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Obstetrics & Gynecology 2001;97:625-629
© 2001 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Galactography and Exfoliative Cytology in Women With Abnormal Nipple Discharge

HANS-PETER DINKEL, MD, ANDREA MARIA GASSEL, MD, THOMAS MÜLLER, MD, STEVEN LOURENS, MD, MARGA ROMINGER, MD and ALEXANDER TSCHAMMLER, MD

From the Departments of Radiology and Gynecology, Luitpoldkrankenhaus, University of Würzburg, Würzburg, Germany, the Department of Radiology, University of Giessen, Giessen, Germany, and the Department of Radiology, Inselspital Bern, University of Berne, Berne, Switzerland.

Address reprint requests to: Hans-Peter Dinkel, MD University of Bern Institute of Radiology Inselspital Bern CH 3010 Berne Switzerland E-mail: hans-peter.dinkel{at}insel.ch


   Abstract
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Abstract
Materials and Methods
 Results
 Discussion
 References
 
Objective: To evaluate galactography and cytology in women with nipple discharge without clinical or mammographic evidence of cancer.

Methods: During a 12.5-year period, 384 women (15–85 years, mean age 47.5 ± 14 years) were referred for galactography and smear cytology for recent onset of spontaneous, non-milky nipple discharge. Patients with clinical or mammographic evidence of tumor underwent excisional biopsy directly. Among 314 galactograms, 189 [60.2%; 95% confidence interval (CI) 54.5%, 65.6%] biopsies were recommended. A further 11 patients were scheduled for biopsy because of mammography or cytology.

Results: Sixteen of 182 biopsied patients had malignancies (8.8%; CI 5.3%, 14.1%). Combined rate of papillomas, papillomatous proliferation, and malignant tumors was 59.9% (109 of 182; CI 52.4%, 67.0%). Biopsy was malignant in three of 56 women (5%) with nonhemorrhagic discharge and in 13 of 97 (13%) with hemorrhagic discharge (P = .26). Exfoliative cytology revealed 11 false-negatives, four false-positives, five true-positives, and 153 true-negatives (sensitivity 31.2%, CI 11%, 58%; specificity 97.4%, CI 93%, 99%). In ten of 158 patients (6.3%) with suspicious galactography, cancer was found by biopsy. Sensitivity of galactography for malignancy was 83% (CI 51.6%, 97.9%) and specificity was 41% (CI 35.2%, 46.5%). Galactographic sensitivity for any (benign or malignant) neoplasm was 94% (93 of 99; CI 87%, 98%) and specificity was 55% (119 of 215; CI 48%, 62%). Half of the cancers were detected exclusively by galactography.

Conclusion: Cytology is helpful when positive and galactography localizes the source of discharge. Biopsy is indicated when palpation, mammography, cytology, or galactography is suspicious.

Abnormal nipple discharge (secretion other than in pregnancy or lactation1) occurs in all adult age groups, often regarded as a foreboding of cancer. However, the role of malignancy is overestimated.2 Investigation modalities include exfoliative cytology3–6 and galactography.7–11 The aim of this study was to evaluate the frequency of benign and malignant tumors and assess the diagnostic value of galactography and cytology in women with abnormal nipple discharge without clinical or mammographic evidence of cancer.


   Materials and Methods
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Abstract
 Materials and Methods
Results
 Discussion
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A manual search of the daily records of our university hospital’s gyneco-radiological unit revealed roughly 75,000 women referred for mammography between January 1, 1985, and June 30, 1997. Among these, 384 consecutive patients had been referred for galactography because of abnormal nipple discharge [mean age 47.5 years, range 15–85 years, standard deviation (SD) 14.0 years]. Only those with recent onset of spontaneous, persistent, non-milky discharge (hemorrhagic or serous) underwent further work-up. Women with secretion of hormonal origin or drug-induced milky discharge do not undergo galactography at our institution, and were automatically excluded. Galactography was performed only in patients in whom discharge emanated from a solitary orifice or only a few orifices. Mammography in craniocaudal and lateromedial projections was performed on a Mammomat 2 before galactography (Siemens, Erlangen, Germany). Those with clear clinical or mammographic evidence of tumor did not undergo galactography but breast biopsy directly. However, in several cases mammography or palpation were equivocal and galactography and cytology were also performed. Exfoliative cytology was graded using Papanicolaou stains categorized as "normal = I/II," "dubious = III," "suspicious = IV," "positive = V," or "specimen contains no cells = 0."

The galactographic technique used has been described previously.8,9,12 Galactographic patterns serving as the primary indication for excisional biopsy were ductal stops (Figure 1Go) and filling defects (Figure 2Go), as these patterns imply presence of an intraductal neoplastic process.1,9,13 Further galactographic patterns serving as an indication for excisional biopsy included extraductal compression or architectural distortion.1,3,10



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  		Figure 1. A 47-year-old patient with right-sided straw-colored nipple discharge, present for 6 months. Craniocaudal galactography demonstrates a concave cutoff, situated a few centimeters behind the nipple (arrow), caused by an intraductal filling defect. Such an appearance indicates the presence of an intraductal polyp, which may be indistinguishable, however, from a malignant intraductal tumor.

 


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  		Figure 2. A 45-year-old patient with right-sided hemorrhagic nipple discharge. Craniocaudal galactogram reveals a large cauliflower-like filling defect in the retromamillary lactiferous sinus.

 
Galactography was contraindicated in 53 of 384, technically impossible in seven of 384, and not readable because of extravasation in ten of 384, leaving 314 successfully performed galactographies. Of these, 189 examinations [60.2%; 95% confidence interval (CI) 54.5%, 65.6%] were suspicious and biopsy was recommended. In addition, 11 women were scheduled for biopsy because of suspicious mammographic or smear results. Of 70 women who did not undergo galactography, a further 14 underwent biopsy. Of these 214 recommended biopsies, 32 were not performed (15%), leaving biopsy results in 182 cases, 158 of which had been prompted by galactography. A definite cytology result was available in 351 patients, both biopsy and cytology results in 173.


   Results
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Abstract
 Materials and Methods
 Results
Discussion
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Table 1Go shows the results of 182 excisional biopsies forming the basis of our study. Of 182 biopsied patients, 16 had malignancy (8.8%; CI 5.3%, 14.1%). The frequency of finding a benign papilloma, papillomatous proliferation, or a malignant tumor was 59.9% (109 of 182; CI 52.4%, 67.0%).


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  		Table 1. Histologic Diagnoses
 
Type of discharge was specified in 309 patients (80.5%), and was hemorrhagic in 161 of 309 (52.1%; CI 46.4%, 57.8%). Malignancy was found in 5% of patients with nonhemorrhagic discharge and in 13% with hemorrhagic discharge (Table 2Go); the difference was not significant by {chi}2 (P = .26). However, patients who underwent biopsy had a significantly higher percentage of hemorrhagic discharge, demonstrating that this finding had been regarded as suspicious for malignancy and prompted biopsy.


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  		Table 2. Type of Discharge by Diagnosis
 
Assuming benign conditions in patients not having undergone biopsy (reasons for doing so will be elucidated below), the incidence of malignancy in woman presenting with abnormal nipple discharge without other clear clinical or mammographic evidence of malignancy was estimated at 2.0% (CI 0.4%, 5.8%) in nonhemorrhagic and 8.1% in hemorrhagic discharge (CI 4.3%, 13.7%), the difference being significant (P = .013) in the {chi}2 test.

Bilateral discharge was found in 69 patients (18.0%; CI 14.3%, 22.3%). Carcinoma was confirmed by biopsy in 14 of 315 patients with unilateral (4.4%; CI 2.5%, 7.5%) and 2 of 59 with bilateral discharge (2.9%; CI 0.4%, 10.1%), the difference not being significant in Fisher exact test (P < .75).

Results of exfoliative cytology in 351 patients (173 with biopsy) are shown in Table 3Go.


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  		Table 3. Frequency of Carcinoma by Cytology
 
If the categories of "normal," "dubious," and "no cells" are considered to be negative, and those of "suspicious" and "positive" to be positive, exfoliative cytology revealed 11 false-negatives, four false-positives, five true-positives, and 153 true-negatives in the diagnosis of carcinoma. Exfoliative cytology had a sensitivity of 31.2% (CI 11%, 58%) and a specificity of 97.4% (CI 93%, 99%) among the 173 cases with definite histologic proof. When regarding all 351 patients with smear cytology, sensitivity was 31.2% (CI 11%, 58%) and specificity 98.2% (CI 96%, 99%).

Table 4Go gives an overview of the distribution of galactographic findings of histopathologic results. Ten of 158 (6.3%) patients with galactographic signs of possible malignancy had malignancy confirmed by biopsy (CI 3.1%, 11.6%). Assuming benign conditions in patients not having undergone biopsy, the estimated sensitivity and specificity of galactography for malignancy were 83% (CI 51.6%, 97.9%) and 41% (CI 35.2%, 46.5%), respectively. At least ten malignant tumors were found in 189 patients with suspicious galactographic findings (5.3%, CI 2.6%, 9.8%), compared with 123 or less benign conditions in 125 patients without suspicious galactographic findings (98.4%; CI 94.3%, 99.8%). The sensitivity of galactography for any type of neoplasm (including cancer, benign papilloma, and papillomatosis) was 94% (93 of 99; CI 87%, 98%), specificity 55% (119 of 215; CI 48%, 62%).


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  		Table 4. Biopsy and Galactographic Results
 
The relative importance of examination modalities in the diagnosis of carcinoma in 16 patients [seven invasive, nine ductal cancer in situ (DCIS)] can be illustrated as follows: In two patients with invasive carcinoma, a vague mass was found on physical examination in a radiodense breast; galactography failed in one (cannulation was impossible) and revealed ductal distortion in the other. In four with DCIS, microcalcifications were present; galactography was performed in only one patient (normal), the microcalcifications being situated in another quadrant and not associated with the discharge. In one (with clinging type DCIS), cytology was the only suspicious modality. In one, both cytology and galactography were suspicious. In eight, galactography was the only examination providing suspicion of malignancy.


   Discussion
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Abstract
 Materials and Methods
 Results
 Discussion
References
 
Only a moderate percentage of women with abnormal nipple discharge have malignancy, illustrated by demonstration of malignancy in only 3.2% of patients in the entire study group and 8% of patients undergoing biopsy. Other authors found malignancy in 1%–10% among all patients and 8%–16% in groups undergoing biopsy.1–3,7,9 In our study, the probability of malignancy in bilateral and unilateral discharge was similar, implying that complete investigation is necessary in both cases.

Unlike other authors,14 we think that not only hemorrhagic but also nonhemorrhagic serous discharge indicates galactography. Color of discharge does not allow for prediction of histologic results.1,15 In our study, serous discharge was present in three patients with carcinoma; however, malignancy was found to be four times more frequent in hemorrhagic than in non-hemorrhagic discharge. In a meta-analysis summarizing 11 publications, 25% of the carcinomas (27 of 113) were found to be associated with nonhemorrhagic discharge.9

Positive cytology is suggestive but not pathognomonic of malignancy, and warrants biopsy. In contrast to 100% specificity reported by some authors in the literature,4 we found a considerable number of false-positives in our study (Table 3Go). Furthermore, sensitivity of cytology was low: not even one-third of histologically proved carcinomas were associated with positive cytology.

Some authors suggest cytology should be a selection criterion in setting the indication for galactography,16,17 in stark contrast to our results. In our study, cytology detected carcinoma in only 31% of all malignant cases. Foulot et al18 and Tabar et al9 reported sensitivities of exfoliative cytology as low as of 17% and 11%, respectively. Thus, only "positive" or "suspicious" results are of value in exfoliative cytology. Of the 16 cases of histologically proved carcinoma in our study, diagnosis was made on the basis of cytology alone in only one case (6.3%).

The most frequent galactographic abnormality leading to biopsy was a ductal cutoff or filling defect, produced by an intraductal mass lesion. Considering that it is impossible to distinguish benign and malignant intraductal lesions by galactography,9,19 and furthermore, the low prevalence of cancer in nipple discharge, the relatively low specificity of galactography with respect to cancer is not surprising, consistent with results in the literature.3,8,9,14,20 However, half of the histologically proved carcinomas in this study were suspected exclusively by galactography, whereas palpation, mammography, and cytology were negative, indicating galactography to be an important modality for early cancer detection. Similar results are reported in the literature.2,7,9 Galactography is also useful when not suspicious, as in cases of duct ectasia associated with secretory disease, in which biopsy can be avoided.

We assumed benign conditions in patients not having undergone biopsy. A limitation of every retrospective study, including ours, is that patients with negative or unsuspicious test results usually do not undergo biopsy. However, we had no feedback of a later development of breast cancer in any of these patients. Half of our patients not undergoing biopsy had clinical follow-up (mean more than 5 years). Although this percentage seems small, it is probable that any patient with later cancer development would have been referred to our center, the only major oncology center in a rural area with a stable referral structure. Thus, statistically it is highly probable that our negative control group did not harbor undetected malignancy.

Although diagnosis of malignancy was the main objective of investigation, how often galactographic findings corresponded to papillomas or epithelial proliferations may be of interest. Solitary papilloma is a common benign breast neoplasm and the most common entity associated with abnormal nipple discharge.9,21 Papilloma typically leads to a ductal cutoff or filling defect in galactography (Figures 1Go and 2Go).

Malignant transformation of papillomas remains controversial. The question has been raised as to whether papillomas should be regarded as providing an indication for excision in their own right.14,22 Evidence suggests that neoplasia may develop at former sites of incomplete benign papilloma excision.23,24 In our study, malignant tumors were found in close proximity to preexisting benign papillomas in two cases. We therefore conclude that excision is warranted after demonstration of papilloma.

The surgeon’s approach to abnormal nipple discharge is strongly related to his or her ability to find the etiologic lesion,8 and galactography plays an important role in the correct localization of the discharge source, prior to excisional biopsy.11

In conclusion, demonstration of malignancy associated with abnormal nipple discharge is rare and requires considerable diagnostic effort. In addition to palpation and mammography, exfoliative cytology and galactography should be performed in patients with persistent non-milky discharge. Cytology occasionally gives clues to underlying malignancy. Galactography may demonstrate a non-neoplastic etiology. Galactography is important in localizing isolated sources of discharge (papillomas, intraductal cancer) and guides surgery. Biopsy is indicated when any one or more of the described diagnostic modalities are suspicious for malignancy.


   Footnotes
 
PII S0029-7844(00)01229-1

Received July 5, 2000. Received in revised form November 28, 2000. Accepted December 15, 2000.


   References
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Abstract
 Materials and Methods
 Results
 Discussion
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2. Barth V. Zur Bedeutung der Galaktographie für die Frühdiagnostik des Mammakarzinoms. Dtsch Med Wochenschr 1976;101: 388–9.

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4. Dunn JM, Lucarotti ME, Wood SJ, Mumford A, Webb AJ. Exfoliative cytology in the diagnosis of breast disease. Br J Surg 1995;82:789–91.[Medline]

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6. Ranieri E, Virno F, D’Andrea MR, Carico E, D’Alessio A, Bergomi S, et al. The role of cytology in differentiation of breast lesions. Anticancer Res 1995;15:607–11.[Medline]

7. Ouimet-Oliva D, Hebert G. Galactography: A method of detection of unsuspected cancers. Am J Roentgenol Radium Ther Nucl Med 1974;120:55–61.[Medline]

8. Funderburck W, Syphax B. Evaluation of nipple discharge in benign and malignant diseases. Cancer 1969;24:1290–6.[Medline]

9. Tabar L, Dean PB, Pentek Z. Galactography: The diagnostic procedure of choice for nipple discharge. Radiology 1983;149:31–8.[Abstract/Free Full Text]

10. Rongione AJ, Evans BD, Kling KM, McFadden DW. Ductography is a useful technique in evaluation of abnormal nipple discharge. Am Surg 1996;62:785–8.[Medline]

11. Van Zee KJ, Ortega PG, Minnard E, Cohen MA. Preoperative galactography increases the diagnostic yield of major duct excision for nipple discharge. Cancer 1998;82:1874–80.[Medline]

12. Dinkel H-P. Features of benign and malignant breast disease in galactography. The Radiologist 2000;7:247–57.

13. Pignatelli V, Savino A, Orsitto E, Ruiu U, Kiferle M. Quadri galattografici nella mammella secernente. Radiol Med Torino 1989;77:643–9.

14. Ciatto S, Bravetti P, Berni D, Catarzi S, Bianchi S. The role of galactography in the detection of breast cancer. Tumori 1988;74: 177–81.[Medline]

15. Grillo M, Lehmann WE, Gent HJ. Chromogalactography preceding ductal-lobular unit excision for nipple discharge—With special reference to diagnostic galactography and histology. Ann Chir Gynaecol 1990;79:6–9.[Medline]

16. Wunderlich M. Die Exfoliativzytologie der sezernierenden Mamma. Arch Geschwulstforsch 1977;47:627–33.[Medline]

17. Rimsten A, Skoog V, Stenkvist B. On the significance of nipple discharge in the diagnosis of breast disease. Acta Chir Scand 1976;142:513–8.[Medline]

18. Foulot H, Durand JC, Vielh P, Salmon RJ, Labeta C, Pilleron JP. Ëcoulement par le mamelon sans tumeur palpable. Experience de l’Institut Curie de 1970 a 1984. Presse Med 1988;17:1243–6.

19. Dinkel H-P, Trusen A, Gassel AM, Rominger M, Lourens S, Müller T, et al. Predictive value of galactographic patterns for benign and malignant neoplasms of the breast in patients with nipple discharge. Br J Radiol 2000;73:706–14.[Abstract]

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21. Woods ER, Helvie MA, Ikeda DM, Mandell SH, Chapel KL, Adler DD. Solitary breast papilloma: Comparison of mammographic, galactographic, and pathologic findings. Am J Roentgenol 1992; 159:487–91.[Abstract/Free Full Text]

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