Breast Vol. 14 No. 2 April 2007

Case Report Found in a Mastectomy Specimen: Report of a Case with Special Regard to the Proliferation Pattern

Seishi Kono＊1, Masafumi Kurosumi＊1, Hanako Simooka＊1, Kaori Kawanowa＊1, Hiroyuki Takei＊2, Kimito Suemasu＊2 ＊1Department of Pathology, Saitama Cancer Center, ＊2Breast Clinic, Saitama Cancer Center, Japan.

We report a case of nipple adenoma incidentally found in a mastectomy specimen, and describe its unique histological appearance and the immunohistochemical distribution of Ki-67 positive tumor cells. A 45-year-old woman with no symptoms or sign related to the nipple had a left mastectomy for invasive . A small nipple adenoma, 7 mm in size, was incidentally recognized in the nipple of the resected breast. Histologically, the tumor in the nipple was composed of numerous proliferative ducts with a tubular and florid papillomatous appearance. Many demarcations between squamous cells of the epidermis and tumor cells were recognized in the summit as well as the lateral wall of the nipple. A high Ki-67 labeling index (20.3%) was recognized in the tumor cells in the superficial region, and a low labeling index (0.7%) was seen in the deeper region of the tumor. Based on these proliferative patterns, the symp- toms and clinical signs related to the nipple that are often found in patients with nipple adenoma are thought to be associated with the destruction of the epidermis of the nipple by the invasion of benign tumor cells with high proliferative activity. Breast Cancer 14:234-238, 2007.

Key words: Nipple adenoma, Breast cancer, Ki-67

We report a case of nipple adenoma incidental- Introduction ly recognized in a mastectomy specimen. We demonstrate the unique proliferation pattern of Nipple adenoma is a benign proliferative lesion the tumor and the distribution of Ki-67 positive of the breast that arises from the lactiferous tumor cells and discuss the relationship between of the nipple. Because it often causes nipple dis- the histological findings and the clinical symp- charge, usually bloody or serosanguineous, and toms. nipple erosion, nipple adenoma is sometimes clini- cally misdiagnosed as Paget’s disease of the Case Report breast. Histologically, it can also be difficult to distinguish nipple adenoma from aris- Clinical History ing in the nipple 1-3). The presence of a myoepithe- A 45-year-old premenopausal woman was lial cell layer in neoplastic ducts is thought to be admitted to the Saitama cancer Center with a the most important histological finding for distin- lump of the left breast, but with no symptoms of guishing adenoma from carcinoma 1). Although discharge or erosion of the nipple. On physical there have been many reported cases of nipple examination, 3 elastic, firm but ill-defined masses adenoma, incidental tumors found in mastectomy were palpable. These consisted of two masses 26 specimens are rare 2, 4-8). × 23 and 10 × 8 mm in the upper outer area and one 18 × 18 mm mass in the lower outer area of Reprint requests to Masafumi Kurosumi, Department of Pathology, the left breast. No enlarged axillary lymph node Saitama Cancer Center, 818 Komuro, Ina-machi, Kitaadachi-gun, was recognized. No abnormality such as redness Saitama 362-0806, Japan. E-mail: [email protected] and erosion of the nipple skin was seen, and no tumor or induration of the nipple was palpable. Abbreviations: MMG, ; USG, Ultrasonography; SMA, α-smooth Mammography (MMG) demonstrated an muscle actin irregular tumor shadow with spicula formation, 25 Received March 23, 2006; accepted July 20, 2006 × 25 mm, and a few small high density areas, up

234 Breast Cancer Vol. 14 No. 2 April 2007

Fig 1．a. Marked proliferation of dilated ducts with tubular appearance occupying outer part of nipple (HE stain). b. Immunohistochemistry for CAM 5.2 revealing positive reaction only in tumor cells of nipple adenoma.

Fig 2．a. Glandular cells of nipple adenoma merged to squamous cell layer of epidermis forming apparent frontlines (arrow) in lateral wall of nipple. (HE stain). b. Invasion of CAM 5.2 positive tumor cells to rete ridge of epidermis forming frontlines (arrow) between adenoma and epidermis. to 10 × 12 mm in size, in the outer area of the left abundant collagen fibers and these tumors were breast. However, no abnormal finding was recog- contiguous with each other. Invasion into fat tis- nized in the nipple. Ultrasonography (USG) sue was also often found. On the basis of these revealed two hypo-echoic masses, 26 × 29 mm in pathological findings, invasive the upper outer area and 26 × 22 mm in outer (scirrhous carcinoma) was diagnosed. Micrometas- lower area, with dilated mammary ducts toward tasis, 1 mm in size, was found in only 1 sentinel the nipple. Again, no abnormal finding was found lymph node. in the nipple. On the other hand, an ill-defined tumor, 7 × 6 We obtained small specimens from two lesions mm in size, was incidentally recognized in the out- of the left breast by core needle biopsy and con- er part of the nipple (20 mm in diameter) (Fig 1). firmed invasive ductal carcinoma. We performed A marked proliferation of dilated ducts with a total mastectomy of the left breast with sentinel tubular appearance associated with slight fibrosis lymph node biopsy. histologically resembling sclerosing adenosis was observed in the central to deeper parts of the Macroscopic and Microscopic Findings tumor. Neoplastic ducts with an appearance of Several ill-defined, elastic firm and grey-white florid papillomatosis were seen especially in the tumors, up to 13 × 13 mm in size, were distrib- superficial area of the tumor. Additionally, lumens uted in the outer upper to lower area of the left of ducts in the peripheral region of the tumor breast. Histologically, all tumors were composed were relatively larger than those in the central of small clusters of carcinoma cells surrounded by part. Proliferating neoplastic ducts were distrib-

235 Kono S, et al Nipple Adenoma

Fig 3．Intraductal tumor cells attached to debris of kera- tinization showing protruding appearance (arrow) toward the outside of nipple from the orifice of a . uted radially from the central to the peripheral part of the tumor. However in the superficial parts of the tumor, neoplastic glandular cells were adherent to the squamous cell layer of the epider- mis forming rete ridge elongations and/or keratin , and so making apparent clear demarcations between skin and tumor (Fig 2). Many frontlines between the tumor cells and squamous cells of Fig 4．Tumor cells of nipple adenoma showing a high label- the epidermis were recognized in the summit as ing index of Ki-67 (a) superficially and a low labeling index (b) well as the lateral wall of the nipple. In addition, in a deeper part of the nipple adenoma. tumor cells from the orifice of a lactiferous duct were found in a deep part of the cleft of the nipple summit (Fig 3). However, no erosive or ulcerative ple. Indexes of Ki-67 were 0.7% in the deep area, lesion was found in the epidermis of the nipple. In 6.5% in the central area, and 20.3% in the superfi- most of the tumor, proliferating ducts were com- cial area (Fig 4). posed of double layers of epithelial, internal glan- dular and external myoepithelial cells on HE Discussion stained sections. In 1955, Jones first described nipple adenoma Immunohistochemical Findings as a distinct clinicopathological entity 3). Several The tumor cells that made up the neoplastic reports of nipple indicated that it ducts of the nipple adenoma within the nipple occurs most often in 40- to 50-year-old patients 2, 6, 7). showed positive immunoreactivity to CAM 5.2 Nipple adenoma was found in 1.2% (12 of 967) of (cytokeratin No. 8, 18, 19, Becton Dickinson Co., mastectomy specimens from patients with breast US), and revealed demarcations between the cancer 4) and it has been reported that 37 of 224 tumor and squamous cells of the epidermis, which patients with nipple adenoma had coexistent were negative for CAM 5.2. In addition, only the mammary carcinoma 8). In the World Health Orga- myoepithelial cells of each duct were immunohis- nization classification of breast tumor established tochemically positive for α-smooth muscle actin in 2003, nipple adenoma is defined as, “a compact (SMA, Dako Cytomation Co., Denmark), S-100 proliferation of small tubules lined by epithelial protein (Immuno Tech Co., France) and CD10 and myoepithelial cells, with or without prolifera- (Novocastro Co., UK). The labeling index of Ki-67 tion of the epithelial component, around the col- (MIB1, Dako-Cytomation Co. Denmark) was vari- lecting ducts of the nipple.” Nipple adenomas are able in different parts of the tumor and gradually also classified into three histological types, an increased toward the superficial area of the nip- adenosis pattern with sclerosing or pseudo-inva-

236 Breast Cancer Vol. 14 No. 2 April 2007 sive features, epithelial hyperplasia, or a combina- cells in the epidermal layer in the summit and lat- tion of epithelial hyperplasia and sclerosing adeno- eral wall of the nipple. However, no exposed lesion sis. The present case appears to be of the third caused by the glandular tumor cells in the epider- type, showing a combination of epithelial hyper- mis was recognized. The presence of many front- plasia and sclerosing adenosis. lines formed by tumor and squamous cells of the The most common presenting symptoms of epidermis indicated that the tumor cells of the nipple adenoma are discharge from the surface of adenoma effectively elongated the rete ridge of the nipple, enlargement of the nipple, and erosion the epidermis in the summit and lateral wall of the or ulceration of the epidermis 8). However, in the nipple. Additionally, it was clarified that the label- present case, there were no such symptoms or ing index of Ki-67 as a marker of proliferation of physical findings related to the nipple, and no cells 11, 12) gradually increased toward the nipple abnormal findings on MMG or USG. We think surface. It is thought that tumor cell growth in the that the tumor localized within the nipple was not superficial part of the tumor might be greater detected because of its small size (6×7 mm) and than that in the deeper part, which might be a rea- no symptoms appeared because of the existence son for the relatively high frequency of epidermal of residual squamous cells of the epidermis at the change found in patients with nipple adenoma. demarcation between the tumor cells and the From these proliferative patterns, the symp- squamous cells of epidermis. If the surface of the toms and clinical signs related to the nipple that nipple were affected by tumor cells, some symp- are often found in patients with nipple adenoma toms related to the nipple might have appeared. are thought to be associated with the destruction Occasionally, differentiating nipple adenoma of the epidermis of the nipple by invasion of from invasive carcinoma arising within the nipple benign tumor cells with high proliferative activity. is difficult if cases show a marked invasion-like appearance, and/or aggressive proliferative growth References of intraductal tumor cells. Confirmation of the presence of a layer in neoplastic 1) Goldman RL, Cooperman H: Adenoma of the nipple: a ducts is thought to be the most important finding benign lesion simulating carcinma clinically and for distinguishing adenoma from invasive carcino- pathologically. Am J Surg 119:322-325, 1970. ma. Immunohistochemical staining using prima- 2) Handley RS, Thackray AC: Adenoma of nipple. Br J Cancer 16:187-194, 1962. ry antibodies, such as α-smooth muscle actin, S- 3) Jones DB: Florid papillomatosis of the nipple ducts. 100 protein and CD10 (lymphoblastic leukemia Cancer 8:315-319, 1955. antigen) can be useful for confirming the pres- 4) Fisher ER, Gregorio RM, Fisher B, Redmond C, Vel- 9, 10) lios F, Sommers SC: The pathology of invasive breast ence of myoepithelial cells in neoplastic ducts . cancer. A syllabus derived from findings of the Differentiating nipple adenoma benign tumors of National Surgical Adjuvant Breast Project (protocol epidermal appendages, such as syringocystadeno- no. 4). Cancer 36:1-85, 1975. ma papilliferum and hidradenoma papilliferum is 5) Jones MW, Tavassoli FA: Coexistence of nipple duct adenoma and breast carcinoma: a clinicopathologic thought to be necessary. In the present case, we study of five cases and review of the literature. Mod found intraductal components of adenomatous ele- Pathol 8:633-636, 1995. ments in the nipple, indicating an apparent conti- 6) Nichols FC, Dockerty MB, Judd ES: Florid papillo- matosis of nipple. Surg Gynecol Obstet 107:474-480, nuity to preexisting mammary duct, suggesting 1958. the diagnosis of nipple adenoma. In addition, 7) Perzin KH, Lattes R: Papillary adenoma of the nipple pathological findings similar to sclerosing adeno- (florid papillomatosis, adenoma, adenomatosis). A sis recognized in the present case are characteris- clinicopathologic study. Cancer 29:996-1009, 1972. 8) Rosen PP, Caicco JA: Florid papillomatosis of the nip- tic of nipple adenoma rather than epidermal ple. A study of 51 patients, including nine with mam- appendage tumors. Furthermore, the frontlines mary carcinoma. Am J Surg Pathol 10:87-101, 1986. between squamous cells of the epidermis and 9) Moritani S, Kushima R, Sugihara H, Bamba M, Kobayashi TK, Hattori T: Availability of CD10 tumor cells were found in several separate areas immunohistochemistry as a marker of breast myoep- and indicating that the tumor in this case might ithelial cells on paraffin sections. Mod Pathol 15:397- not have arisen from rete ridges. 405, 2002. Histologically, the present case showed many 10) Yaziji H, Gown AM, Sneige N: Detection of stromal invasion in breast cancer: the myoepithelial markers. advancing borders of glandular epithelial cells of Adv Anat Pathol 7:100-109, 2000. the adenoma merging into squamous epithelial 11) Cattoretti G, Becker MH, Key G, Duchrow M,

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Schluter C, Galle J, Gerdes J: Monoclonal antibodies 12) Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab against recombinant parts of the Ki-67 antigen (MIB U, Stein H: Cell cycle analysis of a cell proliferation- 1 and MIB 3) detect proliferating cells in microwave- associated human nuclear antigen defined by the processed formalin-fixed paraffin sections. J Pathol monoclonal antibody Ki-67. J Immunol 133:1710-1715, 168:357-363, 1992. 1984.

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