Pathology of Papilloma With Atypia or Ductal Carcinoma in Situ 

Updated: Nov 09, 2015
  • Author: Joshua I Warrick, MD; Chief Editor: D Craig Allred, MD  more...
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Definition

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 3 mm or smaller in greatest dimension and is low grade and diagnose DCIS involving a papilloma if the proliferation is 3 mm or larger or is 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 confident

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Epidemiology

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]

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Etiology

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.

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Location

The breast, frequently the central and subareolar portions, is involved.

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Clinical Features and Imaging

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.

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Gross Findings

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.

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Microscopic Findings

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.

DCIS (blue arrow) is seen involving a small focus DCIS (blue arrow) is seen involving a small focus of this IDP (classic IDP present at black arrow). 40x.
Same tumor as above. 200x. This focus shows all th Same tumor as above. 200x. This focus shows all the features of a common, benign IDP, including a single layer of luminal epithelium and a myoepithelial layer (arrow).
Same tumor as above, at blue arrow. 200x. Low grad Same tumor as above, at blue arrow. 200x. Low grade DCIS involves the surface of the IDP at this focus, primarily showing a cribriform pattern.
Same tumor as above, at blue arrow. 400x. This foc Same tumor as above, at blue arrow. 400x. This focus shows classic cribriform, low grade DCIS.
Same tumor as above. 200x. This separate, small fo Same tumor as above. 200x. This separate, small focus of DCIS was also present on the IDP.
Same tumor as above. 400x. The focus of DCIS is lo Same tumor as above. 400x. The focus of DCIS is low grade with a classic cribriform architecture.
DCIS (blue arrow) involving an IDP (classic IDP pr DCIS (blue arrow) involving an IDP (classic IDP present at black arrow). 40x.
Same tumor as above, at black arrow. 200x. This fo Same tumor as above, at black arrow. 200x. This focus shows classic features of a benign IDP, with a single layer of luminal epithelium and a myoepithelial layer.
Same tumor as above, at blue arrow. 200x. The DCIS Same tumor as above, at blue arrow. 200x. The DCIS is characterized by a monotonous proliferation of low grade cells in a cribriform pattern.
DCIS in an IDP. 100x. This IDP is smaller than the DCIS in an IDP. 100x. This IDP is smaller than the previous examples, and the DCIS component accounts for a larger fraction of the lesion.
Same tumor as above. 200x. The DCIS is low grade w Same tumor as above. 200x. The DCIS is low grade with a predominantly cribriform architecture.
DCIS involving an IDP. 20x. This field shows areas DCIS involving an IDP. 20x. This field shows areas of common DCIS with comedo necrosis. An IDP is seen in the lower portion of the field.
Same tumor as above. 200x. DCIS is present on the Same tumor as above. 200x. DCIS is present on the surface of the IDP.
Same tumor as above. 400x. A layer of myoepitheliu Same tumor as above. 400x. A layer of myoepithelium (arrow) is seen underlying a layer of surface epithelium, confirming the suspicion this lesion is composed partly of an IDP.
Same tumor as above. 400x. This focus shows DCIS, Same tumor as above. 400x. This focus shows DCIS, with high grade nuclei and clear cytoplasm, involving the surface of the IDP.
Same tumor as above. 400x. A focus of DCIS separat Same tumor as above. 400x. A focus of DCIS separate from the IDP. This focus has identical histology to the DCIS involving the IDP.

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.

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Immunohistochemistry

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 Papilloma and Small, Peripheral Intraductal Papilloma). The DCIS component stains like common DCIS and lacks myoepithelial marker expression

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Molecular/Genetics

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.

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Prognosis and Predictive Factors

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 more 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 Papilloma).

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Differential Diagnosis

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.

IDP with prominent apocrine metaplasia. 100x. IDP with prominent apocrine metaplasia. 100x.
Same IDP as above. 200x. The IDP is involved by ex Same IDP as above. 200x. The IDP is involved by extensive, well-developed apocrine metaplasia (volumous pink, granular cytoplasm, enlarged nuclei, and prominent nucleoli). Although the cellular proliferation involving the IDP is monomorphic, the prominent apocrine metaplasia and low grade cytology are strong indicators the proliferation is benign.
Same IDP as above. 200x. A transition from normal Same IDP as above. 200x. A transition from normal (i.e. not involved by apocrine metaplasia) surface epithelium to epithelium that has undergone apocrine metaplasia is present.
IDP sampled by core needle biopsy. 40x. IDP sampled by core needle biopsy. 40x.
Same IDP as above. 200x. A prominent epithelial pr Same IDP as above. 200x. A prominent epithelial proliferation involves the IDP.
IDP. 400x. The proliferation is composed of monomo IDP. 400x. The proliferation is composed of monomorphic cells with abundant pink cytoplasm, that form disturbingly round spaces. These features are concerning, but not sufficient for the diagnosis of DCIS.
Same IDP as above. 200x. In contast to the above p Same IDP as above. 200x. In contast to the above previous figure, this cellular proliferation has typical features of UDH.
Same IDP as above. 200x. A definite focus of UDH w Same IDP as above. 200x. A definite focus of UDH without apocrine metaplasia (black arrow) is seen undergoing a transition to early, poorly-developed apocrine metaplasia (blue arrow). Hyperplasia with moderately-developed apocrine metaplasia (yellow arrow) is seen to transition from the poorly-developed apocrine metaplasia. The focus at the yellow arrow looks very similar to the previous concerning focus. As such, the previously shown concerning focus was interpreted as benign hyperplasia with apocrine metaplasia.
Same IDP as above, blue and black arrows. 400x. Same IDP as above, blue and black arrows. 400x.
Same IDP as above, yellow arrow. 400x. Same IDP as above, yellow arrow. 400x.
IDP with prominent apocrine metaplasia. 100x. IDP with prominent apocrine metaplasia. 100x.
Same IDP as above. 400x. This focus shows a monomo Same IDP as above. 400x. This focus shows a monomorphic proliferation with abundant pink cytoplasm and low grade nuclei. The findings are concerning for DCIS
Same IDP as above. 200x. An area of well-developed Same IDP as above. 200x. An area of well-developed, definite apocrine metaplasia (bottom of figure) is adjacent to an area with features very similar to the cellular proliferation in the IDP that was concerning for DCIS. Given the close proximity of this proliferation to definite, benign apocrine metaplasia, it is most likely the monomorphism of the proliferation is a result of early apocrine metaplasia.
Same IDP as above. 400x. Definite well-developed a Same IDP as above. 400x. Definite well-developed apocrine metaplasia (blue arrow) shows transition from moderately-developed apocrine metaplasia (black arrow). Given this moderately-developed apocrine metaplasia is cytologically indistinguishable from the concerning proliferations in the IDP, we interpreted the concerning proliferations as benign.
IDP sampled by core needle biopsy. 40x. IDP sampled by core needle biopsy. 40x.
Same IDP as above. 200x. This IDP is involved by a Same IDP as above. 200x. This IDP is involved by a small proliferation of epithelial cells, seen on the right side of the figure
Same IDP as above. 400x. The cells comprising the Same IDP as above. 400x. The cells comprising the epithelial proliferation are monomorphic, have a moderate amount of pink cytoplasm, and form somewhat uniform spaces. These features are concerning for DCIS.
Same IDP as above. 200x. This focus shows an area Same IDP as above. 200x. This focus shows an area of well-developed apocrine metaplasia (bottom left), and an adjacent focus of hyperplasia. The hyperplasia has undergone apocrine metaplasia, as made evident by comparison with the adjacent area of well-developed apocrine metaplasia. This focus of hyperplasia has very similar histologic features to the previous described proliferation in this IDP concerning for DCIS. As such, the cellular proliferations in this IDP were interpreted as 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, and comedo necrosis.

Apocrine DCIS involving an IDP. 20x. Apocrine DCIS involving an IDP. 20x.
Same tumor as above. 40x. A portion of IDP is pres Same tumor as above. 40x. A portion of IDP is present on the left side of the figure. An expansive proliferation is present on the right side of the figure. Necrosis is present.
Same tumor as above. 40x. The proliferation involv Same tumor as above. 40x. The proliferation involves large areas of the lesion.
Same tumor as above. 100x. Extensive necrosis invo Same tumor as above. 100x. Extensive necrosis involves the lesion.
Same tumor as above. 200x. The epithelial prolifer Same tumor as above. 200x. The epithelial proliferation shows no transition from a benign proliferation, and no transition to a well-developed apocrine proliferation. The cells contain abundant pink cytoplasm, as is seen in apocrine DCIS.
Same tumor as above. 400x. The proliferation is co Same tumor as above. 400x. The proliferation is composed of low-grade, monomorphic cells with abundant pink cytoplasm. Convincing polarization of cells is seen (left side of figure).
Same tumor as above. 100x. In this focus, both ben Same tumor as above. 100x. In this focus, both benign IDP (left side of figure) and the atypical cellular proliferation (right side of figure) are seen. No transition from a benign proliferation is present.
Same tumor as above. 200x. Higher power examinatio Same tumor as above. 200x. Higher power examination confirms the lack of transition from a definite benign proliferation, and shows cellular monomorphism.
Same tumor as above. 100x. Foci of comedo necrosis Same tumor as above. 100x. Foci of comedo necrosis are identified.

Papillary DCIS and DCIS involving a papilloma are entirely different lesions. Papillary DCIS consists of a proliferation of papillary processes showing fibrovascular cores with no myoepithelial cell layer. The presence of a myoepithelial layer, which can usually be demonstrated on immunohistochemistry, is a strong indicator that the lesion is a benign IDP.

It is important to keep 3 concepts in mind when evaluating an IDP involved by a suspicious proliferation. First, IDPs (L/C ST) are common, do 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.

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