Path. Res. Pract. 188,235-240 (1992)
Pleomorphic Adenoma of the Human Female Breast N. J. Agnantisl, N. Maounisl, M. Priovolou-Papaevangelou 1 and I. Baltatzis2 IDepartment of Pathology, 2Department of Electron Microscopy (Papanikolaou Research Center of Oncology), Hellenic Anticancer Institute, "Saint Savvas" Hospital, Athens, Greece
Summary We are presenting an interesting rare benign breast tumor wh ich meets the characteristics of a salivary gland pleomorphic adenoma. The tumor was misdiagnosed during frozen seetion procedure, because several clusters, mainly composed of myoepithelial cells and surrounded by a chondroid matrix, were mistaken for cancerous blasts. Additionally the clinical and mammagraphie findings were very suspicious. Although this particular tumor is very infrequent, the pathologist should be aware of the difficulties in the differential diagnosis during frozen section and thus defer his final answer to the paraffin sections.
Introduction Pleomorphic adenomas of the female mammary gland are rare benign tumors which cause a lot of problems in making a frozen section diagnosis, and in approximately 50% of the cases give the false picture of malignancy. We believe that every experienced pathologist should have these particular lesions in mind and always defer his diagnosis to the permanent histological specimens and use the special immunohistochemical markers for the identification of myoepithelial cells. The presence of these cells guides to the final confirmation of the neoplasm and saves the patient from an unnecessary extensive surgery. Case History
A 62-year-old obese female was admitted in June 1988 with a painless palpable lump of the left breast. There was no information about the time she discovered the mass and besides a cholecystectomy performed many years ago, her past history ~was otherwise non-contributory. 0344·0338/92/0188·0236$3.50/0
Mammography revealed a subareolar lobulated tumor, partly calcified and circumscribed, measured 3 x 3 cm, without skin infiltration (Fig. 1). The excised mass was hard, circumscribed, partly encapsulated and measured 3.2 X 3 X 2.8 cm. The sectioned surfaces were of rocky consistency along with a mixture of soft pale gray tissue and firm, glistening whitish tissue resembling cartilage. Frozen section diagnosis was positive and a modified radical mastectomy was performed. A tumor slab parallel to the one taken for frozen section was sent to the Biochemical Dept. for examination of hormonal levels. The assays showed a positive estrogen (30 Fmol/mg cytosol protein) and a negative progesterone binding activity (6 FmoVmg cytosol protein). The patient is alive and well two years after the diagnosis. Light Microscopy Microscopic examination of paraffin permanent sections revealed an unexpected picture similar to that of a salivary gland pleomorphic adenoma. The tumor was © 1992 by Gustav Fischer Verlag, Stuttgart
236 . N.
J.
Agnantis et a1.
Fig. 1. Low dose mammography of the left breast.
encapsulated by fibrous coUagenous tissue and only focal lobulated extensions were found in it without any sign of invasion. All over the tumor the matrix showed extensive areas of weU-formed cartilage or bone (Fig. 2). Ir was composed of epithelial cells arranged in acini, small ducts, solid islands or trabeculae in a myxoid chondroid matrix. In many areas myoepithelial cells were easily recognized. (Figs. 3 and 4) Sections from the axiallary lymph node sampling showed no metastases. The PAS stain revealed the presence of glycogen and neutral mucins within the epithelial cells as well as in the stroma of the tumor. The Alcian Blue stain for acid mucins (pH 0.2 and 2.5) showed stromal and epithelial mucins. Both $-100 and a1 smoothmuscle actin confirmed the myoepithelial component of the tumor. Electron Microscopy Fig. 5 showed ductal structures (ds) separated from a collagenous stroma (cg) by a basal lamina (bi). TaU, myoepithelial cells (E) were accached to it by hemidesmosomes (arrows). In Fig. 6 the same cells (E) were observed
Fig.2. Tumor matrix consisted of cartilage and bone. Hß X 300
in a higher magnification. Their cytoplasm contain characteristic myofilaments (arrows) with periodic den ties (head arrows). There was an almost total absence other organelles. Furthermore the bordering cells wc rounded and sm aller compared to the myoepithelial cel Their nuclei (N) were irregularly shaped and nucleoli (NI were common. Fig, 7 showed a third type of cells, mu larger than the other two cell types. These cells, demo strated as one large vacuole (V), had an almost emr: cytoplasm and contained lipid droplets (L). Discussion Pleomorphic adenomas of the breast are rare ben i tumors histologically identical to those found in t salivary glands. Although different theories concerning t histogenesis of these rare tumors have been expressed, seems most probable that they have a common origin wi
Pleomorphic Adenoma of the Human Female Breast . 237
Fig.3. Solid islands, small ducts and acini, composed of epithelial and myoepithelial cells. Copresence of cartilage iri the upper right left. H&E x 250
the same tumors developed in the salivary glands. Seventeen eases have previously been reported in the literature. They usually oeeur in women (only one ease reported in a man) between 23 and 78 years of age. Tumors are well-eieumseribed and may attain dimensions of more than 4 em if left untreated 1,2,3,5,7-13. Almost 50 % of the eases, whieh were misdiagnosed as malignant neoplasms on frozen seetion examination, have undergone unneeessarily extensive surgery3. lt is generally aeeepted that the presenee of eartilage and/or bone in benign or malignant lesions renders the differential diagnosis on frozen seetions diffieult. The clusters of myoepithelial eells in a myxomatous stroma ean be mistaken for eaneerous blasts. For this reason the pathologist must be aware and suspieious of this matter and not be influeneed by the clinieal and/or mammographie findings 1,3,9. Pleomorphie adenoma differs from metaplastie eareinoma and meets the following benign histologieal eriteria:
Fig. 4. Island of epithelial and myoepithelial cells surrounded by chondroid matrix. Although there is slight pleomorphism of the epithelial component the lack of mitoses is consistent with a benign process. H&E x 300
1. Fibrous eneapsulation without evidenee of .invasion. 2. Duetal epithelial hyperplasia and absenee of in situ eomponent. 3. Myoepithelial eomponents with metaplasia into myxoid, ehondroid, and/or osteoid stroma. 4. Cytologieally benign features. Besides the routine H&E stain, other eonventional histoehemieal stains may give a guidanee on the correet diagnosis. Furthermore the combination of eleetron mieroseopy and immunohistoehemistry is very useful in identifying the presenee of myoepithelial eells whieh give the final eonfirmation of the identity of this rare neoplasrn4 ,6. Coneerning the bioehemieal examination of the hormonal levels, our results are in agreement with those reported by Segan et a1.7, in whieh only the estrogen reeeptors showed a positive binding aetivity.
238 . N. J. Agnantis et al.
Fig. 5. The legends are included the text.
Local excision is the treatment of choice. Among the reported cases only two recurrences occured. Pleomorphic adenomas of the breast follow the same benign clinical course as salivary gland mixed tumors 1,9. Finally we would like to emphasize once more that the pathologist must be aware of the difficulties that these neoplasms might cause during frozen sections and should thus defer the cases for permanent sections. References 1 Azzopardi JG (1979) Major Problems in Pathology, Vol11: 334-335 W.B. Saunders 2 Cuadros CL, Ryan SS, Miller RE (1978) Benign mixed tumor (pleomorphic adenoma). of the breast: ultrastructural study and review of the literature. J Surg Oncol 36: 58-63
-' Makek M, von Hochstetter AR (1980) Pleomorphic adenl ma of the human breast. J Surg Oncol14: 281-286 4 McClure J, Smith PS, Jamieson GG (1988) Mixed sativa type adenoma of the human female breast. Arch Pathol Lab Mt 106: 615-619 5 Medina A, Uehtinger K (1980) Das pleomorphe Adenom d Mamma. Helv Chir Acta 47: 205-208 6 Orenstein JM, Dardick I, van Nostrand AW (1985) Ultr structural similarities of adenoid cystic carcinoma and pleomo phic adenoma. Histopathology 9: 623-638 7 Segen JC, Foo M, Richer S (1986) Pleomorphic adenoma the breast with positive estrogen receptors. NY State J Med 8 265-266 R Sheth MT, Hathway D, Petrelli M (1978) Pleomorph adenoma ("mixed" tumor) of human female breast mimickil carcinoma clino-radiologically. Cancer, 41: 659-665 9 Sloan JP (1985) Biopsy Pathology of the Breast. Chapm, and Hall Medical, pp 211-216
I
Fig. 6. The legends are included in the text.
Fig. 7. The legends are included in the text.
240 . N.
J. Agnantis et al.
10 Smith BH, Taylor HB (1969) The occurrence of bone and cartilage in mammary tumours. Am J Clin Pathol 51: 610-618 11 Soreide JA, Anda 0, Eriksen L, Holter J, Kjellevold KH (1988) Pleomorphic adenoma of the human breast with local recurrence. Cancer 61: 997-1001
12 Willer R, Uvelius B, Cameron R (1986) Pleomorpr adenoma in the breast of a human female. Acta Chir Scand 15 709-713 13 Zafrani B, Bourquelot R, Chleq C, Mazabraud A (198 Tumeur mixte du sein (adenome pleomorphe). Mixed tumor the breast (pleomorphic adenoma) Ann Pathol5: 213-215
Received October 10, 1990 . Accepted in revised form March 7, 1991
Key words: Breast - Mixed adenoma N.]. Agnantis, 7 D, Eginitou Str., 11528 Athens, Greece
Letter to the Case
v.
Eusebi
Bologna, Italy
Pleomorphic adenomas (PA) are rare benign tumours of the fern ale breast. In the presentation of their case Dr. Agnantis and co-authors 1 have rightly stressed how these tumours can be deceptive especially on frozen sections. The differentiation of these benign conditions from sarcomatoid carcinoma is mandatory as the latter are very aggressive neoplasms 2 • Sarcomatoid carcinomas (SA) can contain large amounts of myxoid stroma and neoplastic cartilage3 . This latter component is sometimes so well differentiated in SA that, to establish the correct diagnosis, a careful search of the malignant epithelial component or areas of more obvious malignancy is often required. This is the reason why pleomorphic adenomas of the breast have to be extensively sampled as overt malignant changes in SA are occasionally confined to minute areas. Ductal adenoma (DA) is a benign condition 4 which has to be differentiated from PA, especially when DA shows sderotic involution changes. The lack of chondroid substance, together with the confinement of DA within ductal compartments as demonstrated by elastic stain, are two criteria which are very helpful in establishing the correct diagnosis. Salivary glands and breast have several types of tumours in common of which PA is an example. These neoplastic conditions share numerous similarities and some differences, which make one reluctant to lump them together. The histology of PA is similar in both sites. Nevertheless squamous metaplasia of epithelial nests is frequent in salivary glands and not recorded in the breast. In adenocystic carcinomas (ACC) on the contrary squamous meta-.
plasia of neoplastic glands has been described in t breastS, while it is hardly seen in ACC of salivary glands. addition in salivary glands the tumour appears to be mo aggressive than in similar cases reported in the breas Adenomyoepithelioma (ADM) is a further tumo described in the breast6 and salivary glands 7 . In this latt site this tumour is usually defined as epimyoepitheli carcinoma (EMC)8. Squamous and apocrine differenti tion of the cells composing the neoplastic glands appear be uniquely confined to the breast6 • ADM in the bre~ tend to recur9 but no cases where metastatic lymph nod were present have been recorded. EMC in salivary glan have a high incidence of recurrence and appear to met~ tasize to cervicallymph nodes in up to 20 per cent of t cases 8.
References 1 Agnantis NJ, Maounis N, Priovolou-Papaevangelou 1 Baltatzis I (1991) Pleomorphic adenoma of the human fern, breast. Present Issue 2 Eusebi V, Cattani MG, Ceccarelli C, Lamorec J (198 Sarcomatoid carcinoma of the breast: an immunocytochemi( study of 14 ca ses. Progress in Surg Pathol10: 83-99 3 Oberman HA (1987) Metaplastic carcinoma of the brea Am J Surg Pathol11: 918-929 4 AzzopardiJG, Salm R (1984) Ductal adenoma ofthe brea alesion which can mimic carcinoma. J Pathol144: 15-23 5 Lamovec J, Us-Krasovec M, Zidar A, Kljun A (1% Adenoid cystic carcinoma of the breast: a histologie, cytolog
Pleomorphic Adenoma of the Human Female Breast N. J. Agnantisl, N. Maounisl, M. Priovolou-Papaevangelou 1 and I. Baltatzis2 IDepartment of Pathology, 2Department of Electron Microscopy (Papanikolaou Research Center of Oncology), Hellenic Anticancer Institute, "Saint Savvas" Hospital, Athens, Greece
Summary We are presenting an interesting rare benign breast tumor wh ich meets the characteristics of a salivary gland pleomorphic adenoma. The tumor was misdiagnosed during frozen seetion procedure, because several clusters, mainly composed of myoepithelial cells and surrounded by a chondroid matrix, were mistaken for cancerous blasts. Additionally the clinical and mammagraphie findings were very suspicious. Although this particular tumor is very infrequent, the pathologist should be aware of the difficulties in the differential diagnosis during frozen section and thus defer his final answer to the paraffin sections.
Introduction Pleomorphic adenomas of the female mammary gland are rare benign tumors which cause a lot of problems in making a frozen section diagnosis, and in approximately 50% of the cases give the false picture of malignancy. We believe that every experienced pathologist should have these particular lesions in mind and always defer his diagnosis to the permanent histological specimens and use the special immunohistochemical markers for the identification of myoepithelial cells. The presence of these cells guides to the final confirmation of the neoplasm and saves the patient from an unnecessary extensive surgery. Case History
A 62-year-old obese female was admitted in June 1988 with a painless palpable lump of the left breast. There was no information about the time she discovered the mass and besides a cholecystectomy performed many years ago, her past history ~was otherwise non-contributory. 0344·0338/92/0188·0236$3.50/0
Mammography revealed a subareolar lobulated tumor, partly calcified and circumscribed, measured 3 x 3 cm, without skin infiltration (Fig. 1). The excised mass was hard, circumscribed, partly encapsulated and measured 3.2 X 3 X 2.8 cm. The sectioned surfaces were of rocky consistency along with a mixture of soft pale gray tissue and firm, glistening whitish tissue resembling cartilage. Frozen section diagnosis was positive and a modified radical mastectomy was performed. A tumor slab parallel to the one taken for frozen section was sent to the Biochemical Dept. for examination of hormonal levels. The assays showed a positive estrogen (30 Fmol/mg cytosol protein) and a negative progesterone binding activity (6 FmoVmg cytosol protein). The patient is alive and well two years after the diagnosis. Light Microscopy Microscopic examination of paraffin permanent sections revealed an unexpected picture similar to that of a salivary gland pleomorphic adenoma. The tumor was © 1992 by Gustav Fischer Verlag, Stuttgart
236 . N.
J.
Agnantis et a1.
Fig. 1. Low dose mammography of the left breast.
encapsulated by fibrous coUagenous tissue and only focal lobulated extensions were found in it without any sign of invasion. All over the tumor the matrix showed extensive areas of weU-formed cartilage or bone (Fig. 2). Ir was composed of epithelial cells arranged in acini, small ducts, solid islands or trabeculae in a myxoid chondroid matrix. In many areas myoepithelial cells were easily recognized. (Figs. 3 and 4) Sections from the axiallary lymph node sampling showed no metastases. The PAS stain revealed the presence of glycogen and neutral mucins within the epithelial cells as well as in the stroma of the tumor. The Alcian Blue stain for acid mucins (pH 0.2 and 2.5) showed stromal and epithelial mucins. Both $-100 and a1 smoothmuscle actin confirmed the myoepithelial component of the tumor. Electron Microscopy Fig. 5 showed ductal structures (ds) separated from a collagenous stroma (cg) by a basal lamina (bi). TaU, myoepithelial cells (E) were accached to it by hemidesmosomes (arrows). In Fig. 6 the same cells (E) were observed
Fig.2. Tumor matrix consisted of cartilage and bone. Hß X 300
in a higher magnification. Their cytoplasm contain characteristic myofilaments (arrows) with periodic den ties (head arrows). There was an almost total absence other organelles. Furthermore the bordering cells wc rounded and sm aller compared to the myoepithelial cel Their nuclei (N) were irregularly shaped and nucleoli (NI were common. Fig, 7 showed a third type of cells, mu larger than the other two cell types. These cells, demo strated as one large vacuole (V), had an almost emr: cytoplasm and contained lipid droplets (L). Discussion Pleomorphic adenomas of the breast are rare ben i tumors histologically identical to those found in t salivary glands. Although different theories concerning t histogenesis of these rare tumors have been expressed, seems most probable that they have a common origin wi
Pleomorphic Adenoma of the Human Female Breast . 237
Fig.3. Solid islands, small ducts and acini, composed of epithelial and myoepithelial cells. Copresence of cartilage iri the upper right left. H&E x 250
the same tumors developed in the salivary glands. Seventeen eases have previously been reported in the literature. They usually oeeur in women (only one ease reported in a man) between 23 and 78 years of age. Tumors are well-eieumseribed and may attain dimensions of more than 4 em if left untreated 1,2,3,5,7-13. Almost 50 % of the eases, whieh were misdiagnosed as malignant neoplasms on frozen seetion examination, have undergone unneeessarily extensive surgery3. lt is generally aeeepted that the presenee of eartilage and/or bone in benign or malignant lesions renders the differential diagnosis on frozen seetions diffieult. The clusters of myoepithelial eells in a myxomatous stroma ean be mistaken for eaneerous blasts. For this reason the pathologist must be aware and suspieious of this matter and not be influeneed by the clinieal and/or mammographie findings 1,3,9. Pleomorphie adenoma differs from metaplastie eareinoma and meets the following benign histologieal eriteria:
Fig. 4. Island of epithelial and myoepithelial cells surrounded by chondroid matrix. Although there is slight pleomorphism of the epithelial component the lack of mitoses is consistent with a benign process. H&E x 300
1. Fibrous eneapsulation without evidenee of .invasion. 2. Duetal epithelial hyperplasia and absenee of in situ eomponent. 3. Myoepithelial eomponents with metaplasia into myxoid, ehondroid, and/or osteoid stroma. 4. Cytologieally benign features. Besides the routine H&E stain, other eonventional histoehemieal stains may give a guidanee on the correet diagnosis. Furthermore the combination of eleetron mieroseopy and immunohistoehemistry is very useful in identifying the presenee of myoepithelial eells whieh give the final eonfirmation of the identity of this rare neoplasrn4 ,6. Coneerning the bioehemieal examination of the hormonal levels, our results are in agreement with those reported by Segan et a1.7, in whieh only the estrogen reeeptors showed a positive binding aetivity.
238 . N. J. Agnantis et al.
Fig. 5. The legends are included the text.
Local excision is the treatment of choice. Among the reported cases only two recurrences occured. Pleomorphic adenomas of the breast follow the same benign clinical course as salivary gland mixed tumors 1,9. Finally we would like to emphasize once more that the pathologist must be aware of the difficulties that these neoplasms might cause during frozen sections and should thus defer the cases for permanent sections. References 1 Azzopardi JG (1979) Major Problems in Pathology, Vol11: 334-335 W.B. Saunders 2 Cuadros CL, Ryan SS, Miller RE (1978) Benign mixed tumor (pleomorphic adenoma). of the breast: ultrastructural study and review of the literature. J Surg Oncol 36: 58-63
-' Makek M, von Hochstetter AR (1980) Pleomorphic adenl ma of the human breast. J Surg Oncol14: 281-286 4 McClure J, Smith PS, Jamieson GG (1988) Mixed sativa type adenoma of the human female breast. Arch Pathol Lab Mt 106: 615-619 5 Medina A, Uehtinger K (1980) Das pleomorphe Adenom d Mamma. Helv Chir Acta 47: 205-208 6 Orenstein JM, Dardick I, van Nostrand AW (1985) Ultr structural similarities of adenoid cystic carcinoma and pleomo phic adenoma. Histopathology 9: 623-638 7 Segen JC, Foo M, Richer S (1986) Pleomorphic adenoma the breast with positive estrogen receptors. NY State J Med 8 265-266 R Sheth MT, Hathway D, Petrelli M (1978) Pleomorph adenoma ("mixed" tumor) of human female breast mimickil carcinoma clino-radiologically. Cancer, 41: 659-665 9 Sloan JP (1985) Biopsy Pathology of the Breast. Chapm, and Hall Medical, pp 211-216
I
Fig. 6. The legends are included in the text.
Fig. 7. The legends are included in the text.
240 . N.
J. Agnantis et al.
10 Smith BH, Taylor HB (1969) The occurrence of bone and cartilage in mammary tumours. Am J Clin Pathol 51: 610-618 11 Soreide JA, Anda 0, Eriksen L, Holter J, Kjellevold KH (1988) Pleomorphic adenoma of the human breast with local recurrence. Cancer 61: 997-1001
12 Willer R, Uvelius B, Cameron R (1986) Pleomorpr adenoma in the breast of a human female. Acta Chir Scand 15 709-713 13 Zafrani B, Bourquelot R, Chleq C, Mazabraud A (198 Tumeur mixte du sein (adenome pleomorphe). Mixed tumor the breast (pleomorphic adenoma) Ann Pathol5: 213-215
Received October 10, 1990 . Accepted in revised form March 7, 1991
Key words: Breast - Mixed adenoma N.]. Agnantis, 7 D, Eginitou Str., 11528 Athens, Greece
Letter to the Case
v.
Eusebi
Bologna, Italy
Pleomorphic adenomas (PA) are rare benign tumours of the fern ale breast. In the presentation of their case Dr. Agnantis and co-authors 1 have rightly stressed how these tumours can be deceptive especially on frozen sections. The differentiation of these benign conditions from sarcomatoid carcinoma is mandatory as the latter are very aggressive neoplasms 2 • Sarcomatoid carcinomas (SA) can contain large amounts of myxoid stroma and neoplastic cartilage3 . This latter component is sometimes so well differentiated in SA that, to establish the correct diagnosis, a careful search of the malignant epithelial component or areas of more obvious malignancy is often required. This is the reason why pleomorphic adenomas of the breast have to be extensively sampled as overt malignant changes in SA are occasionally confined to minute areas. Ductal adenoma (DA) is a benign condition 4 which has to be differentiated from PA, especially when DA shows sderotic involution changes. The lack of chondroid substance, together with the confinement of DA within ductal compartments as demonstrated by elastic stain, are two criteria which are very helpful in establishing the correct diagnosis. Salivary glands and breast have several types of tumours in common of which PA is an example. These neoplastic conditions share numerous similarities and some differences, which make one reluctant to lump them together. The histology of PA is similar in both sites. Nevertheless squamous metaplasia of epithelial nests is frequent in salivary glands and not recorded in the breast. In adenocystic carcinomas (ACC) on the contrary squamous meta-.
plasia of neoplastic glands has been described in t breastS, while it is hardly seen in ACC of salivary glands. addition in salivary glands the tumour appears to be mo aggressive than in similar cases reported in the breas Adenomyoepithelioma (ADM) is a further tumo described in the breast6 and salivary glands 7 . In this latt site this tumour is usually defined as epimyoepitheli carcinoma (EMC)8. Squamous and apocrine differenti tion of the cells composing the neoplastic glands appear be uniquely confined to the breast6 • ADM in the bre~ tend to recur9 but no cases where metastatic lymph nod were present have been recorded. EMC in salivary glan have a high incidence of recurrence and appear to met~ tasize to cervicallymph nodes in up to 20 per cent of t cases 8.
References 1 Agnantis NJ, Maounis N, Priovolou-Papaevangelou 1 Baltatzis I (1991) Pleomorphic adenoma of the human fern, breast. Present Issue 2 Eusebi V, Cattani MG, Ceccarelli C, Lamorec J (198 Sarcomatoid carcinoma of the breast: an immunocytochemi( study of 14 ca ses. Progress in Surg Pathol10: 83-99 3 Oberman HA (1987) Metaplastic carcinoma of the brea Am J Surg Pathol11: 918-929 4 AzzopardiJG, Salm R (1984) Ductal adenoma ofthe brea alesion which can mimic carcinoma. J Pathol144: 15-23 5 Lamovec J, Us-Krasovec M, Zidar A, Kljun A (1% Adenoid cystic carcinoma of the breast: a histologie, cytolog
