Mucinous Carcinoma
Edi Brogi
Mucinous carcinoma (MC) is composed of neoplastic epithelial clusters admixed with extracellular mucin comprising at least 90% of the tumor. The terms mixed mucinous carcinoma or invasive carcinoma with mucinous features are used for tumors with a mucinous component comprising less than 90% of the lesion. Mention of focal mucinous differentiation should always be included in the diagnostic report of an invasive carcinoma with a lesser mucinous component. MC has a relatively good prognosis. Mixed MC and invasive carcinoma with focal mucinous differentiation are best managed as well-differentiated invasive ductal carcinoma (IFDC) of no special type, as the prognosis is not as good as for MC.
CLINICAL PRESENTATION
Incidence
Age
Women with MC are older than those with nonmucinous carcinoma (1,5,6,8,9,10,11,12,13,14). Although MC can occur at any age (range 25-85) (11), the median and the mean age at diagnosis of 11,422 patients with MC in a study based on 1973 to 2002 SEER data (11) were 71 years and 68.3 years, respectively, significantly greater than that for patients with IFDC (p < 0.01). More than 80% of patients with MC are postmenopausal (8) and at least 65 years old (11). Most studies (15,16,17) found no significant difference in the age distribution and median age of women with MC and mixed MC, although in one series (13) the mean age of patients with MC was 75 years (range 59-90) versus 65 years (range 35-89) for patients with mixed MC (p = 0.02).
Family History
Ethnicity
Gender
Clinical Findings
MC can present as a palpable, soft mass, or as a nonpalpable mammographic mass or architectural distortion (12,24,25). In one study (26), 44.6% of 56 MCs were self-detected, 37.5% were detected at mammographic screening, and 17.9% were first identified at clinical examination. A palpable mass was the presenting symptom in 87% of cases in another series (27). Primary MC can also arise in ectopic breast tissue, such as in the axilla or vulva.
Radiology
Tumors with a high mucin content tend to be mammographically and sonographically lobulated or circumscribed (25,28,29,30). The sensitivity of mammograms was only 76.5% for the detection of MC versus 100% for mixed MC (31). Only 37.5% of MC in one series (26) were first detected at mammographic screening. Mammographically detected calcifications in the invasive epithelium and/or in the mucin are found in up to 40% of MCs (12,27,30,32,33). Calcifications can also occur in adjacent ductal carcinoma in situ (DCIS) (14,34) or in a concurrent mucocele-like lesion (35). On ultrasound examination, MC is isoechogenic to the mammary fat (36). The sensitivity of ultrasound was 94.7% for MC versus 100% for mixed MCs in one study (31).
Dhillon et al. (30) reported that 39% of mammographically evident MC ranging in size from 5 to 20 mm (average 11 mm) were not seen on ultrasound. In the same series (30), 38% of MCs were not recognized as abnormal when first encountered in a mammogram or at ultrasound examination. Nonetheless,
patients with delayed diagnosis had no lymph node (LN) metastases at the time of surgical excision.
patients with delayed diagnosis had no lymph node (LN) metastases at the time of surgical excision.
The echographic differential diagnosis of MC includes myxoid fibroadenoma, benign cystic lesions, as well as matrix-producing carcinoma and carcinoma with large central acellular zone (37). MC has a gradually enhancing contrast pattern and very high signal intensity on T2-weighted images at magnetic resonance imaging (MRI) examination (38,39). MC and some types of fibroadenomas are not distinctively different on MRI examination (40,41).
Size
In a study based on 1973 to 2002 SEER data (11), MC had a mean size of 2.2 cm, a median size of 1.6 cm, and 83.2% of tumors measured 3.0 cm or less. More than 50% of MCs in contemporary series measured 2 cm or less (12,16,17,21). MCs larger than 5 cm were observed in only 2.8% (17) and 4.9% (12) of the cases in two studies. The average size of MC without LN metastases was 1.5 cm versus 2.6 cm for MC with LN involvement (21). MCs are smaller than IFDC (11,12) and mixed MCs (15,16,17).
MICROSCOPIC PATHOLOGY
MC is composed of at least 90% of abundant extracellular mucin admixed with invasive neoplastic epithelial cells (Fig. 14.1). The mucinous component of a mixed MC constitutes less than 90% of the tumor (Fig. 14.2). Extensive sampling of a hypocellular MC composed almost entirely of extracellular mucin may be required to detect the neoplastic epithelium (Fig. 14.3). The carcinoma cells of MC are arranged in a variety of patterns, including strands, alveolar nests, papillary and micropapillary clusters, and large cribriform sheets (Fig. 14.4).
 FIGURE 14.1 Mucinous Carcinoma. A: More than 90% of this mucinous carcinoma consists of clusters of carcinoma cells admixed with stromal mucin. Focal solid ductal carcinoma in situ (DCIS) is also present (asterisks). B, C: Needle core biopsy specimens showing varying proportions of extracellular mucin and carcinoma cells. The epithelium forms small nests and trabeculae in B and nests in C. |
Grade
Calcifications
Calcifications associated with MC tend to be coarse and irregular.
Histological Subtypes of Mucinous Carcinoma
Type A, Type B, and Type AB Mucinous Carcinoma
Capella et al. (42) subclassified MC into three morphologic types: A, B, and AB. They described type A MC as having
abundant extracellular mucin and epithelium distributed in “trabeculae and ribbons or festoons” (Fig. 14.5). Type B MC had less-abundant extracellular mucin and consisted of “clumps” of cells with intracytoplasmic mucin and often granular cytoplasm (Fig. 14.6). Type AB MC had “indeterminate” features and constituted 20% of cases. Patients with type A MC tended to be younger than patients with type B MC. The authors suggested that type B tumors constituted a variant of MC with endocrine differentiation. This classification was not prognostically significant in a subsequent study (5). In a recent series (16), type A MCs were found to be smaller than type B (1.4 cm vs. 1.9 cm, respectively), had lower rates of lymphovascular invasion (LVI) (3% vs. 25%) and LN metastases (8% vs. 25%), and were less often HER2-positive (5.4% vs. 25%). These findings need validation in larger series. At present, the presence of type A, B, or AB morphology is not usually commented upon in the final diagnosis of a MC.
abundant extracellular mucin and epithelium distributed in “trabeculae and ribbons or festoons” (Fig. 14.5). Type B MC had less-abundant extracellular mucin and consisted of “clumps” of cells with intracytoplasmic mucin and often granular cytoplasm (Fig. 14.6). Type AB MC had “indeterminate” features and constituted 20% of cases. Patients with type A MC tended to be younger than patients with type B MC. The authors suggested that type B tumors constituted a variant of MC with endocrine differentiation. This classification was not prognostically significant in a subsequent study (5). In a recent series (16), type A MCs were found to be smaller than type B (1.4 cm vs. 1.9 cm, respectively), had lower rates of lymphovascular invasion (LVI) (3% vs. 25%) and LN metastases (8% vs. 25%), and were less often HER2-positive (5.4% vs. 25%). These findings need validation in larger series. At present, the presence of type A, B, or AB morphology is not usually commented upon in the final diagnosis of a MC.
 FIGURE 14.2 Mixed Mucinous Carcinoma. A: In this mixed mucinous carcinoma, the mucinous component represents less than 90% of the tumor. B: In this needle core biopsy sample of a mixed mucinous carcinoma, the neoplastic clusters are embedded in the stroma in some areas (dark arrows), and admixed with abundant extracellular mucin in others (white arrows). |
 FIGURE 14.3 Mucinous Carcinoma, Hypocellular. Only minute and sparse clusters of carcinoma cells (arrows) are present in this core biopsy sample from a hypocellular mucinous carcinoma. |
 FIGURE 14.4 Mucinous Carcinoma, Different Growth Patterns. Needle core biopsy specimens showing different growth patterns. A: Trabecular pattern. B: Festoon growth pattern. C: Cribriform mucinous carcinoma. |
 FIGURE 14.4 (continued) |
Micropapillary Variant of Mucinous Carcinoma
A micropapillary variant of MC has been described (16,43,44). The micropapillae are arranged in small and tightly cohesive clusters or in ring-like structures in a space filled with mucin (Fig. 14.7). Psammomatous calcifications are common (43) (Fig. 14.7). A micropapillary component was recognized in 66.6% (45), 35% (44), and 20% (16) of MC in three separate series, but the percentage of MC with micropapillary morphology required for diagnosis was not defined. In one series (16), MC with and without a micropapillary component had similar average size (1.7 cm and 1.65 cm, respectively), but patients with a micropapillary component were younger (47 years vs. 60 years, respectively). Three of the five (60%) MCs with LN metastases had a micropapillary component, versus only 14% of MCs without LN involvement (16). In another series (46), LVI was present in 9/15 (60%) micropapillary MCs, and LN metastases occurred in 33% of cases. One of 13 patients with follow-up information developed a chest-wall recurrence 9 months after mastectomy. Liu et al. (47) found that 134 patients with MC composed of micropapillary clusters in at least 50% of the tumor were significantly younger (median age 46 years), had more frequent LN involvement (35%), and significantly
reduced 10-year overall survival (OS) and relapse-free survival compared to 397 patients with pure MC with absent or less than 50% micropapillary component.
reduced 10-year overall survival (OS) and relapse-free survival compared to 397 patients with pure MC with absent or less than 50% micropapillary component.
 FIGURE 14.5 Mucinous Carcinoma, Type A. A, B: The mucinous carcinoma in this needle core biopsy sample consists of scattered cohesive clusters of neoplastic cells admixed with abundant extracellular mucin. |
 FIGURE 14.6 Mucinous Carcinoma, Type B. The mucinous carcinoma in this needle core biopsy sample is cellular and consists of numerous neoplastic epithelial clusters admixed with relatively limited extracellular mucin. |
 FIGURE 14.7 Mucinous Carcinoma with Micropapillary Pattern. The mucinous carcinoma in this needle core biopsy sample has micropapillary features, best appreciated at high magnification. A: Focal micropapillary ductal carcinoma in situ (vertical arrow) is associated with the invasive component. Linear arrangement of the neoplastic clusters admixed with mucin at the periphery of the tumor (horizontal arrows) suggests lymphovascular invasion, but definitive diagnosis requires confirmation by immunohistochemistry for endothelial antigens. Collections of small lymphocytes, an uncommon finding in this type of carcinoma, are associated with the tumor (asterisks). B: Some of the neoplastic clusters have a scalloped and irregular outline. C: Upon closer examination, the neoplastic clusters are composed of cells with reversed polarity, as typically seen in invasive micropapillary carcinoma. D: Psammomatous calcifications are often present. |
Mucinous Carcinoma with Signet Ring Cells
Carcinomas with extracellular mucin rarely have signet ring cell morphology. Signet ring cells arranged in large solid clusters or as single cells are more common in type B MC with neuroendocrine features (Fig. 14.8).
Mucinous Carcinoma Associated with Solid and Papillary Carcinoma
MC can also arise in association with solid-papillary carcinoma. These tumors usually are type B MCs with neuroendocrine morphology, and some may also express neuroendocrine markers.
Ductal Carcinoma In Situ
DCIS is associated with two-thirds (14,15) to 92.5% of MC (34). The nuclear grade of DCIS associated with MC was low in 29.3% of cases, intermediate in 61%, and high in 9.8% (34). DCIS with necrosis was present in 17% (14) to 30% (34) of the cases. DCIS with high nuclear grade was more common in association with type B MC and mixed MC (14). In one study (34), 86% of DCIS near MC contained intraluminal mucin, and the latter showed neovascularizion in 70% of the cases. Neovascularization of the mucin in the lumen of ducts involved by DCIS does not constitute evidence of stromal invasion (Fig. 14.9).
Mucocele-like Lesions
The mucocele-like lesion (MLL), an entity first described by Rosen in 1986 (35), consists of mucin-containing cysts that tend to rupture and discharge the secretion into the adjacent stroma (Figs. 14.10, 14.11, 14.12, 14.13, 14.14). Some MLLs present as palpable tumors and appear as well-circumscribed and lobulated lesions on mammography. An increasing number of nonpalpable, small MLLs are detected only by mammography as clustered calcifications without a mass, or mass-lesions with associated
calcifications (48,49,50,51,52,53,54). Ultrasonography shows a hypoechoic, round or lobulated, solid or cystic tumor, sometimes with an ill-defined margin (55,56,57). In one series (53), the calcifications in eight MLLs with DCIS were all clustered/grouped coarse heterogeneous, whereas those associated with MLLs with atypia were clustered/grouped fine pleomorphic in 67% of the cases, and those in MLLs without atypia were clustered/grouped coarse heterogeneous in 53% of the cases. A sonographic mass was detected in 7/17 (41%) MLLs and complex cysts in 6/17 (36%). In another series (51), calcifications constituted the dominant radiologic abnormality in 84.6% MLLs, and ultrasound examination was negative in 8 of 13 cases. Predominantly, cystic MLLs tend to be sampled by fine needle aspiration (FNA) biopsy, whereas needle core biopsy (NCB) is often used to sample a more solid component (see also paragraph on MLL in the section dedicated to the differential diagnosis of mucinous lesions at NCB in this chapter).
calcifications (48,49,50,51,52,53,54). Ultrasonography shows a hypoechoic, round or lobulated, solid or cystic tumor, sometimes with an ill-defined margin (55,56,57). In one series (53), the calcifications in eight MLLs with DCIS were all clustered/grouped coarse heterogeneous, whereas those associated with MLLs with atypia were clustered/grouped fine pleomorphic in 67% of the cases, and those in MLLs without atypia were clustered/grouped coarse heterogeneous in 53% of the cases. A sonographic mass was detected in 7/17 (41%) MLLs and complex cysts in 6/17 (36%). In another series (51), calcifications constituted the dominant radiologic abnormality in 84.6% MLLs, and ultrasound examination was negative in 8 of 13 cases. Predominantly, cystic MLLs tend to be sampled by fine needle aspiration (FNA) biopsy, whereas needle core biopsy (NCB) is often used to sample a more solid component (see also paragraph on MLL in the section dedicated to the differential diagnosis of mucinous lesions at NCB in this chapter).
 FIGURE 14.8 Mucinous Carcinoma, Type B with Few Signet Ring Cells. A: This needle core biopsy from a 40-year-old woman shows fragments of a cellular mucinous carcinoma. B: The carcinoma consists of large and somewhat dyshesive clusters admixed with mucin. A few small clusters are composed of two to three cells, and many single cells are present. Capillaries are evident in the mucin (arrows). C: Some of the neoplastic cells have the signet ring morphology (arrows). |
 FIGURE 14.9 Ductal Carcinoma In Situ (DCIS) with Mucin Neovascularization. The mucin present within the lumen of a duct involved by DCIS has numerous capillaries (arrows). This finding was present near a focus of mucinous carcinoma (not shown). Neovascularization of the mucin in DCIS does not constitute evidence of invasion. |
The biologic behavior of an MLL is likely related to the characteristics of the epithelium composing the lesion, which can be morphologically benign, atypical, or frankly malignant. The epithelium lining the ducts in an MLL without atypia is for most part flat or cuboidal
(Figs. 14.10 and 14.11). Epithelial atypia in a MLL ranges from columnar cell change (CCC) with atypia/flat epithelial atypia (FEA) to atypical ductal hyperplasia (ADH) (Figs. 14.12 and 14.13) (35,58,59). Clear-cut DCIS can also occur near a MLL (35,58,59) (Fig. 14.14). (See also section on NCB of MLLs later in this chapter.)
(Figs. 14.10 and 14.11). Epithelial atypia in a MLL ranges from columnar cell change (CCC) with atypia/flat epithelial atypia (FEA) to atypical ductal hyperplasia (ADH) (Figs. 14.12 and 14.13) (35,58,59). Clear-cut DCIS can also occur near a MLL (35,58,59) (Fig. 14.14). (See also section on NCB of MLLs later in this chapter.)
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