Case 1D -

Intraductal papilloma

History: This core needle biopsy specimen was performed in a 52 year old woman with a subareolar mass. Ultrasound showed a solid, homogenously hypoechoic mass. What is your diagnosis? What is your recommendation? Case #1D - Figure 1 Diagnosis: Intraductal papilloma. Recommendation: If histopathologic findings and imaging concordant and the patient is asymptomatic, then it may be appropriate to follow the patient and recommend six month follow up. Discussion: Papillary lesions of the breast represent a spectrum of entities, both benign and malignant, with different clinical presentations and imaging appearances. The prognosis depends on the number of lesions and the presence of epithelial proliferation. There is little or no evidence that women with single, central papillomas have a significant increased risk of developing breast carcinoma. However, multiple papillomas may be associated with concurrent atypical ductal hyperplasia and in situ carcinoma, thereby carrying an increased risk of subsequent malignancy. The most common papillary lesion is the solitary intraductal papilloma. This benign neoplasm arises in the major ducts in the periareolar or subareolar region and a common cause of clinically significant nipple discharge. Microscopically, papillomas are composed of well-defined fibrovascular cores covered by the usual two population of cells, although many times, the myoepithelium is not easily seen. Apocrine metaplasia is often present as well as areas of fibrosis and sclerosis. The breast imaging features of papillary cancer can overlap with those of the benign more common solid, central intraductal papilloma. The term intracystic papillary carcinoma, encysted noninvasive papillary carcinoma and in situ papillary carcinoma are synonymous terms referring to malignant lesions with an underlying structure of a papilloma. These tumors comprise approximately 1-2% of all breast carcinomas and are more common in the older population. Grossly, intracystic papillary carcinomas are usually well circumscribed, encapsulated and larger than benign intraductal papillomas. Microscopically, the tumor is well defined with a dense collagenous fibrous capsule. The underlying tumor has a microscopic growth pattern that is predominantly frond forming, but in some cases, the papillary structures may not be evident and the tumor may exhibit a more solid papillary pattern. The distinction between a benign intraductal papilloma and papillary carcinoma is determined by uniform cytology of the cells and architectural growth pattern. However, with that said, papillary carcinoma arising in a papilloma is quite challenging diagnostically. These tumors tend to retain areas of benign papilloma and contain a spectrum of epithelial proliferation from atypical hyperplasia to carcinoma. Wide local excision is probably adequate therapy if no extension of in situ carcinoma is beyond the main lesion. Invasive papillary carcinoma occurs infrequently and often is only a small focus of stromal invasion. Solitary masses may be seen mammographically, sometimes with satellite nodules. Mammographic distinction between invasive and intracystic carcinoma is difficult because the small focus of invasion either is not detected or cannot be differentiated from the focal irregular margin of some intracystic tumors. The diagnosis of a papillary lesion on core needle biopsy ranges from 1.5-3.0%. Similar to the finding of atypical lobular hyperplasia, lobular carcinoma in situ, and radial scar at core needle biopsy, there is minimal data on clinical outcome when papillary lesions are diagnosed on core needle biopsy. At present, there are only a few published studies and multiple abstracts that have addressed this question. The studies correlating core needle biopsy and open biopsy have been contradictory and most believe that the diagnosis of a papillary lesion by core needle biopsy is an indication for surgical excision until more data is available. In 1999, Liberman et al. retrospectively reviewed 1,077 consecutive core needle biopsies. Thirty-four (3%) cases were diagnosed as a papillary lesion. Follow up was available in 26 (76.4%) of 34 cases. Twenty-two cases had surgical correlation and 4 cases had a minimum of two years mammographic follow up. The histologic findings of the core needle biopsies of these 26 lesions were benign in 9 (34.6%), atypical in 10 (38.4%), and malignant in 7 (27%). Of the 9 lesions diagnosed benign, 7 were papillomas and 2 showed papillomatosis. No carcinoma was identified at open surgical biopsy in the 7 lesions yielding benign papilloma at core needle biopsy. However, one (50%) of two cases diagnosed as papillomatosis at core needle biopsy revealed ductal carcinoma in situ at excisional biopsy. Surgical biopsy was recommended in this case due to the mammographic-histologic discordance. The 10 papillary lesions with atypical hyperplasia, open surgical biopsy revealed atypical ductal hyperplasia in 5 (50%) cases, benign findings without atypia in 2 (20%) cases, and intraductal carcinoma in 3 (30%) cases. Of the 7 lesions yielding ductal carcinoma in situ at core needle biopsy, all cases had ductal carcinoma in situ at open surgical biopsy with 3 (43%) cases also having invasive carcinoma. The diagnosis of large benign papilloma from a noninvasive papillary carcinoma by core needle biopsy may on occasion cause diagnostic difficulties. Nonetheless, the authors suggest that core needle biopsy can provide adequate samples to differentiate between a papilloma and papillary carcinoma and that the diagnosis of a benign papillary lesion can be reliable when concordant with the mammographic findings. Ioffe et al. also examined the reliability of core needle biopsy in accurately diagnosing papillary lesions. They identified 37 (2.8%) papillary lesions in 1,327 consecutive core needle biopsies. Of the 37 papillary lesions, 28 (75.6%) cases rendered a benign diagnosis, 4 (10.8%) cases revealed atypia, and 5 (13.5%) cases were malignant. Excisional biopsy was available in 8 of the 28 cases with a diagnosis of a benign intraductal papilloma. Five (17.9%) of these 8 lesions were underestimated at core needle biopsy. In situ carcinoma was identified in 3 cases and atypical ductal hyperplasia in 2 cases. Three of the four lesions diagnosed at core needle biopsy as atypical went to open biopsy and all three were underestimated at core needle biopsy. One case was ductal carcinoma in situ and 2 cases were invasive carcinoma at open surgical biopsy. All 5 malignant lesions remained malignant at excisional biopsy. Due to the high incidence of malignant or atypical lesions at excision of benign papillary lesion at core needle biopsy, the authors suggested a more aggressive approach should be taken in the management of these patients. A study at Mayo Clinic was undertaken to determine if it is justified to perform surgical excision on all papillary lesions or whether there are morphologic features found at the time of core needle biopsy that could be useful in determining which lesions should undergo surgical excision. Fifty-eight (2.8%) papillary lesions were identified in 2,067 consecutive core needle biopsies. Surgical correlation was available in 24 cases and a minimum of one year mammographic follow up was available in 30 cases, for a total of 54 (93.1%) papillary lesions with surgical or mammographic follow up. Histologic review was available in all 58 cases. Multiple morphologic features were assessed in the breast core biopsy and included apocrine change, calcifications, sclerosis, hemosiderin deposition, necrosis and mitotic activity. When present, the surrounding uninvolved breast tissue was evaluated. The surgical excisional biopsy was evaluated for the presence or absence of a papillary lesion, presence or absence of a biopsy site, lesion size, and similar histologic features assessed in the breast core needle biopsy. The histology of the core needle biopsy revealed benign findings in 48 (82.8%) cases, atypical in 7 (12.1%) cases, and malignant in 3 (5.2%) cases. Of the 48 cases with a benign diagnosis at core needle biopsy, 14 cases confirmed a benign process at open biopsy and 30 cases had mammographic follow up with no change. Of the 10 cases diagnosed as atypical or malignant on core breast biopsy, all underwent surgical excision. Eight cases showed ductal carcinoma in situ and two cases revealed invasive carcinoma; no cases rendered an atypical or benign diagnosis. Of the morphologic features assessed, sclerosis was significantly associated (p=0.0384) with a benign diagnosis at core needle biopsy. In contrast, hemosiderin deposition and large lesion size was statistically significant (p=0.008) for predicting malignancy. It is our opinion, that when concordant with imaging findings, the histology of the breast core biopsy proves to be accurate in diagnosing a benign papillary lesion. The presence of certain histologic features, such as sclerosis or hemosiderin deposition, may aid in the characterization of the papillary lesion. Ivan et al. recently reported that cellular monotony, lack of myoepithelial cells, and cytologic atypia are the most precise histologic features that may help in predicting carcinoma and atypical papillomas (p<0.0001) than mitotic activity. Overall and similar to previous studies, when the core needle biopsy reveals atypical or malignant histologic findings, surgical excision is indicated. Most importantly, all benign lesions with or without excisional biopsy were still benign at last study follow up. This finding is similar to studies designed by Rosen et al. and Ivan et al. that reported when the histologic diagnosis is benign and there is imaging-histologic concordance, these lesions may be safely managed with imaging follow-up rather than with surgical excision. Lawton and Agoff in the recent USCAP abstracts looked at 28 papillary lesions diagnosed on core needle biopsy. Their conclusion was that benign papillary lesions can be accurately diagnosed on core needle biopsy. No benign papillary lesion diagnosed on core needle biopsy was atypical or malignant at excisional biopsy or in long-term clinical/imaging follow up. However, additional long-term studies are still required to evaluate the clinical course of benign papillary lesions that are not excised after breast core needle biopsy. As mentioned before, papillary lesions are problematic because studies correlating core needle biopsy with open biopsy is contradictory. Below is a summary of all results of papillary lesions diagnosed on core needle biopsy and surgical biopsy findings and/or mammographic follow up. Summary of Surgical Biopsy Findings and Mammographic Follow Up in Women with Papillary Lesion at Core Needle Biopsy* Core Bx No. Excised/Mammo FU Excisional Biopsy Benign Atypical Malignant Benign 162 148 (92%) 7 (4%) 7 (4%) Atypical 72 14 (20%) 24 (33%) 34 (47%) Malignant 35 0 1 (3%) 34 (97%) *Liberman (1999), Ioffe (2000), Philpotts (2000), Bazzochia (2001), Mercado (2001), Rajendiran (2001), Lawton (2004), Mayo Clinic (unpublished) As you can see, the majority of papillary lesions diagnosed as benign remain benign at open biopsy or mammographic follow up. However, there is a 8% chance of finding atypia or malignancy at open biopsy. On the other hand, the finding of malignant papillary lesion at core needle biopsy is confirmed at open biopsy. More importantly, it is strongly recommended that those papillary lesions diagnosed as atypical be excised, since 80% will be found to have in situ or invasive carcinoma at open biopsy. Clinical history including the age of patient and whether the patient is symptomatic together with imaging studies as to the size of the lesion may prove to be helpful in management of papillary lesions diagnosed on core needle biopsy. However, until more data becomes available, many studies recommend excision for all papillary lesions even the papillary lesions with completely benign features on core needle biopsy. A variety of studies have investigated the role of immunohistochemistry (p63 and cytokeratin 5/6) to help improve accuracy of papillary lesions on core needle biopsy. Ali et al. examined the role of p63, a nuclear transcription factor which is expressed in mammary myoepithelial cells, assess whether this ancillary study could help in the diagnosis of papillary lesions on core needle biopsy. It was their opinion that the amount of p63 immunostaining allowed a more confident distinction between benign and atypical/malignant papillary lesions, but a potential for sampling error in benign papillomas remained. Their final recommendation was to excise when there is focal epithelial proliferation in a papilloma with decreased/absent p63 staining. In the recent USCAP abstracts, Nawgiri and colleagues studied the use of cytokeratin 5/6 in papillary lesions. Thirty papillary lesions were diagnosed on core needle biopsy. Cytokeratin 5/6 was evaluated in the luminal epithelial component and the myoepithelial component. Their results shows that all (12/12) benign papillary lesions showed positive immunoreactivity with cytokeratin 5/6. In contrast, 70% of papillary lesions with atypia (7/10) and all cases (8/8) papillary carcinoma in situ lacked cytokeratin 5/6 immunoexpression in the luminal epithelial component (p<0.001). However, there was variable cytokeratin 5/6 expression in the myoepithelial component ranging from absent to strong staining in the papillary lesions with atypia and carcinoma in situ. Overall, they claim there might be some usefulness in applying cytokeratin 5/6 to papillary lesions on core needle biopsy to help distinguish benign papillary lesions form atypical/in situ lesions. As with all ancillary tests used in making a diagnosis, immunohistochemistry should not replace standard H&E morphology. References: Agoff SN and Lawton TJ. Papillary lesions of the breast with and without atypical ductal hyperplasia. Can we accurately predict benign behavior from core needle biopsy? AJCP 2004; 1222:440-443. Bazzocchi M, Berra I, Francescutti GE, Del Frate C, Zuiani C, Puglisi F, Di Loreto C. Papillary lesions of the breast: Diagnostic imaging and contribution of percutaneous needle biopsy with 14-gauge needle. Radiol Med 2001; 101:424-431. 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