Tubular Carcinoma
Edi Brogi
Tubular carcinoma (TC) is a highly differentiated invasive ductal carcinoma composed of at least 90% simple monostratified neoplastic tubules with low-grade cytologic atypia (1). TC constitutes up to 2% of all breast carcinomas (2,3,4,5,6). It tends to have small size and is relatively more frequent among T1 tumors (5,6,7,8,9,10,11,12,13,14,15) and mammographically detected carcinomas (3,7,10,11,16,17). It represents 3% to 4% of stage I and II breast carcinoma (9,10,11,15). TC has an excellent prognosis (5,6,7,8,9,10,11,12,13,14,15).
CLINICAL PRESENTATION
Symptoms
TC usually occurs in peripheral portions of the breast. It rarely arises near the major lactiferous ducts of the nipple or in the subareolar region, where it can raise the differential diagnosis of florid papillomatosis of the nipple. Nipple discharge, Paget’s disease, and skin retraction are rarely associated with TC.
Imaging Studies
TC is frequently detected mammographically as a spiculated mass or an area of architectural distortion. In two recent series, TC constituted only 2% of interval carcinomas, and of carcinomas found in women not participating in a mammographic screening program (3,16) but constituted 8% (3,16) of screen-detected carcinomas. In one study, the average radiographic size of nonpalpable TC was 0.8 cm and that of palpable lesions was 1.2 cm (18). TC often harbors calcifications. The radiologic differential diagnosis of TC includes benign sclerosing lesions, such as radial sclerosing lesion (RSL) and sclerosing adenosis. In particular, TC and RSL are indistinguishable radiologically, and TC can occasionally arise in a RSL (19,20). TC has no distinctive features by ultrasonography or magnetic resonance imaging. Because most TCs are detected by imaging studies, they are often the target of needle core biopsy (NCB) sampling.
Age, Ethnicity, and Gender
TC can occur at any age, but it is more common in postmenopausal women (5,6,8,9,10,11,12,13,14,15,17). A study based on SEER data for breast carcinomas diagnosed in the USA from 1992 to 2007 found that 73.6% of 4,477 TCs occurred in women 50 to 79 years old, 17.5% in women 40 to 49 years old, 6.9% in women older than 80 years, and only 2% in women 30 to 39 years old (4). Between 80% (21) and 90% (4) of TCs occur in non-Hispanic white women. TC constitutes less than 1% of male breast carcinomas (22).
Family History
A high frequency of breast carcinoma has been reported among first-degree relatives of women with TC. A study (10) found that 45% of patients with stage I or II TC had a family history of breast carcinoma, but this finding was not statistically significant compared with the 36% rate in a woman with well-differentiated invasive ductal carcinoma (IFDC) of similar stage. Rakha et al. (11) reported a 20% rate of family history of breast carcinoma in women with TC. Family history of breast carcinoma in women with screen-detected carcinomas was associated with a relative risk of 1.71 for TC compared to 1.57 for any type of invasive carcinoma (23). Family history of breast carcinoma in a first-degree relative tripled the risk of TC in premenopausal women but was not significantly related to TC in postmenopausal patients (21). At least two studies have reported a two- to three-fold increase in the risk of TC in postmenopausal women who used hormone replacement therapy (21,24).
Size
Most TCs are 1 cm or smaller (7,9) (Table 10.1), but larger tumors are encountered occasionally. In one study (11), 59% of 102 TCs measured 1 cm or less, compared to only 30% of 212 IFDC grade I/III; the median tumor size was also significantly smaller.
Multifocality
Few studies have described multifocality in the setting of TC. In one study (25), 5% of 120 patients with TC treated by mastectomy had an additional and separate invasive carcinoma, and 3.3% had multifocal ductal carcinoma in situ (DCIS). In another study (26), invasive lobular carcinoma was identified in 7% of patients with TC. In a recent series (27), 9% of patients with TC had multifocal disease. A second invasive carcinoma of higher histologic grade was present in 15% of cases and consisted of moderately or poorly differentiated IFDC in eight patients, an invasive lobular carcinoma in four patients, and a tubulolobular carcinoma in another patient.
In another study (12), multifocal TC was identified in 9.7% of patients, including eight women with two foci each, one with four foci, and another patient with five foci. In general, it is not possible to comment on tumor multifocality when evaluating NCB material from a single radiologic target.
In another study (12), multifocal TC was identified in 9.7% of patients, including eight women with two foci each, one with four foci, and another patient with five foci. In general, it is not possible to comment on tumor multifocality when evaluating NCB material from a single radiologic target.
TABLE 10.1 Differential Diagnosis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Contralateral Carcinoma
Microscopic Pathology
TC consists of a haphazard and infiltrative proliferation of small glands and tubules lined by a single layer of neoplastic ductal epithelium with low-grade nuclear atypia. The diagnosis of TC applies only to lesions in which at least 90% of the tumor mass has the aforementioned morphology (Fig. 10.1). Multistratification of the neoplastic epithelium and/or complex glandular architecture can be only very focal, if at all present (Figs. 10.1 and 10.2). An IFDC with low nuclear grade and tubular component representing less than 90% of the tumor is classified as well-differentiated (grade I/III) IFDC and does not carry the same excellent prognosis as a TC (11).
 FIGURE 10.1 Tubular Carcinoma. A: A needle core biopsy sample from the tubular carcinoma (TC) shown in (C). B: The neoplastic glands are monostratified and embedded in desmoplastic stroma. C: Residual TC in the excisional biopsy specimen. Note hemorrhage in the surrounding tissue. |
The tubules of TC have slightly angular profile (Fig. 10.1). Tear drop-shaped glands are common (Fig. 10.2). The glandular lumen usually is widely patent, a feature best appreciated at low-power examination (Figs. 10.1 and 10.2). The neoplastic epithelium lining the glands is cuboidal or columnar. The neoplastic cells within a given lesion are usually homogeneous, but some variation in the height of the epithelium is often present, and nearly flat epithelium can be found in continuity with columnar cells within an individual gland (Fig. 10.2). The cytoplasm is relatively abundant and has amphophilic quality. Cytoplasmic snouts often protrude from the apical surface of the glandular epithelium of TC (Fig. 10.2), but this finding is not exclusive to TC. Very uncommon variants of TC feature mucin secretion (Fig. 10.3) or apocrine differentiation (33). Eosinophilic cytoplasm and apical intracytoplasmic granules characteristic of apocrine differentiation usually are not present in TC. The nuclei are basally located, round to oval, and show low-grade atypia, with even chromatin and a smooth nuclear membrane. Focal intermediate grade nuclear atypia may be present. Nucleoli are inconspicuous or inapparent, and tend to be adjacent to the nuclear membrane. Mitoses are rare, and necrosis is absent.
The stroma admixed with TC is rich in myofibroblasts, abundant elastic tissue, and myxoid matrix (Figs. 10.1, 10.2, and 10.4). It tends to be more abundant than in well-differentiated IFDC and separates the neoplastic glands more widely. Elastosis
has been regarded as a hallmark of TC (Fig. 10.5), but it is not present in all cases and can be a prominent feature also of non-TCs and in some benign lesions, especially those with the “radial scar” pattern.
has been regarded as a hallmark of TC (Fig. 10.5), but it is not present in all cases and can be a prominent feature also of non-TCs and in some benign lesions, especially those with the “radial scar” pattern.
 FIGURE 10.2 Tubular Carcinoma. The neoplastic ductules consist of a single layer of uniform cuboidal cells. A: A normal terminal duct is shown on the right for contrast with the angular carcinomatous structures. B: This carcinoma is composed partly of glands with rounded shapes. C: Tubular carcinoma composed of glands of various shapes invades fat. D: Absence of myoepithelium is demonstrated by the myosin immunostain. A blood vessel on the left is myosin-positive. |
 FIGURE 10.3 Tubular Carcinoma with Intracytoplasmic Mucin. A: The carcinoma is composed mainly of glands lined by cuboidal cells. B: Some cells have intracytoplasmic lumina. C: The lumina of some intracytoplasmic vacuoles are outlined in red with the mucicarmine stain (arrow). |
 FIGURE 10.3 (continued) |
 FIGURE 10.4 Tubular Carcinoma and Stromal Desmoplasia. A: The neoplastic glands of tubular carcinoma are admixed with abundant desmoplastic stroma in this needle core biopsy sample. B: At high-power examination, abundant desmoplastic stroma separates the neoplastic glands. Note the tear drop-shaped gland on the right and apical “snouts” around many neoplastic gland lumina. |
 FIGURE 10.5 Tubular Carcinoma and Stromal Elastosis. A: The abundant elastotic stroma associated with this tubular carcinoma in a needle core biopsy sample simulates the elastotic core of a radial scar. The widely open lumina of the neoplastic glands are incompatible with a benign sclerosing lesion and support the diagnosis of tubular carcinoma. No myoepithelium was detected with immunoperoxidase stains for calponin and p63 (not shown). B: This needle core biopsy specimen from a nonpalpable tumor shows basophilic elastic tissue in the stroma of a tubular carcinoma. |
Calcifications are detected microscopically in at least 50% of TC (Fig. 10.6). They are present in the lumen of the neoplastic glands and in the stroma admixed with TC, or are associated with DCIS, atypical ductal hyperplasia (ADH), and columnar cell change (CCC) with or without cytologic atypia. TC does not elicit a notable lymphocytic reaction. Lymphovascular involvement (LVI) is exceedingly rare (6,8,9,11). Clusters of carcinoma can occasionally be identified within vascular spaces in the surgical excision specimen after a needling procedure. Perineural invasion is extremely uncommon, especially in a NCB samples.
 FIGURE 10.6 Tubular Carcinoma and Calcifications. A, B: These needle core biopsy specimens show small, evenly distributed glands with calcifications (black arrows). A minute stromal calcification is also present (white arrow). |
Precursor Lesions Associated with Tubular Carcinoma
DCIS has been described in 21% to 41% of cases of TC in recent series (27,34,35). It usually has papillary, micropapillary, cribriform architecture or a mixed pattern (Fig. 10.7), and low to intermediate nuclear grade. TC is frequently associated with ADH and/or CCC of the terminal duct-lobular unit (TDLU) (27,36) (Figs. 10.8 and 10.9), a lesion previously designated informally as “pretubular” hyperplasia (37). The morphologic spectrum of columnar cell lesions ranges from CCC and columnar cell hyperplasia without atypia (CCH) through CCC and/or CCH with atypia, to ADH and low-grade DCIS. The term flat epithelial atypia (FEA) is also used to indicate atypical CCH (38). Apical snouts are present frequently at the luminal aspect of the epithelium showing CCC/CCH, but they are not exclusive to this alteration.
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