Tumours and dysplasias of the mammary gland

Bull. Org. mond. Sante 1 1974 50 111-133Bull. Wld Hlth Org. J 5 1 IX. Tumours and dysplasias of the mammary gland J. F. HAMPE1 & W. MISDORP 2 As mammary tumours occuir frequently in the dog and cat but rarely in other domestic animals, only the tumours of these two species are classified. The epithelial tumours are termed " complex" when they consist of cells resembling both secretory and myoepithelial cells; these tumours are biologically less malignant than tumours of the " simple " type in which only one of these kinds of cell is present. The carcinomas are subdivided into adeno- carcinoma, solid carcinoma, spindle cell carcinoma, anaplastic carcinoma, squamous cell carcinoma, and mucinous carcinoma. The term " carcinosarcoma or malignant mixed tumour" was used only when there were cells morphologically resembling not only one or both of the epithelial components but also connective tissue cells with their products of differentiation. The benign tumours are classed as adenoma, papilloma, fibroadenoma, or benign soft tissue tumour. The dysplasias are described under the following headings: cyst, adenosis, regular typical epithelial proliferation in ducts and lobules (epitheliosis), duct ectasia, fibrosclerosis, and lobular hyperplasia. This classification deals with malignant and benign tumours and with dysplasias of the mammary gland of the dog and cat. Only in these species could the lesions be studied in sufficient numbers and by the same methods (microscopical, follow-up, post-mor- tem studies) as in the human pathology. Mammary tumours are rare in other domestic animals. The tabulated classification is a composite one for the dog and cat. Some types listed have been found in only one of these species, as indicated in the text. The classification is based mainly on descriptive morphology and only to a much lesser extent on histogenesis. We have followed as far as possible the WHO classification of human breast tumours.a The material on which this study was based was obtained from various centres and comprises about 800 canine and 300 feline specimens, sampled in a highly selective way. This selective sampling makes it difficult to state what proportions of mammary lesions in the dog and in the cat are malignant or 1 Pathologist, Laboratory of Pathology at the Binnen- gasthuis, University of Amsterdam, Amsterdam, Nether- lands. 2 Veterinary pathologist, Department of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands. a Scarff, R. W. & Torloni, H. Histological typing of breast tumours, Geneva, WHO, 1968. benign. In the surgical material in Amsterdam +40% of lesions in bitches and ±85% of those in female cats proved by the development of meta- stases to be malignant. Careful examination of the mammary glands of old dogs and cats, however, would probably reveal many benign lesions. The most important part of the classification deals with malignant tumours and is based on our rather extensive studies of tumours that have already meta- stasized. These tumours have therefore been listed first (for exact numbers of the tumour types studied, see Misdorp et al.b). The next part of the classifica- tion concerns the more debatable, apparently benign, tumours. For the last part, dealing with the more controversial proliferative lesions of dysplasia, we have had to draw on what is known about analogous human conditions. Thus the sequence of these three main divisions is the opposite of that followed in the WHO classification of human breast tumours. We felt compelled to diverge from the human classification in places, especially the part concern- ing malignant tumours, on the one hand because we were not sure that certain tumours in man had their exact counterparts in the dog and cat (or vice versa) and, on the other hand, because the classifica- b Veterinary Pathology, 8: 99-112 (1971), 9: 447-470 (1972), 10: 241-256 (1973). 3171 - 111- 112 J. F. HAMPE & W. MISDORP tion of the human malignant tumours was related partly to their prognosis. In animals, the natural course of malignant neoplasia is often cut short because the patients are subjected to euthanasia. That practice, together with differences in anatomy and physiology, must affect the comparability of disease patterns, even in cases of seemingly identical tumour types. Mammary tumours and lesions in bitches were classified as "complex" when both secretory and myoepithelial cells were present and as " simple " when only one of these types of cell was present. Such a separation has not yet been made by us in the human being and in the cat; however, recent litera- ture clearly points to the importance of further study of this subject (especially in man). Experience with complex tumours in bitches led us to the observa- tion that many lesions-malignant and benign-in the human breast consist partly of myoepithelial cells. On the other hand, knowledge of the growth pattern in human adenosis, for example, has helped us to recognize some types of ductolobular hyper- plasia in bitches. A classification cannot be expected to serve all purposes and certainly not over a long period of time. Yet we are presenting our classification now because we consider that it is adaptable. For example, when we had learned from retrospective and prospec- tive follow-up studies that the entire group of carcin- omas shows a different growth pattern and a dif- ferent biological behaviour depending on whether the tumours are simple or complex, it was easy to adapt the classification accordingly (W. Misdorp & J. Hart, unpublished observations, 1974). The most frequent type ofcarcinoma-the simple type (65%)- generally grows in a highly infiltrative manner, invades lymph vessels, and spreads to regional lymph nodes, remote lymph nodes, and lungs. Survival time is usually short. The complex type of carcinoma (35 Y.) often grows in a more expansive " pushing " way, invades lymph vessels to a lesser extent, spreads to the lungs and, less frequently, to the lymph nodes. Survival is relatively long. The carcinomas were classified according to their predominant histological features. However, canine mammary carcinomas, both simple and complex, can also be categorized according to their level of differentiation as indicated by the degree of tubule formation, the extremes being tubular adenocarcin- oma and solid carcinoma. This principle might be extended to provide a morphological grading of tumour malignancy as in human pathology. Our prospective studies a showed that histological grading of feline mammary carcinomas has prog- nostic significance. In dogs, clinical staging is of far greater significance than histological grading (W. Misdorp & J. Hart, unpublished observations, 1974). From our retrospective study of carcinosarcomas (malignant mixed tumours) we learned that their biological behaviour seems to be related to their carcinomatous part and to be of the same order as in the complex carcinomas. That might justify grouping malignant mixed tumours along with all types of complex carcinomas under one heading. Until there is more definite information from prospective studies, we have drawn the line with the appearance of cartilage and bone (considered to be part of the tumour parenchyma). Malignant mixed tumours, although far less common than their benign counter- parts, occur much more frequently in the dog than in the human being or cat. The mammary sarcomas, unlike the carcinomas, were not classified according to the predominance of some morphological feature of the tumour cells but according to the type of intercellular material present. In the case of sarcomas with multidifferentiation (bone, cartilage, fat, etc.), the use of descriptive terms such as osteochondroliposarcoma has been discontinued in human pathology for primary tumours of bone because retrospective studies showed the decisive importance of one of the com- ponents, e.g., tumorous bone. As data from retro- spective studies are not available for mammary sarcomas of animals, we have used the descriptive terminology. That morphological criteria alone may be mis- leading, as in human pathology, is exemplified by tumours of benign microscopic appearance, which, after a long lapse of time, may give rise to regional or distant metastases-e.g., some papillary cystic adenocarcinomas. In our material such cases represented approximately 10% of the metastasized cases. The metastasized cases of malignant tumours used for our classification represent well-defined morpho- logical end-points. A further group of tumours of variable or unknown biological behaviour has been set apart as being suspect, potentially malignant, or borderline. Follow-up studies indicate that the poten- a Weijer, K. et al. Journal of the National Cancer Insti- tute, 49 (6): 1697-1701 (1972). MAMMARY GLAND tial malignancy of most, if not all, of these tumours had been overrated by us. In bitches, especially, difficulties may arise in the evaluation of highly com- plex tumours, which, without being malignant, may produce that impression on microscopic examina- tion, particularly when studied against a background of human pathology. Another gap in knowledge concerns the possibility that certain types of lesion are not morphological end-points but represent stages of changing morpho- logy along a supposed line of development. The qualification of a lesion as " borderline" therefore might not only reflect uncertainty in the interpreta- tion of the morphological findings but also represent a stage of development of which the end-point is not yet known. In the case of clear-cut cancers, that difficulty might be slight: a microinvasive car- cinoma small, early, or preclinical- may well have the same histomorphological appearance as a fully grown, clinically palpable lump. The possibility that benign or apparently benign tumours in bitches may become malignant should also be considered. Thus, the possibility that a carcinoma or sarcoma might arise in or from a fibroadenoma or mixed tumour was indicated in some of our cases. In the case of proliferative lesions that are not, or not yet, infiltrating malignancies, investigation is needed to determine what morphological entities may arise as the lesions develop. It seems evident from our study that complex adenomas and benign mixed tumours may develop from lobular hyperplasias by apposition and coalescence. The consideration that some lesions may lead to progressive changes and others to regressive changes, whereas some may remain stationary for a long time, is of paramount importance in the study and interpretation of pro- liferation in man as well as in animals. The morpho- logical classification of mammary nonmalignant, or not yet malignant, proliferative lesions (whether called tumours or not) is much more difficult than that of malignant tumours, and such a classification is more open to personal opinion and is more likely to need modification in the near future. We believed that it was far easier to make comparative use of the histological typing of nonmalignant prolifera- tive breast lesions in man than of malignant tumours. Bearing in mind the well-known diver- gencies and controversies in human pathology, we have refrained from using the term " mastopathy" in this classification. We had to decide whether or not to use the terms " precancerous lesion " and " carcinoma in situ ". The former has not been applied to histomorphological or cytonuclear criteria because the interpretation of such lesions requires statistical studies. Nor have we felt sure enough to make the diagnosis of mammary carcinoma in situ, in either its ductal or its ductulolobular forms, in bitches and cats. No counterpart of Paget's disease or of adenoma of the teat in human beings has been found by us in the comparative study of animal material. As in human pathology, opinions differ concern- ing normality in the mammary glands of dogs and cats. As regards bitches, more attention should per- haps be paid to changes in the structure of the mammary tissue in relation to the sexual cycle. Our study was based on routinely stained sections, and, where necessary, special stains (e.g., Gomori's reticulum stain, Lendrum-Masson, and alcian blue) were used. This publication is the fruit of a collaborative study and we acknowledge particularly the assistance ofProfessor E. Cotchin, Professor E. Dahme, Dr L. J. Faulkin, Mr K. W. Head, Dr Anne G. Jabara, Professor J. von Sandersleben, and Dr K. Weijer. Dr L. J. Faulkin provided a large number of small nodular lesions that were found by him in whole- mount specimens of mammary glands of old beagles. The rest of the material came from various breeds and age groups. * * * 113 114 J. F. HAMPE & W. MISDORP HISTOLOGICAL CLASSIFICATION AND NOMENCLATURE OF TUMOURS AND DYSPLASIAS OF THE MAMMARY GLAND I. CARCINOMA A. ADENOCARCINOMA 1. Tubular (a) simple type a (b) complex type b 2. Papillary (a) simple type (b) complex type 3. Papillary cystic (a) simple type (b) complex type B. SOLIX: CARCINOMA (a) simple type (b) complex type C. SPINDLE CELL CARCINOMA (a) simple type (b) complex type D. ANAPLASTIC CARCINOMA E. SQUAMOUS CELL CARCINOMA F. MUCINOUS CARCINOMA II. SARCOMA A. OSTEOSARCOMA B. FIBROSARCOMA C. OSTEOCHONDROSARCOMA (FIBRO-LIPO- OSTEOCHONDROSARCOMA) [COMBINED SARCOMA] D. OTHER SARCOMAS III. CARCINOSARCOMA (MALIGNANT MIXED TUMOUR) a The term " simple " is applied to any type of neoplasm or proliferation composed of cells resembling either secretory epithelial cells or myoepithelial cells. b The term " complex " is applied to any type of neo- plasm or proliferation composed of cells resembling both secretory epithelial cells and myoepithelial cells. IV. BENIGN OR APPARENTLY BENIGN TUMOURS A. ADENOMA B. PAPILLOMA 1. Duct papilloma 2. Duct papillomatosis C. FIBROADENOMA 1. Pericanalicular 2. Intracanalicular (a) noncellular type (b) cellular type 3. Benign mixed tumour 4. Total fibroadenomatous change D. BENIGN SOFT-TISSUE TUMOUR V. UNCLASSIFIED TUMOURS VI. BENIGN OR APPARENTLY BENIGN DYSPLASIAS c A. CYST 1. Nonpapillary 2. Papillary B. ADENOSIS C. REGULAR TYPICAL EPITHELIAL PROLIFERATION IN DUCTS OR LOBULES D. DUCT ECTASIA E. FIBROSCLEROSIS F. GYNAECOMASTIA G. OTHER NON-NEOPLASTIC PROLIFERATIVE LESIONS 1. Noninflammatory lobular hyperplasia 2. Inflammatory lobular hyperplasia c The term " dysplasia " is used as defined in the WHO classification of human breast tumours and not in the sense of certain disorderly proliferations together with a certain degree of cytonuclear atypia. MAMMARY GLAND DESCRIPTION OF TUMOURS I. CARCINOMA Whereas, in man, lymphoplasmocytic infiltration is a feature peculiar to medullary carcinoma, in dogs and cats it is found also in other types of carcinoma that show different grades of stromal reaction. Papillary carcinoma of the human classification is represented in the dog and cat under two headings: papillary and papillary cystic carcinomas. A. Adenocarcinoma 1. Tubular (a) Simple type (Fig. 1-3). In the dog, these tumours occur rather frequently. They show a predominantly tubular arrangement. The cells resemble luminal epithelial cells. About half of the tumours also show papilliferous and/or solid and/or squamous features. Pleomorphism and mitotic activity vary from low to high and necrosis is common. The amount of stroma is usually scanty or moderate. Lymphocytes and plasma cells are present in varying numbers around some tumours but rarely inside them. Histological dif- ferentiation between some tubular adenocarcin- omas and some benign adenomatous lesions may be very difficult, as the benign lesions may also show high mitotic activity or simulate invasive growth. In the cat, these tumours constitute the most frequent type. Some 3000 show papillary, papillary-cystic, and/or solid features. Tubular adenocarcinomas may grow either in a highly invasive way (700%) or in an expansive nodular way (30 Y.). Invasion of lymphatics is frequent (50%). Pleomorphism varies from low to moder- ate and mitotic activity varies from moderate to high. Extensive necrosis is common and the amount of stroma is usually small or moderate. Lymphocytes and plasma cells are usually present around these tumours, often in relatively large numbers. (b) Complex type (Fig. 4, 5). In the dog, the cellular arrangement is predominantly tubular. The tumours are composed of cells of two types, some resembling luminal epithelial cells and others myoepithelial cells. The tumours consist of tubules lined with cuboidal or columnar cells (some of which may show squamous change) and sur- rounded by solid sheets of polyhedral or spindle- shaped cells, the latter often having a vacuolated cytoplasm. Sometimes the surrounding neoplastic myoepithelial cells are arranged in a more-or-less stellate reticulated pattern. Expansive, nodular, lobulated growth is quite common (±50%) and growth along lymphatics is rare (±I10 %). Histolo- gical differentiation between highly differentiated carcinomas of this type and complex adenomas can be very difficult. Numerous mitoses, cellular- ity, and a relatively large amount of necrosis are usually indicative of malignancy. The complex type was not found in the cat. 2. Papillary (a) Simple type (Fig. 6). This type, in which columnar or cuboidal cells within the neoplastic tubules are arranged in a sessile or pedunculated papillary form, occurs frequently in the dog. The stroma of the papillae is scanty. Most of these tumours are purely papillary, but some also show solid areas or areas without papillary growth. In about 80% there are extensive infiltration into the overlying skin and surrounding tissues and invasion of lymphatics. Sometimes it is very difficult to determine whether a papillary adeno- carcinoma is growing in lymphatics or in neo- plastic or preexisting tubules. Pleomorphism and mitotic activity vary from moderate to high. The better-differentiated carcinomas must be distin- guished from benign papillary lesions in the ducts and ductules (including papillary epitheliosis). Sometimes differentiation in cases with atypia but without infiltration remains doubtful. The same type is not infrequently seen in cats. Most of them (±80%) are of a purely papillary type. These tumours usually grow in a highly invasive fashion (80 %) and invasion of lymphatics is common (60%). Pleomorphism varies from low to moderate and mitotic activity varies from low to high. Extensive necrosis is a prominent feature. Lymphocytes and plasma cells are usually present around the tumours, often in relatively large numbers. Granulocytes are often present in the lumina, even in tumours without obvious necrosis. (b) Complex type (Fig. 7). In the dog, these adenocarcinomas are rare. The cells within the neoplastic tubules are mostly arranged in a sessile or pedunculated papillary form. The tumours are 115 J. F. HAMPE & W. MISDORP composed of two types of cell, some resembling luminal epithelial cells and others myoepithelial cells. The papillae in these tumours, covered by cuboidal or columnar epithelial cells, are sur- rounded by solid sheets of cells resembling myo- epithelial cells. Usually these tumours are well defined and do not invade lymphatics. Differentia- tion from adenomas of the complex type may be difficult. Only one case was found in a cat. 3. Papillary cystic (a) Simple type (Fig. 8). This type, which is not uncommon in the dog, shows both papillary and cystic structures. The tumours are composed of cells resembling those of luminal epithelium, mostly columnar or sometimes cuboidal. Most of these tumours are well defined and invasion of lymphatics is rare. Pleomorphism and mitotic activity vary from low to moderate. Papillary cystadenocarcinomas, especially when well dif- ferentiated, are sometimes difficult to distinguish histologically from papillary cystadenomas and cystadenopapillomatosis. Ia the cat, about half the tumours of this type show invasive growth and invasion of lymphatics is sometimes seen. Usually pleomorphism and mitotic activity are not pro- nounced. Papillary cystadenocarcinomas, espe- cially when well differentiated, are sometimes dif- ficult to distinguish histologically from cystadeno- mas, the latter often being multiple. (b) Complex type (Fig. 9). In the dog, this rare type shows both papillary and cystic structures. These tumours are composed of cells resembling luminal epithelial and myoepithelial cells. They show a striking resemblance to the simple type, differing only in the occurrence of solid foci of spindle cells that resemble myoepithelial cells with vacuolated cytoplasm. Some carcinomas of this type, although they have already metastasized, are so highly differentiated that it would be virtually impossible to distinguish them from their benign counterparts without knowledge of the presence of the secondary tumours. This type was not seen in the cat. B. Solid carcinoma (a) Simple type (Fig. 10-12). In this type of carcinoma, which is rather frequent in the dog, the cells are arranged mainly in solid sheets, cords, or masses, without tubular or other lumen for- mation. The cells are either of luminal epithelial or of myoepithelial type. Less than half of the carcinomas that we examined were of purely solid type. The rest contained some foci of aden- omatous differentiation. The degree of pleo- morphism and the mitotic rate vary from moder- ate to high. The amount of stroma ranges from small to moderate. Most solid carcinomas of the simple type show infiltrative growth, and penetra- tion of lymphatics is rather common (60%). Dif- ferentiation between some small solid carcinomas and the solid atypical type of epitheliosis or cancer in situ can be extremely difficult. Some solid car- cinomas are composed of cells with vacuolated cytoplasm (clear-cell subtype). These cells show some resemblance to myoepithelial cells, indicat- ing the possibility of the existence of a purely myoepithelial type of carcinoma. In the cat, half of the tumours of this rather common type are purely solid. The other half contain foci of aden- omatous differentiation. These tumours generally show highly infiltrative growth and permeate along lymph vessels. Moderate-to-large numbers of lym- phocytes and plasma cells are present around most of these tumours. (b) Complex type (Fig. 13). In the dog, the tumour cells are arranged mainly in solid sheets, cords, or masses, without lumina. The cells bear a morphological resemblance to luminal epithelial cells and myoepithelial cells. The predominating solid parts consist of cells with vacuolated cyto- plasm. Masses of these cells surround tubules of which the cells may show squamous metaplasia. Most of these carcinomas (like their adenomatous counterparts) grow in a rather expansive way and penetration of lymphatics is rare. Differentiation between solid carcinomas of the complex type and complex adenomas can be difficult. This type was not seen in the cat. C. Spindle cell carcinoma (Fig. 14, 15) In the dog, this tumour is mostly solid, but it warrants a separate category on account of its very marked spindle cells. These relatively rare carcin- omas may grow in either an expansive or an infiltra- tive manner; the latter kind of growth may be accompanied by penetration of lymphatics. This type, as well as some solid carcinomas of the simple type and the histologically quite similar fibrosarcoma, has probably been included in the group " malignant myoepithelioma" by some authors. Differentiation between spindle cell carcinomas and fibrosarcomas may be difficult, but can be facilitated by the use of reticulin fibre stains. This type was not found in cats. 116 e e,~~~~ N q^jgw rs, *;;,- It>S Xf Fig. 1. Tubular adenocarcinoma, simple type, partly papillary; " lobular " arrangement (dog). Fig. 3. Tubular adenocarcinoma, simple type, well differentiated (cat). Fig. 2. Tubular adenocarcinoma, simple type, not well differentiated; cellular stroma (dog). Fig. 4. Tubular adenocarcinoma, complex type, stellate (myoepithelial) cells and mucoid intercellular material (dog). Fig. 5. Tubular adenocarcinoma, complex type, squa- mous metaplasia; dark foci representing keratin (dog). #a~~~~~~~~~~~~~~%i' Fig.6.Papillary adenocarcinoma, simple type (dog).~~~~~~~~~~~~~~~~~~~~~~ 1%" Fig. 7. Papillary adenocarcinoma, complex type; predominantly solid spindle cell (myoepithelial) area (cat). Fig. 8. Papillary cystic adenocarcinoma, simple type, highly differentiated (dog). Fig. 9. Papillary cystic adenocarcinoma, complex type, highly differentiated (dog). Fig. 10. Solid carcinoma, simple type; some vacuolated, mainly hydropic cells (dog). Fig. 11. Solid carcinoma, simple, clear-cell subtype; adjacent tumour cells in lymphatics (dog). Fig. 12. Solid carcinoma, simple type; medullary appearance, no lymphocytic infiltration, many clear cells (cat). Fig. 13. Solid carcinoma, complex type; solid masses of spindle cells, some vacuolated and stellate; few tubules (dog). Fig. 15. Spindle cell carcinoma, complex type; some tubules (dog). tE-v~~~~~- -~~~A -As. Z=Wv;G- e Fig. 14. Spindle cell carcinoma, simple type; resem- blance to fibrosarcoma; carcinomatous nature confir- med by reticulin stain (dog). Fig. 16. Anaplastic carcinoma; granulocytes in stroma and in tumour cells (dog). Fig. 17. Squamous cell carcinoma; glandular parts and extensive keratinization (dog). Fig. 19. Mucinous carcinoma, adenoid cystic (cat). Fig. 18. Mucinous carcinoma; variable amount of mucin in and between stellate (myoepithelial) carcin- oma cells (dog). Fig. 20. Osteosarcoma (noncombined sarcoma); oste- oid formation by tumour cells (dog). Fig. 21. Fibrosarcoma; concentric growth around a small blood vessel (dog). Fig. 23. Combined sarcoma (fibro-lipo-osteochondro- sarcoma); pulmonary metastasis with highly differ- entiated components (dog). Fig. 22. Combined sarcoma (osteochondrosarcoma); osteoid and cartilage directly produced by spindle- shaped tumour cells (dog). Fig. 24. Carcinosarcoma with merging carcinomatous and chondrosarcomatous parts (dog). Fig. 25. Carcinosarcoma; neoplastic epithelium, bone, and fat (dog). Fig. 27. Adenoma, solid, myoepithelial (dog). Fig. 26. Adenoma, simple (dog). Fig. 28. Adenoma, complex; stellate cells and myxoid intercellular substance (dog). Fig. 29. Duct papilloma (dog). Fig. 31. Fibroadenoma, intracanalicular (dog). %C4~ ~ ~ ~ ' Fig. 30. Fibroadenoma, pericanalicular; predominance of spindle cell (myoepithelial) and/or stromal over- growth (dog). Fig. 32. Benign mixed tumour; fibroadenomatous tissue, cartilage, and bone (dog). A.' . .*.j'. Fig. 33. Total fibroadenomatous change (cat). Fig. 35. Adenosis, fibrosing, simulating malignant infiltrating growth, part of Fig. 48 (dog). \ A 4''~~~~~~~~~~~~ Fig. 34. Papillary cyst (cat). Fig. 36. Regular typical epithelial proliferation (" epi- theliosis ") in lobule and intralobular ducts (dog). : Fig. 37. Regular typical epithelial proliferation; mural type of epitheliosis" in lactational lobule (dog). Fig. 39. Duct ectasia and papillary regular epithelial proliferation (dog). -ftMsf 4w f- a] Fig. 38. Regular typical epithelial proliferation in small duct; part solid, part tubular (dog). Fig. 40. Duct ectasia; grossly spongy mammary gland (cat). Fig. 41. Duct ectasia; " adenomatous" proliferation with ectasia of ducts and acini (cat). Fig. 43. Lobular hyperplasia, noninflammatory, simple; intraluminal secretion (dog). Fig. 42. Fibrosclerosis; focal proliferation of fibrous tissue in and around preexisting ducts and lobules (dog). 'U,''. Fig. 44. Lobular hyperplasia, noninflammatory, com- plex; appositional growth and possible transition into a complex adenoma (dog). Fig. 45. Lobular hyperplasia, noninflammatory, com- plex; possible evolution into a benign mixed tumour (dog). Fig. 47. Lobular hyperplasia, inflammatory type (dog). Fig. 46. Lobular hyperplasia, noninflammatory; the enlarged lobule shows hyperplasia of complex type combined with acinar ectasia (cat). .1, Fig. 48. Lobular hyperplasia, inflammatory type, suggestive of focal fibrosing adenosis or perhaps early carcinoma (dog). A- '."' 'I- ..-.PI ... wa-S" '.: -j "I ." ..ii, , .. - ._-V -T. .4 ;. '. MAMMARY GLAN1 D. Anaplastic carcinoma (Fig. 16) This type, not uncommon in our series of canine tumours, is generally not classifiable as adeno- carcinoma, solid carcinoma, squamous cell carcin- oma, or mucinous carcinoma. The main picture is that of a diffusely infiltrating neoplasm composed of large pleomorphic cells, often with bizarre nuclei, rich in chromatin; some cells are multinucleated. Many mitoses are found. The cytoplasm is eosino- philic and vacuoles are not uncommon. The tumour cells occasionally form very small, ill-defined, tubular structures or very small solid cords. Polynucleated granulocytes are present within the tumour cells and in the stroma of some anaplastic carcinomas. Collagenous stroma is abundant (scirrhous carcin- oma) and contains scattered foci of lymphocytes. Penetration of lymphatics is a common feature. Some extremely anaplastic carcinomas are very hard to recognize as epithelial tumours. This type was not seen in the cat. E. Squamous cell carcinoma (Fig. 17) In the dog, this carcinoma is composed mainly of cells that show characteristics of malignant squa- mous stratified epithelium, such as prickle cells and/or keratinization. In our series these tumours were all of the simple type, but complex ones might occur, the nonsquamous part being composed of two types of cell. This tumour is relatively uncommon in human beings and dogs, and was not found in cats. Considerable variation occurred in the histolo- gical appearance both among tumours and within the same tumour. Half of the squamous cell carcin- omas consist partly of adenomatous tissue, and in some of these distinct keratohyalin granules and keratin lamellae are present. Other squamous cell carcinomas consist of solid sheets and cords with areas of cornification. Basal cells are predominant in the peripheral parts of the sheets and keratohyalin granules are absent or rare. The central parts con- sist of nonlamellated keratin that can easily be mistaken for necrotic tumour tissue. " Shadow" or " ghost " cells are frequently encountered. In most of these carcinomas keratinization occurs abruptly, as is seen in Malherbe's tumour of the skin. Most squamous cell carcinomas are highly infiltrative and invasion of lymphatics is common (50%). Primary mammary squamous cell carcinomas should be dis- tinguished from primary squamous cell tumours derived from the skin, the dermal adnexae, and epi- dermal cysts. This type was not seen in the cat. F. Mucinous carcinoma (Fig. 18, 19) In this carcinoma there is excessive mucin produc- tion. In its typical form it is a rare tumour in women and in female dogs and cats. In the carcinomas of our series, neoplastic myoepithelial cells predomi- nated (complex carcinomas) but their role in relation to mucin production is not clear. On theoretical grounds three types may be expected, since the mucin may arise from secretory epithelial cells, from connective tissue cells, or from myoepithelial cells. Our limited material does not warrant further com- parison and subdivision. It is debatable whether the adenoid cystic type of carcinoma should be included in this group. The few mucinous carcinomas seen in dogs and cats seem to be of a type different from that found in women. In the cat, we found only one carcinoma that showed extensive mucin production, and it was typed as mucinous carcinoma. 11. SARCOMA Mammary sarcomas are quite common in the dog but not in the cat. Sarcomas with metastasis were found only in bitches. A. Osteosarcoma (Fig. 20) These are noncombined sarcomas composed of atypical connective tissue cells producing only oste- oid and/or bone. The amount of the often irregularly formed bone and osteoid trabecules varies among tumours and in various parts of the same tumour. Generally the matrix is most dense in the centre, whereas the cellular areas are usually situated at the periphery. Cystic necrotic areas and haemor- rhagic foci are frequent. The neoplastic cells are pleomorphic and often polyhedral; in some tumours, however, spindle cells predominate. Mitotic figures are frequent in most of the neoplasms. Multi- nucleated giant cells resembling osteoclasts are fre- quently found near neoplastic bone tissue. In the dog no obvious histological differences are found between osteosarcomas occurring in the mammary gland and those found in other soft tissues and in bone. Chondrosarcoma as a noncombined sarcoma was not present in our series. B. Fibrosarcoma (Fig. 21) This term has been adopted to cover under one heading noncombined, morphologically different types of sarcoma composed of spindle cells with various types and amounts of intercellular fibres but 10 129 130 J. F. HAMPE & W. MISDORP without other types of intercellular differentiation. The amount and pattern of reticulin and collagen fibres vary greatly from one tumour to another and within different areas of the same neoplasm. In the bitch the fibres are arranged in a parallel fashion or haphazardly; interlacing bundles of fibres are unusual or at least are not a prominent feature. In some tumours, a concentric arrangement of fibres and cells around proliferating blood vessels is seen. Those cases must be differentiated from haemangio- pericytoma. Oedema and mucoid material are found in the matrix of some tumours, but the presence of mucoid material has not led us to subtype mucinous sarcomas as counterparts of mucinous carcinomas. The degree of pleomorphism and the number of mitotic figures varies considerably among fibrosar- comas. Fibrosarcomas that contain extensive puru- lent and haemorrhagic foci may be difficult to distinguish from encapsulated abcesses, but the peri- pheral part of the lesions usually indicates the correct diagnosis. C. Osteochondrosarcoma (fibro-lipo-osteochondrosar- coma) (combined sarcoma) (Fig. 22, 23) These are malignant tumours composed of neo- plastic osseous and cartilaginous tissue. Some also contain neoplastic fibrous tissue and/or adipose tissue. Direct neoplastic bone formation and indirect neoplastic bone formation via enchondral ossifica- tion are found in most of these tumours. Some tumours, as well as their metastases, consist of highly differentiated tissues. Differential diagnosis between a tumour of this type and benign connective- tissue tumours may be difficult and is sometimes impossible. D. Other sarcomas These were represented by only four cases in the dog: two metastasized mast cell tumours and one reticulum cell sarcoma, which were not different from such tumours in other sites, and one liposar- coma, which seemed to have originated from a benign mixed tumour. The metastases of the latter tumour were of a purely liposarcomatous type. 111. CARCINOSARCOMA (MALIGNANT MIXED TUMOUR) These tumours (Fig. 24, 25) are composed of cells morphologically resembling epithelial components (luminal epithelial, myoepithelial, or both) and of cells resembling connective tissue elements (in the broad sense). The histological picture varies con- siderably both among tumours and within the same tumour. Mixtures of all types of carcinomatous and sarcomatous components can be recognized. A con- siderable number (30 %) have a spindle cell com- ponent that may be considered to be of myoepithelial or connective-tissue origin. Transition-as far as can be judged from histological examination-between the carcinomatous and chondrosarcomatous com- ponents, probably via an intermediate mucinous stage, is seen in 30 Y. of cases. No transition between carcinoma and osteosarcoma is seen. The osteo- sarcomatous component seems to be formed by means of endochondral ossification (secondary bone) in some cases and fibrous cells (primary bone) in others. In the most highly differentiated tumours it is impossible to exclude bone formation via non- malignant stromal metaplasia. Most of these tumours are well defined, only a minority (25 Y.) showing severe infiltration. Penetra- tion of lymphatics, which is present only rarely, seems to be related to the carcinomatous rather than to the sarcomatous component. The lymphogenic and the haematogenic metastatic lesions are of mixed, sarcomatous, or carcinomatous type. Some of these malignant mixed tumours cannot be distinguished on purely histological criteria from benign mixed tumours. The differentiation of malig- nant mixed tumours and carcinomas of complex type can be difficult and arbitrary: in the latter types, fibrous tissue proliferation (considered to be non- tumorous) and some production of mucinous mate- rial may confuse the picture. Malignant mixed tumours and carcinomas or sarcomas considered to have arisen in a (benign?) mixed tumour can be difficult to differentiate. IV. BENIGN OR APPARENTLY BENIGN TUMOURS These notes on benign tumours, as well as those on benign dysplasias (page 131) should be read in conjunction with the WHO classification of human breast tumours.a Some of the lesions in dogs and cats are not described independently but only in comparison with the corresponding lesions in man. Unless otherwise stated, the definitions and descrip- tions of the human lesions should be taken as appropriate for the dog and cat. Our findings indicate the complex type of growth, especially in adenosis and lobular hyperplasias. a Scarff, R.W. & Torloni, H. Histological typing of breast tumours, Geneva, WHO, 1968. MAMMARY GLAND 131 A. Adenoma (Fig. 26-28) " True " adenoma (as applied to women) is of simple, tubular type and consists of secretory epi- thelial cells. This lesion is extremely rare in bitches and female cats. However, we found some cases of solidly growing spindle cell nodules with scanty stroma, which we called simple myoepithelial solid adenoma. Complex adenoma is very frequent in female dogs and cats, but not in women. These tumours are composed of proliferated secretory epithelial cells together with myoepithelial cells. The amount of stroma is not decisive for typing. Overlapping of these tumours with (cellular) fibroadenomas, benign mixed tumours, and (nontumorous) lobular com- plex hyperplasias may occur. Inflammatory and metaplastic changes-as described for nontumorous lobular hyperplasias of inflammatory type-do occur, but are not prominent features. Differential diag- nosis between complex adenomas and complex adeno- carcinomas may be difficult. Adenomas of the teats were not found in dogs or cats. B. Papilloma 1. Duct papilloma (Fig. 29). In the dog and cat, duct (true) papilloma occurs infrequently and tends, like other proliferative lesions, to be of markedly complex type. 2. Duct papillomatosis. Papillary overgrowth in ducts and cysts should be differentiated from " true" papilloma. It may consist in adenosis pro- truding into ductal lumina, particularly in cases where tubules of adenosis (especially in the cat) show ectasia and secondary papillary formation, the whole picture giving rise to the generally accepted term of " duct papillomatosis ". Although we do not con- sider those types of duct papillomatosis as examples of true (multiple) papillomas, they have been placed under this heading and not in the group of the dysplasias. Especially in the cat, differentiation of duct papillomatosis and papillary adenocarcinoma may be difficult. C. Fibroadenoma 1. Pericanalicular (Fig. 30) 2. Intracanalicular (Fig. 31) (a) noncellular type a (b) cellular type a In the human classification the term " simple " is used but that has a quite different meaning in animal histo- pathology (see page 112). 3. Benign mixed tumour (Fig. 32) All the above-mentioned fibroadenomas are essen- tially the same in dogs and cats as in human beings, except that their complex nature is much more prominent and that benign mixed tumours were not found in cats. The term " benign mixed tumour " for the most frequent and best-known tumour in the dog is used when cartilage, bone, and fat are present, even if these features are not pre- dominant. As in man, it is impossible to distinguish metaplasia (e.g., into cartilage) of " ordinary " stroma of the tumour from differentiation or metaplasia of the tumorous myoepithelial component. Overlaps exist between the fibroadenomas of types C.1, C.2(a), and C.2(b), on the one hand, and complex adenomas and benign mixed tumours, on the other hand. 4. Total fibroadenomatous change (Fig. 33). We are not sure whether this lesion should be considered to be a tumour or a proliferative benign dysplastic lesion. It occurs in the cat and has no exact counterpart in man or in the dog. Possibly it is comparable to diffuse bilateral juvenile pseudo- hypertrophy in man or to the nodular form, pro- visionally labelled by us " andromastoma ". These lesions may involve one, several, or all mammary glands in adolescent cats. We have not enough data to comment on later stages or on regression, but we know that the lump may disappear. D. Benign soft-tissue tumour We have found only lipomas and one haem- angioma. Benign mixed tumours sometimes mim- icked chondroma, osteoma, or fibroma. V. UNCLASSIFIED TUMOURS Benign and malignant tumours that cannot be placed in any of the categories described above are assigned to this group. VI. BENIGN OR APPARENTLY BENIGN DYSPLASIAS b A. Cyst 1. Nonpapillary. As in man, double layering of epithelium often seems to be absent; in most cases there are multiple cysts in one or more mammary b The term " dysplasia " is used as defined in the WHO classification of human breast tumours and not in the sense of certain disorderly proliferations together with a certain degree of cytonuclear atypia (see also the comment under Benign tumours, page 130). J. F. HAMPE & W. MISDORP glands, and differentiation from dilated ducts may be arbitrary. 2. Papillary (Fig. 34). As with most proliferative lesions in the bitch, frequently the complex types are found. Differentiation from intracystic and intra- ductal papilloma and from duct papillomatosis may be arbitrary. Oncocytic (apocrine or " pink ") metaplasia of epithelial cells regularly involves papil- lary overgrowth, which may sometimes show cyto- nuclear pleomorphism. B. Adenosis (Fig. 35) The same type of proliferative lesion as in man was exceptional in the species studied. In the rare cases in dogs and cats it was also far less pronounced, and without formation of a clinically detectable lump. Coalescence of multilobular or multiductular foci of adenosis might present as complex adenoma; intralobular adenosis and lobular complex hyper- plasias might be indistinguishable and might in some cases present as duct papillomatosis. In general, adenosis, like other proliferations, can be exoected to be of an even more markedly complex type than in man; however, we also found an almost purely tubular simple type. We have not used the term "adenosis" (sometimes designated as " physio- logical adenosis ") to denote the development of "normal " glandular mammary tissue, whether connected with cyclic changes or not. C. Regular typical epithelial proliferation in ducts or lobules (Fig. 36-38) Contrary to the terminology adopted for human lesions, we have chosen to use the term " epithe- liosis" for this type of hyperplasia. It is applied to epithelial proliferation (or hyperplasia) in preexist- ing structures, and not to epithelial overgrowths in cysts or dilated ducts, adenosis, etc. The prolifera- tion may concern one type of cell only, but the pres- ence of spindle-shaped cells may be suggestive of an admixture with myoepithelial cells. Apart from the growth patterns mentioned in the human classifica- tion, in the dog (as well as in man), the proliferated epithelial cells may be confined to a ductal lining as tall columnar cells with hyperchromatic nuclei. This condition was typed as " mural epitheliosis ". We are not following the highly controversial, advice given in the human classification-namely, to type irregular or atypical epithelial proliferation in the group of noninfiltrating carcinomas. Our ani- mal material was derived chiefly from mammary glands that had been collected to study other lesions. Regular epithelial proliferation was found mainly in bitches and predominantly in ductulolobular regions. Its existence is independent of the presence of nodular lesions; rarely, the epitheliosis itself forms a nodule. Epitheliosis in the bitch generally has a much more uniform growth pattern with cyto- nuclear features that are more regular than those found in man. We have encountered some cases where differentiation from adenopapillary carcinoma was difficult. Our experience until now, however, does not warrant any subdivision of types of epithe- liosis in the bitch, nor any statement on their sig- nificance in carcinogenesis (e.g. sign of increased risk, precancerous lesion). Differences resulting from different sampling methods or from the selection of material should be borne in mind. As in man, we have no data on the significance of epitheliosis (with different grades of atypia) in cases of mastopathy (proliferating mastopathy) as compared with epi- theliosis without concomitant lesions. In the cat some examples of epitheliosis were found, but we must refrain from further subdivisions and inter- pretations at this stage. D. Duct ectasia (Fig. 39-41) Relatively heavy ectasia of ducts is a common finding in female dogs and cats, often leading to a total transformation of the mammary gland into a spongy mass. Inflammation with secondary epithe- lial changes may occur, but is less frequent than in man, and stagnation of secretion does not seem to be a regular feature in these lesions. Ectasia is not confined to ducts; it may also affect terminal duc- tules, intralobular ductules, and even acini, in which case the mammary gland is transformed into some- thing comparable to emphysematous lung tissue. Ectasia may also transform the pattern of structures that were not preexistent, e.g., intraductal adenosis, which-apart from being pedunculated-can assume an obvious papillomatous pattern (especially in the cat). Lobular hyperplasia, including the inflamma- tory type, may also be combined with ectasia. E. Fibrosclerosis (Fig. 42) We have not found the equivalent of the human pseudotumorous form, but a more-or-less localized predominance of fibrosclerotic tissue does occur in the dog. In that species it is not unusual to find fibrosclerotic change in small nodules-e.g., lobular hyperplasias, complex adenomas, and inflammatory nodules. The sclerosis in these cases may assume a pattern reminiscent of a corpus albicans in the ovary, 132 MAMMARY GLANI) or the proliferative nodule may be replaced partly or wholly by broad irregular bands of hyaline colla- genous material. The latter may represent regressive changes or even cicatrization. F. Gynaecomastia Our rare cases were restricted to cases of hormone- active testicular tumours in male dogs. The scarcity of material may be related to selection in sampling. G. Other non-neoplastic proliferative lesions 1. Noninflammatory lobular hyperplasia (Fig. 43- 46). This type of hyperplasia occurs in the dog and cat. The composition of foci or nodules may vary considerably, owing to a predominance of secretory epithelium or myoepithelium. Variations also arise out of ductular and acinar ectasias, sclerosis, and secretion (secretion is especially striking in other- wise nonsecreting mammary glands), without any appreciable amount of inflammatory cells or clear- cut metaplasia. Hyperplasia may be found in part of a lobule, or it may involve a whole lobule or several adjacent lobules. In the last-mentioned case, the affected lobules may coalesce to form not only small nodules but also palpable lumps that may be indistinguishable from complex adenomas. 2. Inflamnwtory lobular hyperplasia (Fig. 47-48). In the dog and cat, the composition of foci or nodules of the inflammatory type may vary even more as a result of metaplasia (mucinous, squamous, or oncocytic), an accumulation of pigmented macro- phages, lymphoplasmocellular infiltration in the stroma, and granulocytes in tubular lumina. These features are found in addition to those described above in lesions of simple hyperplasia. The combina- tion of lobular hyperplasia and marked infiltration of inflammatory cells, together with cellular changes, has led us to adopt the provisional term " inflam- matory nodule ". 133