgraded to DCIS and had MI excision. Two other HRL patients had subsequent standard surgical excision (no cancer found). For diminutive HRLs, DCIS, and invasive cancers, MI excision can achieve the same procedure goals as standard surgical excision. Because MI excision removes less tissue with small incisions, it may reduce the discomfort and expense associated with standard treatment.

This chapter presents a histopathologic classification of the wide variety of noncancerous lesions identified in the human female breast, stratified into categories that predict breast cancer risk in broad terms. The magnitude of risk in these various groups is based on the following assumption: any change that does not indicate an increased risk of subsequent breast cancer greater than 50% above that for women controlled for similar age and length of time at follow-up is assigned no elevation of risk. Many of these lesions are not associated with cellular proliferation and are designated as nonproliferative. Nonproliferative lesions may result in biopsy or present clinical symptoms without an association of increased risk. Other lesions that maintain an association with subsequent breast cancer risk are defined as proliferative lesions.

Lymph nodes, particularly those draining in major anatomic sites like axilla, pelvis, and neck are potential sites for the occasional presence of ectopic tissue, usually representative of the organ being drained. Owing to the uncertainty surrounding the processes causing such findings, and particularly in the setting of lymph node dissection and sampling for cancer staging, intranodal epithelial inclusions, rare as they may be, might be fertile soil for overdiagnosis of metastatic disease. Intranodal papillary inclusions are particularly problematic and challenging because of their complex architecture that may easily mimic a metastasis. From the files of the Breast Consultation Service, Department of Pathology at the Vanderbilt University Medical Center in Nashville, we identified 6 cases in which histopathologic examination of axillary lymph nodes revealed intranodal papillary inclusions (papillary epithelial proliferations). One case showed atypical ductal hyperplasia, 1 showed low-grade ductal carcinoma in situ, and 1 showed usual ductal hyperplasia. The corresponding breast lesions were papillomas in 5 of 6 cases, 2 of which displayed atypical ductal hyperplasia, whereas 3 showed low-grade ductal carcinoma in situ. One case showed intermediate-grade invasive ductal carcinoma, and the associated intranodal papilloma lacked atypia. Our findings suggest that intranodal papillary proliferations are often, although not exclusively, associated with papillary and noninvasive breast neoplasms, hence highlighting the origin of these intranodal lesions as independent de novo nodal processes rather than metastatic deposits.

Vascular tumors commonly arise in the breast and overlying soft tissue. Although classification as benign or malignant is usually straightforward, some cases present diagnostic difficulty, particularly on core biopsy samples. Benign vascular lesions are well circumscribed and lack endothelial hyperplasia, atypia, and anastomosing vasculature. In contrast, malignant vascular tumors are characterized by complex, anastomosing vascular channels that infiltrate the dermis and/or breast parenchyma. Included within this morphological spectrum are atypical vascular lesions associated with prior radiation therapy. Diagnosis of vascular lesions on core biopsy can be challenging because of sampling issues; thus correlation with clinical and radiologic features is critical to avoid under- or overdiagnosis. Complete characterization of some vascular lesions may be only possible after excision. This chapter covers a multitude of benign and malignant vascular lesions of the breast and discusses their diagnostic features and differential diagnoses.

Although uncommon, breast tumors in the pediatric population and adult men are occasionally the target of core needle biopsies. Breast lesions in children and adolescence are rare and more than 95 % of all breast lesions occurring in this age group are benign. In males of all ages, gynecomastia is the most common cause of a breast mass. Atypical ductal hyperplasia and ductal carcinoma in situ are rarely secondarily discovered during the pathologic evaluation of gynecomastia. In adult males, breast cancer is not an inconsequential cause of morbidity and mortality, often due to delay in diagnosis because of limited awareness of the disease compared to female patients.

BACKGROUND: Columnar cell lesions are frequently associated with atypical ductal hyperplasia, lobular neoplasia, and tubular carcinoma, and have been suggested as a precursor lesion for low-grade carcinomas. However, in long-term follow-up studies, columnar cell lesions are associated with only a slight increase in later breast cancer development. If columnar cell lesions are precursor lesions, one would expect subsequent cancers to develop at the same site as the biopsy and to be preferentially of low grade. The goal of this article is to review the clinical and pathologic features of carcinomas that develop after a diagnosis of columnar cell lesion to try to establish whether these lesions are precursors to low-grade invasive carcinoma. METHODS: The authors reviewed biopsies containing columnar cell lesions, using the criteria of Schnitt and Vincent-Salomon, from 77 women in the Nashville Breast Cohort who developed subsequent breast carcinoma. Clinicopathologic features including laterality, type, and grade of the subsequent cancer were recorded. RESULTS: Breast cancer developed a median of 11 years after initial biopsy. The median age at diagnosis was 60 years. The majority of invasive carcinomas were of no special type and of intermediate grade. Moreover, the carcinomas were as likely to occur in the contralateral breast as in the breast that was originally diagnosed with columnar cell lesion, regardless of columnar cell lesion subtype (P = .48). CONCLUSIONS: Carcinoma subsequent to columnar cell lesions may occur in either breast and tends to show a similar grade and type distribution as sporadic breast cancer. These findings argue against columnar cell lesions being a true precursor for low-grade invasive carcinoma. Cancer 2012. © 2011 American Cancer Society.

The correct diagnosis of proliferations within the mammary terminal duct-lobular unit has paramount prognostic and therapeutic implications. Occasionally, the differential diagnosis of compact florid hyperplasia, atypical ductal hyperplasia, and low-grade ductal carcinoma in situ can be quite challenging, with seeming morphologic overlap. This article presents s conceptual and practical understanding of these processes and their impact on subsequent cancer risk, with the intention of assisting the practicing pathologist render accurate and clinically relevant diagnoses for this frequently encountered set of mammary epithelial lesions.

SummaryAtypical ductal hyperplasia (ADH) as an indicator of increased risk for developing breast cancer is well established. Refinement in its molecular characterisation, especially as it relates to risk, continues to be challenging, largely because of its small and very focal nature. Also a challenge is appropriate management of ADH when present on core biopsy. Additional support for ductal carcinoma in situ (DCIS) as a precursor to invasive cancer, as well as recent molecular characterisation of DCIS are presented. The importance of margin assessment in cases of DCIS and the limited role for sentinel lymph node biopsy in this setting are reviewed.

Purpose: The aim of this study was to determine the safety and pathologic response rates following neoadjuvant paclitaxel and radiation in patients with stage II/III breast cancer and to evaluate the use of sequential biopsies to allow an in vivo assessment of biological markers as potential predictive markers of response to this regimen. Patients and Methods: Patients with high-risk, operable breast cancer were treated with three cycles of paclitaxel 175 mg/m2 every 3 weeks, followed by twice-weekly paclitaxel 30 mg/m2 and concurrent radiation. Core biopsies were obtained at baseline and 24 to 72 hours after the first cycle of paclitaxel. After completing neoadjuvant treatment, patients underwent definitive surgery. The primary end point was pathologic complete response, which is defined as the absence of any invasive cancer at surgery. Potential markers of therapeutic response were evaluated including markers of proliferation, apoptosis, p21, HER2, estrogen receptor, and progesterone receptor status. Results: Of the 38 patients enrolled, 13 (34%) had a pathologic complete response. There was no significant difference in baseline Ki-67 between responders (35%) and nonresponders (28%; P = 0.45). There was also no significant change in Ki-67 following paclitaxel administration. Despite this lack of immunohistologic change in proliferative activity, baseline mitotic index was higher for patients with pathologic complete response over nonresponders (27 versus 10, P = 0.003). Moreover, the increase in mitotic index following paclitaxel administration was associated with pathologic complete response. Conclusions: Neoadjuvant paclitaxel/radiation is effective and well tolerated. Tumor proliferation at baseline and response to chemotherapy as measured by mitotic activity may serve as an important indicator of pathologic response to neoadjuvant paclitaxel/radiation.

Imprint cytology (touch prep) is often used for intraoperative examination of sentinel nodes in breast cancer. This allows axillary lymph node dissection (ALND) to be performed immediately for tumor-positive nodes. We evaluated the accuracy of touch prep examination of sentinel nodes and its role in the surgical treatment of breast cancer. We analyzed 169 breast cancer patients who underwent 170 lymphatic mapping procedures with intraoperative touch prep examination. Results from the touch prep were correlated with histopathology and clinical variables. There were 115 true-negative, 35 true-positive, 15 false-negative, and 5 false-positive results. Touch prep had a sensitivity of 70 per cent and specificity of 96 per cent. Positive predictive value, negative predictive value, and diagnostic accuracy were all 88 per cent. The false-negative rate was 30 per cent and correlated with the size of the nodal metastasis and number of involved nodes, but not other patient factors. Touch prep is useful for the evaluation of sentinel nodes in breast cancer, but it has a lower sensitivity than initially reported, particularly in patients with micrometastases. False positive results occur, although they may be reduced after experience with the technique. We recommend that suspicious findings on touch prep should be confirmed by frozen section and that ALND only be performed for histologically documented metastases. We currently perform touch prep only in patients who are at high risk of nodal metastasis or will undergo mastectomy. This improves operative efficiency and limits the impact of false positive and negative results without dramatically increasing the number of patients who require a second surgical procedure.

We report the use of molecular techniques in the diagnosis of a case of culture-negative necrotizing fasciitis occurring in a 32-year-old female with no significant past medical history and who died within 36 hours of admission. Paraffin-embedded tissue sections from the popliteal fossa region obtained at autopsy showed hemorrhage, necrosis, and mild inflammation by hematoxylin and eosin staining. Tissue gram stain showed numerous gram-positive organisms arranged in clusters. The sequences of the first 500 bp of bacterial 16S rRNA gene amplified from the lesion were identical to a Lancefield group A beta-hemolytic Streptococcus pyogenes. Streptococcal pyrogenic exotoxin A and B superantigen genes were detected and an emm type 1 was determined by polymerase chain reaction and sequencing from the lesion. This confirmed the etiology of the patient's rapid deterioration with multisystem organ failure.

Margin status is an important prognostic factor for local recurrence after partial mastectomy for breast malignancy. Options for intraoperative evaluation of margin status include gross examination of the specimen, frozen section, and “touch preparation” cytology. This study evaluates the accuracy of gross examination without other intraoperative pathological analysis as a method of determining margin status. Records of 254 consecutive patients undergoing partial mastectomy for 255 breast malignancies (199 invasive, 56 DCIS) over 6 years were analyzed retrospectively. All women underwent en bloc excision of the primary lesion with gross examination of margin status by the surgeon and pathologist. All suspicious areas were reexcised, and the specimen was inked, serially sectioned at 2–3 mm intervals and examined with hematoxylin and eosin (H&E) stains. Specimens with tumor

Intracytoplasmic and extracytoplasmic features of secretion, similar to lactational changes, occasionally are seen in the nonparous human breast, usually are lobulocentric, and often have aberrant cytologic and nuclear changes. In these “hypersecretory hyperplasias” (HHs; 38 women) there is bubbly cytoplasm with irregular apical cytoplasmic and/or nuclear protrusions. In a review of 138 HH cases the following additional associated changes were found: nuclear atypia (HHA, 22 women), atypical ductal hyperplasia (ADH-HH, 24 women), and ductal carcinoma in situ (DCIS-HH, 54 women). A diagnosis of DCIS-HH requires involvement of true duct(s) and of several contiguous lobular units, emphasizing the importance of extent and overall size and similar cytology and histologic arrangement of intercellular spaces indicating a homogeneous cell population. Cases of HH regularly are characterized as having adjacent and nearby lobular units with quite diverse cytologic patterns. The major impact of this study is to recognize that HHA may be regarded as having uncertain significance when found alone in the usual presentation in a single unit, but that formally defined ADH and/or DCIS may be locally present.

Micropapillomas/papillomas and complex sclerosing lesions of the breast have been associated with a slightly increased risk for subsequent carcinoma, although benign squamous metaplasia and reactive hypercellular stroma are seen within these lesions. There are few reports of these fibrosclerotic lesions associated with metaplastic tumors. Here we describe a series of metaplastic tumors arising within fibrosclerotic breast lesions. Thirty-three metaplastic tumors associated with fibrosclerotic lesions were selected from a breast pathology consultative practice. Relevant clinical and pathological features were reviewed. Representative sections were evaluated immunohistochemically for expression of cytokeratins, vimentin, and smooth muscle and muscle-specific actins. Both the metaplastic component (spindled and squamous cells) and the glandular elements were graded. The metaplastic tumors arose within papillomas (20 cases), complex sclerosing lesions (7 cases), both papilloma and complex sclerosing lesions (3 cases), and nipple adenoma (3 cases). A majority of the metaplastic tumors showed a dominant spindle cell component with various degrees of atypia, ranging from fibromatosis-like (16 cases) to low-grade (13 cases), intermediate-grade (2 cases), and high-grade (2 cases) fibrosarcoma phenotype. Squamous metaplasia was present in 25 cases, and low-grade glandular elements, in 21 cases. Eleven tumors had a low-grade adenosquamous growth pattern. Ductal carcinoma in situ was present in 7 cases, and invasive mammary carcinoma, in 5 cases. The very low-grade tumors were histologically similar to limited areas of stromal reaction and myofibroblastic proliferation, seen in partially sclerotic micropapillomas/papillomas and complex sclerosing lesions, but usually more cellular. Cytokeratin positivity (13+/13 tested) supports the metaplastic nature of the more plump spindled cells. The spindle cells were also positive for vimentin (8+/8 tested) and smooth muscle (2+/5 tested) and muscle-specific actins (6+/6 tested). Spindle cell metaplastic tumors, from fibromatosis-like to fibrosarcoma, may arise within a variety of fibrosclerotic breast lesions.

Clinical decisions about atypical lobular hyperplasia are based on the belief that later invasive breast-cancer risk is equal in both breasts. We aimed to show laterality and subsequent risk implications of invasive breast cancer in women with atypical lobular hyperplasia.We did a retrospective cohort study of 252 women who had undergone 261 benign surgical biopsies that showed atypical lobular hyperplasia from 1950 to 1985, as part of the Nashville Breast Studies. Primary outcomes were development of invasive breast cancer and laterality of cancer compared with side of the biopsied breast.50 (20%) of 252 women treated by biopsy only developed invasive breast cancer. Relative risk of breast cancer in women with atypical lobular hyperplasia was 3.1 (95% CI 2.3-4.3, p0.0001). Of these 50 women, the breast with invasive cancer was the same breast diagnosed with atypical lobular hyperplasia (ipsilateral) in 34 (68%) and the contralateral breast in 12 (24%). The ratio of ipsilateral/ contralateral cancers for atypical lobular hyperplasia without other atypical lesions was 17/5. For six women with atypical lobular hyperplasia plus atypical ductal hyperplasia, the ratio was 1/1.Invasive carcinoma after atypical lobular hyperplasia is about three times more likely to arise in the breast diagnosed with atypical lobular hyperplasia than in the opposite breast without these initial findings. Our findings suggest a model of premalignancy for atypical lobular hyperplasia intermediate between a local precursor and a generalised risk for both breasts. See Commentary page 96

Opportunities to study the natural history of ductal carcinoma in situ are rare. A few studies of incompletely excised lesions in the premammographic era, retrospectively recognized as ductal carcinoma in situ, have demonstrated a proclivity for local recurrence in the original site. The authors report a follow-up study of 45 women with low-grade ductal carcinoma in situ treated by biopsy only, recognized retrospectively during a larger review of surgical pathology diagnoses and original histological slides for 26 539 consecutive breast biopsies performed at Vanderbilt, Baptist and St Thomas Hospitals in Nashville, TN from 1950 to 1989. Long-term follow-up was previously reported on 28 of these women. Sixteen women (36%) developed invasive breast carcinoma, all in the same breast and quadrant as their incident ductal carcinoma in situ. Eleven invasive breast carcinomas were diagnosed within 10 years of the ductal carcinoma in situ biopsy. Subsequent cases were diagnosed at 12, 23, 25, 29 and 42 years. Seven women, including one who developed invasive breast cancer 29 years after her ductal carcinoma in situ biopsy, developed distant metastasis, resulting in death 1–7 years postdiagnosis of invasive breast carcinoma. The natural history of low-grade ductal carcinoma in situ may extend more than four decades, with invasive breast cancer developing at the same site as the index lesion. This protracted natural history differs markedly from that of patients with high-grade ductal carcinoma in situ or any completely delimited ductal carcinoma in situ excised to negative margins. This study reaffirms the importance of complete margin evaluation in women treated with breast conservation for ductal carcinoma in situ as well as balancing recurrence risk with possible treatment-related morbidity for older women.

The diagnosis of atypical ductal hyperplasia (ADH) at needle core breast biopsy (NCB) is typically regarded as an indication for surgical excision. Although ADH is an intermediate risk nonobligate precursor lesion, the rationale for further therapy is the result of a reported high prevalence of a concomitant more advanced lesion (typically ductal carcinoma in situ) as the index lesion. To assess whether certain histopathologic features of ADH in NCB are predictive of open biopsy outcomes, the authors correlated the extent and pattern of ADH in 47 core biopsies (11-or 14-gauge) with the subsequent surgical specimen. Extent of ADH on NCB was ascertained by determining the number of large ducts and/or terminal duct-lobular units affected, with involvement of one large duct or one terminal duct-lobular unit representing a single focus, involvement of one duct and one terminal duct-lobular unit as two foci, and so on. Of the 47 cases, ADH was restricted toor =2 foci in 24 cases (51.1%), confined to 3 foci in 8 cases (17.0%), and involvedor =4 foci in 15 cases (31.9%). The corresponding histopathologic findings at excision were benign lesions without atypia (n = 14), focal residual ADH (n = 13), atypical lobular hyperplasia (n = 3), ductal carcinoma in situ (n = 15), and invasive mammary carcinoma (n = 2). When the number of foci of involvement by ADH on NCB (based on an average of 11.6 cores per case) was correlated with the open biopsy results, all cases of ADH limited toor =2 foci had no worse lesion on excision, whereas ADH present inor =4 foci was found to be a strong predictor of a more advanced lesion on excision (p0.0001, chi2). When histologic pattern was evaluated, all cases of pure micropapillary ADH on NCB showed pure micropapillary ductal carcinoma in situ on excision.

BACKGROUND. The authors previously showed that women with a fibroadenoma have a relative risk of invasive breast carcinoma of approximately 2.0 compared with women of similar age from the general population. This relative risk approaches 1.0 when family history and proliferative changes in the adjacent parenchyma are removed and rises to > 3.0 if the fibroadenoma has complex histology. The risk for developing breast carcinoma in women with atypical lobular hyperplasia (ALH) and atypical ductal hyperplasia (ADH) or their minimal variants within a fibroadenoma is unknown. METHODS. The authors conducted a long-term, retrospective cohort study of 1834 women with adequate follow-up who presented with fibroadenoma at three local hospitals between 1950 and 1968. Histology was reviewed using established criteria, and the patients were categorized with ALH, ADH, minimal atypia, or no atypia. RESULTS. The overall prevalence of ALH or ADH within fibroadenomas was 0.81%. Minimal or true atypia within a fibroadenoma appeared to be correlated with proliferative disease in the adjacent parenchyma but could not predict for the presence there of well-established atypia. Only 7% of women with well-developed atypia developed invasive carcinoma on follow-up. Three women with minimal atypia developed invasive carcinoma. CONCLUSIONS. In this study of a large cohort of women with fibroadenoma, the authors found that atypia within a fibroadenoma cannot predict for the presence of atypia within adjacent breast parenchyma. They also found that atypia confined to a fibroadenoma does not incur a clinically meaningful risk of future breast carcinoma development greater than that of fibroadenoma alone.

Overexpression of ErbB-2/Neu has been causally associated with mammary epithelial transformation. Here we report that blockade of the epidermal growth factor receptor (EGFR) kinase with AG-1478 markedly delays breast tumor formation in mouse mammary tumor virus (MMTV)/Neu + MMTV/transforming growth factor α bigenic mice. This delay was associated with inhibition of EGFR and Neu signaling, reduction of cyclin-dependent kinase 2 (Cdk2) and mitogen-activated protein kinase (MAPK) activities and cyclin D1, and an increase in the levels of the Cdk inhibitor p27 Kip1 . In addition, BrdUrd incorporation into tumor cell nuclei was prevented with no signs of tumor cell apoptosis. These observations prompted us to investigate the stability of p27. Recombinant p27 was degraded rapidly in vitro by untreated but not by AG-1478-treated tumor lysates. Proteasome depletion of the tumor lysates, addition of the specific MEK1/2 inhibitor U-0126, or a T187A mutation in recombinant p27 all prevented p27 degradation. Cdk2 and MAPK precipitates from untreated tumor lysates phosphorylated recombinant wild-type p27 but not the T187A mutant in vitro . Cdk2 and MAPK precipitates from AG-1478-treated tumors were unable to phosphorylate p27 in vitro . These data suggest that increased signaling by ErbB receptors up-regulates MAPK activity, which, in turn, phosphorylates and destabilizes p27, thus contributing to dysregulated cell cycle progression.

In order to develop immunotherapy strategies that are based on eliciting immune responsiveness to the self-antigen, human carcinoembryonic antigen (CEA), we examined whether cytotoxic T lymphocyte (CTL) activity against CEA could be elicited in CEA-transgenic and nontransgenic mice. CEA-transgenic [C57BL/ 6-TGN(CEAGe)18FJP] and nontransgenic mice were primed with CEA-transfected syngeneic fibroblasts in combination with Corynebacterium parvum. Spleen cells from immunized mice were cultured with irradiated syngeneic MC-38 colon carcinoma cells transfected with CEA (MC-38.CEA) as stimulators prior to the measurement of CTL activity. Primed nontransgenic spleen cells showed augmented CTL activity against MC-38.CEA cells as compared with control parental MC-38 cells, nontransfected or transfected with vector only. Moreover, primed CEA transgenic spleen cells showed augmented CTL activity against MC-38.CEA cells that was similar to that observed in nontransgenic mice. All CTL clones derived from either transgenic or nontransgenic mice showed cross-reactivity with MC-38 cells expressing the CEA-related antigen, nonspecific cross-reacting antigen, but not biliary glycoprotein. CEA-specific CTL clones were not identified. Adoptive transfer of cloned CTL resulted in inhibition of MC-38.CEA but not MC-38.BGP tumor growth. Tumor cures were elicited in mice treated with a combination of cloned CTL and cyclophosphamide. Histopathological examination of CEA-expressing colons from either immunized mice or recipients of cloned CTL did not reveal any autoimmune reactions. These studies demonstrate that CTL recognizing cross-reactive class I epitopes on the CEA molecule can be induced in transgenic mice. The expression of these epitopes on tumor cells creates effective targets for CTL in vivo without inducing adverse reactions in CEA-expressing normal tissues. Since anti-CEA CTL have been generated in humans, CEA-transgenic mice may be a useful model to study vaccines that are based on CTL effector mechanisms.

Background.—Under the auspices of the College of American Pathologists, a multidisciplinary group of clinicians, pathologists, and statisticians considered prognostic and predictive factors in breast cancer and stratified them into categories reflecting the strength of published evidence. Materials and Methods.—Factors were ranked according to previously established College of American Pathologists categorical rankings: category I, factors proven to be of prognostic import and useful in clinical patient management; category II, factors that had been extensively studied biologically and clinically, but whose import remains to be validated in statistically robust studies; and category III, all other factors not sufficiently studied to demonstrate their prognostic value. Factors in categories I and II were considered with respect to variations in methods of analysis, interpretation of findings, reporting of data, and statistical evaluation. For each factor, detailed recommendations for improvement were made. Recommendations were based on the following aims: (1) increasing uniformity and completeness of pathologic evaluation of tumor specimens, (2) enhancing the quality of data collected about existing prognostic factors, and (3) improving patient care. Results and Conclusions.—Factors ranked in category I included TNM staging information, histologic grade, histologic type, mitotic figure counts, and hormone receptor status. Category II factors included c-erbB-2 (Her2-neu), proliferation markers, lymphatic and vascular channel invasion, and p53. Factors in category III included DNA ploidy analysis, microvessel density, epidermal growth factor receptor, transforming growth factor-α, bcl-2, pS2, and cathepsin D. This report constitutes a detailed outline of the findings and recommendations of the consensus conference group, organized according to structural guidelines as defined.

PURPOSE: The identification of a subset of patients with axillary lymph node–positive breast cancer with an improved prognosis would be clinically useful. We report the prognostic importance of histologic grading and proliferative activity in a cohort of patients with axillary lymph node–positive breast cancer and compare these parameters with other established prognostic factors. PATIENTS AND METHODS: This Eastern Cooperative Oncology Group laboratory companion study (E4189) centered on 560 axillary lymph node–positive patients registered onto one of six eligible clinical protocols. Flow cytometric (ploidy and S-phase fraction [SPF]) and histopathologic analyses (Nottingham Combined Histologic Grade and mitotic index) were performed on paraffin-embedded tissue from 368 patients. RESULTS: Disease recurred in 208 patients; in 161 (77%), within the first 5 years. Mitotic index and grade were associated with both ploidy and SPF (P ≤ .01). Within the first 5 years of follow-up, mitotic index (P = .004), grade (P = .004), ploidy (P = .006), and SPF (P = .05) were associated with time to recurrence; there was also a significant association with survival. The effect of mitotic index was largely a result of the difference between 0 to 2 mitoses/10 high-power fields (HPF; 5-year recurrence of 31%) and more than 2 mitoses/10 HPF (5-year recurrence of 52%). The 0 to 2 mitoses/10 HPF group was independently associated with improved prognosis at 5 years (P = .002) in regression models that included other standard prognostic factors. CONCLUSION: A subset of axillary lymph node–positive patients with improved prognosis may be identified using a lower (< 3 mitoses/10 HPF) mitotic count than is usually performed.

Diabetic mastopathy, an uncommon form of lymphocytic mastitis and stromal fibrosis, typically occurs in longstanding type 1 diabetes. Nineteen cases meeting predetermined histopathologic criteria for diabetic mastopathy were correlated as to clinical history and disease recurrence. Physical examination revealed palpable discrete masses or diffuse nodularity, both predominantly in the subareolar region. One nonpalpable lesion was detected incidentally during reduction mammoplasty. All cases contained lymphocytic ductitis and lobulitis with varying degrees of keloidal fibrosis, vasculitis, epithelioid fibroblasts, and lymphoid nodule formation. Single mammary lesions were found in 11 patients with type 1 diabetes, 1 with type 2 diabetes, and 3 without diabetes. Four cases were bilateral (3 patients with type 1 and 1 patient with type 2 diabetes). Six of 19 cases recurred (3 ipsilateral, 2 contralateral, and 1 bilateral). We confirm the histopathologic constellation for diabetic mastopathy. However, we question the specificity of these features because of identical findings in patients with type 2 diabetes and nondiabetic patients. We found diabetic mastopathy in men and women, as a solitary mass or bilateral disease, and recurrence in either breast, sometimes multiple. Recognition of potential recurrence is important because it might spare patients with documented diabetic mastopathy from repeated breast biopsies.

The most important prognostic indicator of distant metastasis in breast cancer is histologic documentation of axillary lymph node metastasis. Controversy exists about the importance of micrometastases (

CAG repeat number in the androgen receptor (AR) has been associated with decreased prostate cancer risk, and AR expression has been found in female breast cancer, often associated with apocrine differentiation. Because trinucleotide expansion can alter gene expression and protein function, we hypothesized that it might occur in breast neoplasms. We used a repeat expansion detection technique to determine CAG repeat lengths in DNA from breast biopsies. Three lesion types were microdissected: fibroadenoma (48 cases), ductal carcinoma in situ (DCIS, 24 cases), and invasive mammary carcinoma (18 cases). The maximum number of CAG repeats in either allele of each patient in these three groups was compared. Microsatellite repeat lengths in DCIS were longer than in fibroadenomas or invasive carcinomas (P= 0.017 comparing DCIS vs invasive carcinomas). Two cases of apocrine DCIS had very long repeat lengths, both exhibiting microsatellite lengths at the longest range of normal (32 and 33). Inherited differences in AR CAG length might influence the transition from DCIS to invasive breast cancer, perhaps by modulating function of AR in breast tissue. AR microsatellite polymorphisms could influence cellular differentiation in DCIS lesions, promoting formation of the apocrine subtype in the presence of longer CAG repeats.

Reactive spindle cell nodules (RSCNs) arising postoperatively or after fine-needle aspiration (FNA) have been reported previously in the genitourinary tract and thyroid. We describe 18 cases of similar lesions in breast, associated with a history of core needle biopsy or FNA. The majority of the RSCNs (15 cases) were associated with papillary lesions or complex sclerosing lesions. The RSCNs were nonencapsulated and relatively nodular, measuring 1.5 to 9 mm. They were composed of spindle cells with mild to moderate nuclear pleomorphism and a low mitotic count. A network of small blood vessels, macrophages, and lymphocytes was present in all cases. Immunohistochemically, the spindle cells expressed smooth and specific muscle actins, supporting a myofibroblastic origin. The association of RSCNs with needle trauma to fibrosclerotic lesions, such as complex sclerosing lesions and papillary lesions that regularly have myofibroblasts, suggests an exuberant reparative cause. Recognition of this reactive process will avoid overdiagnosis of mammary spindle cell malignant neoplasm.

Aims Loss of transforming growth factor beta type II receptor (TGFbeta-RII) expression has been associated with resistance to TGFbeta-mediated inhibition of cell proliferation and tumour progression. We investigated whether the expression of TGFbeta-RII is related to the progression of human breast cancer and whether there is a correlation between TGFbeta-RII expression and phenotypic markers of biological aggressiveness. Methods and results Immunohistochemical methods were used to detect TGFbeta-RII in archival breast samples including benign proliferative lesions, ductal carcinoma in situ (DCIS) and invasive mammary carcinomas (IMC). Neoplastic cells showed reduced expression of TGFbeta-RII in comparison to the normal breast tissue and benign lesions. There was a significant inverse correlation between loss of TGFbeta-RII expression and tumour grade within both DCIS (P = 0.004) and IMC (P = 0.001) groups. There was an inverse correlation between TGFbeta-RII expression and both mitotic count (P = 0.001) and clinical stage (P = 0.004). Oestrogen receptor (P = 0.07) and lymph node status (P = 0.10) were not significantly associated with TGFbeta-RII expression. Conclusions These data indicate that decreased expression of TGFbeta-RII may contribute to breast cancer progression and is related to a more aggressive phenotype in both in-situ and invasive carcinomas.

Premalignant breast disease in humans is a concept that admits to a broad range of elements and possible determinants predicting the likelihood of developing breast cancer. Most of these elements are relative, such as the risk of breast cancer for women that is 130 times that of men and peaks at a younger age by about 10 years. Breast cancer is clearly a stochastic, multifactorial process that evolves over many years in which we must make predictions by likelihood. This review will present the most specially defined and reliably proven of these elements, highlighting anatomic and molecular factors.

BACKGROUND In the current study the authors describe the clinicopathologic characteristics of a low grade variant of spindle cell metaplastic tumors of the breast. Previously these tumors have been considered within a larger group recognized as metaplastic carcinoma, including cases with higher grade features. METHODS Breast tumors comprised predominantly of low grade spindle cells, with sparse low grade epithelial elements, were selected. Clinical features as well as macroscopic, microscopic, and immunohistochemical findings were reviewed with emphasis on the biologic behavior and the differential diagnosis from other spindle cell lesions. RESULTS Of 30 tumors fulfilling strict criteria, 20 contained squamous or glandular elements associated with the spindle cells. Ten tumors were comprised entirely of low grade spindle cells with limited clustered epithelioid cells. At the periphery, all tumors showed a proliferation of bland spindle cells infiltrating the adjacent parenchyma and mimicking fibromatosis. The epithelioid cells and some spindle cells expressed both vimentin and one or more cytokeratins. Seven of eight patients treated by excisional biopsy developed local recurrence, whereas only one of ten patients treated with wide excisional biopsy developed a local recurrence. No distant or regional metastases occurred. CONCLUSIONS The presence of limited clusters of epithelioid cells along with a dominant fibromatosis-like pattern may be unique in the breast. The biologic potential of the fibromatosis-like, spindle cell, metaplastic breast tumors most likely is defined by their major histologic phenotype; they are capable of local recurrence with no demonstrated distant spread or regional metastases, as in pure fibromatosis of the breast. Cancer 1999;85:2170–82. © 1999 American Cancer Society.

Variation in tissue fixation, processing, and staining is largely responsible for poor reproducibility of estrogen receptor (ER) immunohistochemistry assays. A frozen, agar-suspended pellet of MCF-7 cells with known ER content was added to each of 55 samples of invasive breast carcinoma (IBC), serving as a control. Image analysis determined percentages of positive area (positive nuclei per total nuclei analyzed) and positive stain (sum of optical density of the positive nuclear area divided by sum of the optical density of all nuclei studied) of MCF-7 cells and IBC. MCF-7 cells had a mean value of 150 fmol/mg of ER by dextran-coated charcoal analysis. Image analysis of MCF-7 cells included with the 55 cases showed a mean positive area of 70.81. Positive staining from the IBC cases ranged from 0 to 98.5. By using the known ER content and the positive area of the MCF-7 cells, a conversion factor was used to translate the positive area of the clinical specimens to a femtomole equivalent, which for the 55 IBCs ranged from 0 to 1,790 (mean, 187). Inclusion of a control with known femtomole quantity of ER provides an internal standard for quality control and ER quantitation.

Tamoxifen, a nonsteroidal antiestrogen, is the endocrine therapy of choice for all stages of breast cancer. Because tamoxifen is well tolerated and has minimal side effects, it is currently being evaluated in large scale trials as a chemopreventive agent for women at risk for developing breast cancer. The potential adverse effects of tamoxifen, specifically the development of proliferative lesions of the endometrium, coupled with the prospect of its wider use, places new emphasis on recognizing tamoxifen-associated histologic and cytologic changes in the female genital tract. The current study evaluated cervical smears from 52 breast cancer patients treated with tamoxifen compared with 21 smears from breast cancer patients who had not received tamoxifen. Cytologic diagnoses were classified according to the Bethesda system. The presence of blood, inflammation, and hormonal effect were also assessed. No squamous intraepithelial lesions were identified. A total of 21 of 38 smears (55%) from patients receiving tamoxifen alone and 11 of 14 smears (78%) from women who received tamoxifen in combination with adjuvant cytotoxic chemotherapy showed atypias compared with only 6 of the 21 breast cancer patients (28%) who did not have hormonal therapy. The number of smears showing atypia was equally divided into changes interpreted as benign reactive and atypical squamous cells of undetermined significance (ASCUS). Of the 19 patients whose smears were classified as ASCUS, 13 patients had a subsequent cervical biopsy and none showed dysplasia or diagnostic human papilloma virus changes. Tamoxifen therapy was not associated with an increase in the presence of blood or inflammation, and no discernible alteration in the hormonal state was seen in the cervical smears. We conclude that the use of tamoxifen may be associated with benign squamous atypia in cervical smears and that the atypia is not associated with intraepithelial lesions.

BACKGROUND Vascular enumeration using antibodies to Factor VIII has been reported to be an independent prognostic indicator of invasive breast carcinoma. METHODS To eliminate potential subjectivity in distinguishing between individual vessels, especially in areas of tangled capillaries, total endothelial area (EA) was assessed using a Samba 4000 image analyzer. One hundred seventy-eight invasive breast carcinomas (Stage 1 and 2, mean follow-up: 71 months) were immumostained for the presence of CD34, the human hematopoietic progenitor cell antigen also present in endothelium, and EA was quantitated within 5 adjacent 20X fields (0.74 mm2). Additionally, these same vessels were manually counted from the image analyzer. Manual counts were also made from a photomicrograph representative of a single 10X field (1.06 mm2). RESULTS High grade carcinomas contained greater endothelial area than low grade carcinomas (P = 0.0001). Endothelial area was prognostically significant (P = 0.004) in univariate analysis of disease-free survival (DFS) and overall survival (OS), as were stage of disease, tumor size, and combined histologic grade (P < or = 0.024). Manual vessel counts from the monitor were significant for OS only. Manual vessel counts from photomicrographs showed no statistically significant association with DFS or OS. In multivariate analysis, EA, but not vessel enumeration, remained as an independent predictor for OS (lymph node negative patients only, n = 87) and for DFS (lymph node positive patients only, n = 91). For the entire group of patients (lymph node negative and lymph node positive) independent predictors of DFS and OS were tumor grade and size (P < or = 0.006). CONCLUSIONS Of the three methods used to evaluate tumor angiogenesis, total endothelial area, as objectively evaluated by image analysis, was the only independent prognostic indicator for OS for patients with lymph node negative invasive breast carcinoma.

The elucidation of molecular alterations that occur during human breast cancer progression may contribute to the development of preventative strategies. Using in situ hybridizations on a cohort of 94 biopsy lesions, quantitatively increased cyclin D mRNA expression levels were observed in only 18% of benign lesions, which confer no or slightly increased breast cancer risk, and 18% of premalignant atypical ductal hyperplasias, which confer a four to fivefold increase in breast cancer risk. The transition to carcinoma was accompanied by frequent cyclin D mRNA overexpression in 76% of low-grade ductal carcinomas in situ, 87% of higher grade comedo ductal carcinomas in situ and 83% of infiltrating ductal breast carcinomas. The data identify a molecular event that may separate benign and premalignant human breast lesions from any form of breast carcinoma.

The Department of Pathology in an academic center plays a critical role in the life of the institution. In addition to playing an essential role in patient care, we pathologists teach our nonpathology colleagues and serve in a consultative role, thus earning the appellation of “the doctor’s doctor.” Traditionally, pathologists have taught medical students in the preclinical years and in pathology electives; in the current climate of curriculum reform, their role is recognized as crucial to the design of the curriculum.1 Far less structured and often underrecognized is the teaching role that pathologists play in the education of residents and fellows in specialties other than pathology. In this issue of AJCP , Bean et al2 have documented the dependence that other departments in academic centers have on the teaching efforts of pathologists. Specifically, the requirements for accreditation by the Accreditation Council for Graduate Medical Education (ACGME) for …

Background. Expression of carcinoembryonic antigen (CEA) has been reported in 10-95% of breast cancer. Its value as a predictor of disease progression is controversial. Methods. The expression of CEA in 202 Stages I and II breast carcinomas was assessed by immunohistochemistry, and the results were correlated with various histologic and clinical parameters to establish CEA's biologic relevance. The mean follow-up of the patients was 6.5 years. The monoclonal antibody used does not cross-react with other molecules in the CEA gene family. Results. One hundred, thirteen (56%) tumors expressed CEA in more than 15% of the cells. Expression of CEA was associated with positive estrogen receptor (ER) status (P = 0.003). Univariate Cox regression analysis showed that, whereas disease free survival (DFS) and overall survival (OS) were not associated significantly with CEA expression, tumor size, nuclear grade, ER status, lymph node metastases, and stage were. When ER status was stratified to CEA expression, patients who were ER negative and had CEA-negative tumors had a 3.9 times higher risk (P = 0.032) of death than did the patients with CEA-positive tumors. Cox regression analysis revealed that ER was the only parameter with significant interacting effect with CEA. Multivariate, stepwise Cox regression analysis showed that CEA expression, tumor size, and nuclear grade were the only significant independent predictors of DFS, and nuclear grade and lymph node metastasis the only significant predicotrs of OS in the ER-positive group. The only significant independent predictor of DFS and OS in the ER-negative group was CEA. When CEA expression was stratified to ER status, patients whose tumors lacked CEA and ER had threefold higher risk of disease relapse (P = 0.002) and a 5.3-fold higher risk of death (P = 0.0001) than those with ER-positive and CEA-negative tumors. Multivariate analysis showed that the association between CEA and ER was enhanced further after compensating for other parameters with independent predictive value. Conclusions. The association between CEA and ER was the most important independent predictor of a subgroup of patients (CEA-negative, ER-positive) with the most favorable prognosis. The results imply that the association of several tumor markers may provide tumor profiles with superior predictive value than a single parameter.

Background. The two major types of noninvasive breast carcinoma, ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS), are quite different in their histopathologic appearance and clinical implications. LCIS is only a marker of an increased risk of later development of invasive carcinoma, whereas most DCIS lesions are at least nonobligate precursors of invasive carcinoma. DCIS is a heterogeneous group of lesions composed of several distinct subtypes, with only the comedo subtype having immediate malignant potential. The authors' purpose was to analyze noninvasive carcinomas for the presence of a gene product (nm23) indicative of a favorable prognosis in invasive carcinomas to determine differences (1) among the different types of CIS and (2) in CIS with and without an accompanying invasive component. Methods. Immunohistochemical methods were used to detect nm23 gene product in archival material from two groups of patients: Group 1 consisted of 54 cases of purely noninvasive carcinoma, and Group 2 consisted of 55 examples of noninvasive carcinoma associated with an invasive component. Results. Among the cases of CIS with no invasion, LCIS and comedo DCIS expressed more nm23 than non-comedo DCIS (P ⩽ 0.03). There were no differences among these CIS subtypes in the group with invasion. Comparing subtypes of CIS in the groups with or without invasion, only comedo DCIS was significantly different, with greater expression in the CIS group with no invasion compared with comedo DCIS associated with an invasive component (P = 0.04). Conclusions. These results support the special nature of LCIS and the heterogeneous nature of DCIS. The in situ component attending an invasive component may be different from an anatomically similar lesion without associated invasion. The absence of nm23 in comedo DCIS may be indicative of invasive capacity.

Utilizing routine histopathologic parameters obtained from appropriately handled lumpectomy and mastectomy specimens, a rational therapeutic plan based on epidemiologic and outcome-based data can be devised for any patient diagnosed with ductal carcinoma in situ (DCIS). In order to make a sound decision when weighing the current treatment options for DCIS--which include excision alone, excision plus radiation, and mastectomy--the following are mandatory: 1) assurance of an accurate diagnosis, 2) assessment of DCIS size and grade, and 3) careful margin evaluation. Accurate grading of DCIS is critical, since high nuclear grade and the presence of necrosis are highly predictive of the inability to achieve adequate margins, of local recurrence, and of the probability of missed areas of invasion. Margin status is the single most important determinant of local control following breast conservation for DCIS; numerous studies have shown that as the margin width increases, the risk of local failure decreases. The pros and cons of irradiating conservatively treated patients with DCIS should be carefully weighed on a case-by-case basis. Despite the 20-year-old dogma that all patients treated with breast conservation should receive postoperative radiation, a subset of patients who can be successfully treated by excision alone has been identified.

Checklists (now referred to as case summaries) have been used for educational and quality improvement purposes in surgical pathology reporting of cancer cases for a number of years, with published protocols, checklists, and structured reports developed by many societies such as the Association of Directors of Anatomic and Surgical Pathology, the College of American Pathologists (CAP), and The Royal College of Pathologists of the United Kingdom. The adoption of checklists designed to improve the quality of patient care is also gaining momentum in various clinical settings, including perioperative suites, emergency departments, and intensive care units. 1,2 In pathology, the use of checklists or structured reporting for histopathologic findings in cancer resection cases has been shown to produce sustained improvement in reporting of critical data elements. 3 However, development, maintenance, dissemination, and revision of such checklists can be labor intensive and costly because the documents must be continuously reviewed and updated as medical knowledge and practices change. This review process is especially important when adherence to pathology reporting protocols is included as a standard for accreditation, as by the Commission on Cancer of the American College of Surgeons in the accreditation of cancer programs. The ‘‘Protocol for the Examination of Specimens From Patients With Pheochromocytomas and Extra-adrenal Paragangliomas,’’ 4 published in this issue of the Archives of Pathology & Laboratory Medicine, represents a ‘‘gold standard’’ approach to reporting of these rare neoplasms based on expert opinion from a distinguished international group of pathologists and endocrinologists. However, it is not an official protocol of the CAP. The CAP cancer protocols are developed by the CAP Cancer Committee and multidisciplinary Cancer Protocol Review Panels, which include pathologists from various practice settings (academics, community practice, and large reference laboratories), surgeons, and medical and radiation oncologists. Protocols undergo a stringent review process that includes posting for public comment, followed by review of all comments by the CAP Cancer Committee, with final revisions to the protocol made in response to this feedback. New cancer protocols officially endorsed by the CAP are developed in response to needs from the larger oncology community. Because the protocol portfolio has matured over the years since the publication of the first CAP cancer checklists in 1986 5 , new protocols are often developed in response to changes in the American Joint Committee on Cancer TNM staging manual. For example, at the time of this writing a new CAP cancer protocol for uterine sarcomas is in the final stages of development in response to a separate staging schema for this tumor type as adopted by the F ´ ederation Internationale de Gyn ´

Cutaneous angiosarcoma can sometimes mimic other benign and malignant lesions, thereby presenting a difficult differential diagnosis. In the two cases of cutaneous angiosarcoma presented herein, extensive foamy cell alteration of tumor cells resembled a reactive xanthogranulomatous process. Foamy cell angiosarcoma is an unusual and deceptively benign morphologic variant of cutaneous angiosarcoma. Critical features for diagnosis include the presence of a deep, permeative, sometimes 'scaffolding' growth pattern and subtle areas of vascular formation.

A method of standardizing mitotic counts is described. This provisional approach, which expresses mitoses as a percentage of breast cancer cells present, holds the promise of facilitating interlaboratory agreement as well as providing a measure of tumor cellularity, probably an independent prognostic indicator in its own right. We suggest that this approach or one similar to it will maximize the evaluation and quantitation of proliferative activity from routinely available histologic material. Furthermore, the method is accomplished with little added effort beyond the customary histologic evaluation.