Sarcoidosis Mimicking Metastatic Breast Cancer

Case 1A 47-year-old premenopausal woman with a history of

chronic neutropenia presented with a palpable mass in her right breast. She had no family history of breast or ovarian cancer and no personal history of mammary or pulmonary dis-ease. Mammography was within normal limits, and an ultra-sound revealed a dense area at the 9 o’clock position. Breast magnetic resonance imaging was performed and revealed a 2 × 3 × 5.5 cm mass in the upper outer quadrant. A core biopsy revealed a well-differentiated invasive lobular carcinoma (Figure 1). There was no evidence of lymphovascular inva-sion; estrogen and progesterone receptors (PgRs) were posi-tive, and immunohistochemistry (IHC) for HER2/neu was negative. Computed tomography (CT) scans demonstrated enlarged bilateral hilar and mediastinal lymph nodes, as well as small to moderately enlarged right axillary nodes. A [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) scan was performed, which revealed uptake in the right breast, right axilla, and bilateral hilar and mediastinal nodes (Figure 2). A bone scan was negative. Spirographic tests revealed a forced vital capacity (FVC) of 3.17 (95% predicted) and a forced expiratory volume in the first second

(FEV1) of 2.7 (100% predicted). She was otherwise feeling well, with no complaints of cough, dyspnea on exertion, fever, or hemoptysis.

Because of the concern for possible metastatic breast cancer (MBC), further evaluation of the mediastinal lymph nodes was pursued. She underwent bronchoscopy and cervical medi-astinoscopy with biopsy of several mediastinal lymph nodes. Pathology revealed nonnecrotizing granulomas, consistent with sarcoidosis (Figure 3). Special stains and cultures for bacteria, fungus, and acid-fast bacilli were negative.

Submitted: Dec 11, 2006; Revised: Jan 22, 2007; Accepted: Jan 29, 2007

1Department of Medical Oncology, Dana-Farber Cancer Institute 2Department of Thoracic Surgery3Department of Radiology4Department of PathologyBrigham and Women’s Hospital5Department of Surgical Oncology, Dana-Farber Cancer InstituteBoston, MA

Address for correspondence: Sara M. Tolaney, MD, Dana-Farber Cancer Institute, 44 Binney St, Mayer 220, Boston, MA 02115 Fax: 617-632-1930; e-mail: [email protected]

Sarcoidosis Mimicking Metastatic Breast Cancer

The clinical and radiographic aspects of sarcoidosis and malignancy might mimic one another, making the distinction between the two difficult in some cases. Although there have been many theories on the link between sarcoidosis and malignancy, the association remains unproven. An unfortunate consequence of the presence of both entities in the same patient is the risk of misdiagnosis and incorrect treatment. We describe 3 patients who presented with locally advanced breast cancer and who were found to have pul-monary findings for metastatic disease that were proven upon biopsy to be consistent with sarcoidosis.

Clinical Breast Cancer, Vol. 7, No. 10, 804-810, 2007Key words: Invasive ductal carcinoma, Invasive lobular carcinoma,

Nonnecrotizing granulomas, Paclitaxel

Abstract

reportcase

Sara M. Tolaney,1 Yolanda L. Colson,2 Ritu R. Gill,3 Stephanie Schulte,4 Margaret M. Duggan,1 Lawrence N. Shulman,1 Eric P. Winer1

Electronic forwarding or copying is a violation of US and International Copyright Laws.Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP,ISSN #1526-8209, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.

Well-Differentiated Invasive Lobular Carcinomain Patient 1

Figure 1

Core biopsy of right breast mass in patient 1 with evidence of well-differentiatedinvasive lobular carcinoma (20× magnification).

804 • Clinical Breast Cancer October 2007

Clinical Breast Cancer October 2007 • 805

Radiographic Imaging from Patient 1Figure 2

(A) Axial CT and fused PET/CT images showing symmetrical hilar uptake consistent with adenopathy. (B) Axial images at the level of the carina showing intense FDG uptake in the subcarinal and the right hilar node.

A

B

The patient underwent a right modified radical mastectomy, and a bone marrow biopsy was also performed concurrently to further evaluate her chronic neutropenia. Pathology from her mastectomy revealed a grade 1 invasive lobular carcinoma spanning the entire mastectomy, present at the superior and inferior superficial margins, as well as at the deep margin. Lymphovascular invasion was present, and 5 of 17 axillary lymph nodes contained evidence of metastatic carcinoma. Her bone marrow biopsy revealed a normocellular marrow without evidence of any granulomatous disease and normal cytogenet-ics. She has recently started treatment with dose-dense doxo-rubicin and cyclophosphamide followed by paclitaxel.

Case 2A 51-year-old postmenopausal woman presented for fur-

ther evaluation for a question of possible MBC. She initially presented 2 years ago with a 1.8 cm right-sided grade 3 inva-sive ductal carcinoma. She underwent lumpectomy and axil-lary node dissection and was found to have 4 of 29 lymph nodes positive for carcinoma. The tumor was estrogen and

PgR negative, and HER2/neu IHC 3+. She was treated at an outside institution with epirubicin for 3 cycles, followed by paclitaxel for 3 cycles and by CMF (cyclophosphamide/methotrexate/5-fluorouracil) for 3 cycles. She then under-went radiation therapy and had CT scans every 6 months for routine staging. At presentation at our institution, she had a CT scan with multiple pulmonary nodules, up to 7 mm in diameter, with hilar and mediastinal adenopathy. There was a 2.7 × 1.7 cm nodule in the distal right hilum that was thought to represent lymphadenopathy versus a lung nodule. She underwent a PET/CT scan, which revealed FDG-avid disease in the mediastinum and hilum; however, her subcentimer pul-monary nodules were not FDG-avid (Figure 4). Spirographic tests revealed an FVC of 3.49 (101% predicted), and an FEV1 of 2.94 (104% predicted).

She underwent a video-assisted exploration of the right hemithorax with excision of a right lower lobe nodule and biopsy of the right hilar node. Histologic examination of the lung tissue revealed multiple nonnecrotizing granulomas, most consistent with sarcoidosis (Figure 5). Similarly, biopsy of the hilar node showed multiple confluent nonnecrotizing granulo-mas (Figure 6). Special stains and cultures for bacteria, fungus, and acid-fast bacilli were negative. Because her pulmonary function tests were normal and she was asymptomatic from her sarcoidosis, treatment of her sarcoidosis was not initiated, and she will be followed with pulmonary function tests and follow-up CT scans.

Case 3A 31-year-old premenopausal woman presented with a left

breast mass. A mammogram revealed a 3.4 cm lesion in the inner quadrant and a 1.2 cm lesion in the outer quadrant of the left breast. Biopsies of both lesions were consistent with grade II/III invasive ductal carcinoma with lymphovascular invasion. The tumors were estrogen and PgR positive and HER2/neu negative. Before undergoing surgery, she underwent staging scans, and the CT scans revealed multiple bilateral pulmo-nary nodules ranging from 4 mm to 1.1 cm and bilateral hilar and small mediastinal lymph nodes. A PET/CT scan revealed multiple areas of intense radiotracer uptake in the left axillary nodes, multiple bulky hilar lymph nodes, a prevascular node, and a right paratracheal node, as well as uptake in the left breast. Some of the multiple small pulmonary nodules were also associated with abnormal radiotracer uptake (Figure 7). She underwent mediastinoscopy, and biopsy of mediastinal lymph nodes demonstrated granulomatous inflammation with focal necrosis, consistent with sarcoidosis (Figure 8). Special stains and cultures for bacteria, fungus, and acid-fast bacilli were negative. Spirographic tests revealed an FVC of 3.7 (111% predicted), and an FEV1 of 3.13 (115% predicted).

Because there was no evidence of metastatic disease, she underwent a left-sided mastectomy and sentinel node biopsy, which revealed grade III multifocal invasive duc-tal carcinoma (Figure 9) and 3 of 3 sentinel lymph nodes had evidence of carcinoma. An axillary dissection was performed, and 10 of 16 lymph nodes were positive. She

Nonnecrotizing Granulomas Consistent with Sarcoidosis in Patient 1

Figure 3

Mediastinal lymph node in patient 1 with multiple nonnecrotizing granulomas, each composed of tightly-clustered epithelioid cells and Langerhans’ giant cells (A) 10× magnification, with the area in the black box shown at (B) 20× magnification.

A

B


Sarcoidosis and Breast Cancer


Sara M. Tolaney et al

went on to receive adjuvant chemotherapy with dose-dense doxorubicin and cyclophosphamide followed by paclitaxel. She is currently undergoing treatment with ovarian sup-pression and an aromatase inhibitor on a clinical trial.

DiscussionSarcoidosis is a systemic granulomatous disease of

unknown etiology, frequently involving the lungs, hilar lymph nodes, skin, and eyes.1 Clinically, patients could be asymptomatic like our patients, and diagnosis can be made on

Radiographic Imaging via PET/CT Scan from Patient 2Figure 4

Coregistered windows at the same imaging level are illustrated in A-C and D-F. (A and D) Chest CT with lung windows; (D) left arrow identifies a right hilar mass, and blue arrow identifies a small pulmonary nodule; (B and E) PET scan; and (C and F) chest CT with mediastinal windows. (B and C) Arrows indicate a mediastinal node; (Eand F) Arrows identify a right hilar mass.

A B C

D E F

Nonnecrotizing Granulomas Within the Lung Parenchyma in Patient 2

Figure 5

Nonnecrotizing granulomas within the lung parenchyma of patient 2 who presented with a right lower lobe lung nodule (20× magnification).

Right Hilar Lymph Node with Confluent NonnecrotizingGranulomas in Patient 2

Figure 6

20× magnification.

a chest radiograph, with the most common finding being bilat-eral hilar lymphadenopathy. Often, however, patients present with respiratory symptoms, weight loss, and fever. Most cases have a self-limiting course, but some patients develop progres-sive disease or fibrosis. Sarcoidosis has been known to imitate other malignant neoplasms and has been described after treat-ment of other tumors, including lung cancer,2 Hodgkin disease,3 testicular cancer,4 osteosarcoma,5,6 melanoma,7,8 colorectal can-cer,9 and thyroid cancer.10 However, there have only been rare case reports of sarcoidosis mimicking MBC.11-14

The association of sarcoidosis and malignancy remains con-troversial. Brincker and Wilbek first noted a statistically sig-nificant increase in the incidence of malignant tumors among patients with sarcoidosis in 1974.15 They crossmatched a national sarcoidosis registry of 2544 subjects with a malig-nancy registry compiled by the Danish national government and found that lymphoma and lung cancer occurred 11 times and 3 times more frequently in patients with sarcoidosis. They proposed that the immunologic deficiencies resulting from sarcoidosis might predispose patients to malignancy. Others have suggested that sarcoidosis is a systemic cell-mediated immune reaction to tumor antigens.16

Other works have also confirmed a relationship between sarcoidosis and malignancy. A retrospective cohort study analyzed 2 cohorts of patients with sarcoidosis, one consist-ing of 474 patients with sarcoidosis from an incidence study in Sweden, and another consisting of 8541 patients from a national Swedish cancer registry.17 They cross-referenced these cohorts to a national cancer registry and death regis-tries and found an increased risk for lymphoma and lung, liver, and skin cancer. Hagerstrand and Linell analyzed 6706 autop-sies and found 22 cases of malignancy among 43 cases (51%) of sarcoidosis.18 Moreover, a large Japanese study followed 1411 patients with sarcoidosis for 3 years and found excess death from leukemia and uterine cancer using standardized mortality risk.19

However, there are others who believe that malignancy might actually precede the diagnosis of sarcoidosis. Suen et al reported 6 cases in which sarcoidosis was diagnosed an average of 9 months after the development of malignancy, and termed this phenomenon the “malignancy-sarcoidosis syndrome.”20

Despite the suggestion that these 2 entities might be linked, there are some who challenge the existence of a relationship between sarcoidosis and malignancy. Romer

Positron Emission Tomography/Computed Tomography Axial, Coronal, and Fused Images from Patient 3Figure 7

Positron emission tomography/CT axial, coronal, and fused images of patient 3 at the level of the inferior pulmonary veins, showing intense uptake in the bilateral hilar nodes and the left breast lesion.




Sara M. Tolaney et al

et al reviewed the cases of sarcoidosis and malignancy that Brincker and Wilber had presented, found that some of these cases were misclassified, and discovered no increased occurrence of malignancy in patients with sarcoidosis.21 The importance of misclassification was also noted by Seersholm et al, who noted misclassification in 3 of 36 malignancies in 254 patients with sarcoidosis.22

Conflicting results among these various studies are caused by the similarities in the clinical and radiologic features of sarcoidosis and malignancy, making misdiagnosis a frequent problem.23,24 Furthermore, histologic confirmation is often not performed. Patients with malignancy might have evidence of sarcoidosis-like granulomas in the vicinity of the tumor, often in lymph nodes draining malignant neoplasms.25 These find-ings are not indicative of systemic sarcoidosis, and have been referred to as sarcoid reactions. The pathogenesis of these reactions is unknown. However, these reactions are thought to be caused by antigens shed by tumor cells that are carried to the draining lymph nodes, inducing a T-cell–mediated response that leads to the formation of noncaseating granulomas.26

Histopathologic features of sarcoidosis include epitheli-oid granulomas that are usually nonnecrotizing and contain Langerhans’ giant cells. However, epithelioid granulomas are not specific for sarcoidosis. The differential diagnosis includes inflammatory conditions, such as tuberculosis and some mycot-ic infections. Although CT scans can be useful in demonstrating characteristic findings of sarcoidosis, they can also be useful in establishing the best approach for a diagnostic procedure, such as a bronchoscopy, mediastinoscopy, or lung biopsy. Characteristic findings of sarcoidosis on CT scan include the presence of medi-astinal and hilar adenopathy, nodular lung disease with upper lobe predominance, peribronchial irregularities, and subpleural micronodules.1 Positron emission tomography scanning has also demonstrated disease activity in sarcoidosis.27,28 Abnormal uptake of FDG also occurs in malignancy, making differentia-tion of sarcoidosis from malignancy difficult.

Although breast cancer can metastasize to intrathoracic lymph nodes, it is unusual for mediastinal or hilar lymph-adenopathy to be the sole site(s) of metastatic involvement. There have been attempts to assess the risk of metastases to hilar and mediastinal lymph nodes in patients with breast cancer. In one series of women with known MBC, the inci-dence of hilar or mediastinal lymphadenopathy was 24%.29 In an unselected series of women treated for breast cancer, the incidence of hilar of mediastinal lymphadenopathy was 1%.30

ConclusionOur cases emphasize the need to establish a definitive

diagnosis of metastatic disease via tissue biopsy. Sarcoidosis and breast cancer occur commonly in middle-aged women. The 3 patients reported in this case report were at high risk for metastatic disease, and the initial clinical diagnoses were consistent with MBC. However, the radiographic findings of mediastinal and hilar adenopathy and pulmonary nodules in 2 patients are typical findings of sarcoidosis and warranted more definitive analysis. These cases highlight the need to consider nonmalignant diagnoses in patients with previous malignancies, and the need to obtain a pathologic diagnosis whenever possible.

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Level 4 Lymph Node with Multiple Nonnecrotizing Granulomas in Patient 3

Figure 8

20× magnification.

Poorly Differentiated Invasive Ductal Carcinoma in Patient 3

Figure 9

Left breast mastectomy of patient 3 with poorly differentiated invasive ductal carcinoma and high-grade ductal carcinoma in situ (20× magnification).

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Sarcoidosis Mimicking Metastatic Breast Cancer