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Authors: Rosen, Paul Peter Title: Rosen's Breast Pathology, 3rd Edition Copyright 2009 Lippincott Williams & Wilkins > Table of Contents > Chapter 2 - Abnormalities of Mammary Growth and Development Chapter 2 Abnormalities of Mammary Growth and Development Hypoplasia and Amastia The most extreme form of mammary hypoplasia is amastia: the complete failure of one or both breasts, including the nipple, to develop, (1,2). As one of the least common developmental abnormalities, amastia is encountered more often in females than in males. Familial amastia has been documented in instances in which a brother and sister (3) and mother and daughter (4) have been affected. It may be accompanied by developmental defects of the ipsilateral shoulder, chest, and/or arm (5). Amastia has been reported in the complex genetic defect of acrorenal ectodermal dysplasia with lipotrophic diabetes (AREDYLD) syndrome (6). In addition to amastia, developmental abnormalities in these young women include skeletal and renal defects and hypodontia. Mammary hypoplasia can occur as a congenital or acquired defect and may be unilateral or bilateral. A diagnosis of unilateral hypoplasia may be made if there is a substantial difference in breast size that far exceeds the mild asymmetry commonly present, and the larger breast is not macromastic. The hypoplastic breast tissue consists of fibrous stroma and ductal structures without acinar differentiation (Fig. 2.1). Ipsilateral mammary hypoplasia has been reported in conjunction with Becker's nevus, a unilateral hairy hyperpigmented lesion (7,8), although breast abnormalities were not described in Becker's original report (9). Concurrent hypoplasia of the ipsilateral pectoralis major muscle has also been reported (10). The pigmented lesions and accompanying mammary hypoplasia occur in males and females (11). High androgen receptor levels have been detected in Becker's nevi (7,12) but not in the skin from the unaffected contralateral chest (7). Hypoplasia or aplasia of the mammary glands and hypoplasia of the nipples occur in the ulnar mammary syndrome, a familial genetic abnormality with autosomal dominant inheritance (13,14,15) caused by mutations in the TBX3 gene, which controls the T-box transcription factor (16). Commonly associated defects include skeletal abnormalities affecting the ulnar rays of the hands, hypoplasia of apocrine glands, and genital anomalies in males. Poland's syndrome includes severe congenital defects of the chest and arm combined with mammary hypoplasia, amastia, or athelia (17). Carcinoma can arise in the hypoplastic breast of a woman with Poland's syndrome (18). Mammary hypoplasia also occurs in Turner's syndrome and in congenital adrenal hyperplasia. Familial hypoplasia of the nipples and athelia associated with mammary hypoplasia has been described in a father and his daughters (19). Hosokawa et al. (20) described the occurrence of a subcutaneous squamous cyst at the site of unilateral athelia, which suggested that the cystic lesion arose from a maldeveloped nipple. Acquired mammary hypoplasia has been observed in women who received irradiation of the mammary region in infancy or childhood (21,22). The most frequent clinical reason for radiation in this age group was the treatment of cutaneous hemangiomas. The severity of hypoplasia was directly related to the dose of radiation. Surgical excision of the prepubertal breast bud, which enlarges in precocious and early breast development, will result in mammary hypoplasia or amastia by removing part or all of the infantile breast anlage. Unilateral atrophy of a previously normal breast associated with infectious mononucleosis has been described in a 17-year-old girl (23). Biopsy revealed normal breast tissue. The rare occurrence of carcinoma arising in an irradiated hypomastic breast has been reported (24). Macromastia Several types of excessive breast growth have been described as forms of macromastia. Adolescent macromastia occurs as a result of progressive growth over 1 or 2 years during adolescence, resulting in breast size that far exceeds normal limits. The breasts do not decrease in size in subsequent years, and breast reduction surgery is invariably required. Although the condition is usually relatively symmetrical, there are instances in which there is substantial disparity in breast size. Histologic examination reveals greatly increased stromal collagen and fat (Fig. 2.2). Epithelial hyperplasia of ducts is present in a minority of cases (25). Pseudoangiomatous stromal hyperplasia is evident in

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some of these individuals. The stromal cells in one instance of P.27 adolescent macromastia, which appears to be pseudoangiomatous stromal hyperplasia in the published illustrations, lacked nuclear estrogen receptor but were positive for nuclear progesterone receptor (26). Biochemical estrogen receptor assays were negative on tissues from a series of 25 patients (ages 17 to 77 years) who had macromastia not associated with pregnancy (27).

Fig. 2.1. Mammary hypoplasia. Breast tissue from a 23-year-old woman with unilateral hypoplasia. A: Ducts that resemble prepubertal breast in collagenous stroma. B: Minimal lobular differentiation is shown. Gravid macromastia develops rapidly, shortly after the onset of pregnancy in the affected individual (28,29,30). It occurs in less than 0.01% of pregnancies (28). The etiology is unknown. Onset very early in pregnancy in some cases has implicated human chorionic gonadotrophin (hCG), possibly through a hypersensitivity mechanism. Fetal sex does not appear to be a factor. The majority of women are primiparous, but in some individuals macromastia does not occur until a second or third pregnancy (28,30,31). Once established, the condition is likely to recur in successive pregnancies, even if the pregnancy terminates in a miscarriage. The chance of recurrence is decreased by reduction mammoplasty, but some patients have required further surgery for regrowth of breast tissue after mastectomy (30,32). In one case, gravid macromastia involved bilateral axillary breasts and one ectopic thoracic breast, as well as both normally situated glands (33).

Fig. 2.2. Adolescent macromastia. A broad area of moderately edematous interlobular stroma surrounding a normal lobule. A variety of pathologic changes has been reported in gravid macromastia. Leis et al. (31) described a case in which the stroma exhibited marked fibrosis, with bands of dense collagenous tissue and thickening of the intralobular fibrous tissue. Thickening of basement membranes was noted, whereas ducts and acini demonstrated a two-layered epithelium with apparently inactive cuboidal cells. Fibrosis and collagenization were also noted by Beischer et al. (28) and Kullander (34). Others have reported fibroadenomas (32,35) and lactational hyperplasia (36). Several authors have

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commented on the presence of dilated lymphatics in the breast tissue. Pseudoangiomatous stromal hyperplasia is often a prominent feature that is evident in retrospect in published illustrations (37), although the condition was not described by this recently introduced term in the reports (see Chapter 38). Rarely, the clinical presentation of neoplastic conditions such as angiosarcoma or lymphoma in the breast may mimic gravid macromastia. Pseudohyperparathyroidism has been associated with gravid macromastia (37). Mastectomy results in prompt remission of the hypercalcemia. Mastectomy or breast reduction are usually undertaken after delivery to ameliorate the incapacitating effects of gravid macromastia including pain, depression, and, in some cases, altered pulmonary function. Necrosis of the skin or parenchyma complicated by infection or bleeding may necessitate mastectomy during pregnancy. The concept that hormonal disturbances contribute to the development P.28 of gravid macromastia has led to attempts at endocrine treatment, although none has been uniformly effective. There have not been consistent hormonal abnormalities in patients who were studied, and it presently appears likely that the fundamental problem lies in abnormal responsiveness of the breast tissues (38). Bromocriptine has been administrated, resulting in reduced prolactin levels in some cases but inconsistent clinical responses (34,38,39). Treatment with tamoxifen was not effective in one case (40). Penicillamine-induced macromastia has been reported in patients receiving this agent for the treatment of rheumatoid arthritis (41), and marked breast enlargement or hypertrophy has been observed in women with human immunodeficiency virus (HIV) infection after treatment with indinavir (42). Ectopic Breast Tissue Ectopic breast tissue occurs along the milk lines, extending bilaterally from the mid-axillae through the normal breasts and then inferiorly to the medial groins (43). In women, the inferior extensions of the milk lines traverse the vulva bilaterally. The embryological anlage of the milk line is the milk ridge, which later undergoes complete atrophy except for short segments that remain in the pectoral region to give rise to normal breasts. Ectopic or supernumerary breasts develop from portions of the milk ridges that fail to atrophy. A study of neonates revealed ectopic or supernumerary nipples in 49 of 2035 infants (2.4%) (44). The abnormality was more frequent in black than in white neonates. Male and female infants were equally affected. Clinically, ectopic breasts are encountered in 1% to 6% of women and considerably less frequently in men (43,45,46,47). Rare instances of familial ectopic breasts and nipples have been described (48,49,50). In one report, the condition consisted of bilateral axillary breasts limited to females in two generations (50). Another report described a male child who had accessory breasts on the thorax and abdomen along the milk lines, and whose mother also had accessory breast tissue (48). A study of 156 white patients with aberrant mammary tissue diagnosed in a dermatology clinic revealed that 18 patients (11.5%) had a relative with the same condition (51). Ectopic nipples are often located on the anterior chest above or below the normal breast. Alterations in the size of accessory breasts were noted with the menstrual cycle and pregnancy. The majority of patients with clinically apparent ectopic breast tissue have unilateral axillary involvement. Bilateral axillary breasts are the second most frequent presentation. Thoracic, abdominal, inguinal, and vulvar ectopic breasts, whether isolated, multiple, or in conjunction with axillary breast tissue, are much less frequent. An association between ectopic nipples and renal anomalies has been described (52). However, this relationship has not been confirmed by other investigators (51). Kenny et al. (44) found ultrasound evidence of a renal abnormality in only 1 of 49 neonates with ectopic nipples. The clinical presentation of ectopic breasts is highly variable. Intra-areolar polythelia is a form of accessory breast in which two or more nipples, usually appearing deformed or dysplastic, occur within the areola (53). The reported occurrence of intra-areolar polythelia in patients with neurofibromatosis (54) may be the result of mistaking cutaneous neurofibromas of the skin of the areola for accessory nipples (55). In some of these cases the glandular tissue of an ectopic breast is partly or entirely replaced by fat and may be diagnosed clinically as a lipoma, especially if the nipple and areola are unapparent (45,56). A complete supernumerary mammary gland with nippleareola complex is uncommon (57).

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Physiologic changes may occur during the menstrual cycle, causing swelling of the gland, and occasionally this can be painful. Lactation from ectopic breast tissue has been reported during pregnancy and the postpartum period (43,58). Spontaneous galactorrhea from an ectopic axillary mammary gland with fully developed nipple was attributed to a pituitary microadenoma in a 28year-old woman (59). Her serum prolactin level decreased to normal after treatment with bromocriptine. The presence of ectopic breast tissue can be confirmed, and lesions arising in these sites can be diagnosed by fine-needle aspiration (FNA) (60). The findings in an aspiration smear are variable, depending on the state of development of the tissue. Typically there are clumps and sheets of uniform, cytologically benign duct cells distributed in a monolayered fashion (61). Proteinaceous secretion and small groups of acinar cells are found in the aspirate of axillary tissue from a lactating patient. Monolayered sheets of benign ductal cells and bipolar stromal cells characterize the specimen obtained from an axillary fibroadenoma. Histologic sections of ectopic breast tissue reveal duct and lobular mammary structures, which may display physiologic changes (Fig. 2.3). Most examples of ectopic nipples (polythelia) occur along the milk line without the development of a breast. Ectopic breasts are more common on the left side (46,57). Examination of 1691 consecutive neonates in one study revealed ectopic nipples in 24 of 1000 live births (62). Others report frequencies ranging from 1.7% (57) to 3.75% (46). There are a number of reports of polythelia, with and without familial occurrence, involving men and women, associated with congenital abnormalities (63,64). An unusual syndrome is the familial occurrence of intra-areolar polythelia (dysplastic divided nipples) in hypoplastic breasts (54). Mehregan (65) described the microscopic pathology of 51 examples of ectopic nipple among 360,000 consecutive skin biopsy specimens. The microscopic components included lactiferous ducts and epidermal thickening with P.29 P.30 P.31 pilosebaceous structures sometimes present (Fig. 2.4). Almost all specimens included mammary glandular tissue in the deep dermis.

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Fig. 2.3. Ectopic breast in axilla. A: Deep dermis of axillary skin showing, from left to right, a hair follicle, a sweat gland, and an ectopic mammary duct. B: Axillary breast tissue with a dilated duct (above), incompletely formed lobule (center), and axillary apocrine gland (right). C: A mammary lobule in axillary breast tissue. D: Mammary lobule with mild epithelial hyperplasia (left) next to a dilated axillary apocrine gland. EG: Gynecomastia-like hyperplasia in axillary ectopic breast tissue. Image (E) shows adnexal glands (left) and mammary glandular tissue (right). Two ill-defined nodules with periductal stromal hyperplasia resembling gynecomastia are present (F,G).

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Fig. 2.4. Ectopic nipple in axilla. A: Skin mound of the nipple with underlying lactiferous ducts. B: Deeper portion of dermis with lactiferous ducts and a lobule (lower right).

Fig. 2.5. Malefemale transsexual breast. A-C: Collagenized stroma with atrophy of ducts and lobules (C). Aberrant Breast Tissue Aberrant breast tissue is defined as mammary glandular parenchyma found in the region of, but beyond, the usual anatomic extent of the breast. Ducts and lobules that make up aberrant breast are structurally normal, but they are not as well organized as in normal or supernumerary breasts. Aberrant breast is by definition anatomically separate from the duct system of the breast and differs in this respect from peripheral extensions of the breast (66). Aberrant breast tissue does not form a nipple and/or areola and is usually not clinically apparent unless it becomes the site of a pathologic

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process or physiologic change such as lactational hyperplasia (see Chapter 33). The Transsexual Breast Female-to-male transsexual conversion involves prolonged androgen administration, which usually begins prior to mastectomy. When compared with normal female breast tissue from reduction mammoplasty operations, the androgen-treated breast had more frequent calcifications (67). The breast tissue displays stromal collagenization and atrophy of ductallobular structures (Fig. 2.5). Cysts and apocrine metaplasia may be present. The expression of estrogen and progesterone receptors and gross cystic disease fluid protein-15 was not significantly different in transsexual breast specimens when compared with normals. Male-to-female transsexuals undergo surgical or chemical castration and estrogen therapy. Chemical castration with cyproterone, a progestational agent, is accomplished by blocking androgen receptors. Breast tissue obtained from six patients after 18 months of combined therapy revealed welldeveloped lobular structures in all cases and pregnancy-like hyperplasia in two patients (68). Breast carcinoma has been reported in male-to-female transsexuals (69). References 1. Pierre M, Bureau H. A propos de deux case d'absence congenitale d'une glande mammaire. Ann Chir Plast 1960;5:137. 2. Trier WC. Complete breast absence. Case report and review of the literature. Plast Reconstr Surg 1965;36:430439. 3. Kowlessar M, Orti E. Complete breast absence in siblings. Am J Dis Child 1968;115:9192. 4. Goldenring H, Crelin ES. Mother and daughter with bilateral congenital amastia. Yale J Biol Med 1961;33:466. 5. Zilli L, Stephani G. Unilateral agenesis of the pectoralis muscles associated with mammary hypoplasia. Friuli Med 1960;15:1522. 6. Breslau-Siderius EJ, Toonstra J, Baart JA, et al. Ectodermal dysplasia, lipoatrophy, diabetes mellitus, and amastia: A second case of the AREDYLD syndrome. Am J Med Genet 1992;44:374 377. 7. Formign M, Alsina MM, Mascar JM, et al. Becker's nevus and ipsilateral breast hypoplasia androgen-receptor study in two patients. Arch Dermatol 1992;128:992993. 8. Glinick SE, Alper JC, Bogaars H, et al. Becker's melanosis: associated abnormalities. J Am Acad Dermatol 1988;9:509514. 9. Becker SW. Concurrent melanosis and hypertrichosis in distribution of nevus unis lateris. Arch Dermatol Syphil 1949;60:155160. 10. Moore JA, Schosser RH. Becker's melanosis and hypoplasia of the breast and pectoralis major muscle. Pediatr Dermatol 1985;3:3437. 11. Sharma R, Mishra A. Becker's naevus with ipsilateral areolar hypoplasia in three males. Br J Dermatol 1997;136:471472. 12. Person JR, Longcope C. Becker's nevus: An androgen-mediated hyperplasia with increased androgen receptors. J Am Acad Dermatol 1984; 10:235238. 13. Franceschini P, Vardeu MP, Dalforno L, et al. Possible relationship between ulnar-mammary syndrome and split hand with aplasia of the ulna syndrome. Am J Med Genet 1992;44:807812. 14. Gilly E. Absence complte des mammeles chez une femme mere. Atrophie du membre superieur droit. Courier Med 1882;32:2728. 15. Schinzel A. Ulnar-mammary syndrome. J Med Genet 1987;24:778781. 16. Davenport TG, Jerome-Majewski LA, Papaioannou VE. Mammary gland, limb, and yolk sac defects in mice lacking Tbx3, the gene mutated in human ulnar mammary syndrome. Development 2003;130: 22632273. 17. Shamberger RC, Welch KJ, Upton III J. Surgical treatment of thoracic deformity in Poland's syndrome. J Pediatr Surg 1989;24:760765. 18. Fukushima T, Otake T, Yashima R, et al. Breast cancer in two patients with Poland's Syndrome. Breast Cancer 1998;6:127130. 19. Nelson MM, Cooper CK. Congenital defects of the breastAn autosomal dominant trait. S Afr Med J 1982;61:434436. 20. Hosokawa K, Hata Y, Yano K, et al. Unilateral athelia with a subcutaneous dermoid cyst. Plast Reconstr Surg 1987;80:732733.

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21. Frst CJ, Lundell M, Ahlbck SO, et al. Breast hypoplasia following irradiation of the female breast in infancy and early childhood. Acta Oncol 1989;28:519523. 22. Kolar J, Bek V, Vrabec R. Hypoplasia of the growing breast after contact x-ray therapy for cutaneous angiomas. Arch Dermatol 1967;96:427430. 23. Haramis HT, Collins RE. Unilateral breast atrophy. Plast Reconstr Surg 1995;95:916919. 24. Funicello A, De Sandre R, Salloum L, et al. Infiltrating ductal carcinoma of the hypomastic breast: A case report. Am Surg 1998;64: 10371039. 25. Sagot P, Mainguen C, Barrire P, et al. Virginal breast hypertrophy at puberty: A case report. Eur J Obstet Gynecol Reprod Biol 1990;34: 289292. 26. Hugh JC, Friedman MH, Danyluk JM, et al. Absence of estrogen receptors in a case of virginal hypertrophy of the breasts related to oral contraceptives. Breast Dis 1993;6:143148. 27. Jabs AD, Frantz AG, Smith-Vaniz A, et al. Mammary hypertrophy is not associated with increased estrogen receptors. Plast Reconstr Surg 1990;86:6466. 28. Beischer NA, Hueston JH, Pepperell RJ. Massive hypertrophy of the breasts in pregnancy: Report of 3 cases and review of the literature, never think you have seen everything. Obstet Gynecol 1989;44: 234243. 29. Ship AG, Shulman J. Virginal and gravid mammary gigantismRecurrence after reduction mammoplasty. Br J Plast Surg 1971;24: 396401. 30. Williams PC. Massive hypertrophy of the breasts and axillary breasts in successive pregnancies. Am J Obstet Gynecol 1957;74:13261341. 31. Leis SN, Palmer B, stberg G. Gravid macromastia: case report. Scand J Plast Reconstr Surg 1974;8:247. 32. Nolan JJ. Gigantomastia. Report of a case. Obstet Gynecol 1962;19:526. 33. Barreto AU. Juvenile mammary hypertrophy. Plast Reconstr Surg 1991;87:583584. 34. Kullander S. Effect of 2 Br-alpha-ergocryptin (CB 154) on serum prolactin and the clinical picture in a case of progressive gigantomastia in pregnancy. Ann Chir Gynaecol 1976;65:227. 35. Lewison EF, Jones GS, Trimble FH, et al. Gigantomastia complicating pregnancy. Surg Gynecol Obstet 1960;110:215. 36. Wlner-Hanssen P, Palmer B, Sjberg NO, et al. Case report. Gigantomastia. Acta Obstet Gynecol Scand 1981;60:525. 37. Van Heerden JA, Gharib H, Jackson IT. Pseudohyperparathyroidism secondary to gigantic mammary hypertrophy. Arch Surg 1988;123:8082. 38. Taylor PJ, Cumming DC, Corenblum B. Successful treatment of D- penicillamine-induced breast giantism with danazol. Br Med J 1981; 282:362. P.32 39. Szczurowicz A, Szymula A. Gravidic macromastia. A problem for the patient and for the doctor. Clin Exp Obstet Gynecol 1996;23: 177180. 40. Hedberg K, Karlsson K, Lindstedt G. Gigantomastia during pregnancy: Effect of a dopamine agonist. Am J Obstet Gynecol 1979;133:928931. 41. Wolf Y, Pauzner D, Groutz A, Walman I, et al. Gigantomastia complicating pregnancy. Case report and review of the literature. Acta Obstet Gynecol Scand 1995;74:159163. 42. Lui A, Karter D, Turett G. Another case of breast hypertrophy in a patient treated with indinavir. Clin Infect Dis 1998;26:1482. 43. DeCholnoky T. Supernumerary breast. Arch Surg 1939;39:926941. 44. Kenny RD, Filippo JK, Black EB. Supernumerary nipples and anomalies in neonates. Am J Dis Child 1987;141:987988. 45. DeCholnoky T. Accessory breast tissue in the axilla. NY State J Med 1951;5:22452248. 46. Iwai T. A statistical study of the polymastia of the Japanese. Lancet 1907;2:753759. 47. Petrek J, Rosen PP, Robbins GF. Carcinoma of aberrant breast tissue. Clin Bull 1980;10:1315. 48. Cellini A, Offidavi A. Familial supernumerary nipples and breasts. Dermatology 1992;185:56 58. 49. Leung AKC. Familial supernumerary nipples. Am J Med Genet 1988;31: 631635. 50. Weinberg SK, Motulsky AG. Aberrant axillary breast tissue: A report of a family with six affected women in two generations. Clin Genet 1976;10:325328.

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51. Urbani CE, Betti R. Familial aberrant mammary tissue: A clinicoepidermiological survey of 18 cases. Dermatology 1995;190:207209. 52. Meggyessy V, Mehes K. Association of supernumerary nipples with renal anomalies. J Pediatr 1987;111:412413. 53. Brightmore T. Bilateral paired nipples. Br J Surg 1972;59:5557. 54. Rintala A, Norio R. Familial intra-areolar polythelia with mammary hypoplasia. Scand J Plast Reconstr Surg 1982;16:287291. 55. Haagensen CD. Anatomy of the mammary gland. In: Diseases of the breast, 3rd ed. Philadelphia: WB Saunders, 1986:146. 56. Shrotria S, Ghilchik MW. Axillary accessory breasts: A clinicopathological study of 35 patients with axillary masses. Breast Dis 1994;7:4352. 57. Kajava Y. The proportions of supernumerary nipples in the Finnish population. Duodecim 1915;31:143170. 58. O'Hara MF, Page DL. Adenomas of the breast and ectopic breast under lactational influences. Hum Pathol 1985;16:707712. 59. nlhizaraci K, Bayram F, ztrk M, et al. Unusual presentation of prolactinoma with spontaneous galactorrhoeae from ectopic breast tissue. Clin Endocrinol 1998;49:136. 60. Das DK, Gupta SK, Mathew SV, et al. Fine needle aspiration cytologic diagnosis of axillary accessory breast tissue, including its physiologic changes and pathologic lesions. Acta Cytol 1994;38:130135. 61. Dey P, Karmakar T. Fine needle aspiration cytology of accessory axillary breasts and their lesions. Acta Cytol 1994;38:915916. 62. Mimouni F, Merlob P, Reisner SH. Occurrence of supernumerary nipples in newborns. Am J Dis Child 1983;137:952953. 63. Hersh JH, Bloom AS, Cromer AO, et al. Does a supernumerary nipple/renal field defect exist? Am J Dis Child 1987;141:989991. 64. Toumbis-Ioannou E, Cohen PR. Familial polythelia. J Am Acad Dermatol 1994;30:667668. 65. Mehregan AH. Supernumerary nipple. A histologic study. J Cutan Pathol 1981;8:96104. 66. Hicken NF. Mastectomy: Clinical and pathological study demonstrating why most mastectomies result in incomplete removal of the mammary gland. Arch Surg 1940;40:614. 67. Burgess HE, Shousha S. An immunohistochemical study of the long-term effects of androgen administration on female-to-male transsexual breast: A comparison with normal female breast and male breast showing gynaecomastia. J Pathol 1993;170:3743. 68. Kanhai RCJ, Hage JJ, van Diest PJ, et al. Short-term and long-term histologic effects of castration and estrogen treatment on breast tissue of 14 male-to-female transsexuals in comparison with two chemically castrated men. Am J Surg Pathol 2000;24:7480. 69. Ganly I, Taylor EW. Breast cancer in a trans-sexual man receiving hormone replacement therapy. Br J Surg 1995;82:341.

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