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Large, Central Intraductal Papillomas 

  • Author: Joshua I Warrick, MD; Chief Editor: D Craig Allred, MD  more...
 
Updated: Jan 17, 2014
 

Definition

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.

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Epidemiology

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.

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Etiology

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.

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Clinical Features and Imaging

Presentation

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]

Clinical relevance

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]

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Gross Description

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.

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Microscopic Description

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.

Figure 1 (20x): IDP (L/C ST) with a multifocal app Figure 1 (20x): IDP (L/C ST) with a multifocal appearance.

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

Figure 2 (200x): IDP (L/C ST) with a branching, fr Figure 2 (200x): IDP (L/C ST) with a branching, frond-like fibrovascular core. Note myoepithelial cells are present beneath the epithelium (arrow).
Figure 3 (200x): IDP (L/C ST) with a fibrovascular Figure 3 (200x): IDP (L/C ST) with a fibrovascular core showing an adenoma-like appearance. Note the myoepithelial cell layer (arrow).

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

Figure 4a (20x): IDP (L/C ST) in a cystically dila Figure 4a (20x): IDP (L/C ST) in a cystically dilated duct.
Figure 4a (200x): Same IDP (L/C ST) as figure 4b. Figure 4a (200x): Same IDP (L/C ST) as figure 4b. This example shows apocrine metaplasia of the epithelial component.
Figure 5a (20x): IDP (L/C ST). Figure 5a (20x): IDP (L/C ST).
Figure 5b (100x): Same IDP (L/C ST) as figure 5a. Figure 5b (100x): Same IDP (L/C ST) as figure 5a. UDH involves the IDP at the top of the figure (arrow).
Figure 5c (400x). Same IDP (L/C ST) as figure 5a. Figure 5c (400x). Same IDP (L/C ST) as figure 5a. Other areas of the IDP show more florid UDH.

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

Figure 6a (20x). IDP (L/C ST). Figure 6a (20x). IDP (L/C ST).
Figure 6b (200x). Same IDP (L/C ST) as figure 6a. Figure 6b (200x). Same IDP (L/C ST) as figure 6a. This example shows a benign epithelial proliferation with apocrine metaplasia.

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).

Figure 7a (20x): IDP (L/C ST) that is partially sc Figure 7a (20x): IDP (L/C ST) that is partially sclerosed.
Figure 7b (200x): same IDP (L/C ST) as figure 7a. Figure 7b (200x): same IDP (L/C ST) as figure 7a. Epithelium has become entrapped within the sclerotic area.
Figure 8 (40x): IDP (L/C ST) showing sclerosis at Figure 8 (40x): IDP (L/C ST) showing sclerosis at the periphery.

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.

Figure 9a (20x): IDP (L/C ST) showing UDH, abundan Figure 9a (20x): IDP (L/C ST) showing UDH, abundant apocrine metaplasia, and sclerosis.
Figure 9b (200x): same IDP as figure 9a. Sclerosis Figure 9b (200x): same IDP as figure 9a. Sclerosis and UDH are present.
Figure 9c (200x): same IDP as figure 9a. Sclerosis Figure 9c (200x): same IDP as figure 9a. Sclerosis and UDH involve this focus of the IDP. Myoepithelial cells are identified (arrow).
Figure 9d (200x): same IDP as figure 9a. This focu Figure 9d (200x): same IDP as figure 9a. This focus of the IDP is involved by a benign epithelial proliferation with apocrine metaplasia.
Figure 9e (400x): same IDP as figure 9a. Florid UD Figure 9e (400x): same IDP as figure 9a. Florid UDH involves the IDP.

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

Figure 10a (40x): Solid IDP (L/C ST) showing an ad Figure 10a (40x): Solid IDP (L/C ST) showing an adenoma-like proliferation.
Figure 10b (400x): same IDP as figure 10a. Promine Figure 10b (400x): same IDP as figure 10a. Prominent epithelial cell and myoepithelial cell layers are identified.

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).

Figure 11a (20x): Nipple adenoma. This example sho Figure 11a (20x): Nipple adenoma. This example shows an adenoma-like proliferation and squamous epithelium.
Figures 11b (100x). same nipple adenoma as 11a. Be Figures 11b (100x). same nipple adenoma as 11a. Benign epithelial hyperplasia with a micropapillary pattern involves the lesion (arrow).
Figures 11c (100x). same nipple adenoma as 11a. Mi Figures 11c (100x). same nipple adenoma as 11a. Micropapillary benign epithelial hyperplasia involves the lesion (arrow).
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Differential Diagnosis

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.

Figure 12a (20x): Intracystic papillary carcinoma Figure 12a (20x): Intracystic papillary carcinoma (IPC). The lesion consists of DCIS filling a cystically dilated space encased by a fibrous wall. Invasion beyond through the fibrous wall is not identified in this example.
Figure 12b (200x): same IPC as figure 12a. The DCI Figure 12b (200x): same IPC as figure 12a. The DCIS in this example shows both papillary (blue arrow) and micropapillary (black arrow) morphologies. Note the absence of a myoepithelial layer in the area with papillary morphology.

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.

Figure 13a (100x): Papillary DCIS. This example sh Figure 13a (100x): Papillary DCIS. This example shows a small space containing a papillary proliferation with delicate fibrovascular cores.
Figure 13b (400x). same DCIS as figure 13a. At hig Figure 13b (400x). same DCIS as figure 13a. At high power, the absence of a myoepithelial layer is identified, confirming the diagnosis of papillary DCIS.

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.

Figure 14a (100x). IDP (L/C ST) with sclerosis and Figure 14a (100x). IDP (L/C ST) with sclerosis and "pseudoinvasion." The epithelium entrapped in the sclerotic area of the lesion could be mistaken for IBC. However, recognizing the proximity of this entrapped epithelium to a sclerosed IDP (L/C ST) should dissuade one from the diagnosis of IBC.
Figure 14b (400x): same IDP (L/C ST) as figure 14a Figure 14b (400x): same IDP (L/C ST) as figure 14a. The area of "pseudoinvasion" is concerning for IBC at high power. However, the overall low power appearance of the lesion should clarify the diagnosis.
Figure 15a (40x): IDP (L/C ST) with sclerosis and Figure 15a (40x): IDP (L/C ST) with sclerosis and pseudoinvasion on core needle biopsy.
Figure 15b (400x): same IDP (L/C ST) as figure 15a Figure 15b (400x): same IDP (L/C ST) as figure 15a. Epithelial and myoepithelial cell (arrow) layers can be seen at high power in this example, confirming the entrapped component is benign.
Figure 16a (100x): IDP (L/C ST) with sclerosis and Figure 16a (100x): IDP (L/C ST) with sclerosis and pseudoinvasion. In this example, the sclerotic area is more cellular than previous example, increasing the concern for IBC.
Figure 16b (400x): same IDP as figure 16a. A defin Figure 16b (400x): same IDP as figure 16a. A definite myoepithelial cell layer is not seen on standard hematoxylin and eosin stained sections at high power.
Figure 16c (400x): Smooth muscle actin (SMA) highl Figure 16c (400x): Smooth muscle actin (SMA) highlights a definite myoepithelial layer in the nests of cells, confirming they are benign entrapped components of the adjacent IDP. SMA expression is also seen in stromal myofibroblasts.
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Immunohistochemistry

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.

Figure 17 (400x): p63 shows nuclear expression in Figure 17 (400x): p63 shows nuclear expression in the myoepithelial cells of IDP (L/C ST)
Figure 18 (400x): SMA shows strong cytoplasmic exp Figure 18 (400x): SMA shows strong cytoplasmic expression in the myoepithelial cell layer of IDP (L/C ST).
Figure 19 (400x): CK 5/6 shows expression in both Figure 19 (400x): CK 5/6 shows expression in both the myoepithelial cell layer (black arrow) and in a subset of the overlying epithelial cells (blue arrow).
Figure 20a (40x): Papillary DCIS with fused fibrov Figure 20a (40x): Papillary DCIS with fused fibrovascular cores.
Figure 20b (400x): Same DCIS as 20a. At high power Figure 20b (400x): Same DCIS as 20a. At high power, fused fibrovascular cores and low-grade cytology are identified.
Figure 20c (400x): Same DCIS as figure 20a. SMA ex Figure 20c (400x): Same DCIS as figure 20a. SMA expression is seen in the vessels lining in the fibrovascular cores, but a definite myoepithelial cell layer is not seen.
Figure 20d (400x): Same DCIS as figure 20a. p63 ex Figure 20d (400x): Same DCIS as figure 20a. p63 expression is not seen, confirming the diagnosis of DCIS.
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Contributor Information and Disclosures
Author

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.

Coauthor(s)

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.

Chief Editor

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.

References
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  2. Ohuchi N, Abe R, Kasai M. Possible cancerous change of intraductal papillomas of the breast. A 3-D reconstruction study of 25 cases. Cancer. 1984 Aug 15. 54(4):605-11. [Medline].

  3. Sohn V, Keylock J, Arthurs Z, et al. Breast papillomas in the era of percutaneous needle biopsy. Ann Surg Oncol. 2007 Oct. 14(10):2979-84. [Medline].

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  5. Lewis JT, Hartmann LC, Vierkant RA, et al. An analysis of breast cancer risk in women with single, multiple, and atypical papilloma. Am J Surg Pathol. 2006 Jun. 30(6):665-72. [Medline].

  6. Di Cristofano C, Mrad K, Zavaglia K, et al. Papillary lesions of the breast: a molecular progression?. Breast Cancer Res Treat. 2005 Mar. 90(1):71-6. [Medline].

  7. Lininger RA, Park WS, Man YG, et al. LOH at 16p13 is a novel chromosomal alteration detected in benign and malignant microdissected papillary neoplasms of the breast. Hum Pathol. 1998 Oct. 29(10):1113-8. [Medline].

  8. Gioffre Florio M, Manganaro T, Pollicino A, Scarfo P, Micali B. Surgical approach to nipple discharge: a ten-year experience. J Surg Oncol. 1999 Aug. 71(4):235-8. [Medline].

  9. Francis A, England D, Rowlands D, Bradley S. Breast papilloma: mammogram, ultrasound and MRI appearances. Breast. 2002 Oct. 11(5):394-7. [Medline].

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  14. Ahmadiyeh N, Stoleru MA, Raza S, Lester SC, Golshan M. Management of intraductal papillomas of the breast: an analysis of 129 cases and their outcome. Ann Surg Oncol. 2009 Aug. 16(8):2264-9. [Medline].

  15. Agoff SN, Lawton TJ. Papillary lesions of the breast with and without atypical ductal hyperplasia: can we accurately predict benign behavior from core needle biopsy?. Am J Clin Pathol. 2004 Sep. 122(3):440-3. [Medline].

  16. Liberman L, Tornos C, Huzjan R, Bartella L, Morris EA, Dershaw DD. Is surgical excision warranted after benign, concordant diagnosis of papilloma at percutaneous breast biopsy?. AJR Am J Roentgenol. 2006 May. 186(5):1328-34. [Medline].

  17. Lee CH, Philpotts LE, Horvath LJ, Tocino I. Follow-up of breast lesions diagnosed as benign with stereotactic core-needle biopsy: frequency of mammographic change and false-negative rate. Radiology. 1999 Jul. 212(1):189-94. [Medline].

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Figure 1 (20x): IDP (L/C ST) with a multifocal appearance.
Figure 2 (200x): IDP (L/C ST) with a branching, frond-like fibrovascular core. Note myoepithelial cells are present beneath the epithelium (arrow).
Figure 3 (200x): IDP (L/C ST) with a fibrovascular core showing an adenoma-like appearance. Note the myoepithelial cell layer (arrow).
Figure 4a (20x): IDP (L/C ST) in a cystically dilated duct.
Figure 4a (200x): Same IDP (L/C ST) as figure 4b. This example shows apocrine metaplasia of the epithelial component.
Figure 5a (20x): IDP (L/C ST).
Figure 5b (100x): Same IDP (L/C ST) as figure 5a. UDH involves the IDP at the top of the figure (arrow).
Figure 5c (400x). Same IDP (L/C ST) as figure 5a. Other areas of the IDP show more florid UDH.
Figure 6a (20x). IDP (L/C ST).
Figure 6b (200x). Same IDP (L/C ST) as figure 6a. This example shows a benign epithelial proliferation with apocrine metaplasia.
Figure 7a (20x): IDP (L/C ST) that is partially sclerosed.
Figure 7b (200x): same IDP (L/C ST) as figure 7a. Epithelium has become entrapped within the sclerotic area.
Figure 8 (40x): IDP (L/C ST) showing sclerosis at the periphery.
Figure 9a (20x): IDP (L/C ST) showing UDH, abundant apocrine metaplasia, and sclerosis.
Figure 9b (200x): same IDP as figure 9a. Sclerosis and UDH are present.
Figure 9c (200x): same IDP as figure 9a. Sclerosis and UDH involve this focus of the IDP. Myoepithelial cells are identified (arrow).
Figure 9d (200x): same IDP as figure 9a. This focus of the IDP is involved by a benign epithelial proliferation with apocrine metaplasia.
Figure 9e (400x): same IDP as figure 9a. Florid UDH involves the IDP.
Figure 10a (40x): Solid IDP (L/C ST) showing an adenoma-like proliferation.
Figure 10b (400x): same IDP as figure 10a. Prominent epithelial cell and myoepithelial cell layers are identified.
Figure 11a (20x): Nipple adenoma. This example shows an adenoma-like proliferation and squamous epithelium.
Figures 11b (100x). same nipple adenoma as 11a. Benign epithelial hyperplasia with a micropapillary pattern involves the lesion (arrow).
Figures 11c (100x). same nipple adenoma as 11a. Micropapillary benign epithelial hyperplasia involves the lesion (arrow).
Figure 12a (20x): Intracystic papillary carcinoma (IPC). The lesion consists of DCIS filling a cystically dilated space encased by a fibrous wall. Invasion beyond through the fibrous wall is not identified in this example.
Figure 12b (200x): same IPC as figure 12a. The DCIS in this example shows both papillary (blue arrow) and micropapillary (black arrow) morphologies. Note the absence of a myoepithelial layer in the area with papillary morphology.
Figure 13a (100x): Papillary DCIS. This example shows a small space containing a papillary proliferation with delicate fibrovascular cores.
Figure 13b (400x). same DCIS as figure 13a. At high power, the absence of a myoepithelial layer is identified, confirming the diagnosis of papillary DCIS.
Figure 14a (100x). IDP (L/C ST) with sclerosis and "pseudoinvasion." The epithelium entrapped in the sclerotic area of the lesion could be mistaken for IBC. However, recognizing the proximity of this entrapped epithelium to a sclerosed IDP (L/C ST) should dissuade one from the diagnosis of IBC.
Figure 14b (400x): same IDP (L/C ST) as figure 14a. The area of "pseudoinvasion" is concerning for IBC at high power. However, the overall low power appearance of the lesion should clarify the diagnosis.
Figure 15a (40x): IDP (L/C ST) with sclerosis and pseudoinvasion on core needle biopsy.
Figure 15b (400x): same IDP (L/C ST) as figure 15a. Epithelial and myoepithelial cell (arrow) layers can be seen at high power in this example, confirming the entrapped component is benign.
Figure 16a (100x): IDP (L/C ST) with sclerosis and pseudoinvasion. In this example, the sclerotic area is more cellular than previous example, increasing the concern for IBC.
Figure 16b (400x): same IDP as figure 16a. A definite myoepithelial cell layer is not seen on standard hematoxylin and eosin stained sections at high power.
Figure 16c (400x): Smooth muscle actin (SMA) highlights a definite myoepithelial layer in the nests of cells, confirming they are benign entrapped components of the adjacent IDP. SMA expression is also seen in stromal myofibroblasts.
Figure 17 (400x): p63 shows nuclear expression in the myoepithelial cells of IDP (L/C ST)
Figure 18 (400x): SMA shows strong cytoplasmic expression in the myoepithelial cell layer of IDP (L/C ST).
Figure 19 (400x): CK 5/6 shows expression in both the myoepithelial cell layer (black arrow) and in a subset of the overlying epithelial cells (blue arrow).
Figure 20a (40x): Papillary DCIS with fused fibrovascular cores.
Figure 20b (400x): Same DCIS as 20a. At high power, fused fibrovascular cores and low-grade cytology are identified.
Figure 20c (400x): Same DCIS as figure 20a. SMA expression is seen in the vessels lining in the fibrovascular cores, but a definite myoepithelial cell layer is not seen.
Figure 20d (400x): Same DCIS as figure 20a. p63 expression is not seen, confirming the diagnosis of DCIS.
 
 
 
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