The literature does not contain well-established reliable information concerning the epidemiologic features of patients with papillary carcinoma. The tumor usually occurs in adults beyond the age of 50 years, and, on average, women with papillary carcinoma are older than women with other types of breast carcinoma. In a review of 35 cases, Fisher et al.¹ stated that “The lesion occurs with a significantly high frequency among … postmenopausal women.” Other publications echo this observation.^6,20 Small series and case reports document the occurrence of papillary carcinomas in women as young as 29 years²¹ and as old as 91 years.²² Grabowski et al.²³ calculated a mean age of approximately 70 years using cases in the California Cancer Registry classified as intracystic papillary carcinoma. Men with papillary carcinoma span the same range of ages. According to Fisher et al.,¹ papillary carcinoma occurs more commonly in “non-Caucasians.”

Nearly 50% of papillary carcinomas arise in the central part of the breast, and as a consequence, nipple discharge has been described in 22% to 34% of patients.^24,25 Bleeding from the nipple occurs in a higher percentage of patients with papillary carcinoma than in women with a papilloma. Paget disease is rarely found in association with papillary carcinoma, but may be present if the lesion arises from major lactiferous ducts within the nipple or if there are additional foci of DCIS in the nipple. Most papillary carcinomas have a slow growth rate. Patients have reported the presence of a discharge or a mass for prolonged periods, and a duration of symptoms for a year or more before presentation is not unusual.^24,25,26,27

Invasive papillary carcinomas present varied radiologic findings. Mammograms often display a multinodular pattern of increased density in a segmental distribution,^5,6 and the nodules sometimes occupy only a single quadrant.^5,6 Solitary masses also occur frequently.²⁰ The masses typically appear round, oval, or lobulated,^5,20,28 and their borders may be either well defined^5,22 or ill defined.^20,29 The differential diagnosis for a well-defined mass includes fibroadenoma (FA), benign cystic lesions, medullary carcinoma, and mucinous carcinoma. Coarse, irregular calcifications may develop in areas of sclerosis or resolved hemorrhage in papillomas or in papillary carcinomas. Calcifications are not abundant in most papillary carcinomas, and when present, they tend to be punctate and associated with the intraductal component.²² In one case,³⁰ the calcifications appeared “rod like.” The sonographic features of papillomas and papillary carcinomas overlap.^31,32 Sonography of invasive papillary carcinomas typically demonstrates masses that appear well defined, solid or mixed solid and cystic, inhomogeneous, and hypoechogenic with posterior enhancement.^5,20,30 The presence of a nonparallel orientation, echogenic halo, posterior acoustic enhancement, and calcifications suggests the diagnosis of papillary carcinoma rather than papilloma.³² Magnetic resonance imaging (MRI) of one case³³ yielded T1-weighted images showing an irregular mass with moderately decreased signal intensity; on T2-weighted images, the carcinoma appeared hypointense. After gadolinium injection, mild and inhomogeneous enhancement was noted. Other cases of invasive and noninvasive papillary carcinoma did not demonstrate specific findings.³⁴ In fact, MRI failed to detect 2 of 13 papillary carcinomas and classified 6 of the remaining 11 as benign or probably benign. Extension of papillary carcinoma into adjacent ducts cannot be reliably assessed by mammography. Galactography may be used to examine patients who have nipple discharge to determine whether papillary lesions are multicentric.³⁵ Filling defects in ducts outlined in a galactogram may be due to papillomas or papillary carcinoma. Clinically detectable enlargement of axillary lymph nodes (ALNs) is unusual except in patients with massive tumors, which tend to develop areas of hemorrhagic necrosis.

Benign luminal and myoepithelial cells make up the epithelium of a papilloma, whereas malignant ductal cells comprise the entire epithelial population of most papillary carcinomas. As a result of uneven stratification and loss of polarity with respect to stromal elements within the lesion (Fig. 14.6), the carcinoma cells of papillary carcinoma grow in a less orderly fashion than do the benign cells of papillomas. They usually do not form two consistently arranged layers composed of distinct cell types. Instead, the carcinoma cells demonstrate
papillary, micropapillary or filiform, cribriform, reticular, or solid growth patterns (Fig. 14.7).

Myoepithelial cells that are distributed relatively uniformly and proportionately with the epithelium in benign papillary lesions are usually overgrown in papillary carcinomas. However, the finding of myoepithelial cells in some parts of a papillary lesion is not inconsistent with a diagnosis of carcinoma.^37,38,39 Myoepithelial cells are prominent mainly in residual areas of a papilloma that has given rise to a papillary carcinoma, and they tend to be less conspicuous or absent in the carcinomatous areas (Fig. 14.8).

The malignant cells of papillary carcinomas demonstrate the same cytologic features as those of commonplace DCIS. Although the cellular attributes vary according to the grade of the carcinoma, common alterations include an increase in the size of the cell and enlargement of its nucleus. In common, low-grade papillary carcinomas, the cells appear uniform, but those of the uncommon high-grade papillary carcinomas demonstrate conspicuous cellular pleomorphism. The nuclei are characteristically hyperchromatic regardless of cytologic grade, and there is usually a high
nuclear-to-cytoplasmic ratio. The mitotic figures vary in number, and they are more numerous in carcinomas that exhibit the most severe cytologic atypia. Mitotic activity is uncommon in papillomas. The presence of more than one mitosis in 10 high-magnification (40×) fields suggests the diagnosis of papillary carcinoma.

The tumor cells sometimes have secretory “snouts” at the luminal surface. The cytoplasm is typically amphophilic, but eosinophilic cells are found in a number of lesions. Papotti et al.³⁷ found apocrine cells that were immunoreactive
for gross cystic disease fluid protein-15 (GCDFP-15) in 75% of papillomas and in 50% of papillary carcinomas. Apocrine areas in a papillary carcinoma exhibit cytologic atypia consistent with the rest of the tumor and, in that way, differ from the bland foci of apocrine metaplasia commonly encountered in papillomas (Fig. 14.9). The presence of cytologically benign apocrine elements is invariably associated with a papilloma rather than a papillary carcinoma.

Describing the epithelium of papillomas, Kraus and Neubecker³⁶ introduced the term complex glandular pattern to refer to the compact, back-to-back arrangement of proliferative glands within the stalk of a papilloma. The authors noted that this close crowding of glands “… was often a source of confusion in that it superficially resembled the cribriform pattern of carcinoma.”³⁶ The cribriform pattern characteristic of low-grade DCIS does occur in papillary carcinomas frequently. To distinguish the “complex glandular pattern” seen in papillomas from the cribriform spaces of papillary carcinoma, one should examine the tissue separating the individual acinar structures. Thin strands of collagen and slender capillaries surround each of the glands that compose the “complex glandular pattern,” whereas the spaces formed in cribriform carcinomas lack these connective stromal elements.

Supporting fibrovascular stroma is present in virtually all papillary carcinomas, but it tends to be less conspicuous in carcinomas than in benign papillary lesions because of the dominance of the epithelial component in carcinomas. A minority of papillary carcinomas have areas in which there are relatively broad fibrous stalks of extensive sclerosis, and consequently the character of the stroma within the lesion is not by itself a reliable diagnostic feature (Fig. 14.10).

Scaring frequently occurs in the periphery of papillary tumors. This process can entrap both benign glands and those harboring in situ carcinoma. The resulting appearance simulates the look of invasive carcinoma and makes the recognition of minimal invasion difficult.

Carcinoma usually extends into ducts at the periphery of a papillary carcinoma. When the interpretation of an orderly papillary tumor is difficult, careful examination of the surrounding ducts can be extremely helpful. The presence of foci of papillary, cribriform, or comedocarcinoma is usually evidence that in situ carcinoma is also present in the papillary tumor. In the same way, study of an epithelial proliferation situated on the wall of the duct harboring a papillary tumor can shed light on the nature of the epithelial cells within the papillary portion.

In almost one-half of the papillomas studied by Kraus and Neubecker,³⁶ the surrounding tissue displayed sclerosing adenosis (SA), and it protruded into ducts and simulated papillomas in a few instances. SA does not coexist with papillary carcinomas commonly.

There is a broad range of mucin secretion demonstrable in papillary carcinomas with the mucicarmine, Alcian blue, and periodic acid-Schiff (PAS) stains (Fig. 14.11). Some papillary carcinomas have no detectable intracellular mucin. In the majority, mucin secretion is not prominent, but a small number of papillary carcinomas have signet ring cells (Fig. 14.12) or abundant and diffuse intracellular mucin secretion (Fig. 14.13). The accumulation of abundant extracellular mucin creates a pattern that resembles invasive mucinous carcinoma, but does not represent invasion when confined within the tumor (Fig. 14.14).

Microcalcifications found in many papillary carcinomas are usually distributed in the glandular portions of the lesion, but they may also be found in the papillary stroma. Calcifications also form in the stroma of papillomas, so neither the presence nor the pattern of calcification provides reliable diagnostic information.

Papillary carcinoma that has arisen in a papilloma sometimes retains areas of papilloma that appear benign or atypical, as well as having foci of more cellular proliferation diagnostic of carcinoma (Figs. 14.8, 14.9, and 14.15). Small areas of papilloma in such lesions are of little consequence, and they should not impede the recognition of the carcinomatous element. In some instances, the diagnosis of papillary carcinoma can be “a ‘shadow land’ even for the most experienced pathologist,”⁴⁰ a situation that Foote and Stewart¹⁴ referred to as “a zone of altered cell growth where the diagnosis of carcinoma versus atypical papillomatosis
is a question of occult distinction and must be accepted or rejected on grounds of faith in the pathologist or lack of it.” “Borderline” papillary lesions that fit this description often have modest or substantial areas of benign papillary proliferation as well as more cellular and atypical components. To make a diagnosis of carcinoma in the latter setting, it is necessary to find one or more low-power microscopic fields where the growth pattern and cytologic appearance constitute one of the established patterns of DCIS. Some authors have illustrated focal DCIS in papillomas, but classified these lesions as “papillomas with atypical ductal hyperplasia.”^41,42 In one of these studies, the relative risk for “subsequent carcinoma” in women with such papillomas was more than four times the risk of women with papillomas that lacked atypical ductal hyperplasia/DCIS.⁴² Underdiagnosis of such lesions is likely to result in inadequate treatment that is reflected in the outcomes of patients in these reports.

Three-dimensional reconstruction of the microscopic structure of papillary lesions has revealed some interesting differences between papillomas and papillary carcinomas.^43,44 In papillomas and usual ductal hyperplasia (UDH), the luminal spaces between the proliferating epithelial cells form a complex but diffusely anastomosing continuous network of channels. On the other hand, in DCIS, the luminal spaces tend to be separate, and they do not form a continuous network. These elegant and painstaking studies have resulted in a more complete appreciation of the structural differences between hyperplastic and carcinomatous papillary lesions.

In additional to histologic study, biochemical analysis of the fluid from cystic papillary lesions may be helpful in the differential diagnosis between cystic papilloma and papillary carcinoma. Matsuo et al.⁴⁵ found an elevated carcinoembryonic antigen (CEA) content in aspirated fluid from a 10-cm cystic breast tumor. CEA was demonstrated immunohistochemically in the carcinoma cells in the resected specimen. Another study compared CEA and human epidermal growth factor 2 (HER2) protein levels in fluid from 6 cystic papillomas, 6 papillary carcinomas, and 42 gross cysts.⁴⁶ Five of the six carcinomas (83%) had elevated levels of both proteins compared with two (33%) of the papillomas and two (5%) of gross cysts.

The growth patterns found in areas of frankly invasive papillary carcinoma usually constitute variations on the architecture of the carcinoma in the underlying in situ papillary tumor (Fig. 14.16). The cytologic characteristics of the invasive component also resemble those of the in situ portion of the lesion, in some cases including apocrine features. Cribriform, comedo, tubular, and mucinous foci may also be present. The invasive element may grow partly or entirely as mucinous
carcinoma, an occurrence usually associated with solid papillary carcinoma. Mucinous differentiation in solid papillary carcinoma is manifest not only by the presence of intracellular and intraluminal mucin but also by the accumulation of extracellular mucin in limited amounts between the neoplastic epithelium and adjacent stroma (Fig. 14.14). This phenomenon can occur within the tumor, adjacent to fibrovascular stalks, and at the border of the tumor. The resultant small pools of mucin are not interpreted as invasive mucinous carcinoma unless they contain detached neoplastic cells. Larger accumulations may surround or disrupt portions of the epithelium, and the resultant appearance is interpreted as invasive mucinous carcinoma when carcinoma cells surrounded by mucin extend into the adjacent stroma (Fig. 14.17).

Clusters of invasive papillary carcinoma cells are particularly prone to shrinkage artifact, and they often appear to lie in spaces, creating the appearance of lymphatic tumor emboli. When one applies strict criteria for the diagnosis of lymphatic invasion, most such foci prove to be artifactual.⁴⁷

The invasive nature of many papillary carcinomas appears obvious, but the recognition of minimally invasive papillary carcinoma can be difficult. Many papillary carcinomas are bounded by zones of fibrosis, recent or resolved hemorrhage, and chronic inflammation, and similar alterations may occur within the lesion. Papillary or glandular clusters of epithelial cells routinely found within these areas present a challenging problem (Fig. 14.18). If one recalls that similar patterns of epithelial dispersal can occur in sclerotic portions of benign papillary lesions, it is possible to determine that these do not constitute foci of invasion in most cases. Groups of neoplastic cells distributed parallel to layers of reactive stroma at the border of a papillary carcinoma usually represent entrapped in situ epithelium rather than invasive carcinoma. An actin immunostain is sometimes helpful in this situation, although staining of reactive myofibroblasts can complicate the interpretation. Myofibroblastic staining is avoided if the p63 immunostain is used, but this procedure is useful only if the p63 stain reveals myoepithelium throughout the papillary tumor. Isolated invasive carcinoma cells can be identified with a cytokeratin immunostain. In general, the most reliable histologic evidence of frank invasion is extension of tumor beyond the zone of reactive changes into the mammary parenchyma and fat (Figs. 14.17, 14.19, and 14.20).

Physicians have known of the existence of predominantly cystic papillary carcinomas since the middle of the 19th century, but the lesion did not become well defined until 100 years later, when Gatchell et al.⁴⁹ and Czernobilsky⁵⁰ published studies of cases from the Mayo Clinic and the Hospital of the University of Pennsylvania, respectively. Czernobilsky described the features of this form of papillary carcinoma as “… a large, usually solitary hemorrhagic cyst surrounded by a fibrous wall into which projects a predominantly papillary adenocarcinoma which often also lines the inner surface of the cyst and the absence of extensive tumor involvement of the tissues surrounding the cyst favor the diagnosis of intracystic carcinoma.” In both reports, this form of carcinoma constituted 0.5% of mammary carcinomas; however, a subsequent study by McKittrick et al.⁵¹ reported a frequency of 2.0%, and among a large group of Swedish and Hungarian women,⁵² intracystic papillary carcinoma accounted for 1.3% of breast carcinomas.

The age of patients with cystic papillary carcinoma ranges from 21⁴⁹ to 94 years,⁵¹ and the lesion affects both women and men. Cases in men have attracted special interest,^{53,54,55,56,57,58,59,60,61,62,63,64,65} and one notes the large proportion of reports in the Japanese literature.⁵⁶ In one series,⁶⁶ intracystic papillary carcinoma accounted for 5% of breast carcinoma in men. The ages of men with cystic papillary carcinoma cluster in the seventh and eighth decades with just a few cases beyond the age of 80 years.⁵⁵ Patients usually report especially long symptomatic intervals. In one case,⁶⁷ the patient noted the appearance of the mass 10 years prior to presentation, and in another, complaints persisted for 59 years before the patient sought medical attention.⁴⁹

Most cystic papillary carcinomas appear well defined on a mammogram,^55,58,60,68 but two cases displayed slightly ill-defined margins,⁶² and two others appeared lobulated.^30,59 Calcifications occur in only a minority of cases.⁶² The calcifications appear linear, amorphous, or stippled. Ultrasonography reveals a complex, predominantly cystic mass with posterior enhancement and one or more mural nodules. Serial studies of one case demonstrated growth of the nodule.⁵⁵ Intracystic carcinomas usually consist of just one cyst, but multilocular examples have been described.^{29,53,58,64,68} Computerized tomography scans reveal the cyst⁶⁹ and may show an inner mass.⁶⁴ MRI has the ability to demonstrate both the cystic and the solid components,^29,58,63 and it can highlight regions of invasion.²⁹ Dynamic MRI studies may yield findings that suggest a malignant neoplasm.^63,70 Pneumocystography highlights the intracystic tumor and thickening of the cyst wall.^52,53

Classical cystic carcinomas present a characteristic macroscopic appearance. They usually measure several centimeters; however, dimensions as large as 18 cm have been recorded,⁶⁷

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