The Management Of Pathological Nipple Discharge Biology Essay

A PROPOSAL FOR DISSERTATION AS PART FULFILMENT OF THE REQUIREMENTS FOR MASTER OF MEDICINE IN THE DEGREE OF SURGERY OF THE UNIVERSITY OF NAIROBI.

DR ALLAN MASINDE SAJABI

DECLARATION

I hereby declare that this study is my original work and has not been presented for dissertation at any other university.

Dr Sajabi Allan Masinde.

MB.Ch.B.(Nrb)

Sign______________________

Date ______________________

SUPERVISORS

MR KIMANTHI KIMENDE S.G

MB.Ch.B, M.MED (Gen Surg), FCS (ECSA)

Lecturer Department of Surgery, University of Nairobi.

Breast surgery

Sign…………………………… Date…………………………

DR. JOSEPH W. GITHAIGA

MB.Ch.B (NRB) MMED SURGERY (NRB)

Cert surgery (Israel) visceral surgery/laparoscopy (munich-hamburg)

Breast surgeon

Sign…………………………… Date…………………………

LIST OF ABBREVIATIONS

ND – Nipple discharge

PND – Pathological nipple discharge

SND – Spontaneous nipple discharge

KNH – Kenyatta National Hospital

ABSTRACT

Background: nipple discharge is a common complain among women. Pathological nipple discharge is surgically significant due the risk of carcinoma of the breast. Clinicians remain divided on the management of patients presenting with pathological nipple discharge and on the utility of triple assessment (clinical examination, breast imaging and nipple discharge cytology). This study aims at verifying the utility of triple assessment in diagnosis of pathological nipple discharge.

Objectives: To assess the value of triple assessment in the diagnosis of breast pathology in patients with pathological nipple discharge.

Design: Analytic cross-sectional study.

Material and methods: a prospective cross-sectional study will be carried on all patients presenting to Kenyatta national hospital with pathological nipple discharge. All patients will undergo triple assessment (clinical examination, breast imaging and nipple discharge cytology). All the patients will have surgery (either microdochectomy or duct excision) which is the current accepted gold standard for managing PND and samples submitted for histology.

Data management/Analysis: The histological results will be compared with those of triple assessment to determine the sensitivity and specificity of the triple assessment modalities in the diagnosis of breast pathology at the Kenyatta National Hospital.

TABLE OF CONTENTS

Declaration ………………………………………………………………………………i

Supervisors………………………………………………………………………………ii

List of abbreviations……………………………………………………………………..iii

Abstract…………………………………………………………………………………...iv

Introduction………………………………………………………………………………1

Literature review………………………………………………………………………….3

Study question………………………………………………………………………….....12

Study justification…………………………………………………………………………12

Objectives…………………………………………………………………………………13

Materials and methods…………………………………………………………………….13

Data management and analysis……………………………………………………………17

Ethical considerations……………………………………………………………………..18

Budget estimates…………………………………………………………………………..19

Time line……………………………………………………………………………………19

References………………………………………………………………………………….20

Appendices…………………………………………………………………………………25

INTRODUCTION

Nipple discharge (ND) is defined as the abnormal release of fluid from the nipples of the breast that is not associated with lactation1. It is the third major reason involving the breasts for which women seek medical attention, after breast lumps and breast pain. It can often be the first sign of an underlying breast pathology2.

The probability of ND in females increases with age as well as with increasing number of pregnancies but it may also occur in adolescent boys as well as pubertal girls. The nature of the discharge may range in color (clear, yellow, dark green or bloody), consistency and composition and may be either unilateral or bilateral3.

ND can be defined as physiologic or pathological, spontaneous or expressed and unilateral or bilateral. Physiologic ND is usually bilateral with the involvement of multiple ducts. Physiologic ND most commonly will occur as a result of stimulation of the breast or nipple but can also be related to the use of medications. Pathologic ND (PND) is surgically significant. PND is usually unilateral, may be bloody and may be associated with a breast lump. PND is also more often localized to a single duct3.

Nipple discharge is common and rarely associated with underlying carcinoma1. The overall incidence of breast carcinoma has been reported as between 10 and 21% in patients with PND and amongst these approximately 1 to 5% complains solely of PND3,4. However, most reports include only the patients undergoing surgery without accounting for those patients managed via non surgical methods4. About 20% of men who undergo surgery for ND have been found to have an underlying carcinoma of the breast. The risk of malignancy increases in those patients who present with bloody ND, a concurrent breast lump and an age above 55 years3. The risk is also increased where there is underlying image abnormality4, 5.

Although ND is usually benign, caused by conditions such as papillomas and duct ectasia, the risk of underlying malignancy remains and therefore further evaluation is often necessary6,7. Clinicians remain divided on the clinical and radiological investigation modalities that can be used to determine the different etiologies of PND8.

The main goal of examination is to differentiate patients with benign ND from those with high risk lesions or carcinoma. Patients complaining of ND need to be approached in a systematic manner in order to define the risk of underlying malignancy8. Studies suggest that by combining diagnostic tests such as mammography, breast ultrasonography and discharge cytology a clinician may be able to arrive at a diagnosis and plan proper management9. This is referred to as triple assessment. The purpose of this study is to determine the utility of triple assessment in managing patients with PND at KNH.

LITERATURE REVIEW

The importance of ND to both the patient and clinician is the possible association with underlying carcinoma2. ND is a rare symptom in men but may herald an underlying malignancy.

ND is a relatively common complaint occurring among 10 to 50% of patients with benign breast disease8. PND can herald an underlying cancer. However, this represents a challenge because the surgeon must differentiate PND from physiological nipple discharge. There is some variation in the opinion held about the relationship of ND with underlying breast pathology. More often, ND is associated with benign intraductal papilloma. It is reported that as many as 80% of women will experience an episode of ND during their reproductive years6. Between 5 to 13% of women undergoing routine examination or examined at a breast referral center report an incidence of spontaneous ND. The incidence of occult malignancy has been reported between 3 and 26%. However studies vary markedly with this proportion and most reports include only the patients undergoing surgery and do not account those patients managed non operatively8. Determining which patient with ND should be managed conservatively versus expectantly is challenging and reports vary from publication to publication7.

The incidence of nipple discharge is reported to be between 2 and 5%2-4,7-9. Studies vary however. Morrogh et al and Foulkes et al report an incidence of 3 to 10%. The median duration of benign discharge has been reported to be about 12 months although many women will opt for duct excision for symptom relief8. There is no consensus about the use of various diagnostic tests available to confirm or rule out breast cancer in patients with ND4.

Seltzer in New Jersey, USA, while reviewing 10,000 consecutive new surgical referrals whose complaints involved the breast reported an incidence of 15% for ND cases9. Adesunkami reviewed patients with breast related complaints at The Wesley Guild Hospital in Nigeria and reported an incidence of 26.7% for patients presenting with ND10. While reviewing patients at the Komfo Anokye Teaching Hospital Breast Care Center in Nigeria, Ohene-Yeboah found that 25% of those who presented to the center with bloody ND had breast carcinoma11. The most common age group of those affected by bloody ND was between 35 and 44 years (56.7%) with 66.7% caused by duct papillomas11.

A retrospective review of patient records at the New York Presbyterian Hospital of Columbia University revealed 85% of the patients presented with bloody ND7. Adepojou et al revealed that 11% of the patients evaluated with ND had either high risk lesions or carcinoma. On average older patients were found to have cancer as compared to the younger ones who were more likely to have benign lesions. The study concluded that all patients above the age of 40 with spontaneous single duct ND should be offered duct excision even with negative radiological examinations7.

In another retrospective study at the Mayo clinic, Arizona, 38% of the patients had bloody ND. Only 8% of the patients had mammographic abnormalities , while 30% had sonographic anomalies (a mass or intraductal masses)8. Of the patients studied only 1% had invasive carcinoma. Mammography and ultrasonography had a sensitivity of 50 and 83% respectively. Grey et al concluded that age, abnormal mammogram and abnormal ultrasound were significant predictors of the presence of carcinomas (60% of patients with both PND and abnormal mammogram had carcinoma). Among the patients managed conservatively who had PND only 1% developed breast carcinoma after a period of 2 years. Among 57 patients with unilateral PND with both a negative mammogram and subareolar ultrasound the risk of carcinoma was 0%8.

The findings mirrored those of other studies where advancement in age was associated with an increased risk of breast carcinoma4,8. In the study by Grey et al cytology was neither sensitive nor specific. Although other studies report an incidence of carcinoma at 3%, Grey at al conclude the risk was significantly smaller and thus clinical follow up (physical examination and mammography every 6 months for 2 years) is sufficient.

A study of 175 patients that included patients with SND and non SND who underwent breast surgery at the Ellis Fischel Cancer center, Columbia, showed that papillomas would most often present with bloody SND5. Of those patients with cancer 75% presented with non bloody SND. The conclusion was that bloody SND is no more suggestive of breast malignancy than non bloody SND5.

At the Memorial Sloan-kettering cancer center, New York, a retrospective study revealed that 31% of the patients with ND were considered to have physiological ND. These were managed conservatively6. Preoperative evaluation enabled identification of 80% of malignant/ high risk lesions. Morrogh et al concluded that clinical stratification alone can reliably identify patients with PND but a difficulty still exists in distinguishing benign from malignant pathology. Of those patients managed expectantly only 1 presented with invasive carcinoma after 9 years which was unrelated to the nipple-areola complex and not associated with persistent ND. The most common cause of PND was papilloma (42%). From the patients who had PND 10% had high risk lesions, consistent with other studies. This highlights that distinguishing between benign physiological ND and PND should be the primary goal when evaluating these patients.

Cabioglu et al studied 146 patients with the chief complaint of ND. Fifty two of these patients had physiological ND and the median duration of ND was 12 months (ranging from 2 to 36 months). Compared with PND, patients with physiological ND were more likely to be less than 40 years. The characteristics of ND as well as findings related to the physical exam, breast imaging and cytology were significantly different between the two groups of patients. Of the patients with physiological ND 85% had normal physical examinations and imaging studies4. Bloody ND was found to be most common among those with benign diseases (61.5% with papillomas). Only 4.3% of their patients with PND had normal findings on both a physical exam and following imaging modalities. Mammographic and sonographic abnormalities were found to be more common in patients with cancer as opposed to benign lesions. Cabioglu et al found that mammography and sonography had a sensitivity and specificity of 64% and 80% respectively.

In Cabioglu et al’s study, 64.4% of the patients had PND. This was found to be higher than other studies12. This was most likely due to the centers status as a referral center. Almost 20% had carcinoma, consistent with other studies.

By contrast Foulkes et al had an incidence of only 5.7% for breast cancer among the patients they studied over a 10 year period12. Ten percent of the patients with blood stained ND had carcinoma while none of those with other colored discharge did. They conclude that duct excision can be avoided in those patients with non blood stained PND to prevent unnecessary surgery, because among this group of patients none were found to have breast cancer. They suggested that all patients above the age of 30 in whom bloody ND can be adequately demonstrated should undergo duct excision

Most of the reports above appear to suggest that the patients with benign/ physiological ND are significantly younger than those with PND4,12. The studies done show that patients with spontaneous PND have a higher risk of breast cancer as compared to those with physiological ND. Results by Goksel et al suggested a predisposition to cancer development with increasing age, higher number of pregnancies and longer duration of lactation13.

Chen et al did a meta-analysis by that included 8 studies and 3,110 patients. This showed that patients with bloody ND have a markedly higher risk of developing breast cancer and that it could be a predictor of breast cancer17.

Dillon et al did a 14 year retrospective review of patients at St Vincent’s University Hospital in Dublin, Ireland, who had presented with ND and underwent exploratory surgery. Following duct excision 4.3% of the patients with PND were diagnosed with carcinoma. No patient with non bloody ND had carcinoma. They concluded that conservative management may be offered particularly to those patients with non bloody ND and in whom no other clinical or radiologic signs of malignancy were found29.

The role of nipple discharge cytology

Cytology of ND continues to receive a small amount of attention. This is mainly due to its reported low sensitivity7,19,21. Nipple fluid cytology may be useful in identifying those patients with premalignant or high risk lesions31.Malignant cells may not always be present in discharge fluid and are present more often if the tumor lies within a major duct and with smaller tumors compared to large ones7. However, the rate of diagnosis can be improved with multiple smears since the discharge is more cellular with the last drops of secretion7.

Sauter et al found that SND cytology was associated with occasional false positives as compared to nipple aspirate fluid cytology in which false positives are rare. In their evaluation, they found that only 47% of cytological samples were sufficient for diagnosis5.

Morrogh et al in their review that include 287 patients found that ND cytology was satisfactory for evaluation in 76% of cases with a positive predictive value of 55%. The sensitivity and specificity was 73% and 59% respectively6.

Lee W-Y reviewed 174 ND specimens vis a vis histology and conclude that ND cytology can be useful in detecting an underlying breast lesion when no other clinical features are present15.

Das D. K et al while reviewing 602 ND smears found that 59.1% proved to be benign while those that were inadequate were 5.6%. Compared with histopathological examinations the lesion was reported to have been correctly identified in 80% of the cases16.

The sensitivity of blood detected in nipple discharge at predicting malignancy can be as high as 83%, although the specificity is approximately 53%24. A study by Gupta et al where they studied 1948 ND smears concluded that ND smears are reasonably specific in diagnosis of malignant or suspicious cases23. A combination of both cytological analysis and breast imaging may be useful in identifying minimal breast lesions as well as premalignant lesions22.

Following a meta-analysis Lang et al concluded that ND cytology is a useful tool in management of patients with PND because it allows examination of the ductal system microenvronment since this is the site of origin of a large number of breast carcinomas32.

In a study by Montroni et al at the University of Bologna, Italy, 23.9% of their patients with PND had breast carcinoma. This study questioned the supposed benign etiology of serous, colored or sero-sanguinous ND. They found that cytological examination had a high specificity, justifying its routine use in the management of patients with PND33.

Carvalho et al retrospectively studied 94 patients at The University Hospital of Coimbra, Portugal, who had duct excision to evaluate the diagnostic accuracy of ND cytology. They found that cytology had a sensitivity and specificity of 40% and 61.3% respectively with a positive predictive value of 53.8%. They concluded that ND cytology was poor in predicting histological diagnosis34.

In a ten year retrospective review of cytology records, Groves et al found that ND cytology had a sensitivity and specificity of 46.5% and 99.5% respectively regarding identification of carcinoma of the breast. In this study 8 carcinomas were not detected via ND cytology35.

Role of imaging

There has been an increase in incidence of intraductal carcinomas since 1980. In more than 50% of cases it appears mammographically as a high density lesion with accompanying calcifications18.

Ultrasound can be useful in evaluating patients with PND. It allows visualization of ductal pathology as small as 0.5mm in diameter4,7. Breast ultrasonography can evaluate the nature of an underlying breast lesion as well its relationship with the ductal system. An ultrasonographer may experience some difficulties in detecting small peripheral masses particularly in excessively fatty breasts. Ductograms can be helpful in localizing intraductal lesions in patients with PND. Magnetic resonance imaging may be useful particularly in those with negative mammographic and sonographic findings. However its utility has not been established7.

At the St Mary’s hospital, London, Lanitis et al studied 76 patients who underwent microdochectomy for PND despite having normal or benign imaging and found that 48.7% of the patients had intraductal papillomas. Eight (10.5%) of the patients had carcinoma. They concluded that preoperative imaging may not be sufficient in patients with PND and recommended michrodochectomy30.

The study by Carvalho et al, while disputing the use of ND cytology, showed that galactography (ductography) was useful in excluding malignant lesions and was most sensitive for duct pathology34.

Lamont et al retrospectively reviewed patients at The Baylor University Medical Centre, Texas, USA, on the impact of galactography. Of the patients studied, 86% had an abnormal ductogram which demonstrated the location and depth of the lesion in 97% of them. They conclude that ductography is accurate in identifying the location of an anomaly in patients with PND and allows a focused surgical approach36.

In 2 separate studies by Hou et al and Van et al, it was found that preoperative galactography increased the likelihood of a specific pathology being found at surgery and that it was a useful diagnostic tool in differentiating benign from malignant lesions in patients with SND37,38. Van et al felt that although duct excision is the gold standard in managing patients with PND, a specific cause is not always found and galactography would be useful for such purposes37.

Hans-Peter et al did a retrospective study at The University of Wuzburg, Germany, and found that galactography had a sensitivity of 94% for neoplasia whether benign or malignant. In this study 50% of the cancers were diagnosed exclusively by galactography39.

In patients with PND ultrasound is useful in identifying the dilated duct as well as possible intraductal or jusxtaductal patholgy40. Rissanen et al studied 52 patients with the objective of evaluating breast sonography in localizing abnormalities in patients with SND41. They concluded that sonography was helpful in localizing intraductal abnormalities especially papillomatous lesions in up to 80% of patients.

STUDY QUESTION

What is the sensitivity and specificity of triple assessment in the management of patients presenting with pathological nipple discharge?

STUDY JUSTIFICATION

The risk of underlying breast carcinoma in patients presenting with ND can be stratified according to clinical factors. History and physical examination can be used to eliminate benign discharge. Since the majority of ND cases are more frequently benign conditions, less operative, non surgical methods can be applied to limit the need for surgical intervention.

Many patients undergo surgery that proves to be wholly unnecessary. It has been suggested that by utilizing the systematic, gold standard approach of Triple Assessment (clinical, radiological and cytological evaluation) the risk of underlying carcinoma can be accurately defined. However, because there is no consensus on how to manage a patient with PND, most are managed based on a clinicians opinion and prior surgical experience. This study sets out to show the utility of triple assessment in managing those patients with PND

OBJECTIVES

MAIN OBJECTIVE

To determine the sensitivity and specificity of triple assessment in the diagnosis of breast pathology in patients with pathological nipple discharge.

SPECIFIC OBJECTIVES

To define the causes of PND in patients at Kenyatta National Hospital.

To assess the sensitivity and specificity of clinical examination, imaging and discharge cytology in the diagnosis of PND.

To determine the incidence of carcinoma of the breast in patients who present with PND.

MATERIALS AND METHODS

Study setting

This prospective study will be conducted at The Kenyatta National Hospital (KNH) breast surgical clinic and surgical wards. KNH is a national teaching and referral hospital in Kenya. It serves Nairobi and its environs and also serves as the referral center for the country and its neighboring countries.

Study population

All patients presenting to the breast clinic with nipple discharge.

Study design

Analytic cross-sectional study.

Methodology

Patients who meet the study criteria will be reviewed in the breast clinic or surgical wards. The historical information sought will include

Age

Parity in female patients

Personal history breast cancer

History of breast cancer in first or second degree relative

Nature and duration of discharge

All patients will be examined thoroughly

A thorough breast examination to determine the presence or absence of a palpable breast mass as well as to rule out superficial lesions that can imitated nipple discharge

Expression of discharge will be performed via pressure to the base of the areolar to determine

The color of discharge

Single versus multiple duct involvement

For the purposes of this study PND will be described as discharge that is spontaneous, unilateral, persistent, and originating from a single duct.

The nipple will be cleaned thoroughly and discharge expressed and placed on slides for examination by the pathologist.

Depending on age and the presence or absence of a palpable mass either mammography or ultrasonography of the breast will be requested. Mammograms will be assessed according to the Breast Imaging Reporting and Data Systems (BI-RADS).

All patients with PND will undergo surgery (microdochectomy, which is the currently accepted gold standard) and samples will be submitted for histology. Histopathological results will then be compared to those of the triple assessment.

SAMPLING

1. Sample size determination

For populations that are large, Cochran (1963:75) developed an equation to yield a representative sample for proportions.

Where:

Z2 is the abscissa of the normal curve that cuts off an area at the tails (1 - equals the desired confidence level, e.g., 95%)1,

e is the desired level of precision (or sampling error),

p is the estimated proportion of an attribute that is present in the population, and

q is 1-p.

The value for Z is found in statistical tables which contain the area under the normal curve, where the value of Z correspond to 1.96

The incidence of nipple discharge of the breast has been reported as between 5% and 13%. Using a value of 5%

q is 1-p therefore q is 0.95

The level of precision, e, is valued at ±5% (0.05)

Substituting these values in the formula above,

N=72.99

N= 73 patients

2. Sampling procedure

Purposive sampling of patients with PND attending the KNH Beast Clinic will be done until the sample size is realized.

Inclusion critera

All patients with PND who consent (or where applicable consent given by the guardian) to be a part of the study

Exclusion criteria

Patients with history of trauma to the chest/ breast

Lactating/ pregnant women

Those who decline to give consent

Data management and analysis

Data will be collected using a data sheet formulated and administered by the principal investigator

Data collected will be entered into Microsoft excel and stored safely.

SPSS (statistical package for social sciences) version 17 will be used for statistical analysis of data.

The mean and median ages of presentation with ND will be documented and tabulated. The ages of those with PND will be compared to those with physiological discharge and statistical significance determined. A p value of less than or equal to 0.05 will be considered statistically significant.

The chi square test will be used to determine associations between the variables of age, findings on mammography/ ultrasonography and nipple discharge cytology.

The fisher’s exact test will be used to determine the associations between the categorical variables of the nature of ND, breast imaging and cytopathological results.

A comparison will be made between clinical examination, breast imaging and discharge cytology results with histological examination of microdochectomy specimens. The specificity and sensitivity of these investigations will be determined as well as the positive and negative predictive values.

The resulting data will be presented using pie charts, bar graphs and tables, where appropriate.

Recommendations on the use of triple assessment at KNH will then be made based on the results obtained.

ETHICAL CONSIDERATIONS

Approval will be sought from the department of surgery, university of Nairobi

Approval will also be sought from the Kenyatta National Hospital ethics and research committee.

All patients will sign a consent form after being fully informed of the study. Those declining to be a part of the study will not be denied further treatment.

Patient confidentiality will be guaranteed. Patients’ names will not be used on the data collection form.

Participants will be allowed to withdraw from the study at any point in time should they wish to do so and this will not in any way affect their further management at the institution.

Study limitations

Non breast causes of nipple discharge such as endocrine disease and medical conditions.

Patients who opt out of the study.

Differing technical knowledge between different pathologists and radiologists.

BUDGET ESTIMATES

ITEM

COST

Research fees

2,000

Stationery, printing

6,000

Cytology @ 100

7,800

Mammography/ultrasonography

80,000

Statistician

20,000

Miscellaneous

10,000

Contingencies

20,000

TOTAL

145,800

TIME LINE

October – November 2011

Proposal writing and submission for ethical approval

December – March 2012

Data collection

April 2012

Dissertation writing

May 2012

Presentation of finding

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Foulkes R, Heard G, Boyce T, et al. duct excision is still necessary to rule out breast cancer in patients presenting with spontaneous blood stained nipple discharge. International Journal of Breast Cancer 2011; 2011:1-6

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APPENDIX: 1

DATA COLLECTION FORM

Study number ……………………………………..

Ip/op number ………………………………………

Age ………………………………….

Nipple discharge

Duration…………………………….

Colour………………………………..

Spontaneous………………………. /provoked…………………………..

Unilateral…………………………../bilateral……………………………….

Single duct…………………………/multiple ducts………………………..

Breast lump: yes/ no…………………….

Size…………………………

Location……………………

Mammography/ ultrasonography findings _______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

Nipple discharge cytology

_______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

Michrodochectomy histology

_______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________