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Ductal carcinoma in situ-like structures in metastatic breast carcinoma
ARTICLE IN PRESS
Pathology – Research and Practice 200 (2005) 831–834 www.elsevier.de/prp
TEACHING CASE
Ductal carcinoma in situ-like structures in metastatic breast carcinoma Radzislaw Kordek Department of Pathology, Chair of Oncology, Medical University of Lodz, Ul. Paderewskiego 4, 93-509 Lodz, Poland Received 26 April 2004; accepted 20 August 2004
Abstract In this report, we present two cases of axillary lymph node metastatic breast carcinoma with features mimicking ductal carcinoma in situ (DCIS): one was of the comedo-like type and the other was suggestive of the micropapillary type. In the first case, the primary tumor presented DCIS of the comedo type; however, in the second case, the primary tumor consisted only of the invasive ductal component. Immunohistochemistry against smooth muscle actin, S100protein, CK5/6, CD10, P63, and 34bE12 did not identify myoepithelial cells either in DICS of the first primary tumor or in both metastases. These features probably do not represent the true DCISs, but only mimic them. This observation suggests that a proportion of ‘‘primary DCIS’’ may constitute an invasive pseudo-DCIS carcinoma, and immunohistochemical identification of myoepithelial cells may be helpful in such cases. r 2004 Elsevier GmbH. All rights reserved. Keywords: Breast carcinoma; Metastases; In situ; Comedo
Introduction
Case I
A pattern reminiscent of ductal carcinoma in situ (DCIS) is rare in metastatic breast carcinoma [1,7]. Barsky et al. regarded such a phenomenon as ‘‘real DCIS’’, as proof of the true reversion of the primary tumor’s metastatic phenotype [1]. However, according to a more widely accepted point of view, these structures only mimic DCIS [7]; therefore, one might suggest that a proportion of ‘‘primary’’ DCIS may actually represent an invasive pseudo-DCIS carcinoma. This report presents two cases of axillary lymph node mestastatic breast carcinoma with features mimicking DCIS—a comedo-like type and a micropapillary type.
A 53-year-old woman presented with a left breast mass measuring 2.5 cm in diameter. Core biopsy revealed infiltrating ductal carcinoma grade 3. Mastectomy was performed, and histology confirmed the diagnosis of infiltrating ductal carcinoma grade 3, without an intraductal component. Thirteen lymph nodes were also examined, and three of them contained metastases: two metastases were small, with a diameter up to 3 mm, while one was larger (1 cm). A structure mimicking micropapillary intraductal carcinoma was observed in a larger metastasis (Fig. 1). Neither in primary carcinoma nor in DCIS-like structures of the secondary tumor were myoepithelial basal cells identified by immunohistochmistry (all from DAKO, EnVision system) for smooth muscle actin, S100-protein, CK5/6, CD10, P63, and 34bE12. Around the DCIS-like focus, we noted a focal band of eosinophilic material reminiscent of basement membrane.
Abbreviation: Ductal carcinoma in situ, DCIS Tel.: +48 42 689 57 81; fax: +48 42 689 54 22. E-mail address: [email protected] (R. Kordek). 0344-0338/$ - see front matter r 2004 Elsevier GmbH. All rights reserved. doi:10.1016/j.prp.2004.08.006
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Fig. 1. DCIS-like structures mimicking micropapillary intraductal carcinoma within lymph node; case I. H&E, 20.
Fig. 3. Primary tumor from case 2 presenting invasive and comedo carcinoma. DCIS-like structures presented no myoepithelial cells, identified with a wide panel of antibodies (P63, SMA, S100-p, CK5/6 and CD10). H&E, 40.
were found at the periphery of DCIS of comedo type (Fig. 3).
Discussion
Fig. 2. Higher magnification of the DCIS-like structure from case 1. H&E, 100.
Case II A 56-year-old woman was admitted to the Oncologic Hospital for treatment of a large tumor in her left breast. A fine needle aspiration biopsy led to the diagnosis of carcinoma, and a radical mastectomy was subsequently performed. The tumor, measuring 5 cm, was histologically diagnosed as an infiltrating ductal carcinoma grade 3, with an extensive intraductal component of the comedo type. Two of 16 axillary lymph nodes contained foci of metastatic carcinoma, and both metastases contained structures mimicking comedo carcinoma (Fig. 2). Immunohistochemical staining for myoepithelial basal cells with antibodies for smooth muscle actin, S100protein, CK5/6, P63, and CD10 revealed no positivity at the periphery of the metastatic comedo-like structures. Moreover, in the primary tumor, no myoepithelial cells
Observations of in situ-like structures in metastatic breast carcinoma are not new. A case report on micropapillary ‘‘DCIS’’ occurring within the breast cancer metastasis has been published [7]. In this case, micropapillary elements were surrounded by a band of material resembling basal membranes with a discontinuous staining for both collagen IV and laminin [7]. In 1997, Barski et al. found DCIS-like elements in 21% of 200 metastatic breast carcinomas and in the majority of cases; these were of the comedo type [1]. These ‘‘metastatic DCIS’’ always presented intact basal membranes, but never demonstrated basal myoepithelial cells. Of note, in all of the cases, ‘‘DCIS’’ within metastasis exhibited the same pattern as did the DCIS component in a given primary tumor. Such ‘‘DCIS-like’’ elements are occasionally observed in everyday practice, but in a proportion that is lower than that reported by Barsky et al. Of a few hundreds of breast cancers recently investigated at our department, we encountered only two cases, which means that such cases account for only less than 1%. Barsky et al. suggested that these features, observed within metastases, allow for the interpretation of a real DCIS, and they may be regarded as proof of the reversion of the primary tumor’s metastatic phenotype [1]. By contrast, Lee et al. described these structures as merely ‘‘DCIS-like’’. In my opinion, it would be more accurate to call such features DCIS-like structures (Fig. 4).
ARTICLE IN PRESS R. Kordek / Pathology – Research and Practice 200 (2005) 831–834
833
Fig. 4. Lymph node from case 2 with subcapsular comedo-like metastatic carcinoma. H&E, 40.
Fig. 5. Higher magnification of one of these structures. They also presented no myoepithelial cells. H&E, 100.
The presence of basal membranes may not be regarded as proof of uninvasiveness, as many types of malignant invasive tumors have such membranes. For instance, they are common in basaloid squamous carcinoma of the rectum or esophagus, in invasive basal cell carcinoma of the skin, and in different malignant salivary tumors [3,8,10]. The DCIS-like structures within breast carcinoma metastases reported by Barsky et al. were always surrounded by basal membranes [1]. These membranes, although fragmented, could also be found in invasive and metastatic breast carcinomas [4,7]. Linear laminin expression around the tumor nests has been reported in 70% of invasive carcinomas [5]. On the other hand, disrupted basal membranes – identical to those found in metastatic structures – were also found in a high proportion of intraductal cancers [2,15,16]. Thus, the presence of continuous membrane is not a proof of intraductal carcinoma. Even neural invasion in intraductal carcinoma of the breast was also observed, but this phenomenon may also be observed in benign breast processes [12] (Fig. 5). Myoepithelial cells may be highlighted by antibodies against specific cytokeratins (as 14), S-100 protein, or anti-alpha-smooth muscle actin; however, P63 was recently regarded as the most sensitive and specific marker of myoepithelial cells, although this is comparable to staining for S-100 protein [9,13]. Stefanou et al. found P63/S-100p-immunopositive myoepithelial cells in all in situ carcinomas. Thus, with these cells being absent, one should always be aware of the possibility that the features observed represent only an in situ-like structure – as in the cases presented in this report. Nests of invasive breast carcinoma usually do not have basal myoepithelial cells, and some investigators even stress that the identification of these cells may play an important role in distinguishing invasive carcinoma
from its mimics [13–15]. On the other hand, myoepithelial cells do not always occur in carcinoma in situ [13]. Barsky et al. reported that DCIS-like structures within metastases never possessed myoepithelial cells, but they were always identifiable in DCIS structures in primary tumor [1]. Our observation does not support this observation, because in our second case, the DCIS-like structures in both primary and secondary tumors showed no myoepithelial cells, although we used a wide panel of antibodies [6]. This observation suggests that, in primary tumor, we also observed only DCIS-like structures, not a real DCIS. One should be aware of a hypothesis also recollected by Barsky et al. and others, according to which some primary DCIS do not necessarily represent an uninvasive carcinoma, but may be invasive in a pushing fashion. This may be particularly true for a comedo DCIS, where the basal lamina is often disorganized and a stromal response is often observed [11]. Moreover, in this subtype, myoepithelial cells are usually absent and its worse prognosis and more complex molecular alterations are widely documented. Our observation emphasizes the need for a careful examination of unclear DCIS cases, with immunohistochemistry against P63 and S-100 protein, because one might suspect that at least a proportion of the high grade DCIS having no myoepithelial cells may represent an invasive cancer growing in such an ‘‘expanding’’ or ‘‘pushing’’ fashion.
References [1] S.H. Barsky, S.A. Doberneck, M.D. Sternlicht, D.A. Grossman, S.M. Love, Revertant DCIS in human axillary breast carcinoma metastases, J. Pathol. 183 (1997) 188–194.
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[2] S. Damiani, M. Ludvikova, G. Tomasic, S. Bianchi, A.M. Gown, V. Eusebi, Myoepithelial cells and basal lamina in poorly differentiated in situ duct carcinoma of the breast. An immunocytochemical study, Virchows Arch. 434 (1999) 227–234. [3] L. El-Shabrawi, P.E. LeBoit, Basal cell carcinoma with thickened basement membrane: a variant that resembles some benign adnexal neoplasms, Am. J. Dermatopathol. 19 (1997) 568–574. [4] V.I. Guelstein, T.A. Tchypysheva, V.D. Ermilova, A.V. Ljubimov, Myoepithelial and basement membrane antigens in benign and malignant human breast tumors, Int. J. Cancer 53 (1993) 269–277. [5] E. Ioachim, A. Charchanti, E. Briasoulis, V. Karavasilis, H. Tsanou, D.L. Arvanitis, N.J. Agnantis, N. Pavlidis, Immunohistochemical expression of extracellular matrix components tenascin, fibronectin, collagen type IV and laminin in the breast cancer: their prognostic value and role in tumour invasion and progression, Eur. J. Cancer 38 (2002) 2362–2370. [6] M. Lacroix-Triki, E. Mery, J.-J. Voigt, L. Istier, Ph. Rochaix, Value of cytokeratin 5/6 immunostaining using D5/16 B4 antibody in the spectrum of proliferative intraepithelial lesions of the breast. A comparative study with 34bE12 antibody, Virchows Arch. 442 (2003) 548–554. [7] A.H. Lee, T.P. Telfer, R.R. Millis, Metastatic breast carcinoma with appearance resembling micropapillary ductal carcinoma in situ, J. Clin. Pathol. 48 (1995) 380–382. [8] R. Raitz, M.D. Martins, V.C. Araujo, J. Oral Pathol. Med. 32 (2003) 290–296.
[9] D. Stefanou, A. Batistatou, A. Nonni, E. Arkoumani, N.J. Agnatis, p63 expression in benign and malignant breast lesions, Histol. Histopathol. 19 (2004) 465–471. [10] K. Takubo, K. Mafune, Y. Tanaka, T. Miyama, K. Fujita, Basaloid squamous carcinoma of the esophagus with marked deposition of basement membrane substance, Acta Pathol. Jpn. 41 (1991) 59–64. [11] P. Tang, S. Teichberg, B. Roberts, S.I. Hajdu, Ultrastructure of the periductal area of comedo carcinoma in situ of the breast, Ann. Clin. Lab. Sci. 31 (2001) 284–290. [12] W.Y. Tsang, J.K. Chan, Neural invasion in intraductal carcinoma of the breast, Human Pathol. 23 (1992) 202–204. [13] X. Wang, I. Mori, W. Tang, M. Nakamura, Y. Nakamura, M. Sato, T. Sakurai, K. Kakudo, p63 expression in normal, hyperplastic and malignant breast tissues, Breast Cancer 9 (2002) 216–219. [14] R.W. Werling, H. Hwang, H. Yaziji, A.M. Gown, Immunohistochemical distinction of invasive from noninvasive breast lesion: a comparative study of p63 versus calponin and smooth muscle myosis heavy chain, Am. J. Surg. Pathol. 27 (2003) 82–90. [15] R.H. Wetzels, R. Holland, U.J. van Haelst, E.B. Lane, I.M. Leight, F.C. Ramaekers, Detection of basement membrane components and basal cell keratin 14 in noninvasive and invasive carcinomas of the breast, Am. J. Pathol. 134 (1989) 571–579. [16] W.Q. Zheng, L.M. Looi, P.L. Cheah, A comparison of the patterns of laminin expression in fibroadenoma, fibrocystic diseases, pre-invasive and invasive ductal breast carcinoma, Pathology 33 (2001) 303–306.
Pathology – Research and Practice 200 (2005) 831–834 www.elsevier.de/prp
TEACHING CASE
Ductal carcinoma in situ-like structures in metastatic breast carcinoma Radzislaw Kordek Department of Pathology, Chair of Oncology, Medical University of Lodz, Ul. Paderewskiego 4, 93-509 Lodz, Poland Received 26 April 2004; accepted 20 August 2004
Abstract In this report, we present two cases of axillary lymph node metastatic breast carcinoma with features mimicking ductal carcinoma in situ (DCIS): one was of the comedo-like type and the other was suggestive of the micropapillary type. In the first case, the primary tumor presented DCIS of the comedo type; however, in the second case, the primary tumor consisted only of the invasive ductal component. Immunohistochemistry against smooth muscle actin, S100protein, CK5/6, CD10, P63, and 34bE12 did not identify myoepithelial cells either in DICS of the first primary tumor or in both metastases. These features probably do not represent the true DCISs, but only mimic them. This observation suggests that a proportion of ‘‘primary DCIS’’ may constitute an invasive pseudo-DCIS carcinoma, and immunohistochemical identification of myoepithelial cells may be helpful in such cases. r 2004 Elsevier GmbH. All rights reserved. Keywords: Breast carcinoma; Metastases; In situ; Comedo
Introduction
Case I
A pattern reminiscent of ductal carcinoma in situ (DCIS) is rare in metastatic breast carcinoma [1,7]. Barsky et al. regarded such a phenomenon as ‘‘real DCIS’’, as proof of the true reversion of the primary tumor’s metastatic phenotype [1]. However, according to a more widely accepted point of view, these structures only mimic DCIS [7]; therefore, one might suggest that a proportion of ‘‘primary’’ DCIS may actually represent an invasive pseudo-DCIS carcinoma. This report presents two cases of axillary lymph node mestastatic breast carcinoma with features mimicking DCIS—a comedo-like type and a micropapillary type.
A 53-year-old woman presented with a left breast mass measuring 2.5 cm in diameter. Core biopsy revealed infiltrating ductal carcinoma grade 3. Mastectomy was performed, and histology confirmed the diagnosis of infiltrating ductal carcinoma grade 3, without an intraductal component. Thirteen lymph nodes were also examined, and three of them contained metastases: two metastases were small, with a diameter up to 3 mm, while one was larger (1 cm). A structure mimicking micropapillary intraductal carcinoma was observed in a larger metastasis (Fig. 1). Neither in primary carcinoma nor in DCIS-like structures of the secondary tumor were myoepithelial basal cells identified by immunohistochmistry (all from DAKO, EnVision system) for smooth muscle actin, S100-protein, CK5/6, CD10, P63, and 34bE12. Around the DCIS-like focus, we noted a focal band of eosinophilic material reminiscent of basement membrane.
Abbreviation: Ductal carcinoma in situ, DCIS Tel.: +48 42 689 57 81; fax: +48 42 689 54 22. E-mail address: [email protected] (R. Kordek). 0344-0338/$ - see front matter r 2004 Elsevier GmbH. All rights reserved. doi:10.1016/j.prp.2004.08.006
ARTICLE IN PRESS 832
R. Kordek / Pathology – Research and Practice 200 (2005) 831–834
Fig. 1. DCIS-like structures mimicking micropapillary intraductal carcinoma within lymph node; case I. H&E, 20.
Fig. 3. Primary tumor from case 2 presenting invasive and comedo carcinoma. DCIS-like structures presented no myoepithelial cells, identified with a wide panel of antibodies (P63, SMA, S100-p, CK5/6 and CD10). H&E, 40.
were found at the periphery of DCIS of comedo type (Fig. 3).
Discussion
Fig. 2. Higher magnification of the DCIS-like structure from case 1. H&E, 100.
Case II A 56-year-old woman was admitted to the Oncologic Hospital for treatment of a large tumor in her left breast. A fine needle aspiration biopsy led to the diagnosis of carcinoma, and a radical mastectomy was subsequently performed. The tumor, measuring 5 cm, was histologically diagnosed as an infiltrating ductal carcinoma grade 3, with an extensive intraductal component of the comedo type. Two of 16 axillary lymph nodes contained foci of metastatic carcinoma, and both metastases contained structures mimicking comedo carcinoma (Fig. 2). Immunohistochemical staining for myoepithelial basal cells with antibodies for smooth muscle actin, S100protein, CK5/6, P63, and CD10 revealed no positivity at the periphery of the metastatic comedo-like structures. Moreover, in the primary tumor, no myoepithelial cells
Observations of in situ-like structures in metastatic breast carcinoma are not new. A case report on micropapillary ‘‘DCIS’’ occurring within the breast cancer metastasis has been published [7]. In this case, micropapillary elements were surrounded by a band of material resembling basal membranes with a discontinuous staining for both collagen IV and laminin [7]. In 1997, Barski et al. found DCIS-like elements in 21% of 200 metastatic breast carcinomas and in the majority of cases; these were of the comedo type [1]. These ‘‘metastatic DCIS’’ always presented intact basal membranes, but never demonstrated basal myoepithelial cells. Of note, in all of the cases, ‘‘DCIS’’ within metastasis exhibited the same pattern as did the DCIS component in a given primary tumor. Such ‘‘DCIS-like’’ elements are occasionally observed in everyday practice, but in a proportion that is lower than that reported by Barsky et al. Of a few hundreds of breast cancers recently investigated at our department, we encountered only two cases, which means that such cases account for only less than 1%. Barsky et al. suggested that these features, observed within metastases, allow for the interpretation of a real DCIS, and they may be regarded as proof of the reversion of the primary tumor’s metastatic phenotype [1]. By contrast, Lee et al. described these structures as merely ‘‘DCIS-like’’. In my opinion, it would be more accurate to call such features DCIS-like structures (Fig. 4).
ARTICLE IN PRESS R. Kordek / Pathology – Research and Practice 200 (2005) 831–834
833
Fig. 4. Lymph node from case 2 with subcapsular comedo-like metastatic carcinoma. H&E, 40.
Fig. 5. Higher magnification of one of these structures. They also presented no myoepithelial cells. H&E, 100.
The presence of basal membranes may not be regarded as proof of uninvasiveness, as many types of malignant invasive tumors have such membranes. For instance, they are common in basaloid squamous carcinoma of the rectum or esophagus, in invasive basal cell carcinoma of the skin, and in different malignant salivary tumors [3,8,10]. The DCIS-like structures within breast carcinoma metastases reported by Barsky et al. were always surrounded by basal membranes [1]. These membranes, although fragmented, could also be found in invasive and metastatic breast carcinomas [4,7]. Linear laminin expression around the tumor nests has been reported in 70% of invasive carcinomas [5]. On the other hand, disrupted basal membranes – identical to those found in metastatic structures – were also found in a high proportion of intraductal cancers [2,15,16]. Thus, the presence of continuous membrane is not a proof of intraductal carcinoma. Even neural invasion in intraductal carcinoma of the breast was also observed, but this phenomenon may also be observed in benign breast processes [12] (Fig. 5). Myoepithelial cells may be highlighted by antibodies against specific cytokeratins (as 14), S-100 protein, or anti-alpha-smooth muscle actin; however, P63 was recently regarded as the most sensitive and specific marker of myoepithelial cells, although this is comparable to staining for S-100 protein [9,13]. Stefanou et al. found P63/S-100p-immunopositive myoepithelial cells in all in situ carcinomas. Thus, with these cells being absent, one should always be aware of the possibility that the features observed represent only an in situ-like structure – as in the cases presented in this report. Nests of invasive breast carcinoma usually do not have basal myoepithelial cells, and some investigators even stress that the identification of these cells may play an important role in distinguishing invasive carcinoma
from its mimics [13–15]. On the other hand, myoepithelial cells do not always occur in carcinoma in situ [13]. Barsky et al. reported that DCIS-like structures within metastases never possessed myoepithelial cells, but they were always identifiable in DCIS structures in primary tumor [1]. Our observation does not support this observation, because in our second case, the DCIS-like structures in both primary and secondary tumors showed no myoepithelial cells, although we used a wide panel of antibodies [6]. This observation suggests that, in primary tumor, we also observed only DCIS-like structures, not a real DCIS. One should be aware of a hypothesis also recollected by Barsky et al. and others, according to which some primary DCIS do not necessarily represent an uninvasive carcinoma, but may be invasive in a pushing fashion. This may be particularly true for a comedo DCIS, where the basal lamina is often disorganized and a stromal response is often observed [11]. Moreover, in this subtype, myoepithelial cells are usually absent and its worse prognosis and more complex molecular alterations are widely documented. Our observation emphasizes the need for a careful examination of unclear DCIS cases, with immunohistochemistry against P63 and S-100 protein, because one might suspect that at least a proportion of the high grade DCIS having no myoepithelial cells may represent an invasive cancer growing in such an ‘‘expanding’’ or ‘‘pushing’’ fashion.
References [1] S.H. Barsky, S.A. Doberneck, M.D. Sternlicht, D.A. Grossman, S.M. Love, Revertant DCIS in human axillary breast carcinoma metastases, J. Pathol. 183 (1997) 188–194.
ARTICLE IN PRESS 834
R. Kordek / Pathology – Research and Practice 200 (2005) 831–834
[2] S. Damiani, M. Ludvikova, G. Tomasic, S. Bianchi, A.M. Gown, V. Eusebi, Myoepithelial cells and basal lamina in poorly differentiated in situ duct carcinoma of the breast. An immunocytochemical study, Virchows Arch. 434 (1999) 227–234. [3] L. El-Shabrawi, P.E. LeBoit, Basal cell carcinoma with thickened basement membrane: a variant that resembles some benign adnexal neoplasms, Am. J. Dermatopathol. 19 (1997) 568–574. [4] V.I. Guelstein, T.A. Tchypysheva, V.D. Ermilova, A.V. Ljubimov, Myoepithelial and basement membrane antigens in benign and malignant human breast tumors, Int. J. Cancer 53 (1993) 269–277. [5] E. Ioachim, A. Charchanti, E. Briasoulis, V. Karavasilis, H. Tsanou, D.L. Arvanitis, N.J. Agnantis, N. Pavlidis, Immunohistochemical expression of extracellular matrix components tenascin, fibronectin, collagen type IV and laminin in the breast cancer: their prognostic value and role in tumour invasion and progression, Eur. J. Cancer 38 (2002) 2362–2370. [6] M. Lacroix-Triki, E. Mery, J.-J. Voigt, L. Istier, Ph. Rochaix, Value of cytokeratin 5/6 immunostaining using D5/16 B4 antibody in the spectrum of proliferative intraepithelial lesions of the breast. A comparative study with 34bE12 antibody, Virchows Arch. 442 (2003) 548–554. [7] A.H. Lee, T.P. Telfer, R.R. Millis, Metastatic breast carcinoma with appearance resembling micropapillary ductal carcinoma in situ, J. Clin. Pathol. 48 (1995) 380–382. [8] R. Raitz, M.D. Martins, V.C. Araujo, J. Oral Pathol. Med. 32 (2003) 290–296.
[9] D. Stefanou, A. Batistatou, A. Nonni, E. Arkoumani, N.J. Agnatis, p63 expression in benign and malignant breast lesions, Histol. Histopathol. 19 (2004) 465–471. [10] K. Takubo, K. Mafune, Y. Tanaka, T. Miyama, K. Fujita, Basaloid squamous carcinoma of the esophagus with marked deposition of basement membrane substance, Acta Pathol. Jpn. 41 (1991) 59–64. [11] P. Tang, S. Teichberg, B. Roberts, S.I. Hajdu, Ultrastructure of the periductal area of comedo carcinoma in situ of the breast, Ann. Clin. Lab. Sci. 31 (2001) 284–290. [12] W.Y. Tsang, J.K. Chan, Neural invasion in intraductal carcinoma of the breast, Human Pathol. 23 (1992) 202–204. [13] X. Wang, I. Mori, W. Tang, M. Nakamura, Y. Nakamura, M. Sato, T. Sakurai, K. Kakudo, p63 expression in normal, hyperplastic and malignant breast tissues, Breast Cancer 9 (2002) 216–219. [14] R.W. Werling, H. Hwang, H. Yaziji, A.M. Gown, Immunohistochemical distinction of invasive from noninvasive breast lesion: a comparative study of p63 versus calponin and smooth muscle myosis heavy chain, Am. J. Surg. Pathol. 27 (2003) 82–90. [15] R.H. Wetzels, R. Holland, U.J. van Haelst, E.B. Lane, I.M. Leight, F.C. Ramaekers, Detection of basement membrane components and basal cell keratin 14 in noninvasive and invasive carcinomas of the breast, Am. J. Pathol. 134 (1989) 571–579. [16] W.Q. Zheng, L.M. Looi, P.L. Cheah, A comparison of the patterns of laminin expression in fibroadenoma, fibrocystic diseases, pre-invasive and invasive ductal breast carcinoma, Pathology 33 (2001) 303–306.