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Annals of Oncology Advance Access originally published online on November 28, 2007
Annals of Oncology 2008 19(4):682-687; doi:10.1093/annonc/mdm546
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© The Author 2007. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

breast cancer

Metastases to the breast: role of fine needle cytology samples. Our experience with nine cases in 2 years

F. Fulciniti1,*, S. Losito1, G. Botti1, D. Di Mattia1, A. La Mura1, C. Pisano2 and S. Pignata2

1 Section of Pathology, Cytopathology Service
2 Department of Gynecological Oncology, National Cancer Institute, Fondazione G. Pascale, Naples, Italy

* Correspondence to: Dr F. Fulciniti, Section of Pathology, Cytopathology Service, National Cancer Center, Fondazione G. Pascale, Via Mariano Semmola 1, I-80131 Naples, Italy. Tel/Fax: +39-081-5903849; E-mail: franco.fulciniti{at}gmail.com


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Background: The increased survival due to the introduction of effective antineoplastic regimens has caused a modification of the natural history of numerous malignancies. Follow-up of neoplastic patients often includes the evaluation of masses in various body sites by fine needle cytology (FNC) in order to rule out cancer recurrence. Besides primary neoplasms, the breast can host a number of metastases: these rarely do have a typical presentation, so FNC is requested for their cytomorphological assessment.

Patients and methods: This report describes nine consecutive cases in which a cytopathological diagnosis of metastasis to the breast was carried out on FNC samples.

Results: Primary sites were identified on cytomorphological and immunocytochemical bases and were represented by the ovary (three cases), melanoma (two cases), endocervix (one case), endometrium (one case), lung (one case) and prostate (one case).

Conclusion: The cytopathological diagnosis of metastatic neoplasms to the breast is not always straightforward, especially in the absence of a clinical history of cancer. The usage of improved cytopathological criteria combined with immunocytochemistry may be of great diagnostic help in the identification of breast metastases.

Key words: breast neoplasms, clinical cytology, diagnostic cytopathology of tumors, fine needle cytology, metastases to the breast


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Fine needle cytology (FNC) is frequently requested on palpable breast masses developing in neoplastic patients [1–9]. Breast involvement by metastatic neoplasms versus primary malignancies is relatively rare (0.5%–6.6%) [10, 11], but it could turn out to be higher by the systematic usage of combined imaging techniques and FNC. While FNC is a fast diagnostic tool in detecting malignancy, the cytopathological diagnosis of metastatic neoplasms to the breast is not always straightforward, mainly due to the paucity of definite mammographic criteria and to the often confusing clinical–cytological picture of metastases. Another frequent problem in the clinical practice is the necessity to exclude synchronous and metachronous neoplasms involving the breast in the clinical setting of genetically determined multiple primary malignancies.

The aim of this paper is three-fold: to describe our findings in nine cases of metastatic neoplasms to the breast, to analyze the diagnostic criteria useful for their identification and to discuss the utility of classical radiological criteria on the final diagnosis where feasible.


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The database of the Cytopathology Laboratory and Service was searched for all cases in which a cytopathological diagnosis of metastasis to the breast had been formulated from January 2005 to July 2007. Nine such cases were found out of 1140 new diagnoses of primary breast carcinoma diagnosed by FNC in the same period (0.78%).

All FNC were carried out on outpatients on palpable lesions, using a 23-25G needle, without suction. The obtained material was smeared onto four or more slides and stained with Diff-QuikTM (DQ) after air drying or with Papanicolaou (PAP) after wet fixation in 95% ethanol. Spare, stained or unstained ethanol-fixed, air-dried smears or needle washings fixed in CytolytTM and processed as liquid-based preparations were processed for immunocytochemistry (ICC) by using an indirect immunoperoxidase-based kit (LSAB, Dako, Milan, Italy), commercially available mAbs and polyclonal antibodies and a semiautomated immunostainer (Dako) (see Table 1 for specifications). As the subjects were outpatients, they usually carried their imaging studies with them, so the imaging results were only transcribed by the cytopathologist taking the fine needle sample and very little documentation was available for photography.


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  		Table 1. Clinicopathological data of nine patients with breast metastases

 
cases 1 and 2 : metastatic melanoma
Two females aged 59 and 52 years, respectively, with a previous history of Clark's stage 3 melanoma of the back and scapular region, presented with nodular breast lesions 1.5–2.5 cm in diameter (Table 1). In case 1, the dense, well-delimited lesion had been mammographically interpreted as a possible cyst, while in case 2 two nodules with different mammographic features had been described: a well-delimited dense lesion in the lower outer quadrant (LOQ) and a stellate lesion in the upper outer quadrant (UOQ).

These features corresponded to two different neoplasms in the same breast: amelanotic metastatic melanoma in the LOQ and ordinary infiltrating duct carcinoma in the UOQ. Both lesions were correctly recognized by FNC in this case. In both cases, the cytological diagnosis of metastatic melanoma was rather easy and ICC was carried out as an ancillary test with confirmatory aim (Figure 1A–C). Histopathological examination disclosed, in both cases, metastases of melanoma within intramammary lymph nodes. In case 2, a G2 infiltrating duct carcinoma was also present in the OUQ. Four of 27 axillary lymph nodes contained metastatic deposits of duct carcinoma.


Figure 1
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  		Figure 1. Fine needle cytology sample, case 2 (Table 1). Amelanotic melanoma: note the dispersed population of (A) epithelioid and (B) fusiform cells typical of the lesion. (C) Immunocytochemistry (ICC) for HMB45 showing diffuse cytoplasmic positivity of the neoplastic cells. (A) Diff-Quik, medium power; (B) Papanicolaou, medium power; (C) ICC, high power.

 
case 3: prostatic carcinoma
A 70-year-old man with a 3-year history of prostatic carcinoma presented with a hard periareolar nodule in his right breast. FNC was carried out and the cytopathological picture showed a G2 carcinoma with frequent glandular and acinar pattern and intense cellular necrosis. ICC stain for prostate-specific antigen (PSA) was positive in the cytoplasm of most of the well-preserved neoplastic cells (Figure 2A–C). Further computed tomography and magnetic resonance imaging work-up demonstrated the presence of widespread abdominal and mediastinal lymphadenopathy and multiple osteolytic lesions of the axial skeleton; total serum PSA was 1020 ng/ml. The patient was lost to follow-up after diagnosis.


Figure 2
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  		Figure 2. Fine needle cytology sample, case 3: metastatic prostatic carcinoma. (A) A loose group of atypical glandular cells of medium size can be seen in a necrotic background. (B) The same cells show evidence of cytoplasmic secretion on Papanicolaou (PAP)-stained smear. Notice their prominent nucleoli. (C) Liquid-based cell preparation from the same case. Immunocytochemistry (ICC) stain for prostate-specific antigen showing diffuse cytoplasmic positivity of the neoplastic cells. (A) Diff-Quik, medium power; (B) PAP, medium power; (C) ICC, medium power.

 
case 4: endometrial adenocarcinoma
A 78-year-old lady was sent for FNC of a poorly defined mass in the UOQ of her right breast associated to skin dimpling, cutaneous redness and marked tenderness on palpation. The lady had a 4-year history of stage 3, G2 endometrial adenocarcinoma. The cytopathological picture showed monolayered sheets and branching glandular clusters of small cylindrical cells in a necrotic background. They had small nucleolated nuclei and eosinophilic cytoplasm with an overall ‘endometroid’ appearance; focal areas of adenosquamous differentiation were observed, with larger polygonal cells with dense cytoplasm. Diagnostic smears were tested for estrogen receptor (ER) and progesterone receptor (PR) with positive result for both in >75% of the neoplastic cells and for p53 protein, that was over-expressed (Figure 5A–C). A diagnosis of metastatic endometrial adenocarcinoma was made. The patient died shortly after with widespread disease.


Figure 5
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  		Figure 5. Fine needle cytology sample, case 4, metastatic endometrial adenocarcinoma. (A) A cohesive group of carcinomatous cells showing distinct glandular arrangement with peripheral nuclear palisading. (B) The glandular aggregates suggest an ‘endometrioid’ appearance on Papanicolaou (PAP)-stained material. (C) Some cohesive groups of malignant cells show ‘squamoid’ differentiation. (A) Diff-Quik, low power; (B) PAP, low power; (C) PAP, low power.

 
cases 5–8: ovarian and endocervical serous carcinomas
Four females—age range 42–71 (median age 47.5) years—were sent for cytopathological evaluation of bilateral well-delimited breast nodules (case 5) or single stellate mammographic densities (cases 6–9). In case 9, an omolateral axillary lymphadenopathy was also sampled by FNC.

All patients had a previous history of stage 3 ovarian G2 or G3 serous carcinoma (cases 5, 7, 8) or stage 3 endocervical G3 serous carcinoma (case 6, Table 1). After surgery the patients had been treated with polychemotherapy. In cases 6 and 7, debulking radiotherapy had also been administered to the pelvis (30–45 Gy).

The cytopathological picture in these cases showed a medium cell epithelial malignancy arranged in papillary clusters (Figure 3A–C). The neoplastic cells displayed round nuclei with evident nucleoli and a moderate quantity of greyish cytoplasm in DQ-stained smears. In case 5, several well-formed psammomatous microcalcifications were evident both in the DQ- and in the PAP-stained smears (Figure 3C). ICC stains demonstrated cytoplasmic positivity for Ca 125 (Figure 4C) and diffuse nuclear staining for WT-1.


Figure 3
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  		Figure 3. Fine needle cytology sample, case 5, metastatic low-grade serous adenocarcinoma of the ovary. (A) A group of carcinomatous cells of medium size with distinct papillary organization can be observed. (B) the neoplastic cells show small single nucleoli and whorl-like configuration within papillary tips. (C) The same papillary fronds are often centered by orangiophilic psammoma bodies. (A) Diff-Quik, low power; (B) Papanicolaou (PAP), medium power; (C) PAP, medium power.

 

Figure 4
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  		Figure 4. Fine needle cytology sample, case 8, metastatic G3 serous adenocarcinoma of the ovary. (A) Some loose papillary fronds of carcinomatous cells with distinct nuclear atypias can be seen. (B) The papillary organization of the cellular cluster is somewhat enhanced by the immunocytochemical staining for CK 7. (C) Immunocytochemistry (ICC) stain for Ca 125 displaying diffuse cytoplasmic positivity of the neoplastic cells. (A) Diff-Quik, medium power; (B) ICC, low power; (C) ICC, medium power.

 
In case 8, the cytological picture, in both the breast and the lymph node samples, showed a medium cell epithelial malignancy organized as single cells, sheets and trabecular or papillary clusters (Figure 4A–C). The neoplastic cells had centrally placed, nucleolated round nuclei; the cytoplasms were moderately developed, well-delimited, greyish in DQ-stained and transparent to pinkish in PAP-stained smears. ICC stains were carried out on additional wet-fixed smears: these were negative for ER and PR and for Her-2. Ca 125 and WT-1 stains were diffusely positive. A final diagnosis of metastatic G3 serous carcinoma was reached.

case 9: metastatic lung adenocarcinoma
A 59-year-old lady presented with a history of exacerbating dyspnea and a poorly delimited mass in the upper inner quadrant of her right breast, with skin dimpling and reddening. The lady had received a diagnosis of hypoplasia of the right lung many years before. At the moment FNC sample was taken, she had a massive right-sided pleural effusion and was febrile. The cytopathological picture on the obtained sample showed a G2 papillary adenocarcinoma with numerous reactive osteoclast-like giant cells (Figure 6A–C). While immunocytochemical staining for ER and PR were negative, TTF-1 staining showed diffuse nuclear reactivity in the malignant cells (Figure 6B). A cytopathological diagnosis of metastatic adenocarcinoma of lung origin rich in osteoclast-like reactive giant cells was made, that was confirmed radiologically after pleural drainage.


Figure 6
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  		Figure 6. Fine needle cytology sample, case 9, metastatic peripheral lung adenocarcinoma. (A) A group of medium-sized carcinomatous cells showing complex papillary arrangement can be observed in a clean background. (B) TTF-1 immunocytochemistry (ICC) stain showing distinct nuclear positivity in all the malignant cells. (C) Carcinoembryonic antigen ICC showing distinct cytoplasmic and membrane positivity in the carcinomatous cells. (A) Diff-Quik, low power; (B) ICC, low power; (C) ICC, medium power.

 

   discussion
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Despite the rarity of metastases to the breast, small or more extensive reports dealing with their cytopathological presentation have been published by most institutions in which FNC is routinely adopted as a diagnostic technique [1–9]. Melanomas, lung carcinoma and ovarian carcinoma, together with hematolymphoid malignancies, rank among the commonest primary sites, as also reflected in this relatively small series [10, 11].

In the diagnosis of metastases to the breast, the most meaningful factors are represented by the clinical history, the cytopathological picture and the immunocytochemical profile of the neoplasm. As also in our cases, in fact, the radiological presentation of metastases may be misleading. In our series, a previous history of a malignant neoplasm was always present and this information had an enormous impact on the formulation of a correct diagnosis. Nevertheless, some cytopathological differential diagnostic problems in this setting exist. For instance, a classic issue is the differential diagnosis between primary breast carcinoma, especially dissociated, high-grade ductal or apocrine type and amelanotic epithelioid melanoma [1, 3, 6, 8, 9]. Two points may be worthwhile signaling: the possible help in a correct diagnosis given by the radiological presentation of a well-delimited opaque nodular mass in metastatic melanoma (in our cases, this corresponded to two metastatic intramammary lymph nodes) and, on the contrary, the negative contribution of keratin immunostaining, if this is not used in conjunction with other melanoma markers in a given situation since, as it is known, some cases of epithelioid melanoma may express cytokeratin intermediate filaments [5, 12, 13]. The issue may be further complicated by the association of metastatic melanoma and breast carcinoma, as in case 2 of our series (Table 1). This association has also been described in the literature [14].

The next numerous group of metastases were represented by ovarian (and endocervical) serous papillary carcinomas. With this respect, among the useful diagnostic criteria, were the presence of psammoma bodies and the papillary architecture of the cell clusters. The immunocytochemical stains for Ca 125 and WT-1 had a 100% efficiency in this group of tumors. Metastatic papillary carcinomas should be cytologically distinguished by primary papillary and micropapillary carcinomas of the breast. The latter represents a complex group of lesions for cytopathologists that has been well addressed to in the literature [15]: we would only like to underline the fact that psammoma bodies in combination with papillary epithelial cell groups have been found also in primary mucinous breast carcinomas [16, 17] and stress the usefulness of AE1–AE3 or MUC 1 immunocytochemical stain to detect the so-called ‘inside out’ pattern of cytoplasmic positivity in micropapillary carcinomas [18, 19].

Prostate carcinoma is one of the commonest metastases to the breast in males and its diagnosis might be difficult if one ignores the clinical history or if the metastasis is precessive with repect to the primary tumor [2]. PSA ICC was of great help in our case, due to the intense cellular necrosis, partly obscuring the cytological presentation.

With regard to the clinical presentation, we were struck by the ‘inflammatory mastitis’ presentation of metastatic adenocarcinoma of, respectively, endometrial and lung origin. Similar clinical pictures have been already recorded in the cytological [20] and radiological literature [21] and are pathologically explicable with tumor spreading into superficial dermal lymphatic vessels.

Our findings further confirm the relative rarity of metastatic involvement of the breast also in an outpatient setting and underline the primary role of cytomorphological and immunocytochemical work-up in the diagnostic assessment of secondaries to the breast.


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This paper was made possible by a generous donation by the Lega Italiana per la Lotta ai Tumori, Sezione di Napoli.

Received for publication October 24, 2007. Revision received October 26, 2007. Accepted for publication October 27, 2007.


   References
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 Abstract
 introduction
 case reports
 discussion
 funding
 References
 
1. Sneige N, Zachariah S, Fanning TV, et al. Fine-needle aspiration cytology of metastatic neoplasms to the breast. Am J Clin Pathol (1989) 92:27–35.[Web of Science][Medline]

2. Schmitt FC, Tani E, Skoog L. Cytology and immunocytochemistry of bilateral breast metastases from prostatic cancer. Report of a case. Acta Cytol (1989) 33:899–902.[Web of Science][Medline]

3. Domansky H. Metastases to the breast from extramammary neoplasms. A report of six cases with diagnosis by fine needle aspiration cytology. Acta Cytol (1996) 40:1293–1300.[Web of Science][Medline]

4. Raptis S, Kanbour AI, Dusenberg D, Kanbour-Shakir A. Fine-needle aspiration cytology of metastatic ovarian carcinoma to the breast. Diagn Cytopathol (1996) 15:1–6.[CrossRef][Web of Science][Medline]

5. Cangiarella J, Fraser Symmans W, Cohen JM, et al. Malignant melanoma metastatic to the breast. A report of seven cases diagnosed by fine-needle aspiration cytology. Cancer Cytopathol (1998) 84:160–162.

6. Deshpande AH, Munshi MM, Lele VR, Bobhate SK. Aspiration cytology of extramammary tumors metastatic to the breast. Diagnostic Cytopathol (1999) 21:319–323.[CrossRef]

7. Ward R, Conner G, Delprado W, Dalley D. Metastatic adenocarcinoma of the cervix presenting as an inflammatory breast lesion. Gynecol Oncol (1989) 35:399–405.[CrossRef][Web of Science][Medline]

8. David O, Gattuso P, Razan W, Moroz K. Unusual cases of metastases to the breast. A report of 17 cases diagnosed by fine needle aspiration. Acta Cytol (2002) 46:377–382.[Web of Science][Medline]

9. Shukla R, Pooia B, Radhika S, Nijhawan R. Fine-needle aspiration cytology of extramammary neoplasms metastatic to the breast. Diagnostic Cytopathol (2005) 32:193–197.[CrossRef]

10. Abrams HL, Spiro R, Goldstein N. Metastasis in carcinoma. Analysis of 1000 autopsied cases. Cancer (1950) 3:74–85.[CrossRef][Web of Science][Medline]

11. Hajdu SI, Urban JA. Cancers metastatic to the breast. Cancer (1972) 29:1691–1696.[CrossRef][Medline]

12. Fetsch PA, Marincola FM, Abati A. Cytokeratin positivity in fine-needle aspirates of metastatic malignant melanoma: fact or fiction? Diagn Cytopathol (1999) 20(6):393–396.[CrossRef][Web of Science][Medline]

13. Filie AC, Simsir A, Fetsch P, Abati A. Melanoma metastatic to the breast: utility of fine needle aspiration and immunohistochemistry. Acta Cytol (2002) 46(1):13–18.[Web of Science][Medline]

14. Koh HK, Sober AJ, Carey RA. Possible association between malignant melanoma and breast cancer. Arch Dermatol (1987) 123:712–713.[Abstract/Free Full Text]

15. Simsir A, Waisman J, Thomer K, Cangiarella J. Mammary lesions diagnosed as "papillary" by aspiration biopsy. Cancer (2003) 99:156–165.[CrossRef][Medline]

16. Ng WK. Fine-needle aspiration cytology findings of an uncommon micropapillary variant of pure mucinous carcinoma of the breast: review of patients over an 8-year period. Cancer (2002) 19(4):682–687.

17. Pillai KR, Jayasree K, Jayalal KS, et al. Mucinous carcinoma of breast with abundant psammoma bodies in fine-needle aspiration cytology: a case report. Diagn Cytopathol (2007) 35(4):230–233.[CrossRef][Web of Science][Medline]

18. Pettinato G, Pambuccian SE, Di Prisco B, Manivel JC. Fine needle aspiration cytology of invasive micropapillary (pseudopapillary) carcinoma of the breast. Report of 11 cases with clinicopathologic findings. Acta Cytol (2002) 46(6):1088–1094.[Web of Science][Medline]

19. Madur B, Shet T, Chinoy R. Cytologic findings in infiltrating micropapillary carcinoma and mucinous carcinomas with micropapillary pattern. Acta Cytol (2007) 51(1):25–32.[Web of Science][Medline]

20. Nance FC, Mac Vaugh H III, Fitts WT Jr. Metastatic tumor to the breast simulating primary inflammatory carcinoma. Am J Surg (1966) 112:932–935.[CrossRef][Web of Science][Medline]

21. Bartella L, Perry NM, Malhotra A, et al. Metastases to the breast revisited: radiological-histopathological correlation. Pictorial review. Clin Radiol (2003) 58:524–531.[CrossRef][Web of Science][Medline]


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