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2021

Best Cases from the AFIP Intracystic Papillary Carcinoma of the Breast1 EDITOR’S NOTE Everyone who has taken the course in radiologic pathology at the Armed Forces Institute of Pathology (AFIP) remembers bringing beautifully illustrated cases for accession to the Institute. In recent years, the staff of the Department of Radiologic Pathology has judged the “best cases” by organ system, and recognition is given to the winners on the last day of the class. With each issue of RadioGraphics, one or more of these cases are published, written by the winning resident. Radiologic-pathologic correlation is emphasized, and the causes of the imaging signs of various diseases are illustrated.

María Cristina Hernández Rodríguez, MD • Astrid López Secades, MD Jesús Martín Angulo, MD History

A 73-year-old woman presented with a palpable mass in the left breast. Physical examination revealed a 3 × 3-cm subareolar breast mass with associated retraction of the skin and nipple.

Imaging Findings

At mammography, a high-opacity mass of 4.5 cm with obscured margins and retraction of the skin and nipple was seen in the retroareolar region of the left breast (Fig 1). Mammography also showed coarse calcifications with a benign aspect, a finding suggestive of calcified fibroadenomas. Ultrasonography (US) revealed an oval and circumscribed complex mass of 4 cm, with macrolobulated margins. It was predominantly cystic and contained internal septa and a solid nodule of 2.2 cm (Fig 2). The lesion showed some posterior acoustic enhancement. Breast magnetic resonance (MR) imaging was performed to confirm the findings and to exclude multicentricity and multifocality. The examination was carried out with a 1.5-T imaging system equipped with a double breast coil. The lesion appeared as an oval, circumscribed, predominantly cystic mass with an associated lobulated soft-tissue mass projecting into the cystic lumen.

Abbreviations: ICPC = intracystic papillary carcinoma, MEC = myoepithelial cell RadioGraphics 2010; 30:2021–2027 • Published online 10.1148/rg.307105003 • Content Codes: From the Departments of Radiology (M.C.H.R., A.L.S.) and Pathology (J.M.A.), Hospital de Cabueñes, Calle de los Prados 395, 33203 Gijon, Asturias, Spain. Received January 5, 2010; revision requested January 28; final revision received March 25; accepted April 8. All authors have no financial relationships to disclose. Address correspondence to M.C.H.R. (e-mail: [email protected]). 1

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RSNA, 2010 • radiographics.rsna.org

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Figure 1.  Mediolateral oblique (a) and craniocaudal (b) mammograms of the left breast show a high-opacity mass (straight arrows) with obscured margins in the retroareolar region, with associated skin and nipple retraction (curved arrow). Arrowhead = coarse calcification suggestive of a calcified fibroadenoma.

On T1-weighted images, the tumor was predominantly hypointense due to its main cystic component, with slightly perceptible internal material (Fig 3a). On T2-weighted fat-saturated images, the lesion was hyperintense, and the internal solid mural mass had intermediate signal intensity (Fig 3b). Postcontrast dynamic study after intravenous administration of gadolinium contrast material showed fast enhancement of the solid portion of

Figure 2.  (a) US image shows the complex mass, which has a large cystic component (straight arrow). An irregular mural nodule (curved arrow) projects into the lumen. There is some posterior acoustic enhancement (arrowhead). (b) US image shows a septum (arrow) inside the cyst.

the lesion. The entire cyst wall showed thickening and enhancement (Fig 3c), as did the septa. The enhancement rate was greater than 100% during the first 2 minutes, followed by washout of contrast material (type III curve) (Fig 3d). No multifocality or multicentricity was detected, and no lymphadenopathy was demonstrated. The radiologic findings were all suspicious for malignancy, specifically a malignant papillary tumor.

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Figure 3.  Breast MR imaging. (a) Axial T1-weighted image (repetition time msec/echo time msec = 720/9.8, section thickness = 3 mm, matrix = 256 × 224, field of view = 36 × 36 cm) shows the hypointense mass in the retroareolar region of the left breast. Material of intermediate signal intensity (arrowhead) protrudes into the lumen of the lesion. Significant retraction of the nipple-areolar complex and skin is evident (arrow). (b) Axial T2-weighted fat-saturated image (6960/80.2, section thickness = 3 mm, matrix = 256 × 192, field of view = 36 × 36 cm) shows the predominantly cystic nature of the lesion, which is hyperintense (white arrow). The septum (black arrow) and the mural mass (*) are also seen. (c) Contrast material–enhanced dynamic T1-weighted threedimensional fast spoiled gradient-echo image (7.7/4.2, inversion time = 50.0 msec, section thickness = 3 mm, matrix = 256 × 192, field of view = 36 × 36 cm) shows fast enhancement of the solid portion of the lesion (arrowhead). The entire cyst wall and the septa are thickened and show enhancement. (d) The enhancement curve of the lesion shows a type III pattern. The maximum uptake peak of the solid mass occurred at 2 minutes after contrast material administration, with posterior washout.

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Pathologic Evaluation

Lumpectomy of the cyst in the left breast was performed, followed by axillary extirpation of the sentinel node. Intraoperative biopsy resulted in a lumpectomy specimen that weighed 55 g and measured 6 × 5 × 3 cm. Gross pathologic analysis of the cut specimen showed a cystic cavity full of solid papillary formations, some free and some attached to the wall of the cyst (Fig 4). The intraoperative diagnosis was intracystic papillary tumor. Results of the intraoperative biopsy of the sentinel node were indicative of benignity. Microscopic analysis of the tumor showed arborizing fibrovascular connective tracts coated by epithelium with a monotonous atypical cell population and with papillary architecture (Fig 5a). These cells demonstrated a low mitotic index. No necrosis or calcification was present. Foci of atypical hyperplasia and abundant areas of papilloma were also detected. Margins of resection were free. Additional immunohistochemical staining showed clear loss of MECs (Fig 5b) and a high rate of estrogen and progesterone receptors. On the basis of these findings, the pathologic diagnosis was intracystic papillary carcinoma (ICPC) of the breast.

Discussion

ICPC is a rare malignant tumor that accounts for 1%–2% of all breast carcinomas (1,2). Tumors of this type usually arise in dilated ducts, not in cysts, and are called intracystic only when the cystic component is relatively large, as in our case. The tumor usually does not demonstrate invasive growth, although several cases of invasive ICPC have been reported (3,4). This tumor may be uni- or multifocal (1) and can be found as a pure form or may be associated with ductal carcinoma in situ or invasive carcinoma (2,5). Clinically, ICPC usually appears in postmenopausal women, with an average age of onset of about 69.5 years (range, 27–99 years) (6), which is higher than that for the common types of breast cancer (3). It may manifest with no symptoms, as a slowly enlarging palpable mass (7), or as bloody nipple discharge (about 22%–34% of cases) (1,6,8). Retraction of the nipple and skin may be an associated clinical finding, which generally is associated with cancers that are large

Figure 4.  Photograph of the gross specimen shows a cystic cavity (arrow) full of papillary formations (arrowheads), some free and some attached to the wall, as well as septa (*).

enough to be palpable at physical examination (9). Although extremely rare, cases of ICPC in men have been reported in the literature (6,10), and it seems that more such cases have been detected in recent years. Mammographic findings are often nonspecific. ICPC is usually seen as a round, oval, or lobulated circumscribed mass because its appearance reflects the dilated duct or cyst rather than the internal tumor. It is most frequently situated in the retroareolar region (1,2,8,11). ICPCs tend to be larger than intracystic papillomas, but this finding does not necessarly help differentiate malignancy from a benign process (3). Spiculation is also a common feature (1,2,8,11), and nipple retraction may be detected (9). These findings are not always due to invasion and can be related to sclerosis and inflammation of the surrounding tissue, with resultant disruption of the regular rounded contour of the lesion, as occurred in our case. The cyst wall is typically thickened and fibrotic. Entrapment of malignant cells within a sclerotic wall can mimic an invasive process (12). Multiple masses may be present, often within one quadrant (4). Occasionally, satellite nodules, pleomorphic microcalcifications, or both are present (2,11). Based on the mammographic appearance alone, the differential diagnosis in the age range of these tumors includes cyst, mucinous or medullary carcinoma, hematoma, and metastasis (7).

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Figure 5.  (a) Photomicrograph (original magnification, ×100; hematoxylin-eosin stain) shows solid monotonous atypical cell proliferation with a papillary architecture. Arrow = frond. (b) Photomicrograph (original magnification, ×400; p63 stain) shows very low expression of the p63 marker (arrows), a finding suggestive of clear loss of myoepithelial cells (MECs).

At sonography, ICPC appears as single or multiple predominantly cystic masses, with or without septa, and with solid papillary masses projecting into the cystic lumen from the inner wall (1,7); the solid papillary masses have an irregular branching pattern with peripheral fronds (13). The tumor often demonstrates posterior acoustic enhancement (4) due to its predominantly cystic component. The presence of fluid-debris levels in the cyst is usually related to spontaneous bleeding (13), which results from ruptured capillaries in the cyst wall or hemorrhagic infarction of the tumor cells (1). Color Doppler sonography can show blood flow in the tumor owing to its vascular pedicle, a finding that can help differentiate it from a blood clot. Intracystic papillomas or ICPCs may be diagnosed with sonography if they do not occupy the entire cyst lumen. Otherwise, in the case of a solid ICPC, they are not distinguishable from other solid masses (10,14). Although much is known about the MR imaging appearances of the most frequent histologic breast cancer subtypes (ductal and lobular invasive carcinomas), much less is known about the MR imaging appearances of rare histologic types of breast cancer, such as papillary (15). Moreover, significant overlap exists among the MR imaging patterns of different papillary enti-

ties (14,16). Nevertheless, MR imaging does have high sensitivity for papillary lesions, enables confirmation of the solid and cystic components of the ICPC, is more reliable than US in ensuring that no other lesions have been overlooked, and allows good preoperative planning (11,14). Furthermore, breast MR imaging is a noninvasive diagnostic method. At breast MR imaging, the tumor usually appears as a round or oval mass with well-defined margins, an appearance that corresponds to its encapsulated gross appearance. The internal composition is typically heterogeneous, with multiple nodular masses of intermediate signal intensity projecting from the periphery into the lumen. The signal intensity also depends on the intracystic fluid composition: If the contents of the cyst are serous, it will have low signal intensity on T1-weighted images and high signal intensity on T2-weighted images; if the cyst has hemorrhagic contents, it will be hyperintense on both T1- and T2-weighted images and fluidfluid levels may be seen on T2-weighted images. This intracystic hemorrhage is a characteristic common finding at pathologic examination of papillary carcinomas (8,14).

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Contrast-enhanced MR imaging may show marked enhancement of the cyst walls, septa, and mural nodules. These findings correspond to the vascularized supporting stroma (2,8). Therefore, the kinetic features reflect the abundance of blood vessels in the papillary stalk. Time–signal intensity curves obtained for the mural nodules with dynamic MR imaging can show a great increase in signal intensity at a peak of 3 minutes, a finding that indicates the presence of cancer (16); on the other hand, benign papillomas often show early and rapid uptake of gadolinium contrast material (11). For this reason, the round or oval shape with smooth margins and the mixture of solid and cystic components are the main features that allow differentiation of ICPC from other types of cancer (14). Fine-needle aspiration and core needle biopsy may be unable to allow differentiation between in situ and invasive lesions because invasion is often identified at the periphery of the tumor. Therefore, surgical excision is performed for adequate histologic diagnosis and treatment (1). Evaluation of papillary lesions remains one of the most problematic areas in breast pathology (17). At gross pathologic examination, ICPC appears as a friable or bosselated well-circumscribed mass within a cystic space (1,17). In the case of the solid variant (solid ICPC), the cystic component is absent. Hemorrhagic areas in the solid components of the tumor as well as blood and fluid in the cystic spaces are frequently observed. The cystic wall contains a layer of fibrosis, which limits invasion into surrounding parenchyma (14). At microscopy, ICPC is characterized by one or several nodules of papillary carcinoma surrounded by a thick fibrous capsule (17). This is the reason why the classic term intracystic could be changed to encapsulated (ie, encapsulated papillary carcinoma) (18). The histologic hallmark of both benign and malignant papillary tumors is the characteristic architecture, with an epithelial frond-forming growth pattern supported by a fibrovascular stalk (1,2,14). These solid fibrovascular cores that protrude into the cystic lumen are lined by one or more layers of epithelial malignant cells (5,19).

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ICPC may have various cellular patterns (cribriform, stratified spindle cell, compact columnar epithelial, or transitional cell form) or a combination of patterns (2,5). The nuclear grade (1 to 3) of the monotonous population of cells is based on nuclear hyperchromasia, pleomorphism, and nuclear-cytoplasmic ratio. ICPC shows typical histologic findings, which are low or intermediate nuclear grade, absence of necrosis, and positive estrogen receptors and negative C-erbB2 marker at immunohistochemical studies. High nuclear grade and the presence of necrosis seem to be indicators of more aggressive tumors (5). The key finding in differentiating ICPC from a benign papilloma is the absence of an MEC layer (even if only partial absence) in the malignant form (14,17); this key finding is obtained with immunohistochemical studies. There are different MEC markers, such as p63, calponin, smooth muscle actin, and common acute lymphoblastic leukemic antigen (CD10). The most commonly used marker is p63, with a detection rate for MECs in benign papilloma of up to 99%–100% (17,19). Therefore, the first role of pathologic examination is to identify the presence of MEC interposed between the stromal fibrovascular cores and the overlying epithelial cells; this finding is useful in differentiating papilloma from papillary carcinoma in situ. The second role of pathologic examination is to assess the presence or absence of a complete MEC layer around the papillary lesion, a finding that is particularly important in cases of ICPC (19). On the basis of these criteria, ICPC demonstrates a papillary configuration with an incomplete or absent MEC layer within the papillae, a finding indicative of its malignant nature (carcinoma), and with an absent outer layer at the periphery of involved spaces (17,19). In any case, we must take into account that some authors have reported that this MEC layer is absent in all cases and other authors have concluded that it is not always absent in ICPC (absent in only 72% of cases) (19). The treatment of choice for pure ICPC is surgical excision, which may take the form of mastectomy or, more frequently, segmental resection (2,20). There is little consensus on the roles of local radiation therapy or endocrine

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therapy in the treatment of isolated ICPC; however, patients with an adjacent focus of ductal carcinoma in situ or microinvasive carcinoma are treated according to the standard of care for the most aggressive component (20). Therefore, the recognition of associated lesions in cases of ICPC is very important, and the presence of associated lesions must be established when they are seen outside the capsule of the tumor. Recognition of associated lesions is crucial for prognostic reasons (5). Axillary lymph node dissection or sentinel lymph node mapping is suggested in patients in whom invasion is likely (1), whereas axillary node sampling seems to play no role in the staging evaluation in cases of pure ICPC (20). Pure ICPC has a slow growth rate and an excellent prognosis, with a 10-year survival rate approaching 100% (1,2). Fayanju and colleagues (20) demonstrated that the overall outcomes after treatment of ICPC are excellent, both in patients with pure ICPC and in those with associated non-ICPC disease. In our case, the patient underwent lumpectomy, extirpation of the sentinel node, and complementary radiation therapy, with a very good outcome. Acknowledgments.—The authors thank Luis Echevarría

Franco, Pedro García González, and Nicasio Baniela Alonso for general support and Jesús M. Capilla Ampudia, Silvia Alvarez Almarza, and Francisco Domínguez Iglesias for material support. Finally, the authors thank Tomás Hernández Corral and Miguel Gonzalo Domínguez for moral support.

References 1. Dogan BE, Whitman GJ, Middleton LP, Phelps M. Intracystic papillary carcinoma of the breast. AJR Am J Roentgenol 2003;181(1):186. 2. Wagner AE, Middleton LP, Whitman GJ. Intracystic papillary carcinoma of the breast with invasion. AJR Am J Roentgenol 2004;183(5):1516. 3. Akagi T, Kinoshita T, Shien T, Hojo T, AkashiTanaka S, Murata Y. Clinical and pathological features of intracystic papillary carcinoma of the breast. Surg Today 2009;39(1):5–8. 4. Liberman L, Feng TL, Susnik B. Case 35: intracystic papillary carcinoma with invasion. Radiology 2001;219(3):781–784. 5. Leal C, Costa I, Fonseca D, Lopes P, Bento MJ, Lopes C. Intracystic (encysted) papillary carcinoma

Hernández Rodríguez et al  2027 of the breast: a clinical, pathological, and immunohistochemical study. Hum Pathol 1998;29(10): 1097–1104. 6. Grabowski J, Salzstein SL, Sadler GR, Blair S. Intracystic papillary carcinoma: a review of 917 cases. Cancer 2008;113(5):916–920. 7. Wilkes AN, Feig SA, Palazzo JP. Breast imaging case of the day: intracystic papillary carcinoma of the breast. RadioGraphics 1998;18(5):1310–1313. 8. Soo MS, Williford ME, Walsh R, Bentley RC, Kornguth PJ. Papillary carcinoma of the breast: imaging findings. AJR Am J Roentgenol 1995;164(2): 321–326. 9. Da Costa D, Taddese A, Cure ML, Gerson D, Poppiti R Jr, Esserman LE. Common and unusual diseases of the nipple-areolar complex. RadioGraphics 2007;27(Spec No.):S65–S77. 10. Blaumeiser B, Tjalma WA, Verslegers I, De Schepper AM, Buytaert P. Invasive papillary carcinoma of the male breast. Eur Radiol 2002;12(9):2207–2210. 11. Brookes MJ, Bourke AG. Radiological appearances of papillary breast lesions. Clin Radiol 2008;63(11): 1265–1273. 12. Mulligan AM, O’Malley FP. Papillary lesions of the breast: a review. Adv Anat Pathol 2007;14(2): 108–119. 13. Ganesan S, Karthik G, Joshi M, Damodaran V. Ultrasound spectrum in intraductal papillary neoplasms of breast. Br J Radiol 2006;79(946): 843–849. 14. Linda A, Zuiani C, Girometti R, et al. Unusual malignant tumors of the breast: MRI features and pathologic correlation. Eur J Radiol 2009 May 13. [Epub ahead of print] 15. Linda A, Londero V, Mazzarella F, Zuiani C, Bazzocchi M. Rare breast neoplasms: is there any peculiar feature on magnetic resonance mammography? Radiol Med 2007;112(6):850–862. 16. Tochika N, Takano A, Yoshimoto T, et al. Intracystic carcinoma of the male breast: report of a case. Surg Today 2001;31(9):806–809. 17. Collins LC, Schnitt SJ. Papillary lesions of the breast: selected diagnostic and management issues. Histopathology 2008;52(1):20–29. 18. Hill CB, Yeh IT. Myoepithelial cell staining patterns of papillary breast lesions: from intraductal papillomas to invasive papillary carcinomas. Am J Clin Pathol 2005;123(1):36–44. 19. Tse GM, Tan PH, Moriya T. The role of immunohistochemistry in the differential diagnosis of papillary lesions of the breast. J Clin Pathol 2009;62(5): 407–413. 20. Fayanju OM, Ritter J, Gillanders WE, et al. Therapeutic management of intracystic papillary carcinoma of the breast: the roles of radiation and endocrine therapy. Am J Surg 2007;194(4):497–500.