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Home , Breast disease, Duct ectasia of breast, Galactorrhea, Mastitis

gineco ro mastology Discharge: Evaluation and Management

S. Zervoudis(1,2,3), P. Economides(1), G. Iatrakis(1), D. Polyzos(1), K. Lykeridou(2), I. Navrozoglou(3) (1) Lito Hospital, Dept of Mastology, Athens Greece (2) ATEI University of Athens, Athens, Greece (3) University of Ioannina, Dept of Obst/Gyn, Unit, Ioannina, Greece Corresponding author: Prof. S. Zervoudis Lito Maternity Hospital, Dept. of Mastology 7, Mousson Street, Athens 11524, Greece E-mail: [email protected]

Abstract is a common symptom carcinoma. Techniques used in nipple dis- women complain of. It is classified as nor- charge evaluation include , mal or abnormal depending on features ultrasound, cytology, duct endoscopy, the such as laterality, cycle variation, quantity, mammary pump, ductography, immuno- color or presentation (induced vs sponta- chemical methods and surgical excision of neous). It can be related to benign condi- the pathological ducts. tions such as intraductal papilloma, duct Keywords: nipple discharge, galactor- ectasia, plasma cell , rhea, papilloma, duct ectasia, mammary or malignant such as ductal or papillary pump

Introduction „ Local: herpes zoster, , thoracic trauma, and medications are Nipple discharge is a common pre- trauma, previous surgery of the included in the . senting symptom women complain of. breast or the thoracic cage. The patient who is curious to check for Three out of ten women who present „ General: , headache, myxoede- discharge may cause continuous me- to their doctor for a breast examination ma, visual disturbances. chanical stimulation. In such cases dis- have nipple discharge. Nipple discharge The spontaneous or induced nipple continuation of the stimulation will dis- is 7% to 10% of all breast symptoms(1). discharge may be identified either by continue the process. Common features of nipple discharge the patient accidentally or during cli- Women should be advised to avoid are the following: nical examination. Less commonly it checking themselves for discharge „ It may be unilateral or bilateral. may present during mammography se- since benign discharge may resolve „ It presents cycle variation. condary to pressure. when the nipple is left alone(3,4). Medi- „ It is induced or spontaneous. 1ot all nipple discharge is abnormal. cations linked to nipple discharge are „ It may be clear, serous, milky, yellow, Therefore it is necessary to categorize antihypertensives, , phenothia- green, pink or slightly bloody, brown it to normal, abnormal or to attribute it zines, tranquilizers, antidepressants, an- or black (old ). to galactorrhea according to history and tipsychotics and others(5), summarized „ It may originate from one or mul- . in Table 1(6): tiple ducts In drug induced galactorrhea the „ It may be of small, moderate or large Normal Discharge discharge is milky, bilateral, it originates quantity. Normal discharge is non-spontaneous, in many ducts and it is copious in The discharge may be accompanied and is usually bilateral. It is serous quantity. The diagnosis is reached by a by other clinical findings such as: and originates in many ducts. Multiple good history and it will be confirmed by „ Breast findings: mastodynia, palpa- duct discharges are rarely caused by the discontinuation of the medication. ble mass, palpable lymph node, pru- (2). In cases not related to breast No further workup is indicated in ritus or depression. pathology, mechanical stimulation, these cases and the patient should be

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Table 1. Medications and herbs associated with Galactorrhea(6)

„ Antidepressants and anxiolytics „ Phenothiazines - Alprazolam - Chlorpromazine - Buspirone - Prochloperazine - Monoamine oxidase inhibitors - Others - Moclobemide - Selective serotonin reuptake inhibitors „ Other Drugs - Citalopram - Amphetamines - Fluoxetine - Anesthetics - Paroxetine - Arginine - Sertraline - Cannabis Image 1 -Tricyclic antidepressants - Cisapride - Cyclobenzaprine even if the discharge „ Antihypertensives - Danazol contains blood. It is associated with an - Atenolol - Dihydroergotamine underlying malignancy in 1.2% to 15% - - of patients(7-12). One should identify the - Reserpine - Isoniazid Verapamil quadrant that is involved by applying - - pressure on the breast and this way the - Octreotide „ - Opiates affected duct can be easily localized. - Histamine H2-receptor blockers - Rimantadine Lesions that may be linked to abnor- - - Sumatriptan mal discharge are intraductal papillomas, - Ranitidine - Valproic acid duct ectasia, mastitis, fibrocystic changes, - Farotidine carcinoma and Paget’s disease (Image 1). „ Herbs Bloody, unilateral and discharge ori- „ Hormones - Anise ginating from one duct are features - Conjugated and medroxyprogesterone - Blessed thistle associated with suspicious lesions(13). In - Medroxyprogesterone contraceptive injections - Fennel such cases an intraductal malignancy - Oral contraceptive formulations - Fennugreek seed cannot be excluded and therefore sur- - Marshmallow - Nettle gical intervention should not be delayed. - Red clover According to various reports, cancer is - Red Raspberry diagnosed in 5%(14), to 7.5%(15) or even in up to 11%(16). reassured. During and post- Abnormal nipple discharge Galactorrhea partum (until after 2 years) nipple dis- Abnormal nipple discharge is defined Galactorrhea is typically bilateral, it charge is normal and milky in nature. as non-lactational, persistent, sponta- originates in many ducts and the dis- The same applies after a spontaneous neous and unilateral(7-12). It is usually charge is milky. This is typical in phar- or termination of pregnancy in located in one duct. As it is usually spon- macological galactorrhea and disconti- the second trimester. taneous, it may as well disappear. It nuation of the medication will eliminate In the remaining cases, nipple dis- may be green or grey, serous or bloody the finding. charge may or may not be associated in appearance. The most common ca- Table 2 may be used to categorize nip- with malignancy. use of this discharge is usually benign ple discharge according to its nature.

Table 2. Nipple discharge features based on its nature(17) Nature of Discharge Etiology Localization Ducts involved

Postpartum Medications Milky Bilateral Multiple Hyperprolactinemia Chiari-Frommel syndrome Intraductal Papilloma Serous/Serosanguinous Unilateral One Intraductal cancer Intraductal Cancer Bloody Unilateral One or two Trauma Green Fibrocystic Disease Bilateral Multiple

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Etiology of Nipple Discharge differential diagnosis between benign process proceeds or follows the di- 1. Benign diseases intraductal papilloma and papillary car- latation of the duct. We believe that Intraductal papilloma cinoma. the primary process is the dilatation Intraductal papilloma is a local intra- The management of a papilloma re- of the duct and the accumulation of ductal with simultaneous quires a surgical procedure: microdo- amorphous “cheese-like” secretion. The formation of a vascular and neural axis chectomy or pyramidectomy(15,24,25): it con- acute inflammation may be caused by that eventually becomes macroscopically sists of dissection of the affected duct. A epithelial rupture and diffusion of the visible. Solitary or multiple papillomas small sound is used to catheterize the contents into the fibrous duct-wall are the most common cause of nipple duct where the discharge is originating and the underlying structures. These discharge reported (35%-62%)(7,10,11,18-22). and methylene blue dye is injected in contents consist of neutral fat and lipid Sixty-80% of intraductal papillomas are order to visualize the duct branches. crystals that are typical of duct ectasia. accompanied by spontaneous or in- After the nipple has been stabilized, the The chronic granulation-type reaction duced bloody, serous, aqueous, or sero- dye colored duct is dissected from the may develop foreign body-like giant sanguinous discharge, one of its main nipple to the depth and the specimen cells and a multiform inflammatory cell clinical findings. A 5% risk of developing has a triangular shape. After meticulous population. As the whole process in duct into invasive carcinoma has been repor- hemostasis has been obtained, rebuil- ectasia is long in duration, sometimes ted(23). ding of the retroareolar area is performed plasma cells are dominant in the in- Papillomas affect women 35-50 years and a small drain is placed. flammatory infiltrations. This finding old, they vary in size, they are round or Duct ectasia impressed some pathologists who used lobular, they have a broad base or they Duct ectasia is the cause of nipple the term “plasma cell mastitis” in order are pedunculated, they may be located discharge in 11% of patients(7). to describe duct ectasia. in any quadrant, although the more There is a broad terminology used Other findings in duct ectasia are the frequent location is in a big duct behind in various reports for the same entity: following: the nipple, they may be single or multiple “varicocele-like tumor”, ”plasma-cell „ Serous or green-white nipple dis- and they are not usually accompanied mastitis”, “obstructive mastitis”, galacto- charge in 20% of the cases. by a palpable mass. Nevertheless, if the phoritis”, “duct ectasia” and “periductal „ Nipple inversion that leads to fi- papilloma is greater than 1cm and close mastitis” are some of the terms used. brosis and development of ring or to the nipple, it may be palpable. The last two terms are widely used tubular calcifications. This finding The presence of multiple papillo- and are the most representative of the is typical in the mammogram and mas is called papillomatosis, a com- pathology. The other terms mentioned especially when the disease is in ad- mon finding in menopausal wo- earlier represent different stages of vanced stages. men. Scattered areas of increased the same entity. Duct ectasia usually „ Apocrine metaplasia with or with- density with microcalcifications are accompanies benign breast conditions out epithelial hyperplasia. The epi- the mammographical finding in papil- (epithelial hyperplasia, papillomatosis) thelial layer consists of widened lomatosis. (This presentation is not but may also be associated to breast atrophic cells. typical of the disease). In intraductal cancer. This condition may be managed with papillomas, there is bloody flow only The diagnosis is set by high sensitivity but in persistent or recurrent if there is a communication between ultrasonic evaluation together with a cases, with surgical excision of the ducts the cyst and the duct. The remaining cytological assessment of the discharge below the nipple. A focused excision is clinical findings are the typical of a cyst. and if the discharge originates from one preferred rather than a complete suba- When bloody fluid is aspirated from the duct, by the ductography. reolar excision since the later technique cyst, a differential diagnosis between Duct ectasia is different from cystic is associated with higher rates of seroma the benign intracystic papilloma and disease, as it is an inflammatory pro- formation, nipple numbness and nipple cancer must be made by the cytological cess, affecting usually the ducts below inversion(15,26). evaluation of the specimen(13). the nipple. It develops gradually ei- Plasma cell mastitis Papillomas may be diagnosed by ther through the ductal system or the Plasma cell mastitis is a rare type ductography, in which there is one or breast lobes. Its presentation also va- of chronic mastitis characterized by multiple contrast filling defects of smooth ries depending on the duration of the the presence of multiple plasmocytes contour in the duct or interruption of process. cells in microscopical examination. It contrast flow in the duct where the Clinically it presents as a firm stable is usually found in multiparous women papilloma exists. Similar may be as mass under the nipple, similar to a ma- and is caused by the condensation of well, the presentation of ductal cancer. lignant mass. It is more common in the the breast discharge. Typical findings The diagnosis is confirmed by cytology perimenopausal years. It is interesting include thickened ducts and fibrosis where papillomatous formations are to mention that in 1/3 of mastectomy that may be multicentric. In palpation visualized and by ductography where specimens in women over 50 years, there is a firm mass impression and fi- interruption of contrast flow in the duct sub-clinical duct ectasia was diagnosed. brosis may lead to nipple inversion. It is identified where the papilloma is The cause is unknown although breast- may be accompanied by serobloody and located. Ductography will facilitate the feeding may be related. It is unknown and thick nipple discharge. Cancer should be surgical management and simplify the contradictive whether the inflammatory included in the differential diagnosis.

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Other woman that presents with nipple dis- Other syndromes that are indirectly charge must be managed according to related to the breast discharge are neuro- her age by tests such as mammography, hormonal causes such as the amenorrhea- ultrasound and cytology. Early cancer galactorrhea syndrome (Chiari-Frommel), cases are difficult to be identified, es- pituitary adenomas, , pecially in young women with dense mellitus etc. Investigations such . as TSH, T3, T4, and levels are ne- Mammography cessary in such cases. Hyperprolactinemia The clinical examination and mam- must be ruled out with CTs and visual field mography are first line diagnostic tests. In a few selected cases, tests should approaches. Mammography may re- include measurement of estradiol levels, veal calcifications that must be eva- Image 2 progesterone and androgens. luated. It is associated with a 9.5% 2. Malignant diseases: carcinomas false-negative rate and a 1.6% false-po- All types of breast carcinoma (Ductal, sitive rate in detecting Lobular, Tubular, Medullar etc.) are in patients with nipple discharge(8). The breast ultrasonography is com- sometimes diagnosed because of the Mammography is recommended to plementary to mammography and will symptom of nipple discharge. Special any patient presenting with abnormal guide fine needle aspiration (FNA) and importance should be attributed to Pa- nipple discharge, although it has poor will help in obtaining cytology speci- pillary carcinoma despite the fact it is positive predictive value (16,7%). This mens from the abnormal area. The ul- a rare malignancy (<1%). It is usually percentage reveals that it is not reliable trasonographical findings of the most intraductal and may present initially as in the diagnosis of the underlying cause common causes of nipple discharge are a unilateral nipple discharge that origi- of nipple discharge. Any mammographic presented in table 3. nates in one duct. abnormality should correspond with More than 50% of the cases it appears the quadrant of the breast from which mammographically as a high-density the discharge originates for it to be lesion with accompanying calcifications. considered relevant to the cause of the Ductography and cytology are used to discharge. Because of its low sensitivity reach the diagnosis. Since almost 50% (59%) in the diagnosis of malignant of lesions showing papillary features duct pathology, it has limited value as a on cytology prove to be malignant, all screening method in the management cases reported as papillary on cytology of nipple discharge. Almost 50% of Image 3: Intraductal papilloma should be excised urgently for histologic the patients who are diagnosed with assessment(27). malignant breast disease and who un- Cytology Today it may be diagnosed by high derwent mammography did not have Cytological evaluation of nipple dis- sensitivity ultrasonic evaluation by an exact diagnosis of the corresponding charge can be done directly from the nip- experienced physician. duct pathology and there are studies ple. Lately, cytology has been improved that confirm that mammography is by new techniques of “duct lavage” and Evaluation/Techniques inadequate in the diagnosis of abnor- “duct endoscopy” (“ductoscopy”)(30). These Because the majority of nipple dis- mal nipple discharge(28). Only half of later techniques are designed to check charge cases are more frequently due to the patients presenting with nipple dis- the abnormal cells that travel from the benign conditions, less operative, non- charge who were found to have cancer ducts to the nipple (Image 4.) Biological surgical methods are applied to limit the had an abnormal mammogram, mostly markers could also be analyzed in the need for surgical intervention(16). The microcalcifications; (Image 2). liquid specimen. Nevertheless, this tech- nique has high false negative findings, it is unrevealing and is not helpful in Table 3. Ultrasonographical findings in common nipple localizing a tumor(7,11). discharge etiology(29) Etiology Findings Intraductal papilloma (Image 3) Ovoid hyperechoic mass Single or multiple tubular anechoic Duct ectasia subareolar structures Calcifications, mass lesion with irregular shape or irregular borders, hypoechoic, with Intraductal carcinoma loss of bilateral edge shadowing, posterior acoustic transmission, non-uniform internal echotexture Image 4

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It should be mentioned that in previ- Mammary pump ous investigations in asymptomatic wo- Zervoudis(34) has developed a simple men with nipple discharge, a diagnosis instrument called “mammary pump” in of malignancy was made in 35% of cyto- order to obtain additional cytological logy specimens (70% were suspicious for specimen from tumors that are in close malignancy). proximity to the nipple (Image 7). Duct endoscopy ( Ductoscopy) This instrument can be also used to First developed in Asia during the 90’s, increase spontaneous nipple discharge this technique is performed under local that originates from benign breast lesions, anesthesia. It permits the visualization of for cytology. The principle of this technique the mammary ducts and it may be used is to suction cells from the breast ducts for direct diagnosis of papillomas, cancer Image 6 with negative pressure and to collect fluid and direct cytological evaluation(31). En- with cells from the galactophoric tree. doscopy may also be combined with breast is gently massaged in order to The mammary pump is made of a 20cc local techniques aiming to manage the identify the duct where the discharge syringe with its front end cut open by lesion such as radiofrequencies, lasers originates. After catheterization of the scissors. The syringe is adapted to a FNA and microwaves. duct by a fine cannula, approximately gun that is used for cytology sampling. 10cc of normal saline are injected and the liquid is then aspirated and sent to cy- tology. Then the duct is catheterized by an endoscope ranging from 1.1 to 0.5 mm in external diameter with a working channel of 0.35 to 0.45 mm that provides depth of perception during visualization. The findings can be classified to the following(33): „ Obstructing endoluminal lesions. „ Epithelial surface anomalies. Image 5 „ Papillomatous lesions (Image 6). Image 7. Zervoudis’s Mamary pump: „ Intra-duct scars adhesions & duct sucking technique Duct endoscopy, is performed by obliteration. direct visualization of the lesion with „ Intra-ductal calcification. The suctioning technique begins after the a special instrument, the microendo- Practical and technically feasible, skin has been prepared with antiseptic scope (0,1- 0,2 mm in diameter), that is duct endoscopy can be used even in the solution in circular massage movements connected to a source of light (Image 5). absence of nipple discharge or in normal over the breast from the periphery to the Tumors up to 0,1mm in diameter can be non-ectatic ducts. It is a very promising nipple for about 1 minute. The mamma- visualized at a maximum distance of 10 technique especially when good biopsy ry pump is then placed on the nipple and cm(32). instruments will be developed, since 8-10 suctioning attempts are performed The first step of the technique consists the findings will be correlated to his- with a negative pressure of 3 cm. The pa- of an irrigation lavage during which the topathology(33). tients very well tolerate the technique.

Table 4. Masood Cytologic classification(35) MASOOD CYTOLOGIC CLASSIFICATION Cellular Cellular Chromatin Myoepithelial Anisonucleosis Nucleoli SCORE arrangement Pleomorphism clumping cells Monolayer Absent Absent Absent Absent Many 1

Nuclear overlapping Mild Mild Micronucleoli Rare Moderate 2 Micro Clustering Moderate Moderate and/or rare Occasional Few 3 micronucleoli Predominantly Loss of cohesion Conspicuous Conspicuous Frequent Absent 4 macronucleoli Score 6-10 = non proliferative breast disease Score 15-18 = Proliferative breast disease with atypia Score 11-14 = Proliferative breast disease without atypia Score 19-24 = Cancer

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The mammary pump collects fluid It has been shown to be accurate in from the nipple and the smear is providing the location and depth of applied and stained on slides by using ductal abnormalities when a single duct the Papanicolaou and Diff-Quick tech- is identified as the source. niques. The Masood(35) semi-quantita- Data regarding the location of the tive cytology score is used to classify lesion greatly facilitate biopsy, especially the breast lesions (Table 4). Classical with deep lesions. Galactography-aided cytology and liquid-cytology with cen- wire or coil localization is a practical trifuge techniques can be used as well. localization method for intraductal The mammary pump is a comple- lesions not detectable on mammography mentary technique that increases the or sonography(36). It improves the diag- numbers of cells used in the diagnosis nostic yield of surgical biopsy from 67% in of breast disease. It applies to the non-studied patients to 100% in patients evaluation of any nipple discharge receiving a ductography. After the lesion Image 9 and tumours in close proximity to the has been localized, excision will follow. nipple, and may be used as an adjunct Nevertheless, ductography cannot be to FNA. The accuracy of the mammary effectively used for the differentiation of pump in the detection of abnormal cells a benign versus a malignant lesion(37). is 84% for typical hyperplasia lesions, Immunochemical/Hemoccult 61% for atypical hyperplasia and 70% for (Beckman-Coulter, Palo Alto, CA) intraductal carcinoma. These findings The identification of blood in the represent the correct diagnosis of the fluid (blood in small quantities) may cytology specimen obtained by the be potentially useful with concomitant mammary pump compared with the cytological review. Blood identification histological findings of the surgical kits with the Hemoccult technique biopsy. The technique has accuracy are useful, but not necessarily in the greater than 80% in the diagnosis of in- prediction of the final pathology fin- vasive ductal and lobular , when dings. The positive predictive value Image 10 the lesion is less than 4-5 cm from the of the technique is <10%(38) to 20%(39). nipple. Therefore, the technique can However, in 5-28% of cases, bloody or be used in the early diagnosis of breast Hemoccult-positive discharge is more cancer and the positive results may be likely to be associated with cancer(40). used in the design of future studies. In general it should be underlined Ductography that mammography, ductograms, cyto- Ductography (galactography) is per- logy and Hemoccult staining, used se- formed by dilatation, catheterization parately are inadequate in the correct and injection of a water-soluble contrast diagnosis(16). by a 2cc Telebrix syringe. Craniocau- Surgical Procedures dal, lateral and compression views are Biopsy should be performed if there obtained (Image 8). The results may be is an accompanying palpable mass. Image 11 characterized as Normal, Ductal dila- Also, when nipple discharge persists tation, Filling defect or Cutoff sign(26). in one or two single ducts or when it is The probe is then reinserted and the bloody, biopsy should be performed by affected duct is marked. A limited cir- terminal duct excision(14,41).The classical cum-areolar incision is made to raise Image 8 surgical technique “excision of the major the areolar skin flap. The probed duct is ducts” described by Urban(25) is today then identified close to its attachment on supplanted by more conservative surgical the underside of the nipple and carefully techniques called or dissected free of the surrounding tissues microdolichectomy or pyramidectomy. and the unaffected ducts over a length of Microdochectomy procedure(42): 5-6 cm towards its proximal end. Finally After identifying the orifice of the dis- the duct is removed by transaction and charging duct by gentle pressure on the nip- is marked with a single suture to orien- ple, the duct is probed with a fine lacrimal tate the specimen. probe that is passed gently peripherally as Many variations of the classical tech- far as possible without disrupting it. After nique are described in the literature. gentle dilatation the probe is temporarily Our team has published in 2007 an ori- removed and a 22G intravenous cannula is ginal minimal surgical variation of the inserted into the duct in order to inject 1-2 classical technique; we called it: ”Transnip- ml of methylene blue dye. ple pyramidectomy”(15) (Images 9-10-11).

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la horizontally for 1 cm in each side, and Conclusions we perform a “transnipple-transareolar Nipple discharge is a common pyramidectomy”. complaint (7-10% of all breast symp- The specimen looks like a pyra- toms). It is necessary to determine mid: the peak represents the be- the exact location (origin) and the ginning of the pathological duct cause of the discharge. Despite marked by a stitch; the base of the the most frequent causes are duct pyramid with the corresponded ectasia and benign papilloma we lobules is marked with methylene should remind that breast cancer blue colorant (image 12). is found in 6 to 8 % of pathological The choice of the technique depends nipple discharge. Cytology remains Image 5 on the anatomy of the breast, on the a good indicative tool for diagnosis, age of the patient, and on the necessi- but in the majority of the cases it is The duct(s) that cause the pathological ty to excise less or more ducts. In ge- necessary to obtain a histological discharge are excised through a trans- neral in older patients, irrespectively diagnosis by the surgical procedure. nipple approach in a pyramid-shaped of whether the discharge is localized Moreover the surgery will treat the specimen. The initial steps described to one or multiple ducts, major duct lesion definitively in cases on benign earlier in microdochectomy are identi- excision is preferred to provide com- cause. Recently the development of cal. After the injection of methylene blue prehensive histology because breast endoscopic tools and fiber optics will dye, a horizontal transnipple incision is cancer is more frequent (DCIS or in- allow safer diagnosis and treatment made, the nipple is opened with forceps vasive cancer), and to avoid probable without any sacrifice in function and the proximal part of the marked duct further discharge from other ducts(43). and excellent aesthetic results(44). is grasped and excised. The technique In young patients when the discharge Today there are simple non-invasive has excellent aesthetic and functional is localized to one or two ducts, be- or minimally invasive techniques results and preserves nipple sensation. cause the aesthetic point and because that can be used in the evaluation Sometimes, when the excision of many the option of breast-feeding must be and management of this condition the pathological ducts is necessary we preserved microdochectomy can be which provide very good results in extend the nipple`s incision to the areo- performed(15). the majority of the cases. „

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