Vol. 14 No. 3 July 2007

Case Report A Rare Case of Invasive Ductal with Hyperprolactinemia

Tomoi Sato＊1, Ichiro Muto＊1, Masaki Hasegawa＊1, Takashi Aono＊1, Takayuki Okada＊1, Tetsuro Tamura＊2, and Takeshi Sakai＊3 Department of ＊1Surgery, ＊2Neurosurgery and ＊3Pathology, Niigata Prefectural Central Hospital, Japan.

We report here a rare form of invasive composed of a mass protruding from the tip of the nipple in a 43-year-old woman with hyperprolactinemia. She had been amenorrheic for 15 years fol- lowing an incomplete pituitary adenomectomy for . She presented with a mass on the left nipple that had been growing for 6 months. Morphologically, the mass resembled of the nipple. Another mass was located in the subareolar region. She underwent mastectomy after invasive ductal car- cinoma was diagnosed. Histopathologically, the tumor of the nipple was invasive ductal carcinoma, which had extended intraductally from another invasive ductal carcinoma in the subareolar region, and had infil- trated the epidermis of the nipple (Paget’s disease). MR successfully detected the rela- tionship between the tumors. Postoperatively, the plasma prolactin level was abnormally high, while the plasma estradiol level was quite low, although macro-pituitary adenoma was not detected by MRI. The patient was treated with bromocriptine mesilate, in addition to adjuvant chemotherapy for , and the plasma prolactin level has since normalized. Breast Cancer 14:302-306, 2007.

Key words: Breast cancer, Prolactin, Adenoma of the nipple, Prolactinoma, Paget’s disease

mass, 1 mm in size, without pruritus in the left Introduction nipple 6 months prior to presentation, and the mass had gradually enlarged. She had no notable Although prolactin stimulates the initiation and family history, but had undergone pituitary ade- promotion of breast cancer in rodents1), whether it nomectomy for prolactinoma 15 years previously. does so in humans is unclear, and the association She had been amenorrheic for a year before the of breast cancer and prolactin-producing pituitary surgery and thereafter. However, the plasma pro- adenoma (prolactinoma) is extremely rare2-9). Bre- lactin level did not normalize postoperatively, and ast cancer generally occurs in the terminal ducts bromocriptine mesilate was given for one year. in the peripheral portion of the breast, and inva- However, she discontinued follow-up and received sive ductal carcinoma of the nipple is also rare10, 11). no medication thereafter. On examination, there We report here an extremely rare form of invasive was a mass, 1.2 × 0.9 × 0.7 cm in size, protruding ductal carcinoma composed of a mass protruding from the tip of the left nipple (Fig 1). The surface from the tip of the nipple in a woman with hyper- was dry with a small scab. A mammary prolactinemia after pituitary adenomectomy for opened in the middle of the mass, and serosan- prolactin-producing tumor. guinous fluid discharged from the opening. Anoth- er hard mass, 1.6 cm in size, was located in the Case Report subareolar region. There was no palpable axillary lymphadenopathy. Mammography revealed no A 43-year-old nulliparous woman had noted a abnormality. Ultrasound examination revealed a hypoechoic, irregular mass, 1.6 × 1.5 × 1.2 cm in size, without posterior shadowing or enhancement Reprint requests to Tomoi Sato, Department of Surgery, Niigata in the subareolar region (Fig 2). Papillotubular car- Prefectural Central Hospital, 205 Shinnan-cho, Joetsu City, Niigata, 943-0192, Japan. cinoma was suspected according to the histologi- E-mail: [email protected] cal classification of the Japanese Breast Cancer 12) Received October 16, 2006; accepted January 12, 2007 Society . The mass in the nipple and the relation-

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Fig 3．MR mammography revealed that the masses in the Fig 1．A mass, 1.2 × 0.9 × 0.7 cm in size, protruded from the nipple and the subareolar region enhanced quickly and were tip of the left nipple. The surface was dry with a small scab. A probably connected via intraductal spread. There were other mammary duct opened in the middle of the mass, and sero enhanced nodules near the tumor in the subareolar region, sanguinous fluid discharged from the opening. indicating an intraductal lesion.

secretory materials. Five of the 14 axillary lymph nodes exhibited metastasis. Both estrogen and progesterone receptors were strongly expressed in all cancer cells, although that of human epider- mal growth factor receptor 2 was not (score 0). Two weeks after mastectomy, blood examina- tion for follow-up of the prolactinoma revealed that the plasma prolactin level was abnormally high (Table 1), indicating residual prolactin-producing pituitary adenoma. The plasma estradiol level was as low as that seen in the postmenopausal state (Table 1). Other hypophyseal hormone levels were Fig 2．Ultrasound examination revealed a hypoechoic, irreg- ular mass, 1.6 × 1.5 × 1.2 cm in size, without posterior shad- almost normal (Table 1). Brain MRI revealed no owing or enhancement in the subareolar region, suspected to obvious recurrence of pituitary adenoma (Fig 5). be papillotubular carcinoma according to the histological clas- Thereafter, bromocriptine mesilate was given, sification of the Japanese Breast Cancer Society. with normalization of the plasma prolactin level (15.6 ng/ml). The patient received epirubicin and ship between the two masses were unclear on ultra- cyclophosphamide followed by paclitaxel for adju- sound examination. MR mammography revealed vant chemotherapy. Currently, she is doing well that the two masses quickly enhanced and were with hormonal therapy. probably connected to each other via intraductal spread (Fig 3). Biopsies of both masses revealed Discussion invasive ductal carcinoma. The patient underwent mastectomy and left axillary lymphadenectomy. Neoplasms of the nipple/areolar region include Histologically, the tumors, both of which were such as invasive ductal carcinoma10, 11) and invasive ductal carcinoma (papillotubular carcino- Paget’s disease13), adenoma of the nipple14, 15), and ma (Fig 4)), were connected via intraductal spread intraductal . Differentiation of these con- in the major (Fig 4A, B, D). The ditions is very important, since surgical procedu- tumor in the nipple was covered with the epider- res and prognoses among them vary15). In the pre- mis, into which clusters of cancer cells with large sent case, the appearance of the mass, which pro- nuclei and abundant pale cytoplasm (Paget’s cells) truded from the nipple, was quite similar to that of had infiltrated (Fig 4C). In the normal tissue, the adenoma of the nipple reported by Sugai et al.14) mammary lobules were distended and contained and Kijima et al.15), and we therefore initially sus-

303 Sato T, et al Unique Breast Cancer with Prolactinoma

ABC

DE

Fig 4．Histology of the tumors in the areolar/subareolar region (hematoxylin and eosin stain). A: Panoramic view shows tumors above and under the nipple, which are intraductally connected. B: Panoramic view of another section of the tumor at the tip of the nipple. The intraductal component of the major lactiferous duct is connected to the tumor in the nipple. C: Magnified view of the tumor above the nipple shows invasive ductal carcinoma, covered with epidermis, into which Paget’s cells have infiltrated (arrow- heads). D: Magnified view of the major lactiferous duct shows intraductal carcinoma. E: Magnified view of the tumor in the sub- areolar region shows invasive ductal carcinoma in the breast parenchyma.

Table 1．Plasma Hormone Concentration

Results Normal prolactin (ng/ml) 254.3 6.1-30.5 Growth hormone 1.7 0.3-1.6 (ng/ml) adrenocorticotropic 22.9 7.4-55.7 hormone (pg/ml) follicle-stimulating 1.5-16.6 for premenopausal 14.3 hormone (mIU/ml) female ＜157.8 for postmenopausal female luteinizing hormone 1.1-88.3 for premenopausal 7.6 (mIU/ml) female 0.8-64.3 for postmenopausal female 20-550 for premenopausal, estradiol (pg/ml) 13 nonpregnant female Fig 5．Brain MRI image. There was no detectable mass ＜21 for postmenopausal inside the sella turcica. However, the left cavernous sinus was female slightly swollen with low enhancement relative to the right (arrowheads). Residual prolactinoma might have been present Cortisol (μg/dl) 14 4.0-18.3 in this region.

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Table 2．Reported Cases of Breast Cancer with Prolactinoma

Ax Author Year Sex Age R/L Localization Size (cm) ER PgR Histology Treatment Interval Prognosis metastases

Daniels 1976 F 33 L Upper outer 1.5 4/7 IDC Mastectomy＋Rx PT→BC: 6Y Buytaert 1981 F 29 R Upper outer Pea-sized 7/22 IDC Mastectomy＋Cx PT→BC: 2Y Olsson 1984 M 48 B-R Subareolar 5 0 NIDC (min inv) Mastectomy＋Rx PT→BC: 26Y No rec B-L Subareolar 5 0 NIDC (min inv) Mastectomy＋Rx 36Y Theodorakis 1985 F 31 L Subareolar 2 0 ＋ ＋ IDC Mastectomy PT→BC: 3Y 1y no rec Haga 1993 M 68 L Subareolar 3 ＋＋ ＋ IDC Mastectomy＋CxHx Synchronous Strungs 1997 F 52 R Upper 5 1/18 ＋ IDC Mastectomy＋Hx Synchronous 18m no rec F 34 R Subareolar 1.4 17/22 ＋ IDC Mastectomy＋RxCx PT→BC: 9Y 5m no rec Volm 1997 M 70 B-R Subareolar ? 2.5 0 ＋ ＋ IDC Mastectomy＋Hx PT→BC: 7Y 6m died B-L Subareolar ? 1.9 1/15 ＋ ＋ IDC Mastectomy＋Hx Forloni 2001 M 45 B-R Subareolar 1 0 ＋ ＋ NIDC Mastectomy Synchronous 2y no rec B-L Subareolar 1 0 ＋ ＋ IDC Mastectomy Sato 2006 F 43 L Subareolar 1.6 5/14 ＋ ＋ IDC Mastectomy＋CxHx PT→BC: 16Y 7m no rec

Ax, axillary lymph nodes, R/L, right or left, B-R, bilateral-right, B-L, bilateral-left, IDC, invasive ductal carcinoma, NIDC, noninvasive ductal carcinoma, PT, pituitary tumor, BC, breast cancer, Rx, irradiation, Cx, chemotherapy, Hx, hormonal therapy

pected adenoma. indicating secondary Paget’s disease13). Since Pag- It is very difficult to distinguish adenoma of et’s disease is generally characterized by erosion the nipple from breast cancer with imaging modal- or ulceration of the nipple, the pattern of exten- ities. In the present case, ultrasound examination sion in the present case is extremely rare. suggested the tumor in the subareolar region to Plasma prolactin concentration can temporarily be papillotubular carcinoma. Takao et al.16) report- increase as a result of breast manipulation, anes- ed that papillotubular carcinoma, which comprises thesia, or stress18, 19). In the present case, the plas- only 15% of invasive ductal of the nip- ma prolactin concentration far exceeded the phys- ple, was a histological subtype requiring careful iological range after mastectomy reported by Wang differentiation from adenoma of the nipple. Coex- et al. (up to 100 ng/ml)19), indicating the presence istence of adenoma of the nipple and breast carci- of residual prolactinoma, although MRI did not noma has also been reported17). In the present case, detect macro-pituitary adenoma. Histological find- MR mammography successfully detected the rela- ings in normal breast tissue, which exhibited dis- tionship between the two tumors of the nipple and tention of the mammary lobules with secretory the subareolar region. Thereafter, we preopera- materials, supported the presence of preoperative tively confirmed these tumors to be invasive duc- hyperprolactinemia in the present case. Only 9 tal carcinoma histologically. cases of breast cancer associated with prolactino- Tumor resection is adequate treatment for ade- ma have thus far been reported2-9). The clinical noma of the nipple, due to its benign nature, and characteristics of these cases, including the pre- mastectomy should be avoided. In the present sent one, are summarized in Table 2. case, based on the diagnosis and the presence of Four of the 10 patients were male, and 3 of the intraductal spread, mastectomy was performed. 4 had bilateral disease, indicating that careful, Histologically, it appeared that the tumor in the periodic examination of the is required in nipple was invasive ductal carcinoma, composed cases of male prolactinoma. Patient age ranged of a mass at the tip of the nipple which had origi- from 29 to 70 years (mean 45.6, median 44). Alth- nally developed in the subareolar region and ex- ough 4 males were included, it is of interest that tended intraductally through the major lactiferous breast cancer associated with prolactinoma tends duct. Infiltration of Paget’s cells was also observed to be located in the areolar/subareolar region, in the epidermis covering the tumor in the nipple, though the reason for this is unclear. In all cases,

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