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Background
Medullary carcinoma of the breast is a variant of breast cancer. These tumors have a similar presentation to other breast cancers but are distinguished by a characteristic histologic appearance. In addition, pure medullary carcinomas have a better prognosis than usual cases of infiltrating ductal carcinoma. Part of the problem in reviewing cases of medullary carcinoma, both under the microscope and in the medical literature, has been the lack of uniform criteria in establishing the diagnosis. Occasionally cases of infiltrating ductal carcinoma have been included, skewing the survival data. Pathologists must adhere to strict histologic criteria in establishing the diagnosis.
EPIDEMIOLOGY CHARACTERIZATION INCIDENCE 5-7% of breast cancers AGE RANGE-MEDIAN 10% <35 years
Mean varies from 46-54 yearsMore common in Japanese Black>white
PATHOGENESIS CHARACTERIZATION BRCA-1 Mutations at BRCA1: the medullary breast carcinoma revisited.
Eisinger F, Jacquemier J, Charpin C, Stoppa-Lyonnet D, Bressac-de Paillerets B, Peyrat JP, Longy M, Guinebretiere JM, Sauvan R, Noguchi T, Birnbaum D, Sobol H.
Department of Genetic Oncology, Institut National de la Sante et de la Recherche Medicale CRI 9703, Paoli-calmettes Institute, Marseille, France.
Cancer Res 1998 Apr 15;58(8):1588-92 Abstract quote
BRCA1-associated breast cancers (BRCA1-BCs) frequently harbor a high histoprognostic grade, p53 alterations, and estrogen receptor negativity. Although these parameters predict a poor outlook, the overall survival in BRCA1-BCs is equivalent to or even better than that in sporadic cases. These features are reminiscent of what is observed for breast carcinoma of the medullary type, a high-grade tumor with a particular favorable course.
To explore a possible relationship between this phenotype and BRCA1 mutations, we first compared 32 BRCA1-BCs and 200 consecutive cases of breast cancer without familial history for the prevalence of typical medullary breast carcinoma (TMC) using the criteria given by Ridolfi et al. [R. Ridolfi et al, Cancer (Phila.), 40: 1365-1385, 1977]. Second, we searched for BRCA1 mutations in a set of 18 cases of TMC, using denaturing gradient gel electrophoresis and Cleavase fragment length polymorphism scanning. Six of 32 (19%) BRCA1-BCs were of the TMC type, compared to 0 of 200 controls (P < 0.0001). Among the 18 TMCs, 2 BRCA1 nonsense mutations were found. This corresponds to almost 7 times the contribution of BRCA1 mutations in the general population. Two additional missense mutations were identified.
Together, these results suggest that, although TMC and BRCA1-BCs are not strictly coincidental, an important connection between the two populations does exist.
LYMPHOCYTES Cytotoxic phenotype of tumor infiltrating lymphocytes in medullary carcinoma of the breast.
Yakirevich E, Izhak OB, Rennert G, Kovacs ZG, Resnick MB.
Department of Pathology, The Lady Davis Carmel Medical Center, Haifa, Israel.
Mod Pathol 1999 Nov;12(11):1050-6 Abstract quote
Medullary carcinoma (MC) of the breast is considered to carry a more favorable prognosis than other subtypes of infiltrating ductal carcinoma This is a biological paradox because its clinical behavior contrasts with its anaplastic morphology. MC is characterized by a dense lymphocytic infiltrate.
In this study, we determined the cytotoxic potential and activity of tumor infiltrating lymphocytes (TILs) in MC by CD3, CD8, TIA-1, and granzyme B immunostaining on paraffin-embedded sections.
Fourteen cases of typical MC (TMC) and 15 cases of atypical MC (AMC) classified according to Ridolfi criteria, and 19 cases of poorly differentiated infiltrating ductal carcinoma (PDC) were studied. TILs were quantified separately into two groups: cells infiltrating tumor nests and cells within stroma The number of CD8+ and TIA-1+ cells infiltrating tumor cell nests were markedly increased in TMC and AMC, as opposed to the PDC subgroup (159.6+/-132.8; 77.4+/-59.3; 9.4+/-10.5 and 171.2+/-152.4; 72.3+/-55.0; 10.8+/-12.7 per high power field, respectively). The number of tumor infiltrating granzyme B+ cells was significantly greater in TMC and AMC, as compared with the PDC subgroup (82.1+/-64.9, 33.9+/-19.7, and 3.1+/-5.1, respectively). Although no significant difference was found between the number of stromal CD3+ and CD8+ lymphocytes among the three subgroups, stromal granzyme B+ cells were significantly elevated in TMC and AMC as compared with the PDC subgroup.
Finally, the relative proportion of granzyme B+ as opposed to CD3+ intraepithelial and stromal lymphocytes was greater in TMC and AMC as compared with the PDC subgroup (0.52+/-0.29; 0.47+/-0.31; 0.19+/-0.18 and 0.18+/-0.11; 0.13+/-0.11; 0.06+/-0.05, respectively).
The presence of increased numbers of activated cytotoxic lymphocytes in MC of the breast may be a key mechanism active in the host versus tumor response leading to improved prognosis.
MICROSATELLITE INSTABILITY Microsatellite Instability Is Infrequent in Medullary Breast Cancer
Soo-Chin Lee, MD, Karin D. Berg, MD, Mark E. Sherman, MD, Constance A. Griffin, MD, and James R. Eshleman, MD, PhD
Am J Clin Pathol 2001;115:823-827Abstract
Microsatellite instability (MSI), characterized by contraction or expansion in microsatellite length or short tandem repeats compared with germline lengths, is found in 85% to 90% of colon cancer arising in hereditary nonpolyposis colorectal cancer families. These cancers commonly have characteristic histologic appearances, including medullary features with intense lymphoid infiltrates. In pancreatic cancer, a rare medullary histologic subtype more often demonstrates MSI than the more common adenocarcinoma subtype.
We hypothesized that the medullary histologic pattern might correlate with MSI in additional tumor types and analyzed 8 cases of typical and atypical medullary carcinoma of the breast. Tumor and normal DNA was extracted from paraffinized tissue blocks of tumor and histologically uninvolved axillary lymph nodes, respectively. We analyzed the tumors for instability in 5 primary (BAT25, BAT26, D17S250, D5S346, D2S123) and 3 alternative (BAT40, D18S55, D18S58) microsatellites recommended at the National Cancer Institute–sponsored conference for diagnosis of MSI in colorectal cancer.
All 8 tumors were microsatellite stable at the 8 loci, suggesting that MSI is not commonly associated with medullary or atypical medullary breast carcinoma, in contrast with the reported association with medullary tumors of the colon and pancreas.
LABORATORY/RADIOLOGIC/OTHER TESTS CHARACTERIZATION Radiograph Often presents with a well circumscribed tumor
GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION General Median 2-3 cm
Usually a moderately firm discrete tumor with a lobulated or nodular cut surfaceMay have necrosis or hemorrhage
Bilateral 3-18% of patients with medullary carcinoma in one breast Asynchronous bilateral medullary carcinoma of the breast.
Young JS, Sterchi MJ, Hopkins M.
Department of General Surgery, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC, USA.
South Med J 1997 Apr;90(4):423-5 Abstract quote
We report a case of bilateral medullary carcinoma of the breast occurring asynchronously in a young woman and review the epidemiology of this form of breast cancer.
Clinical and radiographic surveillance are necessary in the follow-up of all women with medullary carcinoma of the breast to ensure that further disease is detected rapidly and treated properly.
Multicentricity Microscopic foci of cancer found outside the primary quadrant in 10% of cases
HISTOLOGICAL TYPES CHARACTERIZATION Classic Syncytial growth pattern of poorly differentiated tumor cells with a high mitotic rate
There is a prominent lymphoplasmacytic reaction with a circumscribed microscopic appearance-inflammatory reaction must involve 75% of the periphery and must be present diffusely throughout the substance of the tumor
No glandular or fatty breast tissue should be found within the invasive portion of the tumor
Medullary carcinoma of the breast: a clinicopathologic study with appraisal of current diagnostic criteria.
Wargotz ES, Silverberg SG.
Department of Pathology, George Washington University Medical Center, Washington, DC 20037.
Hum Pathol 1988 Nov;19(11):1340-6 Abstract quote
Fifty-three cases of mammary carcinoma originally diagnosed as medullary carcinoma (MC) or infiltrating duct carcinoma (IDC) with medullary features were reviewed and reclassified using the strictly defined histologic criteria applied a decade ago by Ridolfi et al.
Our study interval (1961 to 1982) allowed for a minimum follow-up of 5 years for each patient, with a mean follow-up period of 7.2 years. When reclassified, 24 tumors fulfilled the criteria for MC, 16 tumors were determined to be atypical MC, and ten tumors were found to be IDC; the observed 5-year survival rates were 95%, 80%, and 70%, respectively. These findings confirmed those of other investigators, that when specific criteria are applied, MC proves to be a form of mammary carcinoma with a favorable prognosis. However, we also found that when tumors were excluded from the MC category solely on the basis of in situ carcinoma, focal marginal infiltration, or a sparse mononuclear infiltrate, the survival rate of these patients was similar to that of patients in the medullary category.
Thus, we propose that one of these criteria alone should not suffice to exclude the diagnosis of MC. On the other hand, tumors with two or more of these atypical features, or with extensive marginal infiltration, no mononuclear cellular infiltrate, and/or less than 75% syncytial growth, should be classified as IDC with medullary features. Typical MC with bland nuclei or a focal microglandular growth pattern only were not observed in this series; however, these findings should probably also cause a tumor to be classified in the IDC category.
By dividing our cases into two rather than three groups, we found a statistically significant difference between the survival rates of 94% and 64% for MC (34 tumors) and IDC (14 tumors), respectively. Although the latter figure probably exceeds the survival rate for IDC without medullary features, the difference does not appear great enough to warrant a separate diagnostic category.
Inter- and intraobserver variability in the histopathological diagnosis of medullary carcinoma of the breast, and its prognostic implications.
Pedersen L, Holck S, Schiodt T, Zedeler K, Mouridsen HT.
Department of Oncology ONA, Finsen Institute, Rigshospitalet, Copenhagen.
Breast Cancer Res Treat 1989 Oct;14(1):91-9 Abstract quote
One hundred thirty-one breast carcinomas with medullary features, registered in the Danish Breast Cancer Cooperative Group from 1977-1982, have been histopathologically reviewed by two senior pathologists and classified as typical medullary carcinoma (TMC), atypical medullary carcinoma (AMC), and non-medullary carcinoma (NMC). Diagnostic criteria were based on those put forward by Ridolfi et al. and Fisher et al.
The procedure was repeated with an interval of about one year by both pathologists. The diagnostic interobserver agreement was 72% with a Kappa of 0.55. The intraobserver agreement was 77% and 63% with Kappa values of 0.64 and 0.44, respectively. To see whether the observed inter- and intraobserver variability had any prognostic implications, diagnostic subgroups for both pathologists were analyzed with Kaplan Meier plots for recurrence-free survival (RFS) and with log rank tests. In the first evaluation pathologist 1 segregated a group of TMC with a significantly better RFS than for the NMC group, and pathologist 2 segregated a group of TMC with a corresponding strong trend. These findings could not, however, be reproduced in the second evaluation.
The study indicates that the criteria of TMC and AMC as proposed by Ridolfi et al. need to be sharpened and simplified in order to reduce inter- and intraobserver variability. Larger studies with a control group of infiltrating ductal carcinomas are mandatory to elucidate the clinical importance of the diagnoses of Typical and Atypical Medullary Carcinoma of the breast.
Medullary carcinoma of the breast, proposal for a new simplified histopathological definition. Based on prognostic observations and observations on inter- and intraobserver variability of 11 histopathological characteristics in 131 breast carcinomas with medullary features.
Pedersen L, Zedeler K, Holck S, Schiodt T, Mouridsen HT.
Department of Oncology ONK, Rigshospitalet, Copenhagen, Denmark.
Br J Cancer 1991 Apr;63(4):591-5 Abstract quote
In a previous study of 131 breast carcinomas with medullary features, we evaluated the diagnostic inter- and intraobserver variation and its prognostic implications using the criteria of typical (TMC) and atypical (AMC) medullary carcinoma of the breast put forward by Ridolfi et al. (1977).
We found a considerable interobserver variation as well as intraobserver variation, with significant implication on prognosis, and concluded that the histopathological definition of MC must be sharpened and simplified in order to increase the diagnostic reproducibility. In the present study of the same population of 131 patients with breast carcinomas with medullary features we have examined inter- and intraobserver variation concerning 11 histopathological characteristics. Furthermore, we have analysed the prognostic importance of these 11 histopathological features, and the prognostic implications of the observed inter- and intraobserver variation. Based on the observations, we have eliminated criteria with poor inter-/intraobserver agreement as well as those implying no or minimal impact on the prognosis.
We propose a new simplified histopathological definition of medullary carcinoma of the breast (MC), retaining reproducible, prognostically significant criteria (syncytial growth pattern and diffuse, moderate or marked mononuclear infiltration). The prognosis of MC, based on this definition, is significantly better than those of infiltrating ductal carcinomas grade II + III.
Medullary carcinoma of the breast. A multicenter study of its diagnostic consistency.
Rigaud C, Theobald S, Noel P, Badreddine J, Barlier C, Delobelle A, Gentile A, Jacquemier J, Maisongrosse V, Peffault de Latour M, et al.
Institut Jean-Godinot, Reims, France.
Arch Pathol Lab Med 1993 Oct;117(10):1005-8 Abstract quote
Nine pathologists from different institutions reviewed in a double-blind study 16 breast tumors previously indexed as typical medullary carcinoma, atypical medullary carcinoma, or infiltrative ductal carcinoma. A set of 16 slides was circulated two times among the nine pathologists.
The diagnoses of typical and atypical medullary carcinomas were based on a definition given by Ridolfi et al. The interobserver and intraobserver agreement was low, with a kappa value of less than .50. The only histological criterion that had more than 50% agreement was the presence or absence of an in situ component in the tumor, assuming that the disagreement of one pathologist is accepted.
This study is a snapshot of the problems encountered in the diagnosis of typical medullary carcinoma in a routine context and it shows high levels of variations in diagnostic consistency.
Medullary carcinoma of the breast: interobserver variability in histopathologic diagnosis.
Gaffey MJ, Mills SE, Frierson HF Jr, Zarbo RJ, Boyd JC, Simpson JF, Weiss LM.
Department of Pathology, University of Virginia Health Sciences Center, Charlottesville, USA.
Mod Pathol 1995 Jan;8(1):31-8 Abstract quote
To assess the interobserver reproducibility for the diagnosis of medullary carcinoma of the breast (MC), 53 previously diagnosed MCs were independently assessed by six observers for growth pattern, nuclear grade (NG), inflammation, tumor margin, intraductal component, and glandular features.
Tumors were reclassified as MC, atypical MC, or infiltrating ductal carcinoma according to the histopathologic criteria of Ridolfi et al. (Cancer 40:1365, 1977), Wargotz and Silverberg (Hum Pathol 19:1340, 1988), and Pedersen et al. (Br J Cancer 63:591, 1991). NG was the most reproducible parameter, and tumor margin was the least, with consensus agreement by four of six observers for 49 (92%) and 26 (49%) of cases, respectively.
Utilizing the histopathologic criteria proposed by Ridolfi et al., Wargotz and Silverberg, and Pedersen et al., consensus diagnoses were achieved in 37 cases (70%), 46 cases (87%), and 51 cases (96%), respectively.
A consensus diagnosis of MC in all three systems was unassociated with tumor size, axillary lymph node status or overall survival (median follow-up: 89 mo). The consensus (or better) reclassification of 44/53 (83%), 35/53 (66%), and 27/53 (51%) previously diagnosed MC as atypical MC or infiltrating ductal carcinoma by the criteria of Ridolfi et al., Wargotz and Silverberg, and Pedersen et al., respectively, suggests that MC was previously over-diagnosed.
While the scheme of Pedersen et al. is the most reproducible, additional follow-up information is necessary to determine the biological significance of this classification system. To minimize these difficulties in practice, pathologists should carefully adhere to published criteria and indicate the classification system utilized.
VARIANTS ATYPICAL MEDULLARY CARCINOMA Resembles the usual classic case but lacks all the features
Must have at least 75% syncytial growth but does not have the other two features (circumscription, lymphoplasmacytic infilrate)
SPECIAL STAINS/IMMUNOPEROXIDASE/OTHER CHARACTERIZATION Lymphocytes IgG cells predominate
Many T lymphocytesHormone receptors >90% are estrogen and progesterone receptor negative Flow cytometry Usually aneuploid or polypoid IMMUNOPEROXIDASE CYTOKERATIN Medullary carcinoma of the breast: a tumour lacking keratin 19.
Larsimont D, Lespagnard L, Degeyter M, Heimann R.
Department of Pathology, Institut Jules Bordet, Brussels, Belgium.
Histopathology 1994 Jun;24(6):549-52 Abstract quote
The presence of keratin 19 (K19) was searched for by immunostaining in 16 medullary carcinomas, comprising 12 typical and four atypical cases, in 29 undifferentiated high-grade carcinomas (NOS-HG) with conspicuous lymphoid response and in 12 well differentiated low-grade carcinomas (NOS-LG).
The medullary carcinomas were all negative whereas 23 of the high-grade and all 12 low-grade carcinomas expressed K19. Staining for K19 could be of value in the differential diagnosis of these tumours.
Furthermore, these findings, with other observations, raise the possibility that medullary carcinoma cells could be linked to precursor cells of the terminal duct lobular units because both populations share several characteristics.
Keratin 19 in paraffin sections of medullary carcinoma and other benign and malignant breast lesions.
Dalal P, Shousha S.
Department of Histopathology, Charing Cross and Westminster Medical School, London, England.
Mod Pathol 1995 May;8(4):413-6 Abstract quote
This investigation was aimed at studying the distribution of keratin 19 in various histological types of invasive breast carcinoma and benign breast lesions using two different antibodies, comparing the results, and assessing the significance of the finding.
In particular, the usefulness of using the absence of keratin 19 immunostaining as a marker for medullary carcinoma was examined. Paraffin sections of 49 invasive breast carcinomas and 40 benign lesions were examined by the avidin-biotin complex immunoperoxidase technique using two commercially available keratin 19-specific monoclonal antibodies, BA17 and RCK 108.
The results showed that the latter antibody stained more cases and the intensity of its staining was more pronounced than BA17. Most medullary and poorly differentiated invasive ductal carcinomas were BA17 negative and RCK108 negative or weakly positive. Moderately and well-differentiated ductal, invasive lobular, tubular, and most mucinous carcinomas were mostly positive with both antibodies, whereas a case of signet ring and a case of spindle cell carcinoma were negative with the two antibodies. Thirty eight of the 40 benign lesions examined showed variable numbers of positive cells, reflecting in general the pattern seen in normal ducts and acini.
It is concluded that although keratin 19 seems to be completely absent or at most only weakly represented in paraffin sections of medullary carcinoma, similar reactions are obtained with poorly differentiated ductal tumors. Different antibodies may give different reactions, but well-differentiated ductal and invasive lobular tumors are usually more strongly stained, whereas signet ring and spindle cell carcinomas seem to be negative.
Medullary breast carcinoma vs. poorly differentiated ductal carcinoma: an immunohistochemical study with keratin 19 and oestrogen receptor staining.
Jensen ML, Kiaer H, Melsen F.
Institutes of Pathology, Aarhus University Hospital, Svendborg Hospital, Denmark
Histopathology 1996 Sep;29(3):241-5 Abstract quote
Sixty breast carcinomas previously indexed as medullary carcinomas over a 24-year-period were reviewed and reclassified according to definitions suggested by Ridolfi et al. as typical medullary carcinoma, atypical medullary carcinoma, and non-medullary carcinoma.
Paraffin sections of tumour tissue were examined by an avidin-biotin complex method using two keratin 19-specific monoclonal antibodies (BA17, DAKO and clone 170-2-14, Boehringer) and a monoclonal oestrogen receptor antibody (DAKO).
For comparison 52 ductal carcinomas of grade II and grade III were immunostained as well. The results showed that all 60 tumours with medullary features and all 52 ductal carcinomas reacted moderately to strongly positive with anti-keratin 19 (Boehringer). The staining was diffuse in all cases, except one case of ductal carcinoma (grade III), which stained focally. Immunostaining with the second keratin 19 antibody (BA17) revealed similar results with positive staining in 59 (95%) cases of carcinomas with medullary features and 51 (98%) cases of ductal carcinomas. Only one case in each group did not express keratin 19 (BA17), one re-classified case of non-medullary carcinoma with neuroendocrine features and one case of ductal carcinoma of grade III. None of the 13 cases of typical medullary carcinoma were oestrogen receptor positive and only seven (12%) of the carcinomas with medullary features (2 atypical, 5 non-medullary) were oestrogen receptor positive with quantitative values from 20 to 100%. The 52 ductal carcinomas of grade II and III were oestrogen receptor positive in 56% and 47% of cases.
It is concluded that keratin 19 staining is of no particular value in differentiating medullary from poorly differentiated ductal carcinoma. A carcinoma with positive oestrogen receptor staining is not likely to be a typical medullary carcinoma.
HER2 NEU
Differential amplification and overexpression of HER-2/neu, p53, MIB1, and estrogen receptor/progesterone receptor among medullary carcinoma, atypical medullary carcinoma, and high-grade invasive ductal carcinoma of breast.
Xu R, Feiner H, Li P, Yee H, Inghirami G, Delgado Y, Perle MA.
Department of Pathology, Mount Sinai School of Medicine of New York University, New York, NY, USA.
Arch Pathol Lab Med. 2003 Nov;127(11):1458-64. Abstract quote
CONTEXT: Medullary carcinoma (MC) is a special type of breast cancer that has a better prognosis than atypical medullary carcinoma (AMC) and high-grade invasive ductal carcinoma (HGIDC) with prominent lymphocytic infiltrates. What accounts for the different clinical courses of these carcinomas, despite their similar histology, is unknown. To address this issue, we performed a comparative study of amplification and overexpression of HER-2/neu and expression of several other important biochemical markers (p53, MIB1, and estrogen receptor [ER]/progesterone receptor [PR]) in these 3 cancer groups.OBJECTIVE: To evaluate HER-2/neu, p53, MIB1, and ER/PR as markers in the differential diagnosis of MC, AMC, and HGIDC.Design.-Nine cases of MC, 13 cases of AMC, and 16 cases of HGIDC with prominent lymphocytic infiltrates were identified according to strict histologic criteria. All tests were performed on formalin-fixed, paraffin-embedded archival tissues. HER-2/neu gene amplification was examined by fluorescence in situ hybridization using PathVysion HER-2 DNA probes. Expression of HER-2/neu, p53, MIB1, and ER/PR was detected by immunohistochemistry. chi2 and Student t tests were applied for statistical analyses.
RESULTS: None of 9 cases of MC examined had either amplification or overexpression of HER-2/neu (0%). In contrast, HER-2/neu amplification was observed in AMC (46%, P <.025) and HGIDC (56%, P <.005). All 3 categories of tumors had similar percentages of expression of p53 (78% of MC, 77% of AMC, and 69% of HGIDC) and MIB1 (89% of MC, 92% of AMC, and 94% of HGIDC). Immunostaining for ER/PR was rarely positive in either MC or AMC, and there were no significant differences of expression of ER/PR between these 2 lesions (P >.05). However, the expression rate of ER/PR (31%/44%) in HGIDC is higher than in both MC (P =.05) and AMC (P =.01).
CONCLUSIONS: Medullary carcinoma of breast is distinct from AMC and HGIDC with prominent lymphocytic infiltrates in amplification and overexpression of HER-2/neu. This difference may account for its different clinical and biological behavior, and may potentially aid in diagnosis and management of these groups of patients.
ELECTRON MICROSCOPY Medullary carcinoma of the breast: an ultrastructural morphometric study of nine cases.
Lloreta J, Marinoso ML, Corominas JM, Canas MA, Serrano S.
Department of Pathology, Hospital Universitari de Mar (IMAS-IMIM-Autonomous University of Barcelona, Spain. \
Ultrastruct Pathol 1997 Nov-Dec;21(6):499-507 Abstract quote
Ultrastructural and morphometric features of 10 medullary carcinomas of the breast (MC) were investigated. Cases with a long follow-up were selected by applying stringent histologic criteria. All tumors had a homogeneous appearance by light microscopy.
Under transmission electron microscopy, they showed occasional intracellular lumen formation or keratinization. In one tumor squamous differentiation was prominent and diffuse. Tumors with lymph node metastases possessed over 40% more desmosomes than nonmetastatic tumors. The number of cells with three or more nucleoli per nuclear section was significantly higher in metastatic than in nonmetastatic tumors (p = .02). Classic cases of MC of the breast display a relatively uniform appearance.
However, subtle differences can be identified between metastatic and nonmetastatic tumors by ultrastructural morphometry. Although these differences are not associated with changes in the outcome of patients in this study, they seem to bear some relationship to the peculiar behavior of MC.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES INTRAMAMMARY LYMPH NODE Intramammary lymph nodes: cytologic findings and implications for fine-needle aspiration cytology diagnosis of breast nodules.
Layfield LJ, Glasgow BJ, Hirschcowitz S, Dodd LG.
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Diagn Cytopathol 1997 Sep;17(3):223-9 Abstract quote
The recognition of intramammary lymphoid proliferations is important because smears of these proliferations would be judged as insufficient by several of the published criteria for specimen adequacy. Alternatively, some might be confused with medullary carcinoma of the breast or adenocarcinomas with a "single-cell" pattern.
We found 19 intramammary lymphoid proliferations in a series of 887 fine-needle aspirates of palpable breast nodules. Six were lymphomas and 13 were benign intramammary lymph nodes.
Smear cellularity ranged from scant to high, but in all cases, lymphocytes dominated the cell population. The cytology of intramammary lymph nodes and lymphoma did not differ from those occurring at other sites.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS Must have pure medullary carcinoma with no infiltrating ductal carcinoma
Less than 75% pure syncytial component associated with poorer prognosis
GENERAL Typical medullary carcinoma of the breast: a clinical and pathological analysis of 52 cases.
Reinfuss M, Stelmach A, Mitus J, Rys J, Duda K.
Department of Radiotherapy, Center of Oncology, Maria Sklodowska-Curie Memorial Institute, Cracow, Poland.
J Surg Oncol 1995 Oct;60(2):89-94 Abstract quote
Fifty-two women with typical medullary breast carcinoma, diagnosed according to criteria of Ridolfi et al. [Cancer 40:1365-1385, 1977] are described. At the time of diagnosis, 90% of the patients were stages I and II. The primary tumor size was < or = to 4 cm in 46 (88.5%) and > 4 cm in 6 (11.5%) patients.
Axillary lymph nodes were microscopically negative in 35 (67.3%) and positive in 17 (32.7%) patients. All 52 women underwent the Patey operation. Seventeen patients with microscopically positive axillary lymph nodes received postoperative irradiation. Of the 52 treated patients, 44 (84.6%) survived 10 years NED.
The only prognostic factor was the microscopical axillary lymph nodes status. In the group of pNO patients, 97.1% survived 10 years NED, pN+ 58.8% only. The sole causes of unsuccessful treatment were distant metastases to lungs, hepar, and bones. Typical medullary carcinoma is a favorable histological type of breast carcinoma with very good prognosis for pNO patients.
Medullary carcinoma of the breast. Prevalence and prognostic importance of classical risk factors in breast cancer.
Pedersen L, Zedeler K, Holck S, Schiodt T, Mouridsen HT.
Department of Oncology R, Herlev Hospital, Copenhagen, Denmark.
Eur J Cancer 1995 Dec;31A(13-14):2289-95 Abstract quote
In an earlier study of 235 breast cancers with medullary features, we concluded from a multivariate Cox regression analysis that only four histopathological features contained significantly positive prognostic information.
In the present study, continuing our work on the same population base, we used these histological characteristics (predominantly syncytial growth pattern, no tubular component, diffuse stromal infiltration with mononuclear cells and sparse necrosis (< 25%), as diagnostic criteria for medullary carcinoma of the breast (MC).
We found a significantly better prognosis for patients with MC than those with non-medullary carcinoma (NMC) or infiltrating ductal carcinoma (IDC). All tumours in the MC group were grade II or III (96% grade III). A significantly different distribution of general risk factors such as lymph node status, invasion, steroid receptor status, and menopausal status, was found between the group of MC and the control group of IDC grades II + III. Further, general risk factors, which are found to be of major prognostic importance in IDC, had little prognostic impact in MC.
We found MC to be biologically unique, and patients with MC have a better than average prognosis compared to that of IDC. We propose a new histological definition of MC, but stress that prospective studies have to be performed.
Prognostic comparison of three classifications for medullary carcinomas of the breast.
Jensen ML, Kiaer H, Andersen J, Jensen V, Melsen F.
Department of Pathology, Aarhus University Hospital, Denmark.
Histopathology 1997 Jun;30(6):523-32 Abstract quote
The aim of this study was to make prognostic comparisons between the modified scheme of Pedersen et al. the definitions of Tavassoli and the Ridolfi criteria for medullary carcinomas.
Sixty breast carcinomas primarily diagnosed as medullary carcinomas were reclassified into typical medullary carcinoma (TMC), atypical medullary carcinoma (AMC) and non-medullary carcinoma (NMC) according to the three classifications. The Ridolfi classification proved to be superior to the two other schemes in discriminating survival differences between the three groups TMC, AMC and NMC. All 13 patients with TMC are still alive indicating an excellent prognosis, while 29% and 39% of the 47 patients in the AMC and NMC category, respectively, have died of their disease. In the simplified system of Pedersen et al. the survival at 10 years for TMC patients decreased to 75% and no significant survival difference between the three groups could be demonstrated. As the prognosis for AMC proved to be worse compared to TMC and in fact was similar to NMC with values of 43% at 10 years in the Ridolfi classification, we find no reasons to maintain this category.
We conclude that as long as no alternative and more easily applicable diagnostic method exists, pathologists should still apply the Ridolfi criteria on these tumours with medullary features leaving two diagnostic possibilities: TMC or NMC (i.e. poorly differentiated ductal carcinoma). Only lesions that fulfil all six criteria without any doubt should be diagnosed as TMC, thus avoiding overdiagnosis and a resulting risk of undertreatment.
FLOW CYTOMETRY DNA ploidy and S-phase fraction in medullary carcinoma of the breast--a flow cytometric analysis using archival material.
Pedersen L, Larsen JK, Christensen IJ, Lykkesfeldt A, Holck S, Schiodt T.
Department of Oncology ONK, Rigshospitalet, Copenhagen, Denmark.
Breast Cancer Res Treat 1994;29(3):297-306 Abstract quote
In a population of 110 primary breast cancers with medullary features, registered in the Danish Breast Cancer Cooperative Group (DBCG) from 1977-82, we have determined ploidy and S-phase fraction (SF) by flow cytometry (FCM) on paraffin embedded tumour tissue.
The distribution of DNA ploidy is not different from the distribution described for breast cancers in general. No difference is found between the subgroups of medullary and non-medullary cancer when using a new simplified histopathological definition of medullary carcinoma of the breast, recently proposed by us.
When using the definition proposed by Ridolfi et al. in 1977, we find significantly more tumours with aneuploidy and high SF in the groups of typical medullary carcinoma (TMC) and atypical medullary carcinoma (AMC) than in the small group of non-medullary carcinoma (NMC), which seems a paradox, as patients with NMC have the worst prognosis. However, the number of patients in the NMC group is very small, and the percentage of aneuploid tumours is very low. In 84 protocolled patients we found no statistically prognostic importance of ploidy or SF, either in the whole group assessed or when stratifying for the histopathological subgroups. However, a prognostic influence of SF can be traced for the non-medullary cancers, according to the new definition, but not for the medullary cancers of the breast.
The result emphasizes the impression of MC as being biologically different from other histological types of breast cancer.
Comparison of DNA content, S-phase fraction, and survival between medullary and ductal carcinoma of the breast.
Cook DL, Weaver DL.
Department of Pathology, University of Vermont College of Medicine, Burlington 05405-0068, USA.
Am J Clin Pathol 1995 Jul;104(1):17-22 Abstract quote
Medullary carcinoma (MC) of the breast has been regarded as a subtype of breast carcinoma with a relatively favorable prognosis despite its high nuclear grade and high mitotic index. High nuclear grade and high mitotic index have been correlated with DNA aneuploidy and high S-phase fraction (SPF) by flow cytometry. Generally in breast cancer, these histologic and DNA content features predict a less favorable prognosis.
To address this paradox, all cases of MC of the breast (20 of 1,365 carcinomas [1.5%]) diagnosed between 1968 and 1982 were compared to age- and stage-matched cases of infiltrating ductal carcinoma (IDC) diagnosed during the same time period. All of the MC and 80% of the IDC had one or more DNA aneuploid stem lines. Average total SPF was 8.1% for MC and 4.8% for IDC. DNA analysis was performed from paraffin blocks (average CV: 4.5% DNA diploid; 4.1% DNA aneuploid), and subjected to computer modeled analysis. Statistically significant differences between presence or absence of DNA aneuploidy (P = .035) and total SPF (P = .029) were demonstrated between the two groups.
Thirteen of 20 patients (65%) with MC (average followup 130 months) were alive at the end of the study period compared to 12 of 20 patients (60%) with IDC (average follow-up 160 months). The difference in crude survival was not statistically significant (P = .867). However, there was a tendency toward early death in MC and late death in IDC. Within the TNM stage-matched patients, no significant difference was demonstrated for tumor size or nodal status when these variables were examined separately.
In conclusion, statistically significant differences in DNA content and proliferative fraction exist between medullary carcinoma of the breast and ductal carcinoma. The biologic and clinical differences demonstrated in this analysis warrant careful consideration before including cases of medullary carcinoma in studies evaluating newer prognostic variables in breast cancer.
5 Year Survival 78%
Death secondary to disease in only 10%
95% 20 year disease free survival for stage I patients and 61% for stage II patients
Metastasis Lower frequency of axillary node metastases than infiltrating ductal carcinoma, NOS TREATMENT Usual course for infiltrating ductal carcinoma of the breast Atlas of Tumor Pathology-Tumors of the Mammary Gland. Third Series. Volume 7. AFIP Press 1993.
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