Large, Central Intraductal Papillomas 

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In the breast, intraductal papilloma (IDP) is a benign lesion that consists of branching fibrovascular cores with overlying layers of epithelial and myoepithelial cells. The large/central subtype (L/C ST) specifically refers to an IDP arising from a large duct. IDP (L/C ST) is generally grossly apparent, solitary, and centrally located in the breast; it has accordingly been referred to as “solitary papilloma” and “central papilloma.” ^{[1, 2]} IDP (L/C ST) stands in contrast to IDP small/peripheral subtype (S/P ST), which originates at the terminal duct lobular unit (TDLU) and is usually located peripherally in the breast, is not grossly apparent, and generally occurs in multiples.

IDP (L/C ST) is primarily found in middle-aged women. In a study of 179 women with solitary papilloma, the mean age at diagnosis was 48 years, and occurrence substantially decreased after age 75 years. ^[1] Younger women were also identified in this series, the youngest was aged 18 years. ^[1]

IDPs are relatively common and are found in 1-5% of breast biopsies. ^{[3, 4, 5]} Current evidence suggests that IDP (L/C ST) is more common that IDP (S/P ST). ^[5] However, the authors’ experience indicates IDP (S/P ST) may be more common. This may be explained by the observation that IDP (S/P ST) and usual ductal hyperplasia (UDH) lie on a histologic continuum, and many lesions the authors consider IDP (S/P ST) may be considered UDH by others.

Molecular evidence has shown that IDPs frequently demonstrate loss of heterozygosity (LOH), involving specific loci on chromosome 16; this suggests they are clonal neoplasms. ^{[6, 7]} However, the studies showing this do not distinguish between IDP (L/C ST) and IDP (S/P ST);therefore, they are unable to evaluate genetic differences between these lesions.

IDP (L/C ST) frequently presents as a unilateral serous or bloody nipple discharge. ^[8] It may also present as a palpable breast mass and may on occasion present as breast pain. ^[9] Mammography reveals no abnormality in most cases but may show duct ectasia, microcalcifications, or a mass. ^{[10, 11, 9]} Ultrasonography may be more sensitive than mammography for detecting IDP (L/C ST) and can reveal duct ectasia, nodules, or a cyst with or without a polyp. ^{[12, 9]} On MRI, IDP (L/C ST) appears as dilated ducts with an associated enhancing, well-circumscribed mass. ^[13] MRI is currently the most sensitive imaging modality for detecting IDP (L/C ST). ^{[13, 9]}

The most pressing clinical question regarding IDP (L/C ST) is whether or not the lesion should be excised. Most studies have shown a small risk (0-3%) of finding ductal carcinoma in situ (DCIS) ^{[14, 15, 16, 17]} on excision of a breast lesion diagnosed as benign IDP (L/C ST) on core needle biopsy (CNB). Accordingly, these studies conclude IDPs (L/C ST) diagnosed on CNB may not require excision if pathology and radiology are concordant. However, other series have shown higher rates of finding carcinoma upon excision of an IDP (L/C ST). ^[18]

The discrepancies between these studies are likely a result of the subjectivity that exists in evaluating epithelial proliferations involving breast papillomas. That is, IDP (L/C ST) is frequently involved by complex atypical proliferations that may closely mimic DCIS. Different pathologists have different thresholds for diagnosing atypia involving IDPs (L/C ST), which extends to diagnoses made using both core needle biopsy and excisional biopsies. This topic is addressed in more detail separately.

IDP (L/C ST) is also associated with a slightly increased bilateral risk of developing invasive breast cancer (reference range, approximately 1.3-2 vs age-matched controls), ^{[1, 5]} which is less than that seen in IDP (S/P ST) (reference range, 3-3.7 vs age-matched controls). ^{[1, 5]}

IDP (L/C ST) grossly appears as a lobulated, soft, tan mass lying in a cystic cavity. The cyst may contain serous or bloody fluid.

A prototypical IDP (L/C ST) consists of a central, branching fibrovascular core that supports a myoepithelial layer and overlying layer of epithelium. The central core branches in a complex manner, which may give the appearance of multifocality on 2-dimensional tissue sections see the image below.

The branches may appear as fronds or have an adenomalike appearance (see the images below).

The epithelium of IDP (L/C ST) frequently undergoes apocrine metaplasia and is often involved by UDH. See the images below.

The UDH may develop apocrine change, as is shown in the images below.

Squamous metaplasia may be seen on occasion. Additionally, IDP (L/C ST) frequently undergoes sclerosis, which may involve a small focus or a large portion of the lesion (see the images below).

The epithelial changes, compounded by sclerosis and the baseline architectural complexity of IDP (L/C ST), can create highly complex lesions. See the images below.

The fibrovascular core in some IDPs (L/C ST) proliferates in a manner that gives the lesion a solid appearance. See the image below.

These have been referred to as duct adenoma and solid papilloma. Rarely, papillary lesions resembling IDP (L/C ST) are encountered with a prominent myoepithelial component. These are referred to as adenomyoepithelioma.

A subset of IDPs (L/C ST) arise just distal to the nipple and are called nipple adenomas by many authors. Excisional specimens from these lesions frequently contain squamous epithelium. They usually have a solid appearance. Involvement by benign epithelial proliferations, which are frequently gynecomastic, is common (see the images below).

The primary differential diagnosis for IDP (L/C ST) includes IDP (S/P ST), DCIS involving a papilloma, encysted noninvasive papillary carcinoma (IPC), papillary DCIS, and invasive breast cancer.

IDP (S/P ST) is similar to IDP (L/C ST) but is much smaller, generally multiple, and occurs more peripherally.

Intracystic (encysted, encapsulated) noninvasive papillary carcinoma (IPC) is a form of DCIS that appears as a large, cystically dilated space containing malignant epithelium that can show various architectural patterns, including micropapillary, papillary, solid, or cribriform. In contrast to IDP (L/C ST), fibrovascular cores that may be seen in the lesion do not have a myoepithelial component. See the images below.

In contrast to IDP (L/C ST), the fibrovascular cores in papillary DCIS do not have a myoepithelial layer, and the epithelial cells show mild-to-moderate cytologic atypia. Papillary DCIS involves dilated TDLUs and small ducts in a fashion similar to common DCIS, in contrast to IPC, which involves a large cystically dilated space. The fibrovascular cores in papillary DCIS are generally slender and delicate, in contrast to the thick fibrovascular cores more typical of IDP (L/C ST). See the images below.

DCIS involving a papilloma is a papillary lesion that has the morphologic features of IDP, including a myoepithelial layer, but is involved by an epithelial proliferation similar to that seen in DCIS. Diagnostic criteria for this lesion are not well established, and thresholds for diagnosis widely vary between pathologists. This is addressed in detail in a separate article.

As IDPs (L/C ST) become sclerotic, the epithelial and myoepithelial components may become entrapped by collagen, giving an appearance that may mimic IBC. This distinction can be difficult to make, especially on needle biopsy, and has accordingly been referred to as “pseudoinvasion.” Features favoring “pseudoinvasion” over true IBC include expression of myoepithelial markers (see immunohistochemistry) in cells nests, low nuclear grade, dense eosinophilic stroma, and close association with a sclerosed IDP (L/C ST). See the images below.

The primary use of immunohistochemistry in IDP (L/C ST) is to highlight myoepithelial cells, which are useful in distinguishing it from IPC, papillary DCIS, and IBC. The myoepithelial cells express typical myoepithelial markers, including p63, CD10, calponin, smooth muscle myosin heavy chain, and smooth muscle actin (SMA), as well as mammary basal cell markers, such as CK5/6, CK14, and CK17. See the images below.

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Joshua I Warrick, MD Fellow in Surgical Pathology, Department of Pathology, University of Michigan Medical School

Joshua I Warrick, MD is a member of the following medical societies: American Society for Clinical Pathology, College of American Pathologists

Disclosure: Nothing to disclose.

D Craig Allred, MD Professor, Department of Pathology and Immunology, Director of Breast Pathology, Washington University School of Medicine

D Craig Allred, MD is a member of the following medical societies: American Association for Cancer Research, College of American Pathologists, United States and Canadian Academy of Pathology, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

D Craig Allred, MD Professor, Department of Pathology and Immunology, Director of Breast Pathology, Washington University School of Medicine

D Craig Allred, MD is a member of the following medical societies: American Association for Cancer Research, College of American Pathologists, United States and Canadian Academy of Pathology, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Large, Central Intraductal Papillomas 

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