Accepted Manuscript Sarcoidosis presenting as metastatic lymphadenopathy in breast cancer Mani Akhtari , Jorge R. Quesada , Mary R. Schwartz , Stephen B. Chiang , Bin S. Teh PII:
S1526-8209(14)00090-1
DOI:
10.1016/j.clbc.2014.05.001
Reference:
CLBC 279
To appear in:
Clinical Breast Cancer
Received Date: 16 April 2014 Accepted Date: 18 May 2014
Please cite this article as: Akhtari M, Quesada JR, Schwartz MR, Chiang SB, Teh BS, Sarcoidosis presenting as metastatic lymphadenopathy in breast cancer, Clinical Breast Cancer (2014), doi: 10.1016/j.clbc.2014.05.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Page 1 of 10 Title: Sarcoidosis presenting as metastatic lymphadenopathy in breast cancer.
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Authors: Mani Akhtari1, Jorge R. Quesada2, Mary R. Schwartz3, Stephen B. Chiang4, Bin S. Teh5 Author Affiliations: 1
Department of Radiation Oncology, University of Texas Medical Branch, Galveston, TX 2
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Department of Internal Medicine, Oncology Division, University of Texas Medical School at Houston, Houston, TX 3
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Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX 4
Department of Diagnostic Radiology and Nuclear Medicine, Houston Methodist Hospital, Houston, TX 5
Department of Radiation Oncology, Houston Methodist Hospital Cancer Center and Research Institute, Houston, TX
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Funding Sources: No funding sources were used for the publication of this study. Corresponding Author: Bin S. Teh M.D.
Department of Radiation Oncology
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Houston Methodist Hospital Cancer Center 6565 Fannin, Ste #DB1-077
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Houston, Texas 77030
Phone: 713-441-4800, Fax: 713-441-4493 Email: [email protected] Number of Words/Characters in manuscript: 2487 words 14,361 characters (No spacing)
ACCEPTED MANUSCRIPT Page 2 of 10 Conflict of Interest:
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All authors have no conflict of interest.
ACCEPTED MANUSCRIPT Page 3 of 10 Clinical Practice Points:
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Sarcoidosis is a systemic, granulomatous disorder that affects the lungs and mediastinal lymph nodes in the majority of the patients. Areas affected by sarcoidosis can exhibit 18F-fluoro-2-deoxy-D-glucose (FDG) avidity on positron emission tomography (PET). We report the case of a 47-year-old woman with T2N0 cancer of the right breast who was initially diagnosed as stage IV due to multiple areas of mediastinal and supraclavicular PET-positive lymphadenopathy. Biopsy of a supraclavicular lymph node showed non-caseating granulomas, consistent with sarcoidosis, leading to appropriate treatment for her stage IIA disease. The imaging characteristics of sarcoidosis and its possible implications in staging and diagnosis of malignancy, more specifically in breast cancer patients, are discussed below.
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ACCEPTED MANUSCRIPT Page 4 of 10 Introduction
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Sarcoidosis is a systemic, granulomatous disorder, which is diagnosed based on the clinical and radiologic findings and confirmed by histological evidence of non-caseating epithelioid cell granulomas1. The primary cause of sarcoidosis is still unknown. The lungs and mediastinal lymph nodes are involved in more than 90% of the patients2. Common initial symptoms include cough, dyspnea, skin lesions such as erythema nodosum, febrile arthritis, uveitis, and parotitis but as many as 50% of patients affected by sarcoidosis are asymptomatic at diagnosis. Intrathoracic lymphadenopathy, including bilateral hilar lymphadenopathy, is the most common radiographic finding of sarcoidosis3. Although, not routinely used, 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) has been studied in the diagnosis and monitoring of sarcoidosis as involved sites exhibit FDG uptake with a pattern, which is indistinguishable from that of malignancy4.
M AN U
These similarities on PET/CT imaging, including FDG avid lymphadenopathy, can complicate diagnosis, staging, and management of cancer patients who also have sarcoidosis. Here we report a case of a patient with estrogen receptor, progesterone receptor, and HER2-neu negative (triple negative) breast cancer and no previous diagnosis of sarcoidosis, in whom metastatic disease was suspected based on the PET/CT findings
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Case Report
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A 47-year-old woman was referred to our clinic in August 2010. She had initially palpated a mass in in her right breast in late 2009, which was followed by diagnostic mammography and ultrasound. Ultrasound of the right breast demonstrated a 16 x 10 x 13 mm hypoechoic mass with irregular borders, as well as a few prominent lymph nodes in the right axilla, the largest measuring 19 x 7 mm. Ultrasound-guided core needle biopsies of the right breast mass demonstrated poorly differentiated, triple negative invasive ductal carcinoma (IDC). BRCA1 and BRCA2 genetic testing did not reveal any mutations. She then underwent partial mastectomy in November 2009. Pathologic evaluation demonstrated a a 2.2 cm poorly differentiated IDC, with no evident lymphovascular invasion or perineural invasion. The closest margin was 3 mm and none of the five sentinel lymph nodes were positive for malignancy, with a final pathological stage of T2N0Mx, IIA. Despite her negative sentinel lymph nodes, her surgical oncologist was concerned about systemic disease given her triple negative breast cancer. She thus underwent staging with a PET/CT in December 2009, which showed multiple areas of increased FDG uptake in bilateral supraclavicular (SCV) lymph nodes (SUV of 15.2 on right and 12.8 on left), superior mediastinal lymph nodes (SUV 14), a small subdiaphragmatic subcentimeter lymph node (SUV 6.7), and multiple matted periportal lymph nodes (SUV 16.6). There were no abnormal axillary nodes. Additionally there were several foci of FDG uptake throughout the lungs correlating with multiple
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small nodules. The radiographic interpretation was that the findings were consistent with widespread metastases from breast cancer. The patient then received 6 cycles of chemotherapy with carboplatin and nab-paclitaxel for presumed stage IV disease. A follow-up PET/CT in August 2010 showed significant improvement in terms of radiotracer uptake (SUV of left SCV lymph node was down to 6.7 from 12.8), but the distribution and size of the lymph nodes had remained stable. These findings, as well as the atypical distribution of her PET-positive disease, particularly no axillary, osseous, or bony involvement, lead us to suspect other etiologies for her radiographic findings. We thus requested a nodal biopsy for definitive diagnosis. Fine needle aspiration and core needle biopsy of the left SCV lymph node showed non-caseating granulomas and no metastatic carcinoma, confirming the diagnosis of sarcoidosis (Figure 1). Based on this finding, she was re-staged as stage IIA rather than stage IV and adjuvant radiation to the right breast was prescribed. Her course of radiation therapy consisted of 50.4 Gy at 180 cGy per fraction delivered via tangents, followed by a tumor bed boost of 10 Gy at 200 cGy per fraction delivered via electrons. She completed her course of radiation therapy in October 2010 with minimal side effects. No further chemotherapy or hormonal therapy was administered.
Discussion
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A follow-up PET/CT in April 2011 showed decreased uptake in the bilateral SCV lymph nodes (SUV 11 compared to 15), mediastinal lymph nodes (SUV 6 compared to 11), periportal lymph nodes (SUV 9 compared to 12), along with multiple bilateral small pulmonary nodules relatively unchanged in size or uptake. The patient underwent repeat bronchoscopy and transbronchial biopsies in August, 2012, which again showed non-caseating granulomas consistent with sarcoidosis. Her most recent mammogram in October 2013 was inconclusive and was followed up by ultrasound of the right breast, which was negative for malignancy. To this date she is doing well with no clinical or radiological evidence of recurrence of breast cancer. Her sarcoidosis has been asymptomatic and deemed of an indolent clinical course with no therapy required to this date.
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Here we have presented the case of a 47 year-old woman with triple negative breast cancer initially treated surgically with a clinical stage of IIA. A postoperative FDG-PET/CT revealed lesions in the lungs and non-axillary nodes suspicious of metastatic disease. She received systemic combination chemotherapy with nab-paclitaxel and carboplatin for presumed stage IV disease, but is a regimen that can be used in either the adjuvant or the metastatic setting in patients with triple negative breast cancer. The atypical radiographic findings and her mixed response to chemotherapy prompted a diagnostic biopsy of her SCV lymph node revealing non-caseating granulomas consistent with sarcoidosis. Clarifying the true nature of the PET/CT findings allowed us to complete treatment with adjuvant radiotherapy for her stage II disease with a curative intent. As the EBCTCG meta-analysis showed, the rate of loco-regional recurrence can be reduced by as much as 17% by adjuvant radiation in node-
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negative women5. It is therefore important to consider histological confirmation of suspicious lymph nodes as seen on PET/CT, especially if it will make a significant difference in the staging and management of the patients such as omission of radiation therapy in patients who would be classified as stage IV. This is especially essential if the radiographic findings do not fit the typical spread pattern of metastases for that specific disease. In regards to breast cancer, axillary lymph nodes are known to be the primary site of spread, with axillary lymph node dissection previously being a standard part of treatment along with mastectomy. However, it is extremely rare to have isolated SCV or mediastinal involvement. In a study of 549 patients who had undergone sentinel lymph node biopsy, 27% of the patients had drainage to non-axillary nodes but none of the patients had drainage to the infraclavicular or SCV lymph nodes without axillary drainage6. Even in patients with SCV lymphadenopathy, where an enlarged lymph node has an 85% chance of being malignant based on a large review of patients with adenopathy who underwent FNA biopsy7, a suspicious lymph node should not be presumed to be malignant if it does not fit with the overall clinical picture.
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FDG-PET/CT is becoming more prevalent in the staging and treatment of breast cancer with numerous studies evaluating its efficacy in staging and monitoring of disease progression8-9. In a recent retrospective study FDGPET/CT was shown to be significantly more accurate for detecting axillary lymph node and distant metastases when compared to conventional staging protocols10. Nevertheless, per the most recent NCCN guidelines, FDG-PET/CT is a category 2B recommendation in patients with stage IIIA disease and even then it is classified as optional for staging purposes11. However, given the faster time to distant recurrence, higher propensity for visceral metastases, and the shorter duration from first recurrence to death in triple negative breast cancer as compared to other breast subtypes12, it was not unreasonable to obtain a PET/CT as part of the initial staging of our patient. In a study of breast cancer patients who underwent staging, re-staging, or monitoring disease response, PET changed the clinical stage in 36% of the patients13. However, as with all imaging studies, including PET-CT, it is important to keep a wide differential when PET-positive areas could result in changing of the clinical stage. It is imperative to consider alternative diagnoses such as sarcoidosis, lymphoma, infection, and other possibilities if the areas of suspected disease do not fit the known patterns of spread. The relationship between sarcoidosis and malignancies continues to remain controversial14-18. Regardless of the correlation, patients with sarcoidosis are known to develop malignancy and sarcoidosis is also known to develop in patients with malignancy19. In both groups of patients, surveillance with FDGPET/CT can become an issue given FDG uptake in areas involved by sarcoidosis. Based on review of the literature summarized above, including FDG uptake in sarcoid lesions4, multiple reports of sarcoidosis that could have been potentially misclassified either as disease progression20, or metastatic disease 2122 based on PET-CT findings, and the increasing utilization of FDG-PET/CT in
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staging and surveillance of malignancies, we recommend pathological confirmation of all suspicious lesions in a) patients with a prior diagnosis of sarcoidosis with a new diagnosis of malignancy if the PET positive areas will lead to a change in staging and available treatment options and b) patients with mediastinal, hilar, SCV, or other areas of lymphadenopathy that do not follow the typical pattern of spread of the disease under question. Conclusion:
SC
We have presented the case of a patient with no previous history of sarcoidosis, who upon undergoing FDG-PET/CT for evaluation of her breast cancer was found to have multiple nodal areas of involvement suspicious for stage IV disease. Biopsy of her supraclavicular lymph node allowed us to diagnose her with sarcoidosis and correctly stage her as IIA.
M AN U
Our case emphasizes the importance of placing imaging findings in the context of the larger clinical picture. FDG-PET positive areas can be due to spread of malignancy but benign conditions as well as secondary primaries are always a possibility. In cancer patients with a co-diagnosis of sarcoidosis, who are found to have positive FDG-PET findings in the lungs and different lymph node regions, we recommend biopsy of all lesions that would result in a change of staging and treatment options.
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Hunninghake GW, Costabel U, Ando M, Baughman R, Cordier JF, du Bois R, Eklund A, Kitaichi M, Lynch J, Rizzato G. Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med. 1999;160.2:736-755. Baughman RP., Teirstein AS, Judson MA, Rossman MD, Yeager HJ, Bresnitz EA, DePalo L et al. Clinical characteristics of patients in a case control study of sarcoidosis. American Journal of Respiratory and Critical Care Medicine. 2001;164.10:1885-1889. Miller BH, Rosado-de-Christenson ML, McAdams HP, Fishback NF. Thoracic sarcoidosis: radiologic-pathologic correlation. Radiographics. 1995;15.2:421-437. Lewis PJ, Salama A. Uptake of fluorine-18-fluorodeoxyglucose in sarcoidosis. Journal of Nuclear Medicine: official publication, Society of Nuclear Medicine. 1994;35.10:1647-1649. Clarke MR, Collins R, Darby S, Davies C, Elphinstone P, Evans E, Godwin J, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;366.9503:2087-2106.
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References:
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Tanis PJ, Nieweg OE, Valdes Olmos RA, Peterse JL, Rutgers EJT, Hoefnagel CA, and Kroon BBR. Impact of non-axillary sentinel node biopsy on staging and treatment of breast cancer patients. British Journal of Cancer. 2002;87.7:705-710. Steel BL, Schwartz MR, Ramzy I. Fine needle aspiration biopsy in the diagnosis of lymphadenopathy in 1,103 patients. Role, limitations and analysis of diagnostic pitfalls. Acta Cytological. 1994;39.1:76-81. Zangheri B, Messa C, Picchio M, Gianolli L, Landoni C, Fazio F. PET/CT and breast cancer. European journal of nuclear medicine and molecular imaging. 2004;31.1:135-142. Heusner TA, Kuemmel S, Umutlu L, Koeninger A, Freudenberg LS, Hauth EAM, Kimmig KR, Forsting M, Bockisch A, Antoch G. Breast cancer staging in a single session: whole-body PET/CT mammography. Journal of Nuclear Medicine. 2008;49.8:1215-1222. Riegger C, Herrmann J, Nagarajah J, Hecktor J, Kuemmel S, Otterbach F, Hahn S, Bockisch A, Lauenstein T, Antoch G, Heusner TA. Whole-body FDG PET/CT is more accurate than conventional imaging for staging primary breast cancer patients. European journal of nuclear medicine and molecular imaging. 2012;39.5:852-863. NCCN clinical practice guidelines. ((2014, 03 06). Retrieved from http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf Dent R, Hanna WM, Trudeau M, Rawlinson E, Sun P, Narod SA. Pattern of metastatic spread in triple-negative breast cancer. Breast cancer research and treatment. 2009;115.2:423-428. Yap CS, Seltzer MA, Schiepers C, Gambhir SS, Rao J, Phelps ME, Valk PE, Czernin J. Impact of whole-body 18F-FDG PET on staging and managing patients with breast cancer: the referring physician’s perspective. Journal of Nuclear Medicine. 2001;42.9:1334-1337. Brincker H, Wilbek E. The incidence of malignant tumours in patients with respiratory sarcoidosis. British Journal of Cancer. 1974;29.3:247-251. Brincker H. Solid tumors preceding or following sarcoidosis. Medical and pediatric oncology. 1987;15.2:82-88. Yamaguchi M., Odaka M, Hosoda Y, Iwai K, Tachibana T. Excess death of lung cancer among sarcoidosis patients. Sarcoidosis. 1991;8.1:51-55. Romer FK, Hommelgaard P, Schou G. Sarcoidosis and cancer revisited: a long-term follow-up study of 555 Danish sarcoidosis patients. European Respiratory Journal. 1998;12.4:906-912. Lower EE, Hawkins HH, Baughman RP. Breast disease in sarcoidosis. Sarcoidosis, vasculitis, and diffuse lung diseases: official journal of WASOG/World Association of Sarcoidosis and Other Granulomatous Disorders. 2001;18.3:301-306. Cohen PR, Kurzrock R. Sarcoidosis and malignancy. Clinics in dermatology. 2007;25.3:326-333. Maeda J, Ohta M, Hirabayashi H, Matsuda H. False positive accumulation in 18F fluorodeoxyglucose positron emission tomography scan due to sarcoid reaction following induction chemotherapy for lung cancer. The
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Japanese Journal of Thoracic and Cardiovascular Surgery. 2005;53.4:196198. 21. Muggia FM, Conti PS, Tjan-Heijnen VCG., Vlasveld LT, De Mulder PHM. Seminoma and sarcoidosis: A cause for false positive mediastinal uptake in PET?. Annals of Oncology. 1998;9.8:924-924. 22. Yao M, Funk GF, Goldstein DP, DeYoung BR, Graham MM. Benign Lesions in Cancer Patients CASE 1. Sarcoidosis After Chemoradiation for Head and Neck Cancer. Journal of clinical oncology. 2005;23.3:640-641.
Figure 1: Non-caseating granulomata Core biopsy of the SCV lymphnode shows non-caseating granulomata with mild lymphoplasmacytic infiltrate in surrounding sclerotic stroma, H&E stain at 20X.
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Figure 2: PET-CT of the left SCV region Showing decrease in SUV between December 2009 (top row) and August 2010 (middle row) and stable disease between August 2010 (middle row) and April 2011 (Bottom row).
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S1526-8209(14)00090-1
DOI:
10.1016/j.clbc.2014.05.001
Reference:
CLBC 279
To appear in:
Clinical Breast Cancer
Received Date: 16 April 2014 Accepted Date: 18 May 2014
Please cite this article as: Akhtari M, Quesada JR, Schwartz MR, Chiang SB, Teh BS, Sarcoidosis presenting as metastatic lymphadenopathy in breast cancer, Clinical Breast Cancer (2014), doi: 10.1016/j.clbc.2014.05.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Page 1 of 10 Title: Sarcoidosis presenting as metastatic lymphadenopathy in breast cancer.
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Authors: Mani Akhtari1, Jorge R. Quesada2, Mary R. Schwartz3, Stephen B. Chiang4, Bin S. Teh5 Author Affiliations: 1
Department of Radiation Oncology, University of Texas Medical Branch, Galveston, TX 2
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Department of Internal Medicine, Oncology Division, University of Texas Medical School at Houston, Houston, TX 3
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Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX 4
Department of Diagnostic Radiology and Nuclear Medicine, Houston Methodist Hospital, Houston, TX 5
Department of Radiation Oncology, Houston Methodist Hospital Cancer Center and Research Institute, Houston, TX
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Funding Sources: No funding sources were used for the publication of this study. Corresponding Author: Bin S. Teh M.D.
Department of Radiation Oncology
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Houston Methodist Hospital Cancer Center 6565 Fannin, Ste #DB1-077
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Houston, Texas 77030
Phone: 713-441-4800, Fax: 713-441-4493 Email: [email protected] Number of Words/Characters in manuscript: 2487 words 14,361 characters (No spacing)
ACCEPTED MANUSCRIPT Page 2 of 10 Conflict of Interest:
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All authors have no conflict of interest.
ACCEPTED MANUSCRIPT Page 3 of 10 Clinical Practice Points:
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Sarcoidosis is a systemic, granulomatous disorder that affects the lungs and mediastinal lymph nodes in the majority of the patients. Areas affected by sarcoidosis can exhibit 18F-fluoro-2-deoxy-D-glucose (FDG) avidity on positron emission tomography (PET). We report the case of a 47-year-old woman with T2N0 cancer of the right breast who was initially diagnosed as stage IV due to multiple areas of mediastinal and supraclavicular PET-positive lymphadenopathy. Biopsy of a supraclavicular lymph node showed non-caseating granulomas, consistent with sarcoidosis, leading to appropriate treatment for her stage IIA disease. The imaging characteristics of sarcoidosis and its possible implications in staging and diagnosis of malignancy, more specifically in breast cancer patients, are discussed below.
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ACCEPTED MANUSCRIPT Page 4 of 10 Introduction
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Sarcoidosis is a systemic, granulomatous disorder, which is diagnosed based on the clinical and radiologic findings and confirmed by histological evidence of non-caseating epithelioid cell granulomas1. The primary cause of sarcoidosis is still unknown. The lungs and mediastinal lymph nodes are involved in more than 90% of the patients2. Common initial symptoms include cough, dyspnea, skin lesions such as erythema nodosum, febrile arthritis, uveitis, and parotitis but as many as 50% of patients affected by sarcoidosis are asymptomatic at diagnosis. Intrathoracic lymphadenopathy, including bilateral hilar lymphadenopathy, is the most common radiographic finding of sarcoidosis3. Although, not routinely used, 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) has been studied in the diagnosis and monitoring of sarcoidosis as involved sites exhibit FDG uptake with a pattern, which is indistinguishable from that of malignancy4.
M AN U
These similarities on PET/CT imaging, including FDG avid lymphadenopathy, can complicate diagnosis, staging, and management of cancer patients who also have sarcoidosis. Here we report a case of a patient with estrogen receptor, progesterone receptor, and HER2-neu negative (triple negative) breast cancer and no previous diagnosis of sarcoidosis, in whom metastatic disease was suspected based on the PET/CT findings
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Case Report
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A 47-year-old woman was referred to our clinic in August 2010. She had initially palpated a mass in in her right breast in late 2009, which was followed by diagnostic mammography and ultrasound. Ultrasound of the right breast demonstrated a 16 x 10 x 13 mm hypoechoic mass with irregular borders, as well as a few prominent lymph nodes in the right axilla, the largest measuring 19 x 7 mm. Ultrasound-guided core needle biopsies of the right breast mass demonstrated poorly differentiated, triple negative invasive ductal carcinoma (IDC). BRCA1 and BRCA2 genetic testing did not reveal any mutations. She then underwent partial mastectomy in November 2009. Pathologic evaluation demonstrated a a 2.2 cm poorly differentiated IDC, with no evident lymphovascular invasion or perineural invasion. The closest margin was 3 mm and none of the five sentinel lymph nodes were positive for malignancy, with a final pathological stage of T2N0Mx, IIA. Despite her negative sentinel lymph nodes, her surgical oncologist was concerned about systemic disease given her triple negative breast cancer. She thus underwent staging with a PET/CT in December 2009, which showed multiple areas of increased FDG uptake in bilateral supraclavicular (SCV) lymph nodes (SUV of 15.2 on right and 12.8 on left), superior mediastinal lymph nodes (SUV 14), a small subdiaphragmatic subcentimeter lymph node (SUV 6.7), and multiple matted periportal lymph nodes (SUV 16.6). There were no abnormal axillary nodes. Additionally there were several foci of FDG uptake throughout the lungs correlating with multiple
ACCEPTED MANUSCRIPT Page 5 of 10
M AN U
SC
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small nodules. The radiographic interpretation was that the findings were consistent with widespread metastases from breast cancer. The patient then received 6 cycles of chemotherapy with carboplatin and nab-paclitaxel for presumed stage IV disease. A follow-up PET/CT in August 2010 showed significant improvement in terms of radiotracer uptake (SUV of left SCV lymph node was down to 6.7 from 12.8), but the distribution and size of the lymph nodes had remained stable. These findings, as well as the atypical distribution of her PET-positive disease, particularly no axillary, osseous, or bony involvement, lead us to suspect other etiologies for her radiographic findings. We thus requested a nodal biopsy for definitive diagnosis. Fine needle aspiration and core needle biopsy of the left SCV lymph node showed non-caseating granulomas and no metastatic carcinoma, confirming the diagnosis of sarcoidosis (Figure 1). Based on this finding, she was re-staged as stage IIA rather than stage IV and adjuvant radiation to the right breast was prescribed. Her course of radiation therapy consisted of 50.4 Gy at 180 cGy per fraction delivered via tangents, followed by a tumor bed boost of 10 Gy at 200 cGy per fraction delivered via electrons. She completed her course of radiation therapy in October 2010 with minimal side effects. No further chemotherapy or hormonal therapy was administered.
Discussion
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A follow-up PET/CT in April 2011 showed decreased uptake in the bilateral SCV lymph nodes (SUV 11 compared to 15), mediastinal lymph nodes (SUV 6 compared to 11), periportal lymph nodes (SUV 9 compared to 12), along with multiple bilateral small pulmonary nodules relatively unchanged in size or uptake. The patient underwent repeat bronchoscopy and transbronchial biopsies in August, 2012, which again showed non-caseating granulomas consistent with sarcoidosis. Her most recent mammogram in October 2013 was inconclusive and was followed up by ultrasound of the right breast, which was negative for malignancy. To this date she is doing well with no clinical or radiological evidence of recurrence of breast cancer. Her sarcoidosis has been asymptomatic and deemed of an indolent clinical course with no therapy required to this date.
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Here we have presented the case of a 47 year-old woman with triple negative breast cancer initially treated surgically with a clinical stage of IIA. A postoperative FDG-PET/CT revealed lesions in the lungs and non-axillary nodes suspicious of metastatic disease. She received systemic combination chemotherapy with nab-paclitaxel and carboplatin for presumed stage IV disease, but is a regimen that can be used in either the adjuvant or the metastatic setting in patients with triple negative breast cancer. The atypical radiographic findings and her mixed response to chemotherapy prompted a diagnostic biopsy of her SCV lymph node revealing non-caseating granulomas consistent with sarcoidosis. Clarifying the true nature of the PET/CT findings allowed us to complete treatment with adjuvant radiotherapy for her stage II disease with a curative intent. As the EBCTCG meta-analysis showed, the rate of loco-regional recurrence can be reduced by as much as 17% by adjuvant radiation in node-
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negative women5. It is therefore important to consider histological confirmation of suspicious lymph nodes as seen on PET/CT, especially if it will make a significant difference in the staging and management of the patients such as omission of radiation therapy in patients who would be classified as stage IV. This is especially essential if the radiographic findings do not fit the typical spread pattern of metastases for that specific disease. In regards to breast cancer, axillary lymph nodes are known to be the primary site of spread, with axillary lymph node dissection previously being a standard part of treatment along with mastectomy. However, it is extremely rare to have isolated SCV or mediastinal involvement. In a study of 549 patients who had undergone sentinel lymph node biopsy, 27% of the patients had drainage to non-axillary nodes but none of the patients had drainage to the infraclavicular or SCV lymph nodes without axillary drainage6. Even in patients with SCV lymphadenopathy, where an enlarged lymph node has an 85% chance of being malignant based on a large review of patients with adenopathy who underwent FNA biopsy7, a suspicious lymph node should not be presumed to be malignant if it does not fit with the overall clinical picture.
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EP
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FDG-PET/CT is becoming more prevalent in the staging and treatment of breast cancer with numerous studies evaluating its efficacy in staging and monitoring of disease progression8-9. In a recent retrospective study FDGPET/CT was shown to be significantly more accurate for detecting axillary lymph node and distant metastases when compared to conventional staging protocols10. Nevertheless, per the most recent NCCN guidelines, FDG-PET/CT is a category 2B recommendation in patients with stage IIIA disease and even then it is classified as optional for staging purposes11. However, given the faster time to distant recurrence, higher propensity for visceral metastases, and the shorter duration from first recurrence to death in triple negative breast cancer as compared to other breast subtypes12, it was not unreasonable to obtain a PET/CT as part of the initial staging of our patient. In a study of breast cancer patients who underwent staging, re-staging, or monitoring disease response, PET changed the clinical stage in 36% of the patients13. However, as with all imaging studies, including PET-CT, it is important to keep a wide differential when PET-positive areas could result in changing of the clinical stage. It is imperative to consider alternative diagnoses such as sarcoidosis, lymphoma, infection, and other possibilities if the areas of suspected disease do not fit the known patterns of spread. The relationship between sarcoidosis and malignancies continues to remain controversial14-18. Regardless of the correlation, patients with sarcoidosis are known to develop malignancy and sarcoidosis is also known to develop in patients with malignancy19. In both groups of patients, surveillance with FDGPET/CT can become an issue given FDG uptake in areas involved by sarcoidosis. Based on review of the literature summarized above, including FDG uptake in sarcoid lesions4, multiple reports of sarcoidosis that could have been potentially misclassified either as disease progression20, or metastatic disease 2122 based on PET-CT findings, and the increasing utilization of FDG-PET/CT in
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staging and surveillance of malignancies, we recommend pathological confirmation of all suspicious lesions in a) patients with a prior diagnosis of sarcoidosis with a new diagnosis of malignancy if the PET positive areas will lead to a change in staging and available treatment options and b) patients with mediastinal, hilar, SCV, or other areas of lymphadenopathy that do not follow the typical pattern of spread of the disease under question. Conclusion:
SC
We have presented the case of a patient with no previous history of sarcoidosis, who upon undergoing FDG-PET/CT for evaluation of her breast cancer was found to have multiple nodal areas of involvement suspicious for stage IV disease. Biopsy of her supraclavicular lymph node allowed us to diagnose her with sarcoidosis and correctly stage her as IIA.
M AN U
Our case emphasizes the importance of placing imaging findings in the context of the larger clinical picture. FDG-PET positive areas can be due to spread of malignancy but benign conditions as well as secondary primaries are always a possibility. In cancer patients with a co-diagnosis of sarcoidosis, who are found to have positive FDG-PET findings in the lungs and different lymph node regions, we recommend biopsy of all lesions that would result in a change of staging and treatment options.
3.
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Figure 1: Non-caseating granulomata Core biopsy of the SCV lymphnode shows non-caseating granulomata with mild lymphoplasmacytic infiltrate in surrounding sclerotic stroma, H&E stain at 20X.
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Figure 2: PET-CT of the left SCV region Showing decrease in SUV between December 2009 (top row) and August 2010 (middle row) and stable disease between August 2010 (middle row) and April 2011 (Bottom row).
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