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Morphologic spectrum of estrogen receptor-negative breast carcinoma. (Original Articles).

It is generally assumed that estrogen receptor (ER)-negative tumors are usually poorly differentiated (grade 3) and carry a poor prognosis. (1) However, not all ER-negative tumors are poorly differentiated. A high percentage of some well-differentiated breast carcinomas (eg, adenoid cystic (2) and secretory (3) carcinomas) are ER negative, and their prognosis is generally good. On the other hand, not all ER-negative poorly differentiated tumors have a bad prognosis. In fact, one of the best known ER-negative poorly differentiated tumors, medullary carcinoma, has an average or better than average prognosis. (4) It has also been recently shown that many breast carcinomas developing in patients with BRCA 1 germ line mutations are grade 3 and ER negative, yet the prognosis of patients with these carcinomas is not different from that of a control group of patients (patients with breast carcinoma and no BRCA 1 germ line mutation). (5) Thus, there is accumulating evidence suggesting that ER-negative breast carcinomas comprise a heterogeneous group of tumors and that there is a need for a clear clinicopathologic classification of these tumors based on a thorough examination of cases. This investigation was aimed at studying the morphology and immunohistochemical characteristics of a consecutive series of ER-negative breast carcinomas to try to identify features that may be more commonly associated with increased aggressiveness as indicated by the presence of axillary lymph node metastases.

RESULTS

Patient Age and Lymph Node Status

A total of 575 patients with primary invasive breast carcinomas were operated on during the study period. Thus, the 74 ER-negative tumors used in this study represented 13% of the total. Information about the axillary lymph node status was available for 60 patients. Of these patients, 34 (57%) had axillary lymph node metastases, and 26 (43%) did not. The 74 patients had an age range of 26-94 years (mean, 55 [+ or -] 14.4 years). For the 60 patients with known node status, the age range was 26-94 years (mean, 53.4 [+ or - ] 15.4 years) for patients with lymph node metastases and 27-68 years (mean, 49.8 [+ or -] 10.3 years) for patients without lymph node metastases. The difference in age was not statistically significant (P = .279).

Tumor Size

The tumors varied in size from 5 to 130 mm, with a mean size of 28.2 mm. Tumors occurring in patients with lymph node metastases ranged in size from 5 to 130 mm and had a mean size of 37.2 [+ or -] 30.2 mm. Tumors occurring in patients without lymph node metastases ranged in size from 5 to 35 mm and had a mean size of 17.8 [+ or -] 8.0 mm. The difference in tumor size between the 2 groups was highly significant (P = .000897).

Histologic Features

The 74 cases included 50 (68%) invasive ductal carcinomas, 21 (28%) medullary or atypical medullary carcinomas (8 typical and 13 atypical), and 1 each of invasive lobular, apocrine, and papillary carcinoma. Most invasive ductal carcinomas (37 cases, 74%) were grade 3; these tumors had cells showing minimal tubule formation, marked nuclear pleomorphism, and abundant mitoses. Some grade 3 invasive ductal carcinomas showed unusual features, including several cases with comedo-type necrosis (Figure 1) and single cases with squamoid differentiation (Figure 2), spindle cell differentiation (Figure 3), an abundance of tumor giant cells (Figure 4), and a ringlike appearance with extensive central necrosis and fibrosis (Figure 5). None of these features was seen in the 501 other breast carcinomas submitted during the same study period, all of which were reported or reviewed by one of the authors (S.S.). Twelve invasive ductal carcinomas (24%) were grade 2 (Figure 6), and 1 of these tumors was composed of small solid groups of cells widely separated by fibrous tissue (Figure 7). Only 1 carcinoma (2%) was grade 1. This tumor consisted mostly of ductal carcinoma in situ (DCIS) elements with small interspersed foci of well-differentiated invasive carcinoma (Figure 8). Both the in situ and invasive elements were ER and PgR negative.

[FIGURES 1-8 OMITTED]

The 8 typical medullary carcinomas had well-defined, noninfiltrating borders and were composed of highly pleomorphic tumor cells arranged in continuous syncytial sheets and showing abundant mitotic activity. The tumors were heavily infiltrated with lymphocytes and showed no associated in situ elements or areas of necrosis (Figure 9). The 13 atypical medullary carcinomas were essentially similar to the medullary carcinomas except for the presence of areas of necrosis, a partly infiltrative border, and/or associated DCIS elements. For the purpose of this study, we grouped the atypical medullary cases with the typical medullary cases because morphologically and immunohistochemically, they are more related to typical medullary carcinoma than to grade 3 invasive ductal carcinoma. (9,10)

[FIGURE 9 OMITTED]

The single case of invasive lobular carcinoma consisted of histiocytoid malignant epithelial cells with large vesicular nuclei and prominent nucleoli, occurring singularly or in short single files and scattered widely in abundant markedly desmoplastic stroma (Figure 10). In the case of invasive papillary carcinoma, the tumor cells were arranged in fingerlike projections (Figure 11). The tumor cells of the case of invasive apocrine carcinoma had abundant eosinophilic cytoplasm and large atypical nuclei and were arranged in tubular structures infiltrating fibrous tissue (Figure 12).

[FIGURES 10-12 OMITTED]

Tumor Type According to Lymph Node Status

Of the 34 cases with known positive lymph nodes, 24 (71%) were invasive ductal carcinomas, 9 (26%) were medullary/atypical medullary carcinomas, and 1 was the single case of invasive papillary carcinoma. Of the 26 cases with known negative lymph nodes, 16 (62%) were invasive ductal carcinomas, 8 (31%) were medullary/atypical medullary carcinomas, 1 was an invasive lobular carcinoma, and 1 was an apocrine carcinoma (Table 2). The difference in incidence of the various types in the 2 groups was not significant (P > .05). Lymph node metastases were present in 24 (60%) of the 40 cases of invasive ductal carcinomas, as compared with 9 (53%) of the 17 cases of medullary/ atypical medullary carcinoma, a difference that was not statistically significant (P > .05).

Tumor Grade

Sixty of the 74 tumors (81%) were grade 3, 13 (18%) were grade 2, and 1 (1%) was grade 1. Of the 60 cases with known lymph node status, 28 of 49 (57%) of the grade 3 tumors had metastasized to the lymph nodes compared with 6 of 11 (55%) of the grade 1 and 2 tumors. The difference was not significant (P > .05).

Immunostaining

Twenty-one (28%) of the 74 tumors were c-erbB-2 positive. Of the 60 cases with known lymph node status, positive staining was seen in 7 (21%) of 34 node-positive cases and in 12 (46%) of 26 node-negative cases (Table 3). The difference was statistically significant (P < .05). The 21 c-erbB-2-positive tumors included 17 invasive ductal carcinomas (34% of all ductal carcinomas), 1 medullary carcinoma (12% of all medullary carcinomas), and the single cases included in the study of invasive lobular, apocrine, and papillary carcinoma.

Positive staining for p53 was seen in 40 (54%) of the 74 tumors. For the 60 cases with known axillary lymph node status, p53 positivity was seen in 18 (53%) of the 34 node-positive cases and in 16 (62%) of the node-negative cases (Table 3), a difference that was not statistically significant (P > .05). The 40 p53-positive tumors included 23 ductal carcinomas (46% of all ductal carcinomas), 6 medullary carcinomas (75%), 9 atypical medullary carcinomas (69%), and the 2 single cases of invasive apocrine and lobular carcinomas. The difference in the incidence of p53 positivity in medullary/atypical medullary versus invasive ductal carcinoma was statistically significant (P < .05).

Staining was positive for vimentin in 19 tumors (26%), for androgen receptors in 38 tumors (51%), and for prolactin receptors in 59 tumors (80%). There was no statistically significant difference between the 2 groups, node-positive and node-negative cases, with regard to the expression of any of these markers (P > .05, for each marker) (Table 3). The 19 vimentin-positive tumors included 4 medullary carcinomas (50% of medullary carcinomas), 5 atypical medullary carcinomas (30%), and 10 invasive ductal carcinomas (20% of all ductal carcinomas). The difference in the incidence of vimentin positivity in medullary/atypical medullary versus invasive ductal carcinomas was statistically significant (P < .05).

COMMENT

The availability of well-characterized monoclonal antibodies for the demonstration of ERs in paraffin-embedded tissue has made it possible to carry out accurate assessment of ER status on routinely processed tumor tissue sections as part of the histopathologic examination of these tumors. Immunohistochemistry has been found to be more accurate than the previously employed biochemical assay, as it allows direct microscopic visualization of stained tumor sections, thus avoiding false-negative and -positive results that can arise from sampling errors. (6,11,12)

We selected for this study cases that were totally ER and PgR negative, with no trace of positive nuclear staining in any of the tumor cells. We adhered to the staining protocol and used proper controls. (6) In addition, in most of these cases, an internal control was provided by ER-positive normal breast ducts that were present in the same section adjacent to the tumor.

It is clear from this study that ER-negative invasive breast carcinomas comprise a heterogeneous group of tumors that includes a variety of histologic types and patterns. Thus, although the majority of tumors in this study (68%) were so-called invasive ductal carcinomas, a high percentage of cases (28%) were of the medullary/atypical medullary type; in these tumors, pleomorphic tumor cells were arranged in syncytial sheets with mostly well-circumscribed borders and a variable degree of lymphocytic infiltration. The 28% is a much higher incidence than the 7% general incidence reported in a large series of cases that included ER-negative and -positive cases. (13) This finding supports previous findings that the great majority of these tumors are ER negative. (4) There were also single cases of invasive papillary, apocrine, and lobular, histiocytoid-type, carcinomas. The first of these 3 cases had lymph node metastases, but the other 2 cases did not. None of the cases encountered in this series were of the classical invasive lobular type or of the tubular, cribriform, or mucinous varieties. In addition, some of the invasive ductal carcinomas exhibited unusual distinctive patterns and features, including squamoid and spindle cell differentiation, bizarre tumor giant cells, areas of comedo-type necrosis, or extensive central fibrosis giving rise to a distinctive ringlike appearance. Two recent reports suggest that these features are consistently associated with ER-negative status. One of these reports has suggested that "high-grade invasive ductal carcinomas with large central acellular zones" may be of myoepithelial origin. (14) Although tumors of myoepithelial origin are known to be ER negative, the ER status of the tumors in that report was not mentioned. The other recent report included 26 cases of "pleomorphic carcinoma of the breast," which were predominantly composed of pleomorphic giant and/or spindle ceils with some tumors also showing squamous differentiation. (15) All 26 tumors in that series were ER negative, and all but one were also PgR negative.

In the present study, not all invasive ductal carcinomas were grade 3, as is commonly expected in ER-negative tumors. Nearly one quarter of these carcinomas (24%) were grade 2, and a single case (2%) was grade 1. Among cases with axillary lymph node dissection, there was no nodal involvement in the single grade 1 case, whereas 6 (60%) of the 10 grade 2 cases and 18 (60%) of the 30 grade 3 cases had lymph node metastases. In addition, lymph node metastases were found in 53% (9 of 17) of all medullary/atypical medullary tumors that, by definition, were all grade 3. Thus, the incidence of lymph node metastasis seems to be similar in grade 2 and grade 3 ER-negative tumors. Examination of a larger number of cases is needed to confirm this observation and to correlate ER-negative tumor grade with patient follow-up.

Tumor size was the only morphologic feature that showed significant correlation with the lymph node status. Tumors with lymph node metastases had an average size of 37.2 mm compared with 17.8 mm for node-negative tumors (P = .000897). Tumor size has been found to be a useful prognostic indicator in several previous large studies involving ER-positive and -negative tumors. (16,17) In addition, this study also demonstrates the wide range of sizes encountered in ER-negative tumors (5-130 mm), a finding that suggests that the ER status of a tumor is determined early in its natural history.

The finding of a significantly higher incidence of lymph node metastases in c-erbB-2-negative tumors (46%) compared with c-erbB-2-positive tumors (21%) is surprising as most, although not all, previous studies have suggested that c-erbB-2 expression is associated with increased aggressiveness of breast carcinomas. (18) However, as Allred et al(18) mention in their review article, this relationship seems to be weak in general and significant only in small subsets of patients. Thus, the combination of ER and c-erbB-2 negativity may indicate increased aggressiveness, especially as the incidence of node positivity in this group in our series (46%) is much higher than the 20% to 30% incidence commonly noted in breast carcinoma in genera. (18) However, more cases have to be examined to see if this finding will hold in a larger series of cases. The very low incidence (5%) of c-erbB-2-positive staining in medullary/atypical medullary carcinomas as compared with the incidence in invasive ductal tumors in this study (34%) is consistent with previous observations. (19-21)

Lastly, the present study failed to show any significant correlation between lymph node metastases and positive immunostaining for p53, vimentin, or androgen receptors in the cases examined. Both p53 (18) and vimentin (22) expression have previously been associated with aggressive tumor behavior, although subsequent studies have failed to confirm the existence of a relationship between vimentin and prognosis in breast cancer. (23,24) The significantly higher incidence of p53 positivity (71% vs 46%) and vimentin positivity (43% vs 20%) in medullary/atypical medullary cases versus invasive ductal cases in our study is consistent with previous findings. (23,25-27)

In conclusion, many of the ER-negative breast carcinomas have distinctive features, including a medullary pattern, the presence of areas of comedo-type necrosis, extensive central fibrosis, bizarre tumor giant cells, and areas of squamoid or spindle cell differentiation as well as apocrine differentiation. These features are in addition to features seen in other histologic types that are known to commonly be ER negative but that were not seen in this series, including metaplastic, adenoid cystic, (2) and secretory (3) carcinomas. Tumor size appears to be the most important indicator of the likelihood of the presence or absence of lymph node metastases. In contrast, tumor grade does not appear to be very useful in this respect, as most (81%) of the ER-negative tumors in this series, whether they had lymph node metastases or not, were grade 3. The wide range of sizes encountered in this series (5-100 mm) suggests that the ER status of a tumor is determined early in its natural history. This finding tends to support the concept of the presence of 2 separate pathways for the development of ER-negative and ER-positive breast carcinomas. (28-30)

MATERIALS AND METHODS

We studied 74 consecutive cases of primary breast carcinoma that were negative for ERs, as assessed immunohistochemically (described subsequently). All of the carcinomas were surgically removed, either by wide local excision or mastectomy, at Charing Cross Hospital, London, between January 1996 and December 1998. Almost all of the cases were originally grossly examined and reported by one of the authors (S.S.). Tumor size was expressed as the maximum diameter of the tumor as measured grossly and was confirmed microscopically. In smaller tumors for which a full cross-section of the whole tumor was included in a single slide, if there was a discrepancy between the 2 measurements, the microscopic measurement was considered the correct one. In cases in which axillary lymph nodes were examined, the lymph nodes were removed surgically by a process of axillary clearance, whereby an average of 24 lymph nodes were obtained and microscopically examined.

Our department routinely assesses the ER and progesterone receptor (PgR) status of all cases of breast cancers. Tissues are stained with the avidin-biotin complex immunoperoxidase technique after an antigen retrieval step using a pressure cooker. (6) For ER staining, we use the primary monoclonal antibody 1D5 (Dako Ltd, Ely, Cambridgeshire, United Kingdom) at a dilution of 1:100 in Tris-buffered saline. For PgR staining, we use the monoclonal antibody NCL-PGR, clone 1A6 (Novocastra, Newcastle Upon Tyne, United Kingdom) at a dilution of 1:80. The results are assessed semiquantitatively using the H scoring system, which takes into consideration the percentage of the stained tumor cells and the intensity of the staining. (6) All cases included in this study had a score of 0 for both ER and PgR. This score indicates that no nuclear staining whatsoever was present in any tumor cell. Cases with H scores greater than 0 and less than 51, which customarily are also considered negative, were not included in this study; we used this approach to avoid including cases in which the expression of the receptors might have been down-regulated by other factors rather than being totally absent. In all cases, the true absence of staining was confirmed by the presence of positive nuclear staining in adjacent normal tissue or by staining in a positive control tissue processed in parallel.

We reviewed archival H&E-stained sections. Tumors were histologically classified according to accepted criteria (7) and graded according to the system of Elston and Ellis. (8) In the latter system, tumors are classified into 3 grades of decreasing differentiation (1, 2, and 3) according to the extent of glandular differentiation, nuclear pleomorphism, and mitotic activity. Grade 1 tumors are well differentiated, with minimal nuclear pleomorphism and mitotic activity, whereas grade 3 tumors are the least differentiated, with minimal or no gland formation, marked nuclear pleomorphism, and prominent mitotic activity.

We selected a representative paraffin block for each tumor, cut new sections from this block, and immunostained the sections for c-erbB-2, p53, vimentin, androgen receptors, and prolactin receptors using the avidin-biotin immunoperoxidase technique. Briefly, the sections were dewaxed and then placed in 30% hydrogen peroxide solution to block endogenous peroxidase. This step was followed by an antigen retrieval step using a pressure cooker, with the exception of sections used for prolactin receptor staining, which were digested with protease (Sigma, Poole, Dorset, United Kingdom) for antigen retrieval. The primary antibodies used and their dilutions and sources are shown in Table 1. Each was applied for 60 minutes at room temperature. The secondary antibody (biotinylated horse antiserum) was then applied for 45 minutes, followed by (after washing) freshly prepared avidin-biotin peroxidase complex (Vector Laboratories, Peterborough, United Kingdom) for another 45 minutes. Diaminobenzidine (Vector) was then applied for 5 minutes, followed by washing and counterstaining with Harris hematoxylin for 1 minute. Positive and negative controls were included in each staining batch. Positive controls included breast sections known to be positive for the antibody used. Negative controls included sections processed in parallel with omission of the primary antibody. Positive staining was identified in the form of dark brown membrane staining for c-erbB-2, nuclear staining for p53 and androgen receptors, and cytoplasmic staining for vimentin and prolactin receptors. A tumor was considered positive when at least 10% of tumor cells were positively stained.

We performed statistical analysis using the unpaired t test for data of unequal variance and the Fisher exact test. Values are expressed as mean [+ or -] SD unless otherwise noted.

We thank Dr Barbara Vonderhaar of the National Cancer Institute, Bethesda, Md, for her generous gift of B6.2 antibody. This work was submitted in partial fulfillment of BSc degree requirements (Mr Scawn).
Table 1. Primary Antibodies

Antibody Dilution Source

c-erbB-2 1:200 Dako, Cambridgeshire, United Kingdom
p53 1:200 Dako
Vimentin 1:50 Dako
Androgen receptors 1:200 BioGenex, Berkshire, United Kingdom
Prolatin receptors 1:200 B. Vonderhaar, PhD, National Cancer
 Institute, Bethesda, Md
Table 2. Relationship Between Tumor Histology and
Axillary Lymph Node Status *

 Lymph Medullary
 Node Invasive and
 Status Ductal Atypical Other Total

Positive 24 (71) 9 (26) 1 (3) 34 (100)
Negative 16 (62) 8 (31) 2 (8) 26 (101)
Total 40 (67) 17 (28) 3 (5) 60 (100)

* Values are expressed as No. (% of row total). Because of rounding,
percentages do not always total 100.
Table 3. Relationship Between Tumor Marker
Positivity and Lymph Node Status in 60 ER-Negative
Breast Carcinomas *

 Cases With Cases With
 Positive Negative
 Lymph Nodes, Lymph Nodes,
 No. (%) No. (%)
Tumor Marker (n = 34) (n = 26)

c-erbB-2 positive 7 (21) ([dagger]) 12 (46) ([dagger])
p53 positive 18 (53) 16 (62)
Vimentin positive 6 (18) 7 (27)
Androgen receptor positive 20 (59) 15 (58)
Prolactin receptor positive 27 (79) 22 (85)

* ER indicates estrogen receptor.

([dagger]) P < .05.


References

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Accepted for publication October 8, 2001.

From the Department of Histopathology, Charing Cross Hospital and imperial College of Science, Technology and Medicine, London, United Kingdom.

Presented in part at the Winter Meeting of the Pathological Society of Great Britain and Ireland, London, January 2000.

Reprints: Sami Shousha, MD, FRCPath, Department of Histopathology, Charing Cross Hospital, Fulham Palace Rd, London W6 8RF, UK (e-mail: s.shousha@ic.ac.uk).
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Author:Scawn, Richard; Shousha, Sami
Publication:Archives of Pathology & Laboratory Medicine
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Date:Mar 1, 2002
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