In the context of breast pathology, the term papillary carcinoma encompasses a morphologically heterogeneous group of lesions, all of which share a growth pattern characterized by the presence of arborescent fibrovascular stalks lined by epithelial cells. Malignant papillary neoplasms of the breast comprise a number of microscopically distinct lesions including ductal carcinoma in situ
(DCIS) arising in an intraductal papilloma, papillary DCIS, enscapsulated papillary carcinoma, solid papillary carcinoma, and invasive papillary carcinoma.[5
] All malignant papillary proliferations of the breast lack an intact myoepithelial cell layer within the papillae, an important feature which allows distinction from benign intraductal papillomas.
Otherwise benign-appearing intraductal papillomas may display proliferative areas which would satisfy criteria for DCIS if observed outside of the context of a papillary lesion. These areas of DCIS are generally composed of uniform appearing cells with low or intermediate grade nuclear aytpia, typically with a solid or cribriform growth pattern. At present, there are no universally accepted guidelines for diagnosing a papilloma with DCIS. Proposed criteria have included the presence of DCIS greater than 3 mm in size,[8
] and DCIS comprising at least a third but less than 90% of the papillary lesion.[7
] Papillary lesions exhibiting atypical features not meeting these thresholds have been classified as atypical papillomas. In contrast, others advocate rendering a diagnosis of DCIS arising in a papilloma regardless of the size or extent of the involved area.[6
Papillary DCIS is characterized by the presence of fibrovascular fronds lined by neoplastic epithelium (). Features of an underlying pre-existing benign papilloma are not present. The lining epithelium is typically comprised of monomorphic, stratified columnar cells; however, solid, cribriform, or micropapillary proliferations may also be observed. Nuclei are usually of low or intermediate grade. The papillae are devoid of myoepithelial cells, though as with other morphologic types of DCIS, a myoepithelial layer is retained at the periphery of the involved duct. Lesions are frequently multifocal and peripheral in distribution.
Encapsulated papillary carcinoma, also known as intracystic papillary carcinoma, is the term used to describe a solitary, centrally located malignant papillary proliferation involving a cystically dilated duct. Histologically, the lesion is well circumscribed, with the involved duct surrounded by a thick fibrous capsule (). The duct is filled by slender fibrovascular stalks lacking myoepithelial cells. Various patterns of epithelial proliferation may be observed, including stratified spindle cell, cribriform and solid arrangements. Low or intermediate nuclear grade is typical of these lesions, with high grade nuclear atypical rarely observed. Although morphologically well delineated and traditionally considered to represent a variant of DCIS, immunohistochemical studies have failed to consistently demonstrate the presence of a myoepithelial cell layer at the periphery of encapsulated papillary carcinomas. The absence of myoepithelial cells has led some investigators to propose that many encapsulated papillary carcinomas are not in situ
lesions, but rather invasive carcinomas with a circumscribed nodular histology.[9
] Other authors, however, feel encapsulated papillary carcinomas are best considered in situ
carcinomas despite the absence of surrounding myoepithelial cells based on the finding of an intact basement membrane, as shown by collagen type IV expression, at the periphery of the majority of encapsulated papillary carcinomas, as well as the demonstrated clinically indolent behavior of these lesions.[7
Encapsulated (intracystic) papillary carcinoma.
A minority of encapsulated papillary carcinomas may be associated with a component of invasive carcinoma (invasive carcinoma arising in an encapsulated papillary carcinoma). The invasive component is characterized by an infiltrative appearance with extension beyond the fibrous capsule of the lesion and an associated stromal reaction (). Invasive areas in general do not display papillary features, but rather exhibit the morphology of an invasive ductal carcinoma, not otherwise specified. In cases of encapsulated papillary carcinomas with associated invasion, it is currently recommended that staging be determined based on the sized of the invasive component only, without consideration of the encapsulated component of the tumor, in order to prevent overtreatment.[5
] In such circumstances, to avoid confusion and ensure appropriate clinical management, one may prefer to report only the size of the unequivocal invasive focus of carcinoma when rendering a final diagnosis; for example, “invasive ductal carcinoma, not otherwise specified (x
cm), arising in association with an encapsulated papillary carcinoma.”
Encapsulated papillary carcinoma with an invasive component.
Solid papillary carcinoma appears microscopically as well circumscribed, densely cellular, expansile nodules of epithelial cells ().[12
] The neoplastic cells are oval or spindle shaped, exhibit low to intermediate grade nuclear atypia, and have a monotonous appearance (). Many cases exhibit neuroendocrine features characterized by argyrophilia and immunoreactivity for chromogranin A. Associated intracellular and extracellular mucin is also a common finding. Although no discrete papillary structures are present, an underlying fibrovascular stromal network is typically observed, supporting classification of the lesion as papillary, despite its solid morphologic appearance. Interestingly, while the nodular appearance of solid papillary carcinoma was initially thought to result from proliferating neoplastic cells involving large or dilated ducts, immunohistochemical studies have demonstrated an absence of myoepithelial cells at the periphery of the nodules in some cases.[13
] As with encapsulated papillary carcinoma, the apparent absence of myoepithelial cells in a subset of solid papillary carcinomas has prompted the suggestion that solid papillary carcinomas may represent invasive tumors with pushing borders, rather than purely in situ
intraductal lesions. Solid papillary carcinomas are often accompanied by associated areas of invasive carcinoma. The invasive component most frequently manifests as a mucinous or neuroendocrine like carcinoma, though other histologic types of invasive carcinoma may also be observed.[12
Solid papillary carcinoma, low magnification.
Solid papillary carcinoma, intermediate magnification.
The term invasive papillary carcinoma is reserved for infiltrating breast carcinomas exhibiting an exclusively papillary morphology, and should be distinguished from the other malignant papillary lesions described previously. Defined as such, invasive papillary carcinomas are extremely rare.[16
] Encapsulated and solid papillary carcinomas are not currently classified as invasive papillary carcinomas, though as previously discussed, a subset of these tumors may represent low grade carcinomas exhibiting an expansile type of invasion. Invasive papillary carcinoma should not be confused with invasive micropapillary carcinoma, which is a clinically and pathologically separate entity. In contrast with invasive papillary carcinoma, invasive micropapillary carcinoma morphologically lacks true fibrovascular cores, and is characterized by neoplastic cells arranged in solid nests or tubules surrounded by clear spaces (). The distinction of invasive papillary from micropapillary carcinoma has relevant clinical implications as the latter is considered an aggressive form of mammary carcinoma frequently associated with lymph-vascular invasion and axillary lymph node metastases.[17
Invasive micropapillary carcinoma.
Pathologic characterization of papillary lesions of the breast is based primarily on morphologic considerations. In particular, loss of myoepithelial cells within the fibrovascular papillae is the most important feature for the identification of malignant papillary proliferations and their separation from benign intraductal papillomas. Myoepithelial cells are, however, frequently difficult to discern on routine hematoxylin and eosin stained preparations. As such, immunohistochemistry is often utilized as an adjunct for evaluating the presence and distribution of myoepithelial cells in papillary neoplasms of the breast. Papillomas exhibit distinct, uniform staining of myoepithelial cells within the constituent papillae of the lesion as well as surrounding the periphery of the involved duct in a contiguous fashion (). In contrast, malignant papillary proliferations generally lack immunohistochemical expression of myoepithelial cell associated antigens within the papillary processes, though focal or patchy areas of immunoreactivity may be present in cases of DCIS arising within a preexisting benign intraductal papilloma. Myoepithelial cells are not consistently detected at the peripheral aspects of papillary DCIS, encapsulated papillary carcinoma, and solid papillary carcinoma, and partial, discontinuous, or absent staining may be observed in these particular lesions (). There are a number of markers that identify myoepithelial cells, the most useful of which include calponin, smooth muscle myosin heavy chain, and p63.[5
] The individual markers exhibit variable sensitivity and also show different degrees of cross reactivity with cell types other than myoepithelial cells such as stromal myofibroblasts, pericytes and vascular smooth muscle cells, which can potentially complicate interpretation of positive staining. Most laboratories thus employ a panel of several myoepithelial cell markers when evaluating difficult papillary lesions.
Intraductal papilloma. Immunohistochemistry for calponin decorates myoepithelial cells in the intraluminal papillary fronds and surrounding the involved duct.
Papillary DCIS. P63 immunohistochemistry shows discontinuous staining along the periphery of the duct. No myoepithelial cells are detected within the papillae.
Antibodies directed against high molecular weight keratins, including keratin 5/6, keratin 14, and 34βE12 have also been utilized in the immunohistochemical assessment of papillary lesions of the breast. These markers are particularly useful in the context of distinguishing usual ductal hyperplasia in a benign intraductal papilloma from papilloma with DCIS and solid papillary carcinoma. Areas of usual ductal hyperplasia in a papilloma are typically characterized by strong staining of the majority of the epithelial cells in a mosaic pattern, while in contrast, malignant papillary proliferations demonstrate diminished to absent expression of high molecular weight keratins by immunohistochemical methods.[14
] It has recently been suggested that evaluation of estrogen receptor (ER) expression may be a useful adjunct to high molecular weight keratin staining, as well. In one study, a series of 82 core biopsies from papillary lesions were subjected to immunohistochemical analysis.[24
] In this series, a combination of ER-low/keratin 5-high staining characterized nonatypical papillomas, while a pattern of ER-high/keratin 5-low staining was more frequently observed in ayptical papillary lesions. In a validation cohort including 30 papillary specimens, 29 cases were correctly classified using this scheme.
Several reports characterize papillary carcinoma using a variety of modalities. With respect to ultrasound, a report of 42 cases of papillary neoplasms suggests three basic ultrasonographic profiles: (1) intraductal mass with or without ductal dilatation, (2) intracysic mass, and (3) solid pattern with an intraductal mass completely filling the duct.[27
] Benign papillomas were noted to have denser and coarser calcifications. In contrast, papillary carcinomas (found primarily in older age groups) were noted to have a larger solid component and a higher frequency of spontaneous intracystic bleed (). A larger experience reported ultrasonographic data from 46 patients with benign papillomas and 22 patients with papillary carcinomas.[28
] In both groups, the shape of lesion was predominantly round or oval, and the margin appeared circumscribed. However, a nonparallel orientation, an echogenic halo, posterior acoustic enhancement and associated microcalcification were more frequently found in malignant as compared to benign lesions (P<0.05). When these features were used to define malignancy, a sensitivity and specificity of 85.7% and 64.9% was determined, respectively. Comparison of ultrasonography to traditional mammography appears to suggest enhanced sensitivity of the former modality. An assessment of 56 specimens excised from 40 patients with papillary tumors suggested detection of 82.1% of these lesions by ultrasound as compared to 37.5% by mammography.[29
Ultrasonographic (A) and magnetic resonance mammographic (B) characterization of a large, invasive papillary carcinoma diagnosed. (Courtesy of Lalit Vora, M.D., City of Hope Comprehensive Cancer Center, Duarte, CA.)
More limited experience is available for magnetic resonance classification of papillary tumors. A study of magnetic resonance mammography data from 468 patients included 27 (5.7%) cases of rare breast neoplasms, with 5 (1.0%) cases of invasive papillary neoplasms.[30
] In general, distinguishing morphologic and kinetic features of rare breast neoplasms were infrequently elicited on magnetic resonance mammography. Rare breast lesions were largely characterized as benign. Larger analyses of magnetic resonance mammography in rare histologic subtypes, including papillary carcinoma, may clarify the utility of this modality in this setting. illustrates a representative case of magnetic resonance mammography in a patient with invasive papillary carcinoma.