Other Special Types of Invasive Ductal Carcinoma

Other Special Types of Invasive Ductal Carcinoma

Frederick C. Koerner


Invasive micropapillary carcinoma is a distinctive form of ductal carcinoma in which the tumor cells grow in morule-like clusters creating an “exfoliative appearance” (1). This growth pattern may be found throughout the lesion (pure invasive micropapillary carcinoma) or as part of an otherwise conventional invasive ductal carcinoma (mixed invasive micropapillary carcinoma). Pure invasive micropapillary carcinomas account for 1% to 2% of the cases in two study groups, each consisting of approximately 1,000 breast carcinomas (2,3). Mixed invasive micropapillary carcinoma occurs more commonly. For example, Pettinato et al. (4) observed a micropapillary pattern in 3.8% of 1,635 breast carcinomas, and Luna-Moré et al. (5) detected micropapillary differentiation in 27 of 986 (2.7%) consecutive breast carcinomas. For practical purposes, one should reserve the category of pure invasive micropapillary carcinoma for those tumors in which at least 75% of the entire excised carcinoma demonstrates the characteristic micropapillary growth pattern. Needle core biopsy (NCB) specimens do not allow one to evaluate this criterion; so one can only suggest the diagnosis of invasive micropapillary carcinoma based on examination of such a specimen.

Clinical Presentation

The reported age at diagnosis ranges from 25 to 92 years, and the mean ages in several series fall in the sixth decade. Patients with lesions composed of more than 50% invasive micropapillary carcinoma tend to be older than patients with less extensive micropapillary growth (5). The literature contains only a few well-documented reports of pure invasive micropapillary carcinoma in men (6,7,8).

The majority of patients present with a palpable mass. Less frequently, screening mammography or other imaging reveals a suspicious density, an irregular mass, a region of calcifications, or another suspicious finding (9,10,11).

The reported carcinomas span from 0.1 to 11 cm. Tumors with more than 50% micropapillary growth tend to be larger (mean size 6 cm) than those with a lesser amount of this pattern (mean size 3.5 cm) (5). The presence of several nodules has been noted (4).

Microscopic Pathology

The invasive carcinoma cells are cuboidal to columnar and they contain finely granular or dense, eosinophilic cytoplasm. The nuclei usually display intermediate- to high-grade atypia. The tumor cells grow in small clusters, which have serrated peripheral borders and sometimes surround central lumina (Fig. 17.1). The clusters lack fibrovascular cores and they exhibit an “inside-out” arrangement with the luminal aspect of the cell facing the outer surface of the cluster (12). A central clear space is often present, but solid groups may also occur. Uncommon variants feature microcystic dilatation of lumina within cell clusters and apocrine change. Mucin may be present in the tumor cells rarely. Necrosis and lymphocytic infiltration are not typical features; however, large tumors may undergo necrosis, and a lymphoid infiltrate may come to permeate the stroma. Microcalcifications, sometimes with psammomatous features, are variably present.

A clear space outlined by stroma surrounds each tumor cell cluster. Endothelial cells do not line these spaces, and they are usually attributed to shrinkage of the clusters during tissue fixation. The spaces generally appear empty, but in some instances mucinous material has been demonstrated using special stains (5). The stroma consists of dense collagenous tissue or a network of delicate collagen bundles. Myxoid stroma has been noted in a minority of cases (10). The sponge-like pattern of spaces filled by tumor cell clusters is duplicated in metastatic foci.

The proclivity of the carcinoma to grow in a sponge-like pattern makes it difficult to identify lymphatic tumor emboli in the vicinity of the primary tumor. By using antibodies to factor VIII and CD31 to mark vascular endothelium, Pettinato et al. (4) demonstrated vascular invasion in 63% of tumors. Intravascular carcinoma cells form papillary clusters identical to the invasive groups present in the mammary parenchyma.

Mixed invasive micropapillary carcinomas usually show a sharp demarcation between the micropapillary and conventional components. The latter usually has the conventional not otherwise specified (NOS) pattern, but invasive mucinous, lobular, cribriform, metaplastic, and tubular types have been reported (11,13,14,15,16).

Ductal carcinoma in situ (DCIS) coexists with the invasive carcinoma in most cases. In pure invasive micropapillary
carcinoma, the DCIS usually has a micropapillary or cribriform architecture, but solid DCIS sometimes occurs. The noninvasive cells usually possess intermediate-grade, hyperchromatic nuclei unlike the bland nuclei characteristic of conventional micropapillary/cribriform DCIS. Prominent necrosis tends to occur in tumors with only a focal invasive micropapillary pattern, and the carcinoma cells in these cases usually have high-grade hyperchromatic nuclei. Calcifications are sometimes found in the noninvasive component.

FIGURE 17.1 Invasive Micropapillary Carcinoma. A: This needle core biopsy specimen shows small nests of carcinoma cells outlined by clear spaces. B, C: The “inside-out” pattern consists of morule-like solid clusters of tumor cells with serrated outer borders. The spaces between the carcinoma cells and the stroma are devoid of secretion. D: Clusters of invasive micropapillary carcinoma occupy the lumen of a lymphatic vessel.

Ultrastructure and Immunohistochemistry

Ultrastructural study has revealed microvilli on the cell surfaces that border the clear spaces. This finding suggests that the cells are oriented as though the spaces around the tumor cell clusters were glandular lumina (5). The distribution of MUC-1 glycoprotein and epithelial membrane antigen (EMA) supports this interpretation. MUC-1 localizes to the apical cell membrane in conventional, gland-forming breast carcinomas, where the glycoprotein contributes to the formation of lumina. In invasive micropapillary carcinoma, MUC-1 localizes on the external surfaces of papillary tumor clusters, adjacent to the surrounding stroma (17). The expression of EMA displays the same pattern (5). This reversal of cell polarity has also been observed as a feature of intralymphatic clusters of carcinoma cells (18,19).

Most cases of invasive micropapillary carcinoma stain for E-cadherin, although Pettinato et al. (4) noted that reactivity was limited to cell membranes between carcinoma cells and that the cell membranes abutting the stroma did not stain. In one series (20), all 12 examples of invasive micropapillary carcinoma stained for GATA3. The tumors typically do not stain for CK5/6, CK14, CK20, EGFR, or c-kit. The majority of invasive micropapillary carcinomas stain for estrogen receptor (ER) and progesterone receptor (PR), and evidence of HER2 overexpression or gene amplification occurs in 10% to 50% of the cases (7,11,21).


Invasive cribriform carcinoma consists of well-differentiated ductal carcinoma cells growing in cribriform and tubular patterns. Published information does not allow one to determine whether invasive cribriform carcinoma represents a low-grade variant of invasive ductal carcinoma or a specific subtype of carcinoma. One should distinguish two subtypes of invasive cribriform carcinoma: classic invasive cribriform carcinoma, in which the invasive carcinoma exhibits a cribriform pattern with or without tubular elements, and mixed invasive cribriform carcinoma, in which less than 50% of the mass has an invasive cribriform pattern and the majority displays neither cribriform nor tubular patterns. Fewer than 6% of invasive mammary carcinomas are invasive cribriform carcinomas, and classic and mixed forms account for approximately equal proportions (27,28,29,30).

Clinical Presentation

The ages of the female patients range from 7 to 91 years. Two reported patients were men (28,31). Choi et al. (32) described a 6-cm invasive cribriform carcinoma occupying a 10-cm malignant phyllodes tumor in a 62-year-old woman.

In a study of eight cases, mammograms revealed spiculated masses spanning 20 to 35 mm in four patients (33). Two of these carcinomas contained calcifications, and so did the carcinoma described by Nishimura et al. (31). Invasive cribriform carcinomas do not have consistent sonographic findings (31,33,34). Magnetic resonance imaging (MRI) performed on one tumor
displayed findings compatible with a carcinoma (34). Data from three studies suggest that a small number of invasive cribriform carcinomas occur as multifocal masses (27,29,30).

FIGURE 17.2 Invasive Cribriform Carcinoma. A, B: The invasive carcinoma in this needle core biopsy specimen has a cribriform structure composed of round or oval glandular spaces formed by thin, rigid bands of tumor cells with low-grade nuclei.

Microscopic Pathology

Invasive cribriform carcinoma exhibits the same sieve-like growth pattern that characterizes conventional cribriform DCIS. The rounded and angular masses of uniform, well-differentiated tumor cells are embedded in variable amounts of collagenous stroma. Sharply outlined, round, or oval glandular spaces are distributed throughout these tumor aggregates, creating a fenestrated appearance (Fig. 17.2). Variable amounts of mucin-positive secretion occupies the lumina (35), which may also contain calcifications (36). The in situ component has a cribriform pattern in most, but not all, classic invasive cribriform carcinomas.

Besides displaying a cribriform pattern, invasive cribriform carcinomas can show areas of tubular growth (Fig. 17.3), and such foci can comprise a substantial proportion of the lesion (28,29,30). The presence of regions showing a tubular pattern does not itself justify the use of the diagnosis of tubular carcinoma. Tumors composed of both cribriform and tubular areas in which the cribriform pattern accounts for more than 25% of the mass should be classified as invasive cribriform carcinomas rather than tubular carcinomas. When the tubular pattern represents more than 75% of the mass, one could consider the diagnosis of tubular carcinoma if the cytologic and architectural features of the tubules seem appropriate. Most NCB specimens do not provide sufficient material to allow one to evaluate the proportions of these two patterns.

FIGURE 17.3 Invasive Cribriform Carcinoma. In the region shown, the cribriform carcinoma in this needle core biopsy specimen has tubular features.


Venable et al. (28) reported that 16 of 16 classic and mixed invasive cribriform carcinomas were ER-positive and that 11 of the tumors (69%) were PR-positive. The classic and mixed cribriform carcinomas did not differ appreciably in their degrees of PR positivity. Other case reports describe positive staining for ER, variable staining for PR, and lack of staining for HER2 (31,37,38), although Zhang et al. (29) noted staining of one carcinoma for HER2.


Secretory carcinoma features the presence of abundant, pale pink or amphophilic secretory material within the cytoplasm of the carcinoma cells and the lumina of the spaces formed by the carcinoma cells. Although secretory carcinoma occurs in children, the majority of cases occur in adults. Consequently, the term “secretory” is preferable to the original designation, “juvenile.” The cellular characteristics of the lesion are identical in patients of all ages.

Clinical Presentation

Secretory carcinoma affects individuals throughout life; only the very young escape the disease. The reported ages of females with secretory carcinoma range from 3 to 91 years (42,43,44). Male patients exhibit a similar age range (3-79 years) (45,46,47). There is a dearth of cases of secretory carcinoma in girls 10 to 15 years of age, and cases in males cluster in the pediatric and adolescent age groups.

Most patients describe a painless, circumscribed mass that may have been present for one or more years. A subareolar tumor is most common in prepubertal girls and males of all ages because their breast tissue is localized in this region; however, even among women, the central region of the breast stands out as a favored location. Secretory carcinoma usually grows as a single mass, but rare cases present with two or more nodules (48,49,50). Secretory carcinomas have arisen in axillary breast tissue (51,52) and from adnexal glands of the axillary skin (53).

Pregnancy has not been implicated in the development of secretory carcinoma, nor has clinical evidence of a hormonal abnormality that would explain the secretory properties of the carcinoma been described. Secretory carcinoma developed in the breast of a male-to-female transgender individual, who had undergone “long-term cross-sex hormone treatment” of an unspecified nature (54).

Associated breast conditions have been described in a few cases. Gynecomastia accompanied a minority of the secretory carcinomas in male patients. The coexistence of juvenile papillomatosis and secretory carcinoma has been reported (55), but the evidence presented to substantiate the diagnosis of juvenile papillomatosis is not convincing in several other reports.

Mammography typically reveals a discrete tumor with smooth or irregular borders (48,56,57), which one could mistake for a fibroadenoma or papilloma. Sonography discloses a solid, hypoechoic to isoechoic mass, which may have a microlobulated border (48,58).

Secretory carcinoma usually forms a circumscribed, firm mass, which may be lobulated; rarely, the tumor has infiltrative margin. The tumors tend to be 3 cm or fewer in diameter (59), although carcinomas spanning 10 cm were reported in two women (60,61) and another spanning 12.5 cm tumor was reported in a man (62).

Microscopic Pathology

Like other forms of ductal carcinoma, secretory carcinoma may exhibit an intraductal component. Kameyama et al. (57) described a purely noninvasive form of secretory carcinoma. Most commonly, the DCIS has a papillary or cribriform (57) pattern of growth, but solid foci and, rarely, comedonecrosis may also be found. The invasive component tends to form a compact mass subdivided by fibrous septa. The borders of the carcinoma usually appear circumscribed, but overtly infiltrative
growth is sometimes present. The neoplastic cells grow in papillary, microcystic, and glandular formations.

FIGURE 17.4 Secretory Carcinoma. This needle core biopsy specimen comes from a circumscribed 2-cm tumor in a 68-year-old woman. The carcinoma has the characteristic microcystic architecture. The tumor cells in this example have small, low-grade nuclei.

The tumor cells vary from secretory to apocrine in their appearance. Cells of a secretory nature possess pale to clear, pink or amphophilic cytoplasm that contains abundant secretion. The low-grade nuclei vary from small to modest in size, and their chromatin from dark and finely dispersed to pale and granular (Fig. 17.4). Nuclei with pale chromatin usually contain small, uniform nucleoli. Cells with apocrine features contain granular, eosinophilic cytoplasm and nuclei with features similar to those of conventional apocrine cells (Fig. 17.5). One usually finds both types of cells in a carcinoma, although one type or the other can predominate. On occasion, cells with apocrine features growing in a solid pattern comprise most of the tumor and thereby obscure the secretory nature of the carcinoma. The cells do not display noticeable mitotic activity or necrosis. One does not usually find microcalcifications in the neoplastic glands or the stroma.

FIGURE 17.5 Secretory Carcinoma with Apocrine Cytology. A: The lesion has a well-circumscribed border and a microcystic growth pattern. The nuclei have prominent nucleoli typically associated with apocrine differentiation. B-D: Secretory carcinoma in needle core biopsy samples from a 41-year-old woman. Note the apocrine cytologic features, the irregular shapes of the microcystic spaces, and the dense secretions.

Secretion accumulates in the tumor cells, in the glands formed by the tumor cells, and in the microcystic spaces associated with the tumor cells. The secretory material appears pale pink or amphophilic with H&E staining, and it often contains lacunae, which create a “bubbly” appearance. The secretion stains with the periodic acid-Schiff (PAS) and Alcian blue methods, and PAS staining persists after diastase digestion. The secretory material reacts variably for mucin. The secretion in microcystic areas resembles thyroid colloid
and the secretion that accumulates in cystic hypersecretory lesions of the breast (Fig. 17.6).

FIGURE 17.6 Secretory Carcinoma with Papillary and Thyroid-like Architecture. A: A low-magnification view shows eosinophilic and basophilic secretion in a carcinoma from a 56-year-old woman. B, C: A papillary architecture is evident. Note the vacuolated secretion. D, E: The eosinophilic secretion with peripheral scalloping and parallel linear cracking resembles thyroid colloid and the secretion in cystic hypersecretory lesions of the breast.

Immunohistochemistry and Molecular Studies

To the extent that it can be determined from the reported data, the results of staining for cellular markers do not differ among secretory carcinomas from females and males nor among tumors from children and adults. Strong staining for α-lactalbumin has been reported (65). The carcinoma cells stain for cytokeratin, EMA, E-cadherin, mammaglobin and, with rare exceptions (61,66), S-100 protein. One report (67) documents nuclear staining for p63 in three of seven cases and staining of the cytoplasm and secretory material for p63 in the remaining four cases. The latter observation may reflect the secretory nature of the carcinoma cells. Variable reactivity for carcinoembryonic antigen (CEA) and GCDFP-15 has been observed, and stains for proteins indicative of endocrine, muscle, and melanocytic differentiation have been negative.

Most secretory carcinomas lack ER and PR. Three carcinomas did not express the androgen receptor (45,54,68). Strong expression of HER2 protein has been detected in one secretory carcinoma (50).

Tognon et al. (69) and Euhus et al. (70) described the presence of the ETV6-NTRK3 fusion gene, a gene previously detected in congenital fibrosarcoma and congenital cellular mesoblastic nephroma, in secretory carcinomas (see Chapter 26). Using fluorescence in situ hybridization, sequencing of reverse transcription polymerase chain reaction (RT-PCR) products, and immunoprecipitation, evidence of this oncoprotein was found in 12 of 13 (92%) secretory carcinomas and in only 1 of 50 (2%) of invasive ductal carcinomas (69). The single conventional invasive carcinoma that demonstrated fusion transcripts contained regions with features suggestive of secretory carcinoma. Testing of other cases of secretory carcinoma and of commonplace breast carcinomas has confirmed the presence of this fusion gene in most secretory carcinomas and the absence of the gene in conventional breast carcinomas (71) and several other lesions with features similar to those of secretory carcinoma (64).

STAT5a, a mammary growth factor, is one of several molecules involved in the transcription of differentiation proteins. Activation of STAT5a in the breast occurs largely as a result of the binding of prolactin to its receptor (72). STAT5a expression is present in the majority of normal mammary gland cells and largely absent in atypical ductal hyperplasia and carcinoma (73). Overexpression of STAT5a occurs in physiologic secretory and lactating mammary epithelium as well as in secretory mammary carcinoma (74).


First described by Rosen and Scott (77), cystic hypersecretory carcinoma (CHC) displays cysts containing eosinophilic secretory material bearing a striking resemblance to thyroid colloid. The majority of cases have been DCIS.

Clinical Presentation

The age distribution of CHC ranges from 34 to 79 years. The mean age falls in the sixth or seventh decade (78,79). All patients, including one African-American, (80) have been women. The presenting symptom is usually a mass or other palpable abnormality. Nipple discharge occurs rarely and can appear bloody (81). Paget disease of the nipple was present in one case (82).

Radiologic imaging has not revealed distinctive findings. Mammograms of cases with invasive components have shown a region of increased density with trabecular thickening (80), a prominent ductal pattern and an irregular density (83), and spiculated masses with calcifications (84). Sonography in one case revealed “…multiple small aggregated anechoic cysts with good through transmission” (85).

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Nov 17, 2018 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Other Special Types of Invasive Ductal Carcinoma
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