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Intracystic Papillary Carcinoma of the Breast: Differential Diagnosis and Management

Intracystic Papillary Carcinoma of the Breast: Differential Diagnosis and Management

SECOND OPINION
Multidisciplinary Consultations on Challenging Cases
The University of Colorado Health Sciences Center holds weekly second opinion conferences focusing on cancer cases that represent most major cancer sites. Patients seen for second opinions are evaluated by an oncologist. Their history, pathology, and radiographs are reviewed during the multidisciplinary conference, and then specific recommendations are made. These cases are usually challenging, and these conferences provide an outstanding educational opportunity for staff, fellows, and residents in training.

The second opinion conferences include actual cases from genitourinary, lung, melanoma, breast, neurosurgery, and medical oncology. On an occasional basis, ONCOLOGY will publish the more interesting case discussions and the resultant recommendations. We would appreciate your feedback; please contact us at second.opinion@uchsc.edu.

E. David Crawford, MD
Al Barqawi, MD
Guest Editors

University of Colorado Health Sciences Center
Univeristy of Colorado Cancer Center Denver, Colorado

In this installment of Second Opinion we present a case of intracystic papillary carcinoma of the breast associated with low-grade ductal carcinoma in situ in a young woman. This is a distinct subtype of intraductal carcinoma that typically presents in postmenopausal women with a favorable prognosis. The differential diagnosis, diagnostic modalities and treatment implications are discussed.

Clinical History

FIGURE 1A

Intracystic Papillary Carcinoma of the Breast—Appearance of hypoechoic mass on ultrasound (A). Fine-needle aspiration of intracystic papillary carcinoma (IPC) at 20x.
FIGURE 1B

Intracystic Papillary Carcinoma of the Breast—Appearance of hypoechoic mass on ultrasound (B). Fine-needle aspiration of intracystic papillary carcinoma (IPC) at 40x.

A 33-year-old premenopausal, nulliparous woman presented to Dr. Christina Finlayson (Surgery) in the breast clinic for evaluation of a palpable left breast mass. On physical exam, the breasts were noted to be symmetric with no obvious skin or nipple abnormalities. On palpation, a 1.5-cm irregular, mobile mass was detected at the 4-to-6 o'clock position in the left breast. On mammographic studies the left breast was found to be extremely dense with no evidence of malignancy. A recommendation for an ultrasound was made in order to evaluate the clinically palpable mass. The patient was subsequently referred for an ultrasound evaluation by Dr. Lara Hardesty (Radiology). The ultrasound demonstrated a hypoechoic area with a thin capsule and smooth border consistent with a solid mass measuring 1.9 X 1.3 X 0.9 cm (Figure 1A). Based on these results, the patient was referred to Dr. Meenakshi Singh (Pathology) for a fine-needle aspiration procedure (FNA) and to Dr. Finlayson for subsequent surgical excision.

Operative and Pathologic Findings

FIGURE 1C

Intracystic Papillary Carcinoma of the Breast—Appearance of hypoechoic mass on ultrasound (C). Subgross appearance of the well circumscribed IPC on hematoxylin-and-eosin–stained slide.
FIGURE 1D

Intracystic Papillary Carcinoma of the Breast—Appearance of hypoechoic mass on ultrasound (D). IPC with fibrosed cyst wall and adjacent low-grade ductal carcinoma in situ at 20x.
FIGURE 1E

Intracystic Papillary Carcinoma of the Breast—Appearance of hypoechoic mass on ultrasound (E). Displaying low-grade monomorphic nuclei at 40x.

Dr. Mugler: What were the FNA findings?

Dr. Singh: On clinical exam, the mass was 1.5 cm and mobile with irregular contours. The aspirate smears were very cellular, with sheets and papillary configurations of overlapping epithelial cells and many detached single cells (Figure 1B), some with nuclear atypia, and many with intact cytoplasm. (Figure 1C). There were many macrophages in the background, suggesting a cystic component. Malignancy could not be excluded based on these findings, and an excisional biopsy was recommended.

Dr. Mugler: What were the gross findings of the excisional specimen?

Dr. Singh: A 2.3 X 1.3 X 1.2 cm ovoid piece of breast tissue was received that on serial sections showed a firm discrete, white surface. A cyst cavity was not appreciated.

Dr. Mugler: What were the histologic findings in the resection specimen?

Dr. Singh: The hematoxylin-and-eosin stained sections showed a well circumscribed, 1.2-cm lesion (Figure 1D). This was composed of a dilated duct surrounded by a fibrosed wall (Figure 1E). Within this space was a solid type of a papillary neoplasm with fibrovascular cores devoid of a myoepithelial cell layer. These cores were lined by sheets of round to oval cells with distinct cell borders and monotonous, low-grade nuclei (Figures 1E, 1F). Mitoses were infrequent.

The cystic nature of the tumor was appreciated in multiple sections at the periphery of the lesion (Figure 1E). The lesion was diagnosed as an intracystic papillary carcinoma (IPC). In the fibrotic cyst wall, there were a few entrapped histologically normal glands (Figure 1G). This presented a pseudoinvasive picture, but no true invasion was identified. The surrounding ducts, however, were expanded by low-grade ductal carcinoma in situ (DCIS), as shown in Figure 1E. The IPC focally extended to the surgical margin, but the surrounding low-grade DCIS did not.

Diagnostic Considerations

Features of IPC

Dr. Mugler: What is intracystic papillary carcinoma?

FIGURE 1F

Intracystic Papillary Carcinoma of the Breast—Appearance of hypoechoic mass on ultrasound (F). Entrapped benign glands within the fibrosed cyst wall of the IPC simulating invasion.
FIGURE 1G

Intracystic Papillary Carcinoma of the Breast—Appearance of hypoechoic mass on ultrasound (G). Fine-needle aspiration of a fibroadenoma at 40x (inset at 20x).

Dr. Singh: Papillary lesions in the breast encompass a spectrum of lesions that include benign papilloma, papillary variants of DCIS, and invasive papillary carcinoma.[1] IPC is a more recently recognized subtype of DCIS that has the structure of a papilloma with epithelium characterized by features sufficient for a diagnosis of carcinoma in situ.[1-4] It is essentially a localized form of intraductal papillary carcinoma that exists in a cystically dilated duct.[5] It may exist as an isolated focus, be associated with DCIS in the surrounding ducts in 40% of cases,[2,5] or show true invasion.

When invasive carcinoma arises in an encysted papillary carcinoma, it is almost always detected at the periphery of the tumor. This can have various growth patterns and is rarely papillary in architecture.[6-9] It is important, however, to note the difference between true invasion and pseudoinvasion. The latter finding is common and results from benign glandular tissue becoming entrapped in the fibrosis surrounding the cystically dilated duct, as was seen in this case.

On FNA, the aspirates are typically highly cellular with complex papillae and single-columnar cells.[1,10] Macrophages tend to be a constant feature.[10] Nuclear hyperchromasia, stratification, and background cell characteristics such as the lack of apocrine metaplasia and the presence of foamy macrophages may provide additional diagnostic clues that the lesion represents IPC. Some, however, believe that it is difficult, if not impossible, to distinguish between benign and malignant papillary lesions of the breast on FNA, as there are no reliable and consistent features that help distinguish between them.[10] Indeed, IPC often requires an excisional biopsy before a definite diagnosis can be rendered.[11-12]

Differential Diagnosis

Dr. Mugler: What is the differential diagnosis for a tumor with this appearance on FNA?

FIGURE 1H

Intracystic Papillary Carcinoma of the Breast—Appearance of hypoechoic mass on ultrasound (H). Benign intraductal papilloma at 40x.

Dr. Singh: A fibroadenoma is in the differential diagnosis based on the cytology, clinical exam, and age of the patient. FNAs of fibroadenomas can also be very cellular but should show two distinct cell populations with both epithelial and myoepithelial cells, the former arranged in a classic "staghorn" configuration (Figure 1H). Naked oval nuclei are seen in the background. Fibroadenomas, although benign, can be problematic to diagnose on FNA specimens because of their abundant cellularity. In a review of 2,197 FNA specimens from the breast, fibroadenomas constituted the largest single cause of equivocal diagnoses.[12] In the same series, other lesions in the differential diagnosis of fibroadenomas included intracystic papillary carcinoma, solitary intraductal papillomas, and atypical ductal hyperplasia (ADH).[12]

In this case, the finding of detached single cells with intact cytoplasm was the most worrisome feature. The papillary configuration of cell clusters also raises the differential of a benign papilloma vs a malignant papillary lesion. Both can share features of high cellularity, discohesiveness, isolated epithelial cells with intact cytoplasm, columnar appearance of cells, relative absence of anisonucleosis, foamy macrophages, and a granular background.[12] Complicating this picture is the fact that intraductal papillomas may also harbor areas of atypical hyperplasia and DCIS,[8,9,13] and this distinction cannot be made on an FNA specimen.

FIGURE 1I

Intracystic Papillary Carcinoma of the Breast—Appearance of hypoechoic mass on ultrasound (I). A p63 immunostain delineates myoepithelial cells (inset at 40x).

Features that may suggest a diagnosis of papillary carcinoma include a monomorphic cell population, mild to moderate pleomorphism, increased mitotic activity, and increased number of single cells with intact cytoplasm.[9,12] It has been suggested by some that the cytologic characteristics of papillomas and papillary carcinomas are indeed distinctive.[1] It has also been suggested that a needle core biopsy is a better diagnostic tool and can reliably distinguish between benign and malignant papillary lesions of the breast.[14] However, both these assertions have been questioned by others[9,10,12] on the basis of potential for sampling error in these sometimes heterogeneous lesions.

On histologic sections, benign intraductal papillomas are easily identified by the presence of benign epithelium covering fibrovascular stalks with an intervening myoepithelial layer (Figure 1I).[9,15] The myoepithelial layer is also usually retained in benign papillomas with partial involvement by ADH or DCIS.[9] In IPC and invasive carcinoma, however, the myoepithelial layer should not be present, and its absence can be confirmed with immunostains such as muscle-specific actin, p63, and calponin.[4] Since papillary carcinomas are usually low-grade carcinomas, cytologic atypia alone may not be a useful criteria to distinguish between papilloma and carcinoma (Figures 1I vs 1F).

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