Papillary carcinomas of the breast (PCB), also termed malignant papillary carcinomas of the breast, are rare forms of the breast cancers. The World Health Organization (2019) classified papillary neoplasms (i.e. benign or cancerous tumors) of the breast into 5 types: intraductal papilloma, papillary ductal carcinoma in situ (PDCIS), encapsulated papillary carcinoma (EPC), solid-papillary carcinoma (SPC), and invasive papillary carcinoma (IPC). The latter four carcinomas are considered here; intraductal papilloma is a benign neoplasm. The World Health Organization regarded solid papillary carcinoma as having two subtypes: in situ and invasive SPC.
PCB develop from the epithelial cells that line the outer surfaces of ducts leading from exocrine glands or organs, blood vessels, or inner surfaces of the cavities in many internal organs. PCB are carcinomas derived from the epithelial cells of mammary gland ducts. They are a clinically, histologically, and biologically heterogeneous group of breast cancers that are often difficult to distinguish from each other as well as from other papillary breast lesions. The identification of PBS tumors may require the input of breast pathologists familiar with papillary lesions of the breast.
The four types of PCB are defined and diagnosed in part by several of their microscopic features including: 1) the presence of tumor invasion into adjacent normal tissues; 2) the presence and location of myoepithelial cells, i.e. cells that normally rest on the basement membrane of mammary gland ducts and function to contract and thereby expel milk from mammary glands (these cells are identified by immunohistochemistry staining tumor tissue with, e.g. cytokeratin 5/6 antibodies that detect two markers of myoepithelial cells, cytokeratin 5 and keratin 6A); 3) the presence of a thick fibrous capsule enclosing the carcinoma; 4) the presence of areas of neuroendocrine differentiation, i.e. sites of accumulated neoplastic cells with features combining those of nerve and hormone-producing cells including in particular the presence of neurosecretory granules, i.e. cytoplasmic granules about 180 nanometers in diameter that are found in neurons and secretory cells; and 5) the presence of signet ring-shaped cells bearing mucin-containing granules.
Papillary ductal carcinoma in situ Presentation Information on the frequency and clinical features of PDCIS is limited since it and EPC were regarded as the same lesion termed intracystic papillary carcinoma until 2012. PDCIS is usually a small symptomless tumor that occurs in postmenopausal women. It is often first detected on routine screening mammography which shows microcalcifications (i.e. tiny deposits of calcium salts too small to be felt) or nodular densities. Rare cases of PDCIS have presented with a bloody nipple discharge. Males have presented with PDCIS: in one institutional review, 51 men aged 19 to 88 years were diagnosed with PDCIS; two of these men had gynecomastia. It is the most common type of ductal carcinoma in situ diagnosed in men. PDCIS tumors may occur alongside of (non-papillary) ductal carcinoma in situ or EPC tumors.
Pathology
The microscopic histopathology of typical PDCIS lesions (refer to adjacent high-power photomicrograph) prepared with a hematoxylin and eosin stain consists of mammary ducts that have papillary fronds (i.e. thin, finger-like or leaf-like structures) lined with one or several layers of neoplastic, columnar-shaped epithelial cells (i.e. tall, narrow cells with their nuclei close to the site of their ductal attachment). The fronds have branching fibrovascular cores. Epithelial cells lining the fronds' inner surfaces commonly form solid, cribriform (i.e. large nests of cells perforated by many rounded, variably sized spaces), or micro-papillary patterns. There may be a second population of epithelial cells lining the papillae that have abundant clear cytoplasm in addition to the usual neoplastic epithelial cells which line the papillae. These cells, which are not myoepithelial cells, have been termed globoid cells. They have eosinophilic cytoplasm (i.e. pink or red cytoplasm due to its uptake of eosin stain). PDCIS tumors with these cells have been termed dimorphic variants of PDCIS. Myoepithelial cells are typically present at the periphery of the fronds but absent within the involved ducts. The presence of a fibrous capsule and/or absence of peripherally located myoepithelial cells are strong indicators that the tumor is an ESP rather than a PDCIS. PDCIS tissues may also contain areas of "Comedo-type necrosis", i.e. areas where dead cells have accumulated.
An Immunohistochemical study conducted in 2009 of 54 individuals diagnosed with PDCIS found that the tumor cells in 34, 31, and 35 cases, respectively, expressed the estrogen receptor, progesterone receptor, and HER2/neu protein. More resent reports find that these tumor cells strongly express the estrogen receptor in most cases and that PDCIS with tumor cells that do not express the estrogen receptor generally have a more malignant microscopic histopathology. While there are no specific gene alterations that have been repeatedly found in PDCIS tumor cells, the isolated cases in which they have been found were alterations similar to those occurring in low grade ductal carcinoma in situ tumors.
Treatment and prognosis PDCIS is managed primarily by surgical removal in the same manner as ductal carcinoma in situ tumors that have the same nuclear grade and estrogen receptor expression by their tumor cells (see treatment of ductal carcinoma in situ). (Nuclear grade describes how closely the nuclei of cancer cells look like the nuclei of normal breast cells; the higher the nuclear grade, the more abnormal appearing the nuclei are and the more aggressive the tumor cells tend to be.) PDCIS has an excellent prognosis with long-term survival rates similar to those for EPC.
Encapsulated papillary carcinoma Presentation EPC, previously grouped with PDCIS and termed intracystic papillary carcinoma, occurs primarily in postmenopausal females. In one large study, individuals diagnosed with EPC ranged from 30 to 93 years old (median age: 69 years) with 2% of the cases being diagnosed in men. A large institutional review recorded 14 men aged 55 to 82 years with EPC. EPC usually present as small (e.g., 0.3 to 9 centimeters), palpable masses located underneath the areola (i.e. pigmented area surrounding the breast's nipple); at presentation, 5 to 20% have a nipple discharge which may be bloody. Sonography examinations usually detect round to oval, circumscribed masses that may have a cystic component. Recently, EPC tumors have more often presented in women as symptomless masses first detected by routine mammography screening. In rare cases, individuals who present with what appear to be either in situ or invasive EPC have been found on further examination to have metastases in their nearby axillary (i.e. armpit) sentinel lymph nodes, other axillary lymph nodes, and/or distant tissues.
Pathology
The microscopic histopathology (refer to adjacent high-power photomicrograph) of EPC tissues typically shows papillary structures with fibrovascular cores and proliferating neoplastic epithelial cells growing within cystic spaces, all of which are enclosed within a dense fibrous capsule. In general, EPC tumors do not have areas of neuroendocrine degeneration or myoepithelial cells. The presence of a dense fibrous capsule distinguishes EPC from other papillary breast tumors, particularly PDCIS; the absence of neuroendocrine differentiation areas helps distinguishes EPC from SPC tumors; and the absence of peripherally located myoepithelial cells helps distinguish EPC from PDCIS tumors. EPC tumors may be totally contained within their fibrous capsules or have one or more areas that have invaded through the capsule to normal breast tissues and/or chest muscles; these two variants are termed in situ EPC and infiltrative EPC, respectively. In a study of 25 individuals with EPC, 14 had in situ and 11 had invasive disease with 6 of the invasive tumors rated as high grade (see high grade tumors) based on their microscopic histopathology. Rarely, EPC tumors metastasize to nearby sentinel lymph nodes, other nearby axillary lymph nodes, and/or distant tissues; these metastases have in general shown papillary morphologic features similar to their primary tumors. Uncommonly, EPC tumors co-exists with nearby PDCIS, invasive carcinoma of no special type, invasive cribriform carcinoma of the breast, mucinous carcinoma, or tubular carcinoma tumors.
Immunohistochemical analyses of the tumors cells in most individuals with EPC find strong expression of estrogen and progesterone receptors but not HER2/neu protein. A clinicopathologic study of 49 EPC cases found that 47 cases had tumor cells that expressed estrogen and progesterone receptors while only 8 had tumor cells that expressed HER2/neu protein. However, individuals with a more malignant EPC tumor as determined by microscopic histopathology analyses (about 5%–10% of all cases) often had tumor cells that are triple negative, i.e. do not express estrogen receptors, progesterone receptors, or HER2/neu protein. Gene analyses studies have reported that EPS tumor cells in some individuals have copy number variations such as loses of genetic material in the q (i.e. long) arm of chromosome 16, gains of genetic material in the p (or short) arm of chromosome 16, and gains of genetic material in the q arm of chromosome 1. Studies have also identified individuals with EPS tumors that have hot spot mutations (i.e. disease-causing mutations) in the PIK3CA gene which, when having activating mutations, may promote the development and/or progression of breast and other cancers. Recurrent alterations in two genes involved with chromatin remodeling (i.e. modifying chromatin architecture), KMT2A and CREBBP, have also been identified in the tumor cells of some EPS cases. Alterations in these two genes are, similar to alterations in the PIK3CA gene, associated with the development and/or progression of breast and other cancers.
Treatment and prognosis