Pathology of Papilloma With Atypia or Ductal Carcinoma in Situ

Although intraductal papillomas (IDPs) are benign, they are occasionally involved by a monomorphic, atypical cellular proliferation, morphologically identical to ductal carcinoma in situ (DCIS) or atypical ductal hyperplasia (ADH). Specific terminology for this differs among authorities. Some diagnose atypical papilloma (also known as papilloma with atypia) if the monomorphic cellular proliferation is smaller than 3 mm in greatest dimension and is low grade, and diagnose DCIS involving a papilloma if the proliferation is 3 mm or larger or is intermediate to high grade. ^{[1, 2]} Others advocate the diagnosis of DCIS involving a papilloma irrespective of the size and grade of the atypical cellular proliferation. ^[3]

Large/central IDP subtypes (L/C ST) may be involved by complex, crowded benign cellular proliferations involved by varying degrees of apocrine metaplasia, which can mimic the histologic features of DCIS (see Microscopic Findings). These lesions are difficult to evaluate, and examination of the entire lesion may be required to distinguish them from DCIS involving a papilloma. Given this, the material afforded by core needle biopsy (CNB) may be insufficient to make a confident diagnosis.

Several studies have shown IDPs involved by suspicious cellular proliferations seen on CNB are more commonly associated with cancer upon excision than IDPs without atypia diagnosed on CNB (see Prognosis and Predictive Factors). As such, the term atypical papilloma may refer to an IDP sampled on CNB with features suspicious for DCIS involving an IDP.

For the purposes of this article, the term "DCIS involving a papilloma" is used to describe an IDP involved by a cytologically malignant cell population, regardless of the size of the proliferation. "Atypical papilloma" is used to describe an IDP seen on CNB that is involved by a proliferation that has features suspicious for DCIS involving a papilloma, and therefore requires excision for a more definitive diagnosis.

Determining the population most affected by atypical papilloma and ductal carcinoma in situ (DCIS) involving a papilloma is difficult, as series differ in their design and inclusion criteria for these lesions. However, most studies indicate atypical papilloma and DCIS involving a papilloma occur in a slightly older age group than intraductal papilloma (IDP) (L/C ST) ^{[1, 4]} and are primarily seen in women older than 50 years. ^{[1, 4, 2]}

The authors of this article believe that most cases of ductal carcinoma in situ (DCIS) involving an intraductal papilloma (IDP) (L/C ST) result from the direct extension of independent DCIS into an adjacent IDP (L/C ST). This is based on the knowledge that DCIS is known to primarily arise from the terminal duct lobular unit (TDLU), while IDP (L/C ST) is known to arise from the ducts proximal to the TDLU. ^[5]

In addition, many cases of DCIS involving a papilloma are seen in association with ADH/DCIS in adjacent ductal spaces. ^[1] Therefore, it stands to reason that most cases of DCIS involving a papilloma are collision tumors. However, rare cases have been seen in which a focus of definite DCIS was seen in an IDP, and no other DCIS could be found on thorough examination of the surrounding breast tissue. These cases may represent DCIS arising from the epithelium of the IDP.

DCIS may also involve small peripheral (S/P ST) IDPs. These cases may represent a form of collision tumor or alternatively may represent DCIS and IDP (S/P ST) arising from the same TDLU.

Although the central and subareolar portions of the breast are most commonly involved, any portion of the breast can be involved.

Ductal carcinoma in situ (DCIS) involving a papilloma may present similarly to intraductal papilloma (IDP) (L/C ST); as such, it may present as nipple discharge, a breast mass, or breast pain. They may also present mammographically as calcifications concerning for malignancy.

Ductal carcinoma in situ (DCIS) involving a papilloma grossly resembles an intraductal papilloma (IDP) (L/C ST) and thus appears as a lobulated, soft, tan mass within a cystic cavity. The cyst may contain serous or bloody fluid.

Ductal carcinoma in situ (DCIS) involving a papilloma has microscopic features consistent with its name. It consists of an intraductal papilloma (IDP), showing a fibrovascular core with overlying layers of myoepithelial and epithelial cells, with surface involvement by a monomorphic atypical cellular proliferation like that seen in common DCIS and ADH.

The proliferation is frequently low grade and may take on various morphologies, including cribriform, solid, micropapillary, or virtually any pattern described for DCIS. High-grade cellular proliferations are also seen and are generally associated with high-grade DCIS in adjacent ductal spaces.

Criteria for the diagnosis of atypical papilloma on CNB are more difficult to define. In general, the diagnosis is based on identifying an IDP involved by a cellular proliferation with features suspicious for DCIS. The most concerning such features include cellular monomorphism and architectural patterns seen in DCIS, including true cribriform and micropapillary.

The IDP component demonstrates layers of myoepithelial cells (eg, express p63, smooth muscle actin, h-caldesmon, myosin heavy chain) and overlying epithelium (eg, express CK7, CK8/18), the same as benign IDP (see Large, Central Intraductal Papillomas and Pathology of Small, Peripheral Intraductal Papillomas). Myoepithelial markers highlight myoepithelial cells surrounding the intraductal papilloma and lining the fibrovascular cores. The DCIS component stains like common DCIS and lacks myoepithelial marker expression.

Recent reports have shown that papillomas involved by DCIS show loss of heterozygosity (LOH) at several loci on chromosomes 16p and 16q, indicating these are clonal neoplasms. ^{[6, 7]} Although LOH at several of these loci have been identified in both IDP and DCIS involving a papilloma, LOH at 16q23 appears to be specific for the latter. ^[7] This specific LOH seen in DCIS involving a papilloma may reflect a characteristic abnormality in the lesion. However, further study is needed to confirm this.

DCIS involving a papilloma likely has the same behavior as common DCIS, and the treatment is the same, although papillomas involved by a focus of DCIS of 3 mm or less may be an exception. In the original article describing such lesions, in which they were called papillomas with atypia, Page et al found women with papillomas involved by an atypical monomorphic focus of 3 mm or less had a 9-fold increased risk of invasive breast cancer (IBC) over women with no proliferative breast disease. ^[2] Notably, the confidence interval for this 9-fold increased risk was 1.62-56.91. ^[2]

More recently, a large series by Lewis et al showed that patients with solitary papillomas involved by a monomorphic atypical proliferation of 3 mm or less had only a 5-fold increased risk of developing IBC, ^[1] smaller than 9-fold increased risk described by Page et al and the 10-fold increased risk recognized in women with DCIS. However, this study pooled patients who had ADH and a separate IDP (L/C ST) with patients in whom the focus of ADH directly involved the papilloma. This study may, therefore, underestimate the IBC risk associated with DCIS involving a papilloma when the proliferation is 3 mm or smaller.

Despite their somewhat differing conclusions, these studies show that small foci of DCIS in a papilloma are associated with increased breast cancer risk. However, at present, the exact magnitude of this increased risk is unclear. ^[8]

Several studies have indicated that atypical papillomas diagnosed with CNB require excision, as they may harbor DCIS in the papilloma and/or adjacent duct spaces. ^{[9, 10, 11, 12, 13, 14]} The rate of finding DCIS (or invasive breast cancer in rare cases) on excision of an atypical papilloma ranges from 22% ^[4] to 75% ^[10] . This is higher than the rate of finding DCIS on excision of common benign IDP diagnosed in CNB (see Large, Central Intraductal Papillomas).

The main difficulty in diagnosis lies in differentiating DCIS involving a papilloma from benign IDP (L/C ST) involved by a complex epithelial proliferation with apocrine metaplasia. The apocrine metaplasia causes nuclear enlargement and a uniform increase in cytoplasmic volume, creating the appearance of a monomorphic atypical cellular proliferation. This can closely mimic the appearance of low-grade DCIS.

In benign proliferations (involving an IDP [L/C ST]) that initially contained slit-like spaces, the cytoplasmic expansion brought by apocrine metaplasia may expand these spaces, making them look disturbingly cribriform and further mimicking DCIS. Additionally, the degree to which the epithelium has undergone apocrine metaplasia may differ between cases, with some showing mild partial apocrine metaplasia and others showing classic well-developed apocrine metaplasia.

Cases with early apocrine metaplasia can be particularly problematic, since involved areas may show concerning cellular monomorphism without the reassuring features of unequivocal apocrine metaplasia. In such cases, finding an area that shows transition from a benign proliferation without apocrine metaplasia to a similar proliferation with apocrine metaplasia is a strong indicator the monomorphic proliferation is not DCIS. Similarly, finding an area that shows transition from an area with definite well-developed benign apocrine metaplasia to the monomorphic cellular proliferation of concern is strong evidence that the concerning proliferation is benign.

In rare cases, low-grade apocrine DCIS involves an IDP (L/C ST). These cases can be difficult to differentiate from IDP (L/C ST). Features favoring apocrine DCIS involving a papilloma over benign IDP (L/C ST) include large size of the apocrine proliferation, lack of transition from a usual ductal hyperplasia (UDH)–like proliferation, lack of transition to a well-developed benign apocrine proliferation, high nuclear grade, nuclear pleomorphism with 3-to-1 difference in nuclear size, and comedo necrosis.

Papillary DCIS and DCIS involving a papilloma are entirely different lesions. Papillary DCIS consists of a proliferation of papillary processes showing fibrovascular cores. A myoepithelial layer is present at the periphery but no myoepithelial cells lining the fibrovascular cores are present. The presence of a myoepithelial layer lining the fibrovascular cores, which can usually be demonstrated on immunohistochemistry, is a strong indicator that the original lesion is an IDP.

It is important to keep three concepts in mind when evaluating an IDP involved by a suspicious proliferation. First, IDPs (L/C ST) are common, may not require excision, and are frequently involved by complex benign epithelial proliferations. Second, DCIS involving a papilloma likely represents a collision of DCIS with an IDP (L/C ST), and the DCIS component should therefore have morphology identical to common DCIS. Third, apocrine change involving benign epithelial proliferations in IDPs (L/C ST) may mimic DCIS, especially when it is early and poorly developed.

Considering these concepts, monomorphic proliferations that resemble conventional DCIS and show no evidence of apocrine metaplasia should be considered highly suspicious for DCIS involving a papilloma. Conversely, an epithelial proliferation with features of apocrine metaplasia should be diagnosed as DCIS with caution, especially if it shows transition to areas of benign hyperplasia without apocrine metaplasia or areas of benign, well-developed apocrine metaplasia.