Pathology International

2004;

54

: 781–786

Blackwell Science, LtdOxford, UKPINPathology International1320-54632004 Japanese Society of PathologyOctober 20045410781786Case Report

Mammary mucinous cystadenocarcinomaW-Y. Chen

et al.

Correspondence: Jan-Show Chu, MD, Department of Pathology,College of Medicine, Taipei Medical University, 250 Wu-Hsing Street,Taipei 110, Taiwan. Email: jschu@tmu.edu.tw

Received 16 April 2004. Accepted for publication 27 May 2004.

Case Report

Mucinous cystadenocarcinoma of the breast coexisting with infiltrating ductal carcinoma

Wei-Yu Chen,

1,5

Ching-Shyang Chen,

2

Hsin-Chi Chen,

3

Yi-Ju Hung

1

and and Jan-Show Chu

4,5

1

Department of Pathology, Taipei Municipal Wan-Fang Hospital, Departments of

2

General Surgery,

3

Radiology and

4

Pathology, Taipei Medical University Hospital and

5

Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan

A recently described and rare variant of breast carcinoma,mucinous cystadenocarcinoma (MCA), is reported in a65-year-old post-menopausal woman. She presented witha gradually enlarged breast tumor. A well-circumscribedtumor measuring about 3 cm in diameter was noted in themammographic and ultrasonographic examinations. Themammographic and ultrasonographic findings were indis-tinguishable from more common mucinous carcinoma (col-loid carcinoma) of the breast. The gross appearance of thetumor was well-defined and cystic, consisting of abundanttransparent to bloody mucin, as well as whitish solid parts.Microscopically, the tumor was characterized by abundantextracellular and intracellular mucin. It looked like a muci-nous cystic neoplasm of the ovary and pancreas. Particu-larly, few microscopic foci of ordinary intermediate-gradeinfiltrating ductal carcinoma (IDC) and ductal carcinoma

insitu

(DCIS) were observed around the main lesion in thiscase. A transition from ordinary DCIS to MCA

in situ

wasfound. It might indicate MCA derives from a metaplasiaprocess of ordinary DCIS. MCA can be easily differentiatedfrom mucinous carcinoma by quite different histologic andimmunohistochemical findings. According to the previouslyreported and present cases, MCA of the breast more com-monly affects elderly women and has a relatively favorableprognosis.

Key words:

breast, mucinous carcinoma, mucinous cystadeno-carcinoma

There are a variety of breast tumors with obvious mucinproduction. Mucinous carcinoma is the most common typeamong them. It is characterized by mildly atypical tumor cellsfloating in extracellular mucin pools. Mucinous cystadenocar-cinoma (MCA) is a recently described and rare variant ofbreast carcinoma.

1–4

Abundant intracellular mucin in thetumor cells is found in addition to extracellular mucin. Thetumor cells floating in the mucin are not seen in this tumor.

We present a case of a 65-year-old woman with MCA of thebreast, with coexistence of ordinary infiltrating ductal carci-noma (IDC) and ductal carcinoma

in situ

(DCIS). The litera-ture associated with this tumor will be reviewed.

CLINICAL SUMMARY

A 65-year-old post-menopausal Taiwanese woman (gravida4, para 4) visited the outpatient clinic of Taipei Medical Uni-versity Hospital because of a right breast lump. Neither nippledischarge nor skin retraction was complained. Her pastmedical history was non-contributory. She reported no familyhistory of malignancy. She had not received hormonereplacement therapy prior. The physical examination revealeda firm tumor, about 4

¥

3

¥

2 cm in size, in the upper innerquadrant of the right breast. No palpable axillary lymph nodewas noticed

.

The tumor did not fix to the chest wall and skin.On ultrasonographic examination, the tumor appeared as acircumscribed, isoechogenic to hypoechogenic lesion, mea-suring 30.9

¥

25.8 mm in dimension, with posterior acousticshadow (Fig. 1a). Mammography showed a well-defined,medium to high density, multilobulated mass, measuringapproximately 3.0

¥

2.9 cm in dimension, in the upper innerquadrant of the right breast (Fig. 1b). There was neitherspiculated margins nor intralesional microcalcification.The imaging features indicated a benign lesion or well-circumscribed breast carcinoma such as papillary carcinomaor mucinous carcinoma. Core needle biopsy was obtainedand revealed an unusual mucinous lesion. Total excision wassuggested because of uncertainty about the nature and originof the lesion. After the core needle biopsy, the patient did notpay much attention to the problem and was lost to follow up.Thereafter, she felt gradual enlargement of the tumor andvisited our clinic again 3 months later. Ultrasonographydemonstrated a slight increase of the tumor size to34.0

¥

31.4 mm in dimensions. Then she was admitted toreceive lumpectomy. During this admission, physical exami-nation as well as pelvic and abdominal ultrasonography did

782 W-Y. Chen

et al.

not show other tumors in the abdominal and pelvic organs,especially in the pancreas and ovaries. The tumor markerscreening revealed CA 19–9 was slightly elevated to 60.02

m

/mL (reference range:

<

37

m

/mL). Carcinoembryonic antigen(CEA), CA125 and CA15.3 were within normal ranges.Mucinous cystadenocarcinoma of the breast was diagnosedbased on the lumpectomy specimen and clinical data. Sub-sequent modified radical mastectomy with dissection of axil-lary lymph nodes was done. No residual carcinoma was foundin the mastectomy specimen. All axillary lymph nodes werefree from metastatic carcinoma. The breast carcinoma wasjudged to be at stage IIA (T2N0M0) according to the AmericanJoint Committee on Cancer staging system.

5

Post-operativechemotherapy was prescribed. She remained well anddisease-free for 8 months after the operation.

PATHOLOGICAL FINDINGS

The core needle biopsy of the breast tumor showed accumu-lation of extracellular mucin in a cyst-like space lined bysimple columnar mucinous cells. Papillary structures werealso present (Fig. 2). The epithelial cells displayed basallylocated nuclei and abundant apical mucinous cytoplasm. Thenuclear pleomorphism was not prominent. Mitotic figureswere not seen. Focal hemosiderin deposition was noticed.The histological changes were similar to ovarian or pancre-atic mucinous cystic neoplasms.

The gross examination of the breast tumor, resected bylumpectomy, revealed a well-demarcated cystic tumor mea-suring 3.0

¥

2.8

¥

2.7 cm in size (Fig. 3). The cyst lumencomprised abundant transparent to bloody gelatinous mate-rial. Some whitish solid parts arising from the cyst wall werefound. The whole tumor was submitted for histological study.

Figure 1

Imaging findings of the breast tumor. (

a

) A well-defined,isoechogenic to hypoechogenic lesion on the ultrasonographicexamination. (

b

) A well-circumscribed mass on the craniocaudalview of mammography.

Figure 2

A cyst-like space (arrow) containing mucinous material.The space is covered by a single layer and papillary structures ofmucinous epithelium (hematoxylin-eosin (HE);

¥

40).

Mammary mucinous cystadenocarcinoma 783

Microscopically, the cyst was multilocular and filled with muci-nous material (Fig. 4a). The cyst wall was covered either bya single layer of columnar epithelium or more commonlycomplex branched papillary structures (Fig. 4b). The papil-lary structures had delicate fibrovascular cores. The epithelialcells had abundant intracellular mucin. They varied in severityof nuclear pleomorphism, ranging from minimal to moderatecytologic atypia (Fig. 4c,d). The cells with more obviousnuclear atypia demonstrated nuclear stratification, loss ofpolarity, a high nucleus to cytoplasm ratio, depleted mucinouscontent, and an increase in mitotic figures. Some cells con-tained eosinophilic hyaline globules. Lymphocyte infiltrateand hemosiderin deposition were seen in areas. Beneaththese columnar mucinous epithelial cells, lack of myoepithe-lial cells was confirmed by immunohistochemical stain formuscle specific actin (clone, HHF 35; 1:50 dilution; DakoCy-tomation, Glostrup, Denmark). No desmoplastic reaction wasseen in the stroma around the cyst and epithelial cells. Due

Figure 3

Cut surface of the breast tumor showing a well-demarcated cystic lesion containing transparent to bloody mucinousmaterial. Whitish solid areas are present.

Figure 4

Histological features ofmucinous cystadenocarcinoma of thebreast. (

a

) Cystic spaces containingabundant extracellular mucinous mate-rial. Many papillary structures are seen(HE;

¥

10). (

b

) Branched papillarystructures with fibrovascular cores(HE;

¥

100). (

c

) Bland tumor cells withabundant intracellular mucin (HE;

¥

200). (

d

) Tumor cells with obviouscytologic atypia. They show nuclearstratification, depletion of intracellularmucin, increased nucleus to cytoplasmratio, and and and and and and andand frequent mitotic figures (HE;

¥

200). (

e

) Ordinary intermediate-gradeinfiltrating ductal carcinoma noticedadjacent to the main tumor. It isarranged in small solid nests sur-rounded by lymphoplasma cells(HE;

¥

100). (

f

) Ordinary ductal carci-noma in situ composed of epithelialcells without obvious intracellularmucin. The lumen of the duct containssome mucin (HE;

¥

100).

784 W-Y. Chen

et al.

to lack of myoepithelial cells, the whole tumor was regardedas invasive carcinoma, with an expansile growth fashion.There was no floating tumor cell cluster in the extracellularmucin pools. The tumor morphologically resembled muci-nous cystic neoplasm of the ovary or pancreas. In the breasttissue adjacent to the main tumor, scattered grossly invisiblefoci of intermediate-grade ordinary IDC and ordinary DCISwere noticed (Fig. 4e,f). They measured up to 0.2 cm indiameter. The IDC was arranged in solid nest and occasion-ally tubular patterns. Occasional ducts composed of bothordinary DCIS and MCA

in situ

were seen. The latter wasarranged in a micropapillary pattern. The lumens of the ductswith both types of

in situ

carcinoma were expanded by extra-cellular mucus. No transition from invasive MCA to ordinaryIDC was detected. There was neither tumor necrosis nortumor embolus.

Histochemically, abundant neutral and acidic mucin wasdemonstrated in the extracellular mucin pools and in thecytoplasm of the columnar tumor cells by periodic acid-Schiffwith or without diastase digestion, alcian blue pH 2.5, andmucicarmine stains. In foci of ordinary IDC and DCIS, extra-cellular and intracellular mucin content was scanty in amount.

The primary antibodies used for immunohistochemistrywere listed in Table 1. The columnar mucinous tumor cells inMCA were strongly positive for cytokeratin 7 (CK7) and CEA,but negative for estrogen receptor (ER), progesterone receptor(PR), c-erbB-2, chromogranin A and CDX2. Cytokeratin 20(CK20) positive cells were occasionally seen. The proliferativeindex labeled by MIB-1 was about 20.5%. Many tumor cellsdisplayed positive nuclear staining for p53. The tumor cellsof adjacent IDC and DCIS exhibited the same immunophe-notypes except that they were strongly positive for ER and PR.

DISCUSSION

The microscopic features of this tumor, especially highcolumnar cells with abundant intracellular mucin, are unusual

for primary breast carcinoma, even for mucinous carcinomaand mucocele-like tumor.

6,7

As a result, metastatic mucinouscarcinoma, particularly those originates from the ovary orpancreas, should be ruled out before primary mucinous cys-tadenocarcinoma of the breast is diagnosed. However, thebreast is rarely an early metastatic organ without presenta-tion of primary malignancy.

8,9

Because detailed examinationsin the present case did not reveal any tumor in other organs,the cystic tumor should primarily arise from the breast. Thepresence of ordinary DCIS and infiltrating ductal carcinomaadjacent to the tumor also favored a primary breast carci-noma. The immunohistochemical pattern of the tumor cells(CK7+, CK20 focally+ and CDX2–) is different from thosearising from ovary, pancreas, and colon carcinoma.

1–3,10,11

Ovary and pancreas mucinous adenocarcinoma is usuallyCK7+/CK20+. CDX2, which encodes an important transcrip-tion factor for intestinal differentiation, has been reportedto express focally or diffusely in the ovarian mucinousadenocarcinoma and pancreatic adenocarcinoma.

11

Colonadenocarcinoma most commonly shows a CK7–/CK20+/CDX2+ pattern. The antibody panel including CK7 and CK20may be useful to make a differential diagnosis between pri-mary and metastatic mucinous tumors but detailed clinicalevaluation is necessary, particularly for small core needlebiopsies.

According to the morphological changes and immunohis-tochemical findings, MCA of the breast should be distin-guished from the more common ordinary mucinouscarcinoma. The former consists of many high columnar muci-nous tumor cells, which are absent in the latter. Tumor cellclusters suspended in mucin pool, a diagnostic criteria formucinous carcinoma, is usually not found in MCA. Neuro-endocrine differentiation with expression of chromogranin Ais frequently demonstrated in mucinous carcinoma but not inour case.

12

Lack of expression of ER and PR is exceptionalin mucinous carcinoma.

13

Overexpression of p53 protein andhigh proliferative index in this tumor is rarely detected inmucinous carcinoma.

14

Mucinous cystadenocarcinoma may

Table 1

Primary antibodies used in immunohistochemistry

Antibodies to Clones Working dilution Sources

Cytokeratin 7 (CK7)† OV-TL 12/30 1:50 DakoCytomation, Glostrup, DenmarkCytokeratin 20 (CK20)† Ks20.8 1:50 DakoCytomation, Glostrup, DenmarkChromogranin A† DAK-A3 1:50 DakoCytomation, Glostrup, DenmarkEstrogen receptor‡ 6F11 Prediluted Ventana, Tuscon, Arizona, USAProgesterone receptor‡ PgR636 1:50 DakoCytomation, Glostrup, Denmarkc-erbB-2† 1:400 DakoCytomation, Glostrup, DenmarkKi-67† MIB-1 1:50 DakoCytomation, Glostrup, Denmarkp53† DO-7 1:50 DakoCytomation, Glostrup, DenmarkCDX2† CDX2-88 1:50 Biogenex, San Ramon, CA, USACEA† 1:100 Novocastra, Newcastle, UK

CEA, carcinoembryonic antigen. †Pre-treatment by heat-induced antigen retrieval in a citric acid buffer, pH 6.0. ‡Pre-treatment by heat-inducedantigen retrieval in DakoCytomation target retrieval solution, high pH.

Mammary mucinous cystadenocarcinoma 785

be classified as a cystic type of papillary mucinous carcinomaof the breast by other authors,

15

but we think the tumor hadbetter be separated from ordinary mucinous carcinoma dueto the different histological and immunohistochemicalfeatures.

Including the present case, only eight cases of MCA of thebreast have been reported (Table 2).

1–4

The clinicopatholog-ical features of these cases are summarized in Table 2. Theage of these cases, including the present case, ranged from47 to 96 years at diagnosis (mean age, 68 years). It tendedto occur in an older age group. Seven cases presented withpalpable breast masses and one had a non-palpable massby mammography. The size ranged from 0.8 cm to 19.0 cm(mean size, 6.5 cm). Four patients suffered from large MCA(more than 5 cm). The large size did not mean a rapid growthrate of the tumor because the patient with the 19.0 cm MCAwas reported to have had the tumor for a long time.

1

Thelarge size might be related to neglect of the patient to theslowly growing tumor. Some authors have said that MCAseemed to originate from the main mammary duct near thenipple but MCA in the present case was not very close to thenipple.

3

The clinical presentations and mammographic fea-tures of MCA are similar to those of pure mucinous carci-noma.

12,13,16,17

Both tumors may reveal a circumscribed masslesion by mammography and ultrasonography. The differen-tial diagnosis between the two entities seems to be not pos-sible based on the clinical findings.

In four of these eight cases, invasive squamoid carcinomacells with abundant eosinophilic cytoplasm were noticed.

1,3

They were transformed from the columnar mucinous tumorcells. They grew in a raggedly infiltrative pattern. Invasivecarcinoma with sarcomatoid metaplasia was seen in onecase.

1

These features were not present in our case. Therelationship between the prognosis and these morphologicalchanges is not known because the case number is too small

and the follow-up duration is too short. Only one caseshowed a transition from typical mucinous cystadenocarci-noma to the features of ordinary mucinous carcinoma, whichdisplayed tumor cell clusters floating in extracellular mucin.

2

In this case, the tumor cells remained the characters ofmucinous cystadenocarcinoma, such as abundant intracellu-lar mucin, negative expression of estrogen receptor, sulfo-mucin production, as well as high proliferative index. Two ofthese eight cases revealed metastatic carcinoma in the axil-lary lymph nodes. Lymph node metastases were associatedwith a long history of primary tumor.

1,3

The metastatic focimight contain mucinous and/or squamoid tumor cells.

Of particular difference in the present case, ordinary IDCwas found. The IDC showed positive nuclear expression ofER and PR, different from MCA. This was the first case withcoexistence of MCA and IDC. As we know, mixed mucinouscarcinoma composing of ordinary mucinous carcinoma andIDC has poorer prognosis than pure mucinous carcinoma.

12,16

Whether the coexistence of IDC and MCA will affect theprognosis is not known, it needs longer follow-up duration andmore cases to evaluate. The histogenesis of MCA remainsunclear. The coexistence of ordinary DCIS and MCA in thiscase indicated tumor cells of MCA might be transformed fromepithelial cells of ordinary DCIS via a metaplasia process,accompanied by loss of expression of ER and PR.

Although MCA demonstrated loss of ER and PR expres-sion, overexpression of p53, and high proliferation index, theprognosis of the tumor appeared to be good. Until now,neither tumor recurrence nor death of the disease afterremoval of the tumor and axillary lymph nodes has beenreported during the follow-up period.

In conclusion, mucinous cystadenocarcinoma of the breastis a rare variant of breast cancer. It cannot be correctlydiagnosed according to clinical and imaging studies. It maybe misinterpreted as a benign lesion because the small

Table 2

Clinicopathological features of mucinous cystadenocarcinoma

CaseNo. Reference

Age(years)

Tumorsize (cm)

Lymph nodemetastasis Treatment Follow-up IDC DCIS

MCA

in situ

Ordinary mucinous carcinoma

1 1 54 19.0 + M, LND ANED, 24 months – – – –2 1 67 2.3 – M, LND ANED, 22 months – + – –3 1 49 8.5 – M, LND,

chemotherapyradiotherapy

ANED, 11 months – – + –

4 1 61 0.8 – Lumpectomy,LND

NA – – – –

5 2 74 10.0 – M, LND ANED, 2 years – + – +6 3 96 2.0 + Lumpectomy,

LND46 months† – – – –

7 4 79 6.0 – M, LND 9 years† – – + –Presentcase

65 3.0 – M, LND, chemotherapy

ANED, 8 months + + + –

ANED, alive with no evidence of disease; DCIS, ordinary ductal carcinoma

in situ

; IDC, infiltrating ductal carcinoma; LND, lymph node dissection;M, mastectomy; MCA, mucinous cystadenocarcinoma; NA, not available. †Died of disease other than MCA.

786 W-Y. Chen

et al.

biopsy specimen may only consist of tumor cells with blandnuclei. Total removal of the tumor with detailed histologicaland immunohistochemical examinations can make a correctdiagnosis and a distinction from other mucin-producingbreast tumors.

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