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DOI: 10.1111/jdv.12623
ORIGINAL ARTICLE
Rare benign tumours of the nipple G.A. Spyropoulou,1,* L. Pavlidis,1 M. Trakatelli,2 E. Athanasiou,3 E. Pazarli,4 D. Sotiriadis,2 E. Demiri1 1
Department of Plastic and Reconstructive Surgery, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Thessaloniki, Greece 2 Department of Dermatology, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Thessaloniki, Greece 3 Department of molecular and gene therapy, Hematology Clinic, Papanikolaou General Hospital, Thessaloniki, Greece 4 Department of Pathology, Papageorgiou General Hospital, Thessaloniki, Greece *Correspondence: G.-A. Spyropoulou. E-mail: [email protected]
Abstract Background Benign lesions of the breast in total are much more frequent than malignant ones. However, there are no epidemiologic data on the prevalence of benign or malignant tumours of the nipple, and the bibliography on benign nipple tumours in general is limited. Aims To present some rare cases of benign nipple tumours and review the literature. Materials and methods Four cases of rare benign nipple tumours: neurofibromas, wart, leiomyoma and milium are presented. The literature search on benign nipple tumours was performed using MEDLINE, Pubmed, and Cochrane databases with limits: English language, human species and available abstract. The keyword used was ‘benign nipple tumours’. Results The initial search retrieved 337 articles. The papers were reviewed and the articles that referred to benign lesions that appeared at the nipple specifically were identified. Different entities that were described included: neurofibroma, leiomyoma, milium, florid papillomatosis, syringomatous adenoma, nevoid hyperkeratosis, fibroma, pseudolymphoma and haemangioma. Discussion Differential diagnosis of benign tumours of the nipple can be demanding for the physicians. Many of the symptoms and signs like pruritus, serosanguinous discharge, lichenification, erosion and nodular enlargement are produced by either malignant or benign nipple lesions. Radiology can be unclear in the diagnosis of nipple abnormalities. Conclusion Histological examination of the lesion can be the only definite answer in these cases. Received: 15 January 2014; Accepted: 5 June 2014
Conflicts of interest None of the authors has any conflict of interest to report.
Funding sources No funding was received from any source for this work.
Introduction The nipple is a conic appendage on the human breast which contains the lactiferous ducts and is perforated by duct orifices. The nipples are very sensitive to touch and temperature and their physiologic purpose, is to deliver milk to the infant. They are the ‘mirror’ for many pathologic lesions of the breast as secretions of the mammary gland drain to the nipple. Therefore, abnormal discharges may insinuate pathologic lesions of the breast as intraductal papilloma or cancer.1 Due to the increasing awareness of the possible connection of a nipple lesion to a breast malignancy, nipple tumours can create great distress to the patient. It is therefore, important for the physician to be able to diagnose a benign nipple tumour. According to our review of the literature benign lesions of the breast in total are much more frequent than malignant ones.2–4 However,
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there are no epidemiologic data on the prevalence of benign or malignant tumours of the nipple, and the bibliography on benign nipple tumours in general is limited. In the present study we present some rare cases of benign nipple tumours and review the literature.
Patients and methods Four cases of rare nipple tumours that the authors have operated upon are presented: neurofibromas, wart, leiomyoma and milium. The search of the literature was performed using Pubmed, Medline and Cochrane databases with limits: English Language, human species and available abstract. The keyword used was: ‘benign nipple tumours’. From the initial search, the abstracts were reviewed and only papers that referred to benign lesions that involved the nipple specifically were examined.
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Case reports
Results The initial search retrieved 337 articles. The articles were reviewed and 40 papers that referred to benign lesions that appeared to the nipple specifically were identified. The references of the papers were reviewed and all relevant articles were also examined (total 43). Different entities that were described included: neurofibroma,5–7 leiomyoma,8–18 milium,19,20 florid papillomatosis,9,21–27 syringomatous adenoma,28–32 nevoid hyperkeratosis,33–41 fibroma,42,43 pseudolymphoma and44–47 hemangioma.9 Table 1 summarizes the papers for each entity.
Table 1 Literature review of different entities of rare nipple tumours Nipple tumour
Authors
Neurofibroma
Sherman et al.5 Murat et al.6 Gokalp et al.7
Leiomyoma
Bulman8 Doctor et al.9 Nascimento et al.10 Tsujioka et al.11 Pujol et al.12 Velasco et al.13 Kaufman et al.14 Christenson et al.15 Chaudhary et al.16 Ku et al.17 Pavlidis et al.18
Milia
Mishra et al.19 Berk et al.20
Florid Papillomatosis
Nichols et al.21 Smith et al.22 Doctor et al.9 Perzin et al.23 Miyahara et al.24 Montemarano et al.25 Sugai et al.26 Kijima et al.27
Syringomatous adenoma of the nipple
Rosen28 Coulthard et al.29 Toyoshima et al.30 Wadhwa et al.31 Ichinokawa et al.32
Nevoid hyperkeratosis
Levy-Frankel33 Mold et al.34 Vestey et al.35 Perez-Izquierdo et al.36 D’Souza et al.37 Okan et al.38 Xifra et al.39 Kubota et al.40 Krishnan et al.41
Fibroma of the nipple
Iancu et al.42 Parlakgumus et al.43
Pseudolymphoma of the nipple
Bafverstedt44 Ackerman45 Schmid et al.46 Smyczek-Gargya et al.47
Haemangioma of the nipple
Doctor et al.9
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Neurofibromas We present one case of a female patient with
neurofibromatosis type I that had several neurofibromas in both her nipples (Fig. 1a). The patient found the lesions extremely disfiguring and wanted to have them removed. The neurofibromas were excised under local anaesthetic and the wounds were closed directly. Histology confirmed the diagnosis of neurofibromas (Fig. 1b,c). The patient had no post-operative complications and was satisfied with the final aesthetic result (Fig. 1d). Neurofibromas are benign tumours that arise from the peripheral nerves.48 They present as single or multiple firms, rubbery nodules of varying sizes. They appear first at puberty and consequently, they increase in number and size. In patients with neurofibromatosis type I, they are more common in the alveolar and not so much in the nipple area.5–7 Therapeutic approaches are: surgical resection for painful disfiguring lesions or treatment with CO2 laser.49 Wart We present one case of a 52-year-old female patient with a unilateral, soft, non–tender, pedunculated tumour attached to the nipple with dimensions 4 9 2.5 9 2 cm (Fig. 2a). The surface of the tumour was irregular in appearance and was raised from the tip of the nipple (Fig. 2b). The tumour appeared 22 years ago as a small painless lump. It gradually increased in size provoking symptoms of mild pressure and discomfort. The tumour was excised under local anaesthesia and the wound was closed directly (Fig. 2c). Histologically, the lesion was a verrucous papula, villous formed of squamous epithelium with hyperkeratosis, acanthosis and irregular papillomatosis. The basal layer cells showed mild atypia (MIB-1 positive) and in the upper layers there were clusters of epidermal cells with perinuclear hallo and nuclear atypia (koilocytic atypia) positive for p-16 protein. HPV-DNA test was performed in the formal fixed tissue and revealed the presence of HPV subtype group 30: 31,33,35,39 and 50:51,52,53,56,58,59. (Fig. 2d,e). Wart is a harmless, nongender specific, benign tumour of the skin known as skin tag.50 Differential diagnosis includes keratoacanthoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). It can be easily removed, mostly for aesthetic reasons, with electrofulguration or surgical excision under local anaesthesia.51 Leiomyoma A 35-year-old female patient with a unilateral painful lump on the right nipple presented to our outpatients department. The patient mentioned that the lesion started after an injury she had during breast feeding 3 years ago and it has been slowly growing ever since. The tumour was a pink, nodular mass, 10 mm in diameter, fixed to the underlying mammary papilla (Fig. 3a). An excisional biopsy was performed. Histology (Fig. 3b) and immunohistochemistry (SMA) test confirmed the diagnosis of leiomyoma. Leiomyoma of the nipple is a benign, tender and extremely rare tumour with only 50 cases
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Nipple tumours
Figure 1 (a) Patient with neurofibromatosis type I with several neurofibromas in both her Nipples. (b) Post-operative image after excision and direct closure of neurofibromas. (c) Neurofibroma is composed of a mixture of elongated spindle cells and fibroblasts in a middly collagenous background (haematoxylin–eosin staining, initial magnification 9400). (d) CD34 + staining for fibroblasts in a netlike pattern in neurofibroma. (initial magnification 9400).
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(a)
(b)
(c)
(d)
(a)
(b)
(d)
(e)
(c)
Figure 2 (a) Pedunculated tumour attached to the nipple with dimensions 4 9 2.5x2cm. (b) The surface of the tumour was irregular in appearance and was raised from the tip of the nipple. (c) Immediate post-operative image after excision of the tumour. (d) The lesion was composed of villus formations of hyperplastic squamous epithelium. (e) The majority of epithelial cells were positive for p-16 protein.
reported in the literature until now.8–18 The main reason that leads patients with nipple leiomyomas to their physicians is chronic pain.13
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Therapy includes complete excision of the tumour. Tumours are treated with either surgical resection or laser ablation, with CO2 laser treatment having low recurrence rates.15
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fort to the infant and felt hard and cystic. The diagnosis of a milium was suspected. Indeed, the lesion was incised and white solid material was enucleated confirming the initial diagnosis. According to our review of the literature, there is only one other reported case of primary milium of the nipple20 and four reported cases of primary milium of the areola in general.19,20
(a)
Other nipple tumours Florid papillomatosis Florid papillomatosis or adenoma of the nipple was first described by Jones in 1955. It is also called erosive adenomatosis,22 papillary adenoma23 or superficial papillary adenomatosis.25 The frequency of adenoma is reported to be 0.02%.23 It often presents with symptoms and signs of Paget’s disease and can be confused histologically with ductal carcinoma.9,26 Patients are usually in their third or fourth decade.21 The main presenting symptom is swelling of the nipple. Rarely, the patients report pain, serous or serosanguineous discharge.27 Other symptoms and signs are: erosion of the nipple, itching and bleeding.24 The treatment of choice is limited surgical excision. However, the patient needs to be informed that in this case recurrence is possible.27
(b)
Figure 3 (a) Pink, nodular mass, 10 mm in diameter, fixed to the right nipple. (b) Skin section of the nipple presenting a well-circumscribed mesenchymal tumour in the dermis and underlying mammary gland (magnification 9 20).
Milia A 6 months old female baby presented to our outpatients department with a well circumscribed 5 9 5 mm whitish firm papular lesion on her right nipple (Fig. 4a,b). According to the parents the lesion presented 1 month before consultation. Palpation of the lesion caused no discom(a)
Syringomatous adenoma of the nipple Syringomatous adenoma of the nipple is a very rare benign tumour that was first reported by Rosen in 1983.28 According to our review of the literature there have been 35 cases reported worldwide until now.32 Histologically, the lesion is difficult to distinguish from well-differentiated breast carcinomas, like tubular carcinoma,30 as it has features between a benign adenoma and a carcinoma. However, presentation and imaging can suggest the more likely diagnosis. A syringomatous adenoma is locally invasive but has
(b)
Figure 4 (a) Macroscopic image of nipple milium in a 6-month-old infant. (b) Dermoscopic image of the milium.
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no tendency to metastasize. This is why the term ‘infiltrating syringomatous adenoma’ has been proposed29 and it has been called microcystic adenexal carcinoma, sclerosing carcinoma of the sweat ducts and low-grade adenosquamous carcinoma in the literature.32 The lesion presents as a nipple nodule which may be tender and painful and cause nipple discharge or inversion. Syringomatous adenoma presents usually unilaterally, with only one case of bilateral presentation reported in the literature.29 Differential diagnosis includes florid papillomatosis, adenosquamous carcinoma, adenoid cystic carcinoma and sclerosing syringomatous carcinoma.31 Florid papillomatosis is characterised by epithelial hyperplasia and papillae arising from a lactiferous duct. There is no connection with the overlying epidermis. Adenosquamous carcinoma of the breast arises from the breast parenchyma and involves skin secondarily. On the contrary, syringomatous adenoma arises from the skin; involvement of underlying parenchyma is superficial and secondary. Adenoid cystic carcinoma of the breast or skin of breast may resemble syringomatous adenoma in having small ducts. However, adenoid pattern with basement membrane material and cribriform arrangement are seen, at least focally, in adenoid cystic carcinoma. Sclerosing syringomatous carcinoma resembles syringoma but has a sclerotic stroma. It invades deeply into skeletal muscle and perineural space. It is often located on the face and axilla.31 The treatment of choice is complete local excision. In incompletely excised lesions, recurrence rate is reported to be from 33% to 56%.30 Nevoid hyperkeratosis Nevoid hyperkeratosis of the nipple is a benign condition of unknown aetiology that was first described
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by Levy–Frankel in 1938.33 Usually, both nipple and areola are involved38 with the nipple exclusively involved in 17% of cases.40The lesions are commonly bilateral and rarely unilateral.37 However, some unilateral cases have become bilateral after pregnancy.36 This indication supports the theory of Mold and Jegasothy that some cases may be caused by changing oestrogen levels.34 Nevoid hyperkeratosis of the nipple and areola typically presents as hyperkeratotic, hyperpigmented and sometimes verrucous plaques. Sometimes yellowish discoloration or desquamation may occur.41 The diagnosis of nevoid hyperkeratosis of the nipple and areola is made by exclusion. Differential diagnosis includes Paget’s disease, superficial basal cell carcinoma, dermatophytosis and Bowen’s disease.39 Treatment is performed mostly for aesthetic reasons and generally consists of cryotherapy and topical keratolytic agents.35 Fibroma of the nipple Fibroma of the nipple is an extremely
rare condition. According to our review of the literature there are six cases reported up to date.42,43 Fibroma presents as a nontender, soft, brown-flesh coloured mass with verrucous surface. Surgical excision and histological examination is the appropriate treatment. Pseudolymphoma of the nipple Pseudolymphoma of the nipple is a rare benign proliferative process. It has also been called ‘pseudolymphoma of the breast’,45 lymphadenosis benigna cutis44 or follicular lymphatic hyperplasia.46 History of a tick bite will help in the diagnosis of Borrhelia Burgdoferi infection. In this case the recommended treatment is doxocycline for
Table 2 History parameters, symptoms, signs and imaging features for the differential diagnosis between benign and malignant lesions of the nipple Parameter
Benign
Malignant
Age
Incidence begins to rise during the second decade of life and peaks in the fourth and fifth decades
Incidence continues to increase after menopause
Time of onset
Usually long
Usually short
Retraction
Central, symmetric, slitlike
Inversion of the whole nipple with distortion of the areola
Bilateral presentation
Possible
Unlikely
Metastasis to lymph nodes
Not possible
Possible
Pruritus
Possible
Possible
Serosanguineous discharge
Possible
Possible
Lichenification
Possible
Possible
Erosion
Possible
Possible
Nodular enlargement
Possible
Possible
Nipple calcifications in mammography
Possible
Possible
US detection of one or more dilated subareolar ductal segments extending 3 cm or more within the breast
Unlikely
Possible
MRI findings of bilateral asymmetry or early, delayed or persistent enhancement of the nipple-areolar complex with a retro-areolar mass
Unlikely
Possible
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4 weeks.52 Other hypothetic causative factors are tattooing, herpes or medicine. However, the aetiology remains unknown.47 Haemangioma of the nipple So far there is only one report in the literature concerning haemangioma of the nipple in a 16year-old male patient who complained of bleeding from a small nodule in the nipple.9 The lesion was excised and diagnosis was confirmed.
In conclusion, when a patient comes in with a nipple mass we think that the clinician should follow these steps: (i) complete history (age, time of onset, family history); (ii) clinical examination of the nipple (soft–hard mass, tender–non-tender, inversion, erosion, discharge), breast and ipsilateral axilla (check for enlarged lymph nodes); (iii) consider diagnostic imaging; and (iv) excisional biopsy or incisional biopsy if the lesion is large or if there are indications that it extends into the breast parenchyma (palpation, breast imaging).
Discussion Differential diagnosis of benign tumours of the nipple can be demanding for the physicians. Age is an important factor, as the incidence of benign breast lesions begins to rise during the second decade of life and peaks in the fourth and fifth decades. On the contrary, the incidence of malignant diseases continues to increase after menopause.53 Time of onset is also a significant parameter in the history, as a long-standing lesion is more likely to be benign. Central, symmetric, slitlike retraction usually indicates a benign process, whereas inversion of the whole nipple with distortion of the areola is probably a sign of malignancy.54 Regarding breast imaging, mammography is often normal in the setting of a nipple complaint. A nipple mass can sometimes be seen projecting off of the nipple and nipple calcifications may be present in some diseases. Calcifications are seen in both benign (calcifications of the hair follicles, fat necrosis) or malignant lesions (Paget’s disease, intraductal carcinoma). Ultrasound can demonstrate a subareolar mass and is the next imaging test typically performed for a breast problem. Magnetic resonance imaging (MRI) is the most sensitive test for detecting breast cancer, however, is not typically performed to evaluate a nipple mass. If the patient is found to have Paget’s disease and conventional imaging (mammogram and ultrasound) is normal then a breast MRI is an appropriate study to determine the location of the primary breast cancer and extent of disease. Nipple abnormalities on MRI include bulkiness, bilateral asymmetry or early, delayed or persistent enhancement of the nipple-areolar complex with a retro-areolar mass.55 In general, breast imaging is usually non-contributory in the management of a visible nipple mass. In a woman of screening age (>40 years old) it is important to ensure she was up to date on her screening and to consider ordering a diagnostic breast imaging prior to any significant surgical procedure.56 Table 2 summarizes history parameters, presentation of symptoms and signs and imaging features in benign and malignant lesions of the nipple. Many of the symptoms and signs like pruritus, serosanguinous discharge, lichenification, erosion and nodular enlargement are produced by either malignant or benign lesions. Histological examination of the lesion can be the only definite answer in these cases.9,54
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References 1 Farrow JH. Benign and malignant lesions of the nipple. CA Cancer J Clin 1958; 8: 16–19. 2 Kelsey JL, Gammon MD. Epidemiology of breast cancer. Epidemiol Rev 1990; 12: 228–240. 3 Cole P, Mark Elwood J, Kaplan SD. Incidence rates and risk factors of benign breast neoplasms. Am J Epidemiol 1978; 108: 112–120. 4 Guray M, Sahin AA. Benign breast diseases: Classification, Diagnosis, and Management. Oncologist 2006; 11: 1132–1134. 5 Sherman JE, Smith JW. Neurofibromas of the breast and nipple-areolar area. Ann Plast Surg 1981; 7: 302–307. 6 Murat A, Kansiz F, Kabakus N, Kazez A, Ozercan R. Neurofibroma of the breast in a boy with neurofibromatosis type 1. Clin Imaging 2004; 28: 415–417. 7 Gokalp G, Hakyemez B, Kizilkaya E, Haholu A. Myxoid neurofibromas of the breast: mammographical, sonographical and MRI appearances. Br J Radiol 2007; 80: e234–e237. 8 Bulman JFH. Leiomyoma of the nipple. Br Med J 1951; 2: 975. 9 Doctor VM, Sirsat MV. Florid papillomatosis (adenoma) and other benign tumors of the nipple. Br J Cancer 1971; 25: 1–9. 10 Nascimento AG, Karas M, Rosen PP, Caron AG. Leiomyoma of the nipple. Am J Surg Pathol 1971; 3: 151–154. 11 Tsujioka K, Kashihara M, Imamura S. Cutaneous leiomyoma of the male nipple. Dermatologica 1985; 170: 98–100. 12 Pujol RM, Fernandez MT. A solitary papule on the nipple. Arch Dermatol 1991; 127: 571–576. 13 Velasco M, Ubeda B, Autonell F, Serra C. Leiomyoma of the male areola infiltrating the breast tissue. AJR Am J Roentgenol 1995; 164: 511–512. 14 Kaufman H, Hirsh E. Leiomyoma of the breast. J Surg Oncol 1996; 62: 62–64. 15 Christenson LJ, Smith K, Arpey CJ. Treatment of Multiple Cutaneous Leiomyomas with CO2 Laser Ablation. Dermatol Surg 2000; 26: 319–322. 16 Chaudhary K, Souza S. Leiomyoma of the nipple, and normal subareolar muscle fibers, are oestrogen and progesterone receptor positive. Histopathology 2004; 44: 626–628. 17 Ku J, Campbell C, Bennett I. Leiomyoma of the nipple. Breast J 2006; 12: 377–380. 18 Pavlidis L, Vakirlis E, Spyropoulou GA, Pramateftakis MG, Dionyssiou D, Demiri E. A 35-year-old woman presenting with an unusual post-traumatic leiomyoma of the nipple: a case report. J Med Case Rep 2013; 7: 49. 19 Mishra DK, Singh AK. Persistent congenital milia with naevus spilus. Indian J Dermatol Venereol Leprol 1995; 61: 356. 20 Berk DR, Bayliss SJ. Milium of the areola: A novel regional variant of primary milia. Pediatr Dermatol 2009; 26: 485–486. 21 Nichols FC, Dockerty MB, Judd ES. Florid papillomatosis of the nipple. Surg Gynecol Obstet 1958; 107: 474–480. 22 Smith EJ, Kron SD, Gross PR. Erosive adenomatosis of the nipple. Arch Dermatol 1970; 102: 330–332. 23 Perzin KH, Lattes R. Papillary adenoma of the nipple (florid papillomatosis, adenoma, adenomatosis): a clinicopathological study. Cancer 1972; 29: 996–1009.
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24 Miyahara M, Saito T, Kaketani K et al. Adenoma of the nipple. Surg Today 1992; 22: 368–370. 25 Montemarano AD, Sau P, James WD. Superficial papillary adenomatosis of the nipple: a case report and review of the literature. J Am Acad Dermatol 1995; 33: 871–875. 26 Sugai M, Murata K, Kimura N, Munakata H, Hada R, Kamata Y. Adenoma of the nipple in an adolescent. Breast Cancer 2002; 9: 254–256. 27 Kijima Y, Matsukita S, Yoshinaka H, Owaki T, Aikou T. Adenoma of the nipple: report of a case. Breast Cancer 2006; 13: 95–99. 28 Rosen PP. Syringomatous adenoma of the nipple. Am J Surg Pathol 1983; 7: 739–745. 29 Coulthard A, Liston J, Young JR. Case report: infiltrating syringomatous adenoma of the breast –appearances on mammography and ultrasonography. Clin Radiol 1993; 47: 62–64. 30 Toyoshima O, Kanou M, Kintaka N, Miyashita M, Shigematsu S, Sano J. Syringomatous adenoma of the nipple: report of a case. Surg Today 1998; 28: 1196–1199. 31 Wadhwa N, Mishra K, Agarwal S. Syringomatous adenoma of the nipple: a case report. Pathology 2003; 35: 271–272. 32 Ichinokawa Y, Ohtuki A, Hattori M, Sadamasa H, Hiruma M, Matumoto T. A case of syringomatous adenoma of the nipple. Case Rep Dermatol 2012; 4: 98–103. 33 Levy-Frankel A. Les hyperkeratoses de l’areola et du mamelon. Paris Med 1938; 28: 63–66. 34 Mold DE, Jegasothy BV. Estrogen-induced hyperkeratosis of the nipple. Cutis 1980; 26: 95. 35 Vestey J, Bunney M. Unilateral hyperkeratosis of the nipple: the response to cryotherapy. Arch Dermatol 1986; 122: 1360–1361. 36 Perez-Izquierdo J, Vilata J, Sanchez J, Gargallo E, Milan F, Aliaga A. Retinoic acid treatment of nipple hyperkeratosis. Arch Dermatol 1990; 126: 687–688. 37 D’Souza M, Gharami R, Ratnakar C, Garg BR. Unilateral nevoid hyperkeratosis of the nipple and areola. Int J Dermatol 1996; 35: 602–603. 38 Okan G, Baykal C. Nevoid hyperkeratosis of the nipple and areola: treatment with topical retinoic acid. JEADV 1999; 13: 218–220. 39 Xifra M, Lagodin C, Wright D, Abbruzzese M, Woscoff A. Nevoid keratosis of the nipple. J Am Acad Dermatol 1999; 41: 325–326. 40 Kubota Y, Koga T, Nakayama J, Kiryu H. Nevoid hyperkeratosis of the nipple and areola in a man. Br J Dermatol 2000; 142: 370–393.
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41 Krishnan RS, Angel TA, Roark TR, Hsu S. Nevoid hyperkeratosis of the nipple and/or areola: a report of two cases and a review of the literature. Int J Dermatol 2002; 41: 775–777. 42 Iancu D, Nochomovitz LE. Pseudoangiomatous stromal hyperplasia: presentation as a mass in the female nipple. Breast J 2001; 7: 263–265. 43 Parlakgumus A, Yildirim S, Bolat FA et al. Dermatoses of the nipple. Can J Surg 2009; 52: 160–161. 44 Bafverstedt B. Uber die lymphadenosis benigna cutis. Acta Derm Venerol Stockholm 1943; 24 (Suppl. I): i. 45 Ackerman LV. Tumor of the breast. 6th Annual Seminar. The Narsan Academy of Medicine 1943; 15–16. 46 Schmid U, Eckert F. Das Pseudolymphom-reaktive lymphatische Hyperplasie oder Pr€alymphom? Pathologe 1989; 10: 332–339. 47 Smyczek-Gargya B, Geppert M. Pseudolymphoma of the nipple. Eur J Obstet Gynecol Reprod Biol 1994; 53: 139–141. 48 An HY, Kim KS, Yu IK, Kim KW, Kim HH. Image presentation. The nippleareolar complex: a pictorial review of common and uncommon conditions. J Ultrasound Med 2010; 29: 949–962. 49 Ostertag JU, Theunissen CC, Neumann HA. Hypertrophic scars after therapy with CO2 laser for treatment of multiple cutaneous neurofibromas. Dermatol Surg 2002; 28: 296–298. 50 Doe PT, Grattan CE. Guess what! Skin tag (acrochordon) on the labium majus. Eur J Dermatol 1998; 8: 587. 51 Choudhary ST. Treatment of Unusually Large Acrochordon by Shave Excision and Electrodesiccation. J Cutan Aesthet Surg 2008; 1: 21–22. 52 Gissler S, Heininger U. Borrelia lymphocytoma (‘lymphadenosis benigna cutis’). Arch Dis Child 2002; 87: 12. 53 Mannello F, Tonti GA. Benign breast diseases: classification, diagnosis, and management. Oncologist 2006; 11: 1132–1134. 54 Nicholson BT, Harvey JA, Cohen MA. Nipple-areolar complex: normal anatomy and benign and malignant processes. Radiographics 2009; 29: 509–523. 55 Da Costa D, Taddese A, Cure ML, Gerson D, Poppiti R Jr, Esserman LE. Common and unusual diseases of the nipple-areolar complex. Radiographics 2007;27 (Suppl 1):S65–S77. 56 Yau EJ1, Gutierrez RL, DeMartini WB, Eby PR, Peacock S, Lehman CD. The utility of breast MRI as a problem-solving tool. Breast J. 2011; 17: 273–280. Epub 2011 Apr 8.
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DOI: 10.1111/jdv.12623
ORIGINAL ARTICLE
Rare benign tumours of the nipple G.A. Spyropoulou,1,* L. Pavlidis,1 M. Trakatelli,2 E. Athanasiou,3 E. Pazarli,4 D. Sotiriadis,2 E. Demiri1 1
Department of Plastic and Reconstructive Surgery, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Thessaloniki, Greece 2 Department of Dermatology, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Thessaloniki, Greece 3 Department of molecular and gene therapy, Hematology Clinic, Papanikolaou General Hospital, Thessaloniki, Greece 4 Department of Pathology, Papageorgiou General Hospital, Thessaloniki, Greece *Correspondence: G.-A. Spyropoulou. E-mail: [email protected]
Abstract Background Benign lesions of the breast in total are much more frequent than malignant ones. However, there are no epidemiologic data on the prevalence of benign or malignant tumours of the nipple, and the bibliography on benign nipple tumours in general is limited. Aims To present some rare cases of benign nipple tumours and review the literature. Materials and methods Four cases of rare benign nipple tumours: neurofibromas, wart, leiomyoma and milium are presented. The literature search on benign nipple tumours was performed using MEDLINE, Pubmed, and Cochrane databases with limits: English language, human species and available abstract. The keyword used was ‘benign nipple tumours’. Results The initial search retrieved 337 articles. The papers were reviewed and the articles that referred to benign lesions that appeared at the nipple specifically were identified. Different entities that were described included: neurofibroma, leiomyoma, milium, florid papillomatosis, syringomatous adenoma, nevoid hyperkeratosis, fibroma, pseudolymphoma and haemangioma. Discussion Differential diagnosis of benign tumours of the nipple can be demanding for the physicians. Many of the symptoms and signs like pruritus, serosanguinous discharge, lichenification, erosion and nodular enlargement are produced by either malignant or benign nipple lesions. Radiology can be unclear in the diagnosis of nipple abnormalities. Conclusion Histological examination of the lesion can be the only definite answer in these cases. Received: 15 January 2014; Accepted: 5 June 2014
Conflicts of interest None of the authors has any conflict of interest to report.
Funding sources No funding was received from any source for this work.
Introduction The nipple is a conic appendage on the human breast which contains the lactiferous ducts and is perforated by duct orifices. The nipples are very sensitive to touch and temperature and their physiologic purpose, is to deliver milk to the infant. They are the ‘mirror’ for many pathologic lesions of the breast as secretions of the mammary gland drain to the nipple. Therefore, abnormal discharges may insinuate pathologic lesions of the breast as intraductal papilloma or cancer.1 Due to the increasing awareness of the possible connection of a nipple lesion to a breast malignancy, nipple tumours can create great distress to the patient. It is therefore, important for the physician to be able to diagnose a benign nipple tumour. According to our review of the literature benign lesions of the breast in total are much more frequent than malignant ones.2–4 However,
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there are no epidemiologic data on the prevalence of benign or malignant tumours of the nipple, and the bibliography on benign nipple tumours in general is limited. In the present study we present some rare cases of benign nipple tumours and review the literature.
Patients and methods Four cases of rare nipple tumours that the authors have operated upon are presented: neurofibromas, wart, leiomyoma and milium. The search of the literature was performed using Pubmed, Medline and Cochrane databases with limits: English Language, human species and available abstract. The keyword used was: ‘benign nipple tumours’. From the initial search, the abstracts were reviewed and only papers that referred to benign lesions that involved the nipple specifically were examined.
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Case reports
Results The initial search retrieved 337 articles. The articles were reviewed and 40 papers that referred to benign lesions that appeared to the nipple specifically were identified. The references of the papers were reviewed and all relevant articles were also examined (total 43). Different entities that were described included: neurofibroma,5–7 leiomyoma,8–18 milium,19,20 florid papillomatosis,9,21–27 syringomatous adenoma,28–32 nevoid hyperkeratosis,33–41 fibroma,42,43 pseudolymphoma and44–47 hemangioma.9 Table 1 summarizes the papers for each entity.
Table 1 Literature review of different entities of rare nipple tumours Nipple tumour
Authors
Neurofibroma
Sherman et al.5 Murat et al.6 Gokalp et al.7
Leiomyoma
Bulman8 Doctor et al.9 Nascimento et al.10 Tsujioka et al.11 Pujol et al.12 Velasco et al.13 Kaufman et al.14 Christenson et al.15 Chaudhary et al.16 Ku et al.17 Pavlidis et al.18
Milia
Mishra et al.19 Berk et al.20
Florid Papillomatosis
Nichols et al.21 Smith et al.22 Doctor et al.9 Perzin et al.23 Miyahara et al.24 Montemarano et al.25 Sugai et al.26 Kijima et al.27
Syringomatous adenoma of the nipple
Rosen28 Coulthard et al.29 Toyoshima et al.30 Wadhwa et al.31 Ichinokawa et al.32
Nevoid hyperkeratosis
Levy-Frankel33 Mold et al.34 Vestey et al.35 Perez-Izquierdo et al.36 D’Souza et al.37 Okan et al.38 Xifra et al.39 Kubota et al.40 Krishnan et al.41
Fibroma of the nipple
Iancu et al.42 Parlakgumus et al.43
Pseudolymphoma of the nipple
Bafverstedt44 Ackerman45 Schmid et al.46 Smyczek-Gargya et al.47
Haemangioma of the nipple
Doctor et al.9
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Neurofibromas We present one case of a female patient with
neurofibromatosis type I that had several neurofibromas in both her nipples (Fig. 1a). The patient found the lesions extremely disfiguring and wanted to have them removed. The neurofibromas were excised under local anaesthetic and the wounds were closed directly. Histology confirmed the diagnosis of neurofibromas (Fig. 1b,c). The patient had no post-operative complications and was satisfied with the final aesthetic result (Fig. 1d). Neurofibromas are benign tumours that arise from the peripheral nerves.48 They present as single or multiple firms, rubbery nodules of varying sizes. They appear first at puberty and consequently, they increase in number and size. In patients with neurofibromatosis type I, they are more common in the alveolar and not so much in the nipple area.5–7 Therapeutic approaches are: surgical resection for painful disfiguring lesions or treatment with CO2 laser.49 Wart We present one case of a 52-year-old female patient with a unilateral, soft, non–tender, pedunculated tumour attached to the nipple with dimensions 4 9 2.5 9 2 cm (Fig. 2a). The surface of the tumour was irregular in appearance and was raised from the tip of the nipple (Fig. 2b). The tumour appeared 22 years ago as a small painless lump. It gradually increased in size provoking symptoms of mild pressure and discomfort. The tumour was excised under local anaesthesia and the wound was closed directly (Fig. 2c). Histologically, the lesion was a verrucous papula, villous formed of squamous epithelium with hyperkeratosis, acanthosis and irregular papillomatosis. The basal layer cells showed mild atypia (MIB-1 positive) and in the upper layers there were clusters of epidermal cells with perinuclear hallo and nuclear atypia (koilocytic atypia) positive for p-16 protein. HPV-DNA test was performed in the formal fixed tissue and revealed the presence of HPV subtype group 30: 31,33,35,39 and 50:51,52,53,56,58,59. (Fig. 2d,e). Wart is a harmless, nongender specific, benign tumour of the skin known as skin tag.50 Differential diagnosis includes keratoacanthoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). It can be easily removed, mostly for aesthetic reasons, with electrofulguration or surgical excision under local anaesthesia.51 Leiomyoma A 35-year-old female patient with a unilateral painful lump on the right nipple presented to our outpatients department. The patient mentioned that the lesion started after an injury she had during breast feeding 3 years ago and it has been slowly growing ever since. The tumour was a pink, nodular mass, 10 mm in diameter, fixed to the underlying mammary papilla (Fig. 3a). An excisional biopsy was performed. Histology (Fig. 3b) and immunohistochemistry (SMA) test confirmed the diagnosis of leiomyoma. Leiomyoma of the nipple is a benign, tender and extremely rare tumour with only 50 cases
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Figure 1 (a) Patient with neurofibromatosis type I with several neurofibromas in both her Nipples. (b) Post-operative image after excision and direct closure of neurofibromas. (c) Neurofibroma is composed of a mixture of elongated spindle cells and fibroblasts in a middly collagenous background (haematoxylin–eosin staining, initial magnification 9400). (d) CD34 + staining for fibroblasts in a netlike pattern in neurofibroma. (initial magnification 9400).
3
(a)
(b)
(c)
(d)
(a)
(b)
(d)
(e)
(c)
Figure 2 (a) Pedunculated tumour attached to the nipple with dimensions 4 9 2.5x2cm. (b) The surface of the tumour was irregular in appearance and was raised from the tip of the nipple. (c) Immediate post-operative image after excision of the tumour. (d) The lesion was composed of villus formations of hyperplastic squamous epithelium. (e) The majority of epithelial cells were positive for p-16 protein.
reported in the literature until now.8–18 The main reason that leads patients with nipple leiomyomas to their physicians is chronic pain.13
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Therapy includes complete excision of the tumour. Tumours are treated with either surgical resection or laser ablation, with CO2 laser treatment having low recurrence rates.15
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fort to the infant and felt hard and cystic. The diagnosis of a milium was suspected. Indeed, the lesion was incised and white solid material was enucleated confirming the initial diagnosis. According to our review of the literature, there is only one other reported case of primary milium of the nipple20 and four reported cases of primary milium of the areola in general.19,20
(a)
Other nipple tumours Florid papillomatosis Florid papillomatosis or adenoma of the nipple was first described by Jones in 1955. It is also called erosive adenomatosis,22 papillary adenoma23 or superficial papillary adenomatosis.25 The frequency of adenoma is reported to be 0.02%.23 It often presents with symptoms and signs of Paget’s disease and can be confused histologically with ductal carcinoma.9,26 Patients are usually in their third or fourth decade.21 The main presenting symptom is swelling of the nipple. Rarely, the patients report pain, serous or serosanguineous discharge.27 Other symptoms and signs are: erosion of the nipple, itching and bleeding.24 The treatment of choice is limited surgical excision. However, the patient needs to be informed that in this case recurrence is possible.27
(b)
Figure 3 (a) Pink, nodular mass, 10 mm in diameter, fixed to the right nipple. (b) Skin section of the nipple presenting a well-circumscribed mesenchymal tumour in the dermis and underlying mammary gland (magnification 9 20).
Milia A 6 months old female baby presented to our outpatients department with a well circumscribed 5 9 5 mm whitish firm papular lesion on her right nipple (Fig. 4a,b). According to the parents the lesion presented 1 month before consultation. Palpation of the lesion caused no discom(a)
Syringomatous adenoma of the nipple Syringomatous adenoma of the nipple is a very rare benign tumour that was first reported by Rosen in 1983.28 According to our review of the literature there have been 35 cases reported worldwide until now.32 Histologically, the lesion is difficult to distinguish from well-differentiated breast carcinomas, like tubular carcinoma,30 as it has features between a benign adenoma and a carcinoma. However, presentation and imaging can suggest the more likely diagnosis. A syringomatous adenoma is locally invasive but has
(b)
Figure 4 (a) Macroscopic image of nipple milium in a 6-month-old infant. (b) Dermoscopic image of the milium.
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no tendency to metastasize. This is why the term ‘infiltrating syringomatous adenoma’ has been proposed29 and it has been called microcystic adenexal carcinoma, sclerosing carcinoma of the sweat ducts and low-grade adenosquamous carcinoma in the literature.32 The lesion presents as a nipple nodule which may be tender and painful and cause nipple discharge or inversion. Syringomatous adenoma presents usually unilaterally, with only one case of bilateral presentation reported in the literature.29 Differential diagnosis includes florid papillomatosis, adenosquamous carcinoma, adenoid cystic carcinoma and sclerosing syringomatous carcinoma.31 Florid papillomatosis is characterised by epithelial hyperplasia and papillae arising from a lactiferous duct. There is no connection with the overlying epidermis. Adenosquamous carcinoma of the breast arises from the breast parenchyma and involves skin secondarily. On the contrary, syringomatous adenoma arises from the skin; involvement of underlying parenchyma is superficial and secondary. Adenoid cystic carcinoma of the breast or skin of breast may resemble syringomatous adenoma in having small ducts. However, adenoid pattern with basement membrane material and cribriform arrangement are seen, at least focally, in adenoid cystic carcinoma. Sclerosing syringomatous carcinoma resembles syringoma but has a sclerotic stroma. It invades deeply into skeletal muscle and perineural space. It is often located on the face and axilla.31 The treatment of choice is complete local excision. In incompletely excised lesions, recurrence rate is reported to be from 33% to 56%.30 Nevoid hyperkeratosis Nevoid hyperkeratosis of the nipple is a benign condition of unknown aetiology that was first described
5
by Levy–Frankel in 1938.33 Usually, both nipple and areola are involved38 with the nipple exclusively involved in 17% of cases.40The lesions are commonly bilateral and rarely unilateral.37 However, some unilateral cases have become bilateral after pregnancy.36 This indication supports the theory of Mold and Jegasothy that some cases may be caused by changing oestrogen levels.34 Nevoid hyperkeratosis of the nipple and areola typically presents as hyperkeratotic, hyperpigmented and sometimes verrucous plaques. Sometimes yellowish discoloration or desquamation may occur.41 The diagnosis of nevoid hyperkeratosis of the nipple and areola is made by exclusion. Differential diagnosis includes Paget’s disease, superficial basal cell carcinoma, dermatophytosis and Bowen’s disease.39 Treatment is performed mostly for aesthetic reasons and generally consists of cryotherapy and topical keratolytic agents.35 Fibroma of the nipple Fibroma of the nipple is an extremely
rare condition. According to our review of the literature there are six cases reported up to date.42,43 Fibroma presents as a nontender, soft, brown-flesh coloured mass with verrucous surface. Surgical excision and histological examination is the appropriate treatment. Pseudolymphoma of the nipple Pseudolymphoma of the nipple is a rare benign proliferative process. It has also been called ‘pseudolymphoma of the breast’,45 lymphadenosis benigna cutis44 or follicular lymphatic hyperplasia.46 History of a tick bite will help in the diagnosis of Borrhelia Burgdoferi infection. In this case the recommended treatment is doxocycline for
Table 2 History parameters, symptoms, signs and imaging features for the differential diagnosis between benign and malignant lesions of the nipple Parameter
Benign
Malignant
Age
Incidence begins to rise during the second decade of life and peaks in the fourth and fifth decades
Incidence continues to increase after menopause
Time of onset
Usually long
Usually short
Retraction
Central, symmetric, slitlike
Inversion of the whole nipple with distortion of the areola
Bilateral presentation
Possible
Unlikely
Metastasis to lymph nodes
Not possible
Possible
Pruritus
Possible
Possible
Serosanguineous discharge
Possible
Possible
Lichenification
Possible
Possible
Erosion
Possible
Possible
Nodular enlargement
Possible
Possible
Nipple calcifications in mammography
Possible
Possible
US detection of one or more dilated subareolar ductal segments extending 3 cm or more within the breast
Unlikely
Possible
MRI findings of bilateral asymmetry or early, delayed or persistent enhancement of the nipple-areolar complex with a retro-areolar mass
Unlikely
Possible
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4 weeks.52 Other hypothetic causative factors are tattooing, herpes or medicine. However, the aetiology remains unknown.47 Haemangioma of the nipple So far there is only one report in the literature concerning haemangioma of the nipple in a 16year-old male patient who complained of bleeding from a small nodule in the nipple.9 The lesion was excised and diagnosis was confirmed.
In conclusion, when a patient comes in with a nipple mass we think that the clinician should follow these steps: (i) complete history (age, time of onset, family history); (ii) clinical examination of the nipple (soft–hard mass, tender–non-tender, inversion, erosion, discharge), breast and ipsilateral axilla (check for enlarged lymph nodes); (iii) consider diagnostic imaging; and (iv) excisional biopsy or incisional biopsy if the lesion is large or if there are indications that it extends into the breast parenchyma (palpation, breast imaging).
Discussion Differential diagnosis of benign tumours of the nipple can be demanding for the physicians. Age is an important factor, as the incidence of benign breast lesions begins to rise during the second decade of life and peaks in the fourth and fifth decades. On the contrary, the incidence of malignant diseases continues to increase after menopause.53 Time of onset is also a significant parameter in the history, as a long-standing lesion is more likely to be benign. Central, symmetric, slitlike retraction usually indicates a benign process, whereas inversion of the whole nipple with distortion of the areola is probably a sign of malignancy.54 Regarding breast imaging, mammography is often normal in the setting of a nipple complaint. A nipple mass can sometimes be seen projecting off of the nipple and nipple calcifications may be present in some diseases. Calcifications are seen in both benign (calcifications of the hair follicles, fat necrosis) or malignant lesions (Paget’s disease, intraductal carcinoma). Ultrasound can demonstrate a subareolar mass and is the next imaging test typically performed for a breast problem. Magnetic resonance imaging (MRI) is the most sensitive test for detecting breast cancer, however, is not typically performed to evaluate a nipple mass. If the patient is found to have Paget’s disease and conventional imaging (mammogram and ultrasound) is normal then a breast MRI is an appropriate study to determine the location of the primary breast cancer and extent of disease. Nipple abnormalities on MRI include bulkiness, bilateral asymmetry or early, delayed or persistent enhancement of the nipple-areolar complex with a retro-areolar mass.55 In general, breast imaging is usually non-contributory in the management of a visible nipple mass. In a woman of screening age (>40 years old) it is important to ensure she was up to date on her screening and to consider ordering a diagnostic breast imaging prior to any significant surgical procedure.56 Table 2 summarizes history parameters, presentation of symptoms and signs and imaging features in benign and malignant lesions of the nipple. Many of the symptoms and signs like pruritus, serosanguinous discharge, lichenification, erosion and nodular enlargement are produced by either malignant or benign lesions. Histological examination of the lesion can be the only definite answer in these cases.9,54
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