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Background

This variant of infiltrating ductal carcinoma of the breast has an excellent prognosis. The pathologist is greeted with a collection of lakes of mucin, within which are floating islands of relatively bland tumor cells. In fact, the colloid carcinoma is also known as a mucinous carcinoma. This pattern is reproduced in a few other organs such as the urinary bladder and gastrointestinal tract.

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/Other Diagnostic Testing  
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/Immunohistochemistry/Electron Microscopy  
Differential Diagnosis  
Prognosis and Treatment  
Commonly Used Terms  

EPIDEMIOLOGY CHARACTERIZATION
SYNONYMS Mucinous carcinoma
Colloid carcinoma
INCIDENCE 7% of tumors in women 75 years or older
AGE RANGE-MEDIAN Usually older than nonmucinous tumors

PATHOGENESIS CHARACTERIZATION
GENERAL  


Pathogenesis of Colloid (Pure Mucinous) Carcinoma of Exocrine Organs: Coupling of Gel-Forming Mucin (MUC2) Production With Altered Cell Polarity and Abnormal Cell-Stroma Interaction May Be the Key Factor in the Morphogenesis and Indolent Behavior of Colloid Carcinoma in the Breast and Pancreas.

Adsay NV, Merati K, Nassar H, Shia J, Sarkar F, Pierson CR, Cheng JD, Visscher DW, Hruban RH, Klimstra DS.

 

Am J Surg Pathol 2003 May;27(5):571-8 Abstract quote

In the exocrine organs, breast and pancreas, colloid carcinoma (CC, pure mucinous carcinoma), characterized by well-circumscribed lakes of mucin that contain scanty, detached malignant cells, has a significantly better prognosis than conventional ductal carcinomas (DCs). It has been speculated by us and others that an inverse polarization of cells may be responsible for the accumulation of extracellular mucin. Another possibility is that this mucin is biochemically and biologically distinct from the mucin secreted by the conventional carcinomas of these organs.

This study was undertaken to investigate these two hypotheses: 1) To test whether there is indeed an alteration in cell polarity in CC. Immunohistochemical stains for luminal surface glycoproteins (carcinoembryonic antigen in pancreas and MUC1 in breast) were performed in 18 pancreatic and 30 mammary CCs and compared with the expression pattern in DCs (37 pancreatic and 47 mammary) and normal ducts.

The results disclosed that these glycoproteins were expressed predominantly in the stroma-facing surfaces of CC cells, in contrast to the DCs, in which the expression was either on the luminal surface (in well-differentiated areas) or dispersed throughout the cell, intracytoplasmic in the poorly differentiated areas. Ultrastructural examination performed on 10 breast and two pancreatic CCs showed the condensation of mucigen granules (generally underlying an apical-type cell membrane) in the stroma-facing surface in all cases.

In contrast, in the DCs (five pancreatic and five mammary), no clustering of mucigen granules was identified in the cytoplasm facing the stroma in any of the cases. Furthermore, no external lamina or basement membrane was detected in any of the CCs, whereas in the DCs, a distinct (in 3 of 10) or discontinuous (4 of 10) external lamina separated the tumor cells from the stroma. 2) To determine the expression frequency of MUC2 in CCs and to compare it with that in DCs and normal tissue, immunohistochemical stains with MUC2 (clone ccp58) were performed. MUC2 expression was detected in 18 of 18 pancreatic and 30 of 30 breast CCs and was exceedingly rare in DCs (1 of 136 pancreatic DC and 3 of 47 mammary, p <0.0001 in both organs). No labeling was detected in normal ducts.

In conclusion, it appears that coupling of two factors is important for the distinctive morphologic characteristics and slow growth of CCs: The first one is the alteration in cell orientation as evidenced by the direction of surface glycoproteins and secretory organelles to the stroma-facing surface of the cells and the disruption of cell-stroma interaction as manifested by lack of basal lamina formation. Apparently, this altered polarity allows the CC cells to secrete the mucin toward the stroma. The mucin produced, MUC2 (also called gel-forming mucin), is highly specific for CC and is known to form strong bonds with the stroma, and also was found recently to have tumor suppressor activity. This distinctive mucin, accumulated in the stroma surrounding the CC cells, may act as a containing factor, slackening the spread of the cells.


GROSS APPEARANCE/
CLINICAL VARIANTS
CHARACTERIZATION
GENERAL  
VARIANTS  
ADVANCED  


Locally advanced mucinous carcinoma of the breast with sudden growth acceleration: a case report.

Ishikawa T, Hamaguchi Y, Ichikawa Y, Shimura M, Kawano N, Nakatani Y, Ohnishi H, Maegawa J, Ogino I, Shimada H.

Department of Surgery, Yokohama City University, School of Medicine, Yokohama, Japan.

Jpn J Clin Oncol 2002 Feb;32(2):64-7 Abstract quote

We report a 35-year-old woman with locally advanced mucinous carcinoma of the breast with sudden growth acceleration. A pea-sized mass developed into an ulcerated large tumor within 1 month. After the combination of chemotherapy, radiation and hyperthermia, a radical mastectomy was performed, followed by repair of the skin defect by latissimus dorsi and rectus abdominis musculocutaneous flaps.

Histological examination revealed a pure mucinous carcinoma with axillary lymph node involvement. Estrogen and progesterone receptors were not detected in the tumor. Twenty-five months after treatment, there is no sign of recurrent disease. Pure mucinous carcinoma generally has a less aggressive growth pattern as defined by tumor size, adherence to the overlying skin/bottom fasciae, estrogen and progesterone receptor positive and primary lymph axillary lymph node metastases.

This case showed completely opposite features to all of these typical biological features of pure mucinous carcinomas.

 

HISTOLOGICAL TYPES CHARACTERIZATION
GENERAL  


Human mucinous breast carcinomas and their lymph node metastases. A histological review of 247 cases.

Rasmussen BB.

Pathol Res Pract 1985 Oct;180(4):377-82 Abstract quote

In a histologic reevaluation of 247 primary human mucinous breast carcinomas, 207 tumors fullfilled the criteria for further histopathological evaluation. The criteria for entrance in this survey are that at least 25% of the tumor consists of areas of extracellular mucin with small islands of solid epithelial tumor tissue floating in the mucin, and that the extracellular mucin should comprise at least 33% of the total tumor volume.

The 247 carcinomas that have been further evaluated have been subclassified into two groups: "pure" mucinous breast carcinomas that consist solely of tumor tissue with extracellular mucin production (95 tumors), and "mixed" mucinous carcinomas that also contain infiltrating carcinoma without extracellular mucin (112 tumor). A significantly greater number of mixed carcinomas than pure carcinomas have an aggressive growth pattern--as defined by tumor size, adherence to overlying skin/bottom fascie, and primary axillary lymph node metastases. The histogenesis of the mucinous carcinomas is briefly discussed in relation to the present observations and the literature.

The importance of clearly distinguishing between the mixed and the pure mucinous carcinomas in the diagnosis of these tumors is emphasized.


Mucinous carcinoma of the breast: a pathologic study of 82 cases.

Andre S, Cunha F, Bernardo M, Meneses e Sousa J, Cortez F, Soares J.

Departamento de Patologia Morfologica, Instituto Portugues de Oncologia de Francisco Gentil, Lisboa.

J Surg Oncol 1995 Mar;58(3):162-7 Abstract quote

A series of 82 consecutive cases of mucinous carcinomas of the female breast was investigated for their clinical, morphological, and histochemical features and for the influence of some tumor characteristics on its prognosis.

Two groups, a "pure" subtype (n = 58) and a "mixed" subtype (n = 24), were considered, according to the absence or the presence of concomitant areas with typical infiltrating ductal carcinoma. Eighty patients were followed with an average of 7.4 years. The actuarial survival was 58.5% at 10 years. The group of pure mucinous carcinomas showed a statistically significant better prognosis (P = 0.0007) than that of the group of mixed tumors, as well as a lower percentage of axillary nodal metastasis. Tumor dimension of both pure and mixed mucinous carcinomas influenced the prognosis, since patients with T1 tumors had longer survival than those with T2 tumors (P = 0.05) and the latter showed less mortality than T3 tumor cases (P = 0.036). Node-negative patients also had a more favorable outcome with lower mortality than node positive patients (P = 0.007).

None of the T1 pure mucinous carcinomas had axillary metastasis, which may have implications for the surgical protocols. The evaluation of quantitative and qualitative content in mucosubstances did not correlate with the prognosis. However, sulfomucins were demonstrated in 30.5% of cases; this fact points to add breast carcinoma to the group of neoplasms that may present as a metastatic sulfomucin-producing adenocarcinoma.

Can Mucinous Lesions of the Breast Be Reliably Diagnosed by Core Needle Biopsy?


Andrew A. Renshaw, MD

Am J Clin Pathol 2002;118:82-84 Abstract quote

Lesions of the breast containing extravasated mucin span a continuum from benign mucoceles to invasive mucinous (colloid) carcinoma. It is well known that distinguishing benign from malignant mucinous lesions is difficult in fine-needle aspiration material. Whether these lesions also are difficult to distinguish in core needle biopsy material is not known.

To address this, I reviewed the results of 4,297 breast core needle biopsies. Mucinous lesions were identified in 22 cases (0.51%), and excisional biopsy material was available for 15 of these. At excision, 0 of 8 benign mucinous lesions showed carcinoma, while 7 of 7 mucinous lesions associated with carcinoma at the time of core needle biopsy showed carcinoma at excision.

The vast majority of mucinous lesions of the breast can be diagnosed accurately by core needle biopsy. Whether all such lesions require excision is not known at this time.

VARIANTS  
NEUROENDOCRINE DIFFERENTIATION  
Neuroendocrine differentiation in pure type mammary mucinous carcinoma is associated with favorable histologic and immunohistochemical parameters.

Tse GM, Ma TK, Chu WC, Lam WW, Poon CS, Chan WC.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, NT, Hong Kong.
Mod Pathol. 2004 May;17(5):568-72. Abstract quote  

Mucinous carcinoma of the breast is a specific good prognostic type malignancy occurring in elderly patients. Neuroendocrine differentiation has long been described in mucinous carcinoma, but the significance of such finding is uncertain.

We evaluated the neuroendocrine differentiation profiles of 38 cases of pure mucinous carcinoma and compared the clinicopathological differences between those with and those without neuroendocrine differentiation. The parameters assessed included patients' age, tumor size, nuclear grade, axillary lymph node status at time of diagnosis, percentage area of intratumoral mucin, and the expression of estrogen and progesterone receptors, cerbB2 oncoprotein, and three neuroendocrine markers, namely neurone-specific enolase, chromogranin, and synaptophysin by immunohistochemistry.

Patients' outcome and follow-up period were also documented. Of the 38 cases of pure mucinous carcinoma, 28, 11 and six cases showed positive staining for 1, 2 and 3 of the neuroendocrine markers. For all the groups with variable neuroendocrine differentiation and compared to those without such differentiation, they all showed older patients' age, higher proportion of tumors with lower nuclear grade, lower incidence of axillary lymph node metastasis, a higher progesterone receptor, and lower cerbB2 oncoprotein expression. No difference was detected between tumor size, intratumoral mucinous area, and estrogen receptor status.

In all, 37 patients did not have distant metastases or local recurrences at the end of follow-up period, while one patient with coexisting high-grade ductal carcinoma in situ at time of diagnosis died of breast carcinoma.

Our findings suggest that the identification of neuroendocrine differentiation in pure mucinous carcinoma is associated with more favorable histologic and immunohistochemical parameters.

 

SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHER
CHARACTERIZATION
SPECIAL STAINS  


Mucinous (colloid) adenocarcinomas secrete distinct O-acylated forms of sialomucins: a histochemical study of gastric, colorectal and breast adenocarcinomas.

Saez C, Japon MA, Poveda MA, Segura DI.

Laboratory of Histochemistry, Department of Pathology, Hospital Universitario Virgen del Rocio, Avenida Manuel Siurot s/n, Seville 41013, Spain.

Histopathology 2001 Dec;39(6):554-60 Abstract quote

AIMS: Mucinous (colloid) adenocarcinomas represent a distinct group of tumours defined by the presence of large amounts of extracellular mucins. By using histochemical methods, we analysed mucins secreted by mucinous versus non-mucinous adenocarcinomas and looked for differential secretion profiles.

METHODS AND RESULTS: Sixty-four adenocarcinomas were studied (23 colorectal, 17 gastric, and 24 breast tumours). Thirty-two tumours were of the colloid type. The following methods were applied to paraffin tissue sections: (i) Alcian blue (pH 2.5) and periodic acid-Schiff (PAS); (ii) high iron diamine and Alcian blue (pH 2.5); (iii) periodic acid borohydride, potassium hydroxide, and PAS; (iv) periodic acid-thionine Schiff, potassium hydroxide, and PAS; and (v) periodic acid-borohydride and PAS. Most adenocarcinomas secreted acidic mucins, with sialomucins predominating over sulfomucins, except for non-mucinous adenocarcinomas of the breast which showed predominant neutral mucins. All mucinous adenocarcinomas contained C9-O-acyl sialic acid as mono, di(C8,C9)-, or tri(C7,C8,C9)-O-acyl forms. Acidic mucins secreted by the majority of non-colloid adenocarcinomas consisted of non-O-acylated sialomucins.

CONCLUSIONS: C9-O-acylation of sialic acid is a characteristic feature of mucinous adenocarcinomas and can be readily detected by histochemical methods.

IMMUNOPEROXIDASE  

 

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
MUCINOUS TUMORS  
Aspiration Biopsy of Mammary Lesions With Abundant Extracellular Mucinous Material
Review of 43 Cases With Surgical Follow-up


Karyna Ventura, MD, Joan Cangiarella, MD, Irene Lee, Andre Moreira, MD, PhD, Jerry Waisman, MD, and Aylin Simsir, MD

Am J Clin Pathol 2003;120:194-202 Abstract quote


We reviewed 43 fine-needle aspiration biopsy (FNAB) smears with abundant extracellular mucinous material to determine whether accurate classification of mucinous lesions is achievable on FNAB: 26 had carcinoma (pure colloid carcinoma [CCA], 23; mixed CCA/invasive ductal carcinoma [IDC], 3); 17 had benign lesions on follow-up (benign MLL, 6; fibrocystic change [FCC], 6; myxoid fibroadenoma [MFA], 5). All carcinomas were identified correctly as malignant on FNAB.

The initial cytologic diagnoses in benign cases were benign in 8, atypical in 8, and "suspicious" for carcinoma in 1. CCAs were moderate to markedly cellular with mild to moderate atypia and lacked oval bare nuclei. Marked nuclear atypia was confined predominantly to cases with mixed CCA/IDC. A distinct feature of CCA was thin-walled capillaries. FCCs and benign MLLs had overlapping cytologic features and showed variable cellularity and no or mild atypia. MFAs were markedly cellular with dyscohesion and variable atypia; stromal fragments and oval bare nuclei were present in every case. Mucinous lesions can be divided into 2 categories by FNAB: those that are adenocarcinomas and those that are not. CCAs have distinctive features that allow a definitive diagnosis on FNAB. Unnecessary surgery can be avoided in MFA by careful evaluation of smear characteristics. Cytologic features of FCC and MLL overlap.

Owing to the documented association of MLL with carcinoma, we recommend that lesions that cannot be classified definitively as adenocarcinoma or MFA be considered for conservative excision, even in the absence of atypia.

PAPILLARY TUMORS  


Can true papillary neoplasms of breast and their mimickers be accurately classified by cytology?

Michael CW, Buschmann B.

University of Michigan, Department of Pathology, Ann Arbor, Michigan 48105, USA.

Cancer 2002 Apr 25;96(2):92-100 Abstract quote

BACKGROUND: The cytologic accuracy in assessing malignancy in papillary breast neoplasms (PBNs) is controversial. This is further complicated by overlapping features observed in other breast lesions that produce papillary-like tissue fragments.

METHODS: The authors reviewed 22 fine-needle aspirates (FNAs) from histologically proven papillary neoplasms: papillary carcinoma (PCA; 10 aspirates) and intraductal papilloma (IDP; 12 aspirates). They also reviewed 8 FNAs in which a papillary neoplasm was suggested by cytology but not confirmed by follow-up biopsy: fibroadenoma (6), mucinous carcinoma (1), and cribriform ductal carcinoma in situ (1).

RESULTS: Papillary carcinoma can be distinguished from IDP by the higher cellularity, more complex papillae with thin disorganized fronds, mild to moderate nuclear atypia, and prominent dissociation with many single papillae. Fibrovascular cores (FVCs) were more common in PCA than IDP in which detached fibrous tissue fragments were frequently seen. Atypical IDP exhibited features intermediate between PCA and IDP. Apocrine metaplasia was variably present in IDP, atypical IDP, and fibroadenoma but absent in all carcinomas. Intraductal papilloma can be distinguished from fibroadenoma by their broad ruffled branches, scalloped borders, and tiny tongue-like projections. True papillae were commonly covered by tall columnar cells. Myoepithelial cells were few in IDP but were numerous in fibroadenoma. The epithelial fragments in nonpapillary lesions presented as cellular spheres and/or complex sheets with finger-like projections but lacked FVCs and columnar cells.

CONCLUSIONS: Papillary breast neoplasms can be accurately classified by cytology. Closer evaluation of the tissue fragments architecture and the background can help in separating PBN from their mimics.

 

PROGNOSIS AND TREATMENT CHARACTERIZATION
PROGNOSTIC FACTORS  
GENERAL  


Pure mucinous carcinoma of the breast: a clinicopathologic correlation study.

Avisar E, Khan MA, Axelrod D, Oza K.

Department of Surgery, Beth Israel Medical Center, New York, New York, USA.

Ann Surg Oncol 1998 Jul-Aug;5(5):447-51 Abstract quote

BACKGROUND: Pure mucinous carcinoma (PMC) of the breast has a better prognosis than does invasive ductal carcinoma not otherwise specified and is more prevalent in older patients. We investigated the correlation between prognostic indices and clinical outcome in this histologic subset.

METHODS: A retrospective review was done of patients with PMC treated between 1989 and 1996. Demographic data, pathologic indices of prognosis, axillary nodal status, and outcome were assessed.

RESULTS: Out of 6083 cases of breast carcinoma, 30 were PMC. Only 3 of 25 (12%) axillary dissections were positive. The average age of the group with positive nodes was 57 years, as compared to 69.5 years (95% CI; 63.24-75.76) in the group with negative nodes. All the tumors with positive nodes were aneuploid and had a high nuclear grade, compared to a 31.25% aneuploidy rate in the group without nodal disease (P = .058). Negative ER receptors were found in only 2 of 20 (10%) of the patients tested. Both had axillary disease (P = .016). Tumor size did not correlate with axillary metastasis. Two of the 29 patients died from unrelated diseases. The other 27 patients are alive with no evidence of disease.

CONCLUSIONS: Axillary nodal disease is rare in PMC and correlates with a younger age, aneuploidy, high nuclear grade, or a negative ER receptor status. Sentinel lymph node biopsy may help identify the need for axillary dissection.

RECURRENCE  

Mucinous carcinoma of the breast: recurrence 30 years after mastectomy.

Scharnhorst D, Huntrakoon M.

Department of Pathology and Oncology, University of Kansas Medical Center, Kansas City 66103.

South Med J 1988 May;81(5):656-7 Abstract quote

We have reported a case of mucinous breast carcinoma that recurred in the form of lung and lymph node metastases 30 years after definitive resection.

This case emphasizes the indolent nature of this neoplasm and the need to lengthen the period of follow-up for patients with this form of cancer.

STAGING  


Pure mucinous carcinoma of the breast: is axillary staging necessary?

Paramo JC, Wilson C, Velarde D, Giraldo J, Poppiti RJ, Mesko TW.

Department of Surgery, Mount Sinai Medical Center, Miami Beach, Florida 33140, USA.

Ann Surg Oncol 2002 Mar;9(2):161-4 Abstract quote

BACKGROUND: Mucinous carcinoma of the breast (MCB) may be associated with a low risk of axillary metastases.

METHODS: To evaluate the incidence of axillary nodal metastasis in MCB, a review of all cases from January 1990 to July 2000 was performed. Pure MCB was defined as all tumor cells being completely surrounded by mucin. Patient demographics, tumor size, estrogen receptor status, total number of dissected lymph nodes, and incidence of nodal metastasis were studied. Deeper sections on the lymph nodes from the pure tumors were performed and stained with low-molecular cytokeratin.

RESULTS: Nineteen cases of pure MCB and 41 cases of mixed MCB were identified. Patients with pure MCB were older than those with mixed MCB. Tumor size and estrogen receptor status showed no statistically significant differences between the two groups. None of the patients with pure MCB demonstrated lymph node metastases, whereas 12 of 41 cases with mixed MCB demonstrated metastatic lymph node involvement.

CONCLUSIONS: Because pure MCB seems unlikely to metastasize, axillary lymph node staging in these patients may not be necessary. The presence of lymph node metastases strongly indicates the presence of a mixed MCB.

TREATMENT  

Pathological features of mucinous carcinoma of the breast are favourable for breast-conserving therapy.

Anan K, Mitsuyama S, Tamae K, Nishihara K, Iwashita T, Abe Y, Ihara T, Nakahara S, Katsumoto F, Toyoshima S.

Department of Surgery, Kitakyushu Municipal Medical Centre, Kitakyushu, Fukuoka 802-0077, Japan.

Eur J Surg Oncol 2001 Aug;27(5):459-63 Abstract quote

AIM: The effectiveness of breast-conserving therapy for mucinous carcinoma has not been well documented. We examined clinical and pathological features of cases to determine whether patients with mucinous carcinoma were suitable candidates for this treatment.

METHOD: Cases of pure type (n=52) and mixed type (n=24) mucinous carcinomas were reviewed with emphasis on the risk factors associated with local recurrences after breast-conserving therapy.

RESULTS: Large pure mucinous carcinomas had a low incidence of extensive intraductal spreading (EIS). An inverse correlation existed between the incidence of EIS and tumour size (P<0.05). Comedo type EIS was infrequent (11%) in pure mucinous carcinoma. Incidences of lymphatic vessel invasion (4%) and nodal involvement (4%) were lower in pure mucinous carcinoma than in mixed carcinoma (P<0.05). No nodal involvement occurred in patients with pure mucinous carcinoma less than 3 cm in diameter.

CONCLUSIONS: Patients with pure mucinous carcinomas, except those invading the local skin, are suitable candidates for breast-conserving therapy. Most pure mucinous carcinomas, including a large tumour up to 5 cm in diameter, can be treated with this therapy.

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