http://informahealthcare.com/amy ISSN: 1350-6129 (print), 1744-2818 (electronic) Amyloid, 2014; 21(4): 256–260 ! 2014 Informa UK Ltd. DOI: 10.3109/13506129.2014.958610
ORIGINAL ARTICLE
Lymphadenopathy as a manifestation of amyloidosis: a case series Julie Fu1, David C. Seldin1, John L. Berk1, Fangui Sun1,2, Carl O’Hara1, Haili Cui1, and Vaishali Sanchorawala1 1
Amyloidosis Center, Boston University School of Medicine, Boston, MA, USA and 2School of Public Health, Boston Medical Center, Boston, MA, USA
Abstract
Keywords
Lymphadenopathy as a manifestation of amyloidosis is rare. Of 3008 new patients with amyloidosis evaluated from 1994 to 2013 at a single center, 47 (1.6%) presented with lymph node enlargement leading to a biopsy and the diagnosis. We conducted a retrospective review of the initial presentation, time to progression, and treatment outcomes for these patients. Upon initial evaluation, 14 (30%) had isolated lymphadenopathy while 33 (70%) had evidence of vital organ involvement. Thirty-nine patients (83%) had systemic AL amyloidosis at initial evaluation or developed it on follow up; there was a single case each of AA, wtTTR and V122ITTR and one untyped amyloidosis. Eleven patients (23%) had IgM monoclonal gammopathy and 3 (6%) had histology consistent with lymphoplasmacytic lymphoma. Of the 14 patients with isolated lymphadenopathy, 10 (71%) eventually progressed to other organ disease requiring treatment at a median time of 10 months (range 4–71). This series demonstrates that patients presenting with amyloid lymphadenopathy usually have AL amyloidosis, and should have a thorough evaluation for other organ involvement at diagnosis. If present, treatment should be similar to that of other patients with systemic AL amyloidosis, but if not, patients should be monitored regularly for development of other organ disease over time.
Amyloidosis, lymph nodes, treatment History Received 30 May 2014 Revised 31 July 2014 Accepted 1 August 2014 Published online 10 September 2014
Abbreviations: AA: amyloid protein A; AL: amyloid light chain; BNP: B-type natriuretic peptide; FLC: free light chain; GI: gastrointestinal; wtTTR: wild type transthyretin
Introduction Amyloidosis is a heterogeneous group of protein misfolding disorders in which proteins deposit extracellularly as amyloid fibrils causing organ damage. Amyloidosis can be either systemic or localized. In systemic amyloidosis, deposition occurs in multiple organs distant from the site of production of the precursor protein, while in localized amyloidosis, production and deposition occur in a single tissue organ [1,2]. The most commonly diagnosed type of systemic amyloidosis is light chain (AL) amyloidosis. AL amyloidosis most frequently affects the kidneys and heart, but can also involve the pulmonary system, peripheral and autonomic nervous system, gastro-intestinal tract including the liver, and soft tissues [3]. Localized AL amyloidosis can occur in sites including the tracheobronchial tree, genitourinary tract, breast and skin [4]. We and others have observed amyloidosis presenting as lymphadenopathy [5–8], but this presentation has not been
examined systematically. Additional case reports describe involvement of cervical, axillary, paratracheal, retroperitoneal, mesenteric, inguinal and various combinations of lymph node groups [9–16]. In patients with thoracic involvement and systemic amyloidosis, 75% of patients have been reported to have involvement of the mediastinal or hilar lymph nodes [17]. To better understand the clinical implications of amyloidosis diagnosed in lymph nodes, we retrospectively reviewed all cases with lymphadenopathy as the presenting manifestation of amyloidosis from January 1994 to May 2013 in our tertiary referral center. While this presentation proved to be rare, identification of 47 cases allowed us to delineate the patient characteristics, frequency and type of vital organ involvement, time to progression, treatment outcomes, and survival in this unusual group of patients.
Patients and methods Patients
Address for correspondence: Vaishali Sanchorawala, Section of Hematology/Oncology, School of Public Health, Boston Medical Center, FGH 1007, 820 Harrison Avenue, Boston, MA 02118, USA. Tel: (617) 638-7002. Fax: 617 414 1831. E-mail: Vaishali. [email protected]
Data on 3008 consecutive patients with all forms of amyloidosis seen from January 1994 to May 2013 in the Boston University Amyloidosis Center were reviewed. The Institutional Review Board of Boston University Medical Campus approved data collection and analysis, and written
Lymphadenopathy in amyloidosis
DOI: 10.3109/13506129.2014.958610
informed consent was obtained from each patient, in accordance with the Declaration of Helsinki. Forty-seven patients were identified as having been diagnosed with amyloidosis based upon lymph node biopsy performed because of lymphadenopathy. Biopsies from outside institutions were reviewed, with repeat Congo red staining if necessary for confirmation. Immunohistochemical staining, mass spectrometry, or immunogold electron microscopy was used to type the amyloid deposits. In addition, gene sequencing was performed for cases of ATTR amyloidosis. Patients were evaluated for systemic amyloidosis with extensive testing for a plasma cell dyscrasia, and for involvement of vital organs including heart, kidney, liver, gastrointestinal tract and neurologic system. Data collection Data reviewed for each patient included time from diagnosis to evaluation and organ involvement, including cardiac, pulmonary, renal, neurologic, soft tissue, and hepatic disease. For patients with AL amyloidosis, data included bone marrow biopsy with Congo red staining, CD138 immunohistochemistry, and in situ hybridization for light chain expression, serum free light chain (FLC) measurements, and serum and urine immunofixation electrophoresis. The difference (dFLC) between the involved FLC and the uninvolved FLC at presentation was calculated, where applicable. Serum creatinine, B-type natriuretic peptide (BNP), troponin-I, serum albumin, and alkaline phosphatase levels were collected on almost all patients; troponin-I data were not available until June 2008, BNP was not collected until 2005, thus not all patients had this measurement available. Median overall survival and associated Kaplan–Meier survival curves were calculated for all patients. For patients for whom follow-up information was not available, survival was determined using the social security database.
Results Demographics A total of 47 patients (2%) presented with lymphadenopathy as the presenting manifestation of amyloidosis. There were 25 men (53%). The median age at the time of diagnosis was 63 years (range 33–79).
257
Site of biopsy Diagnostic biopsies were obtained from mediastinal lymph nodes in 14 patients (30%), cervical or supraclavicular nodes in 11 (23%), inguinal nodes in 8 (17%), axillary nodes in 7 (15%), and retroperitoneal, mesenteric, or peripancreatic nodes in 7 (15%) (Figure 1). Organ involvement At diagnosis, 14 (30%) had isolated lymphadenopathy while 33 (70%) had evidence of vital organ involvement in addition to the lymph nodes. At the end of this review (1994–2013), 39 patients (83%) had systemic AL amyloidosis; there was a single case each of AA, wtTTR, V122I TTR and one un-typed amyloidosis (Figure 2). Of those with systemic amyloidosis, the most common organ system involved at diagnosis was cardiac in 18 patients (55%), gastrointestinal tract in 13 (39%), renal in 11 (33%), and pulmonary in 5 (15%). Fifteen patients (45%) had greater than 2 organ systems involved (Table 1). There was no anatomical correlation between the sites of lymph node enlargement and involvement of the other organs. Plasma cell dyscrasia At diagnosis and initial presentation, 29 patients (62%) had evidence of systemic AL amyloidosis; 8 (28%) had kappa, and 21 (72%) had lambda. Of the 47 patients, 11 (23%) had IgM monoclonal protein gammopathy, and there were three cases in which the lymph node histology was consistent with lymphoplasmacytic lymphoma and amyloidosis. At diagnosis, 14 (30%) patients had isolated lymphadenopathy. Of the 14 patients, 7 (50%) had kappa, 5 (36%) had lambda and 2 (14%) were un-typed. Ten of those 14 patients with isolated lymphadenopathy eventually progressed requiring treatment (Table 2). Four patients continued to have isolated lymphadenopathy with a median follow-up time of 12 years (range 3–16). In this group, there was 1 case of kappa, 1 of lambda predominance and 2 patients with unknown type. For the total 47 patients, on bone marrow biopsy: 2 (4%) had55% plasma cells, 33 (70%) had 5–10% plasma cells, and 9 (19%) had 10–20% plasma cells. These data were not available for 3 patients (7%). The median serum free kappa light chain concentration was 26.2 mg/L (range 3–505). The median serum free lambda light chain concentration was
Figure 1. (a) Lymph node stained with Congo red stain (40). (b) Lymph node stained with Congo red stain revealing apple green birefringence under polarization microscopy (40).
258
J. Fu et al.
Amyloid, 2014; 21(4): 256–260
Figure 2. Patient consort diagram.
Table 1. Patient and treatment characteristics.
Table 2. Isolated lymphadenopathy group of 14; 10 progressed.
Characteristic
Patient no.
Median age, y (range) (%) No. male (%) No. with /l isotype No. with non-AL or untyped Isolated lymph node involvement, No. (%) Organ involvement: Cardiac GI Renal Pulmonary 42 organ involvement Baseline laboratory data: BNP, pg/mL Troponin I, ng/mL LVEF (%) IVS (mm) Serum creatinine, mg/dL 24 hour urine protein excretion, mg/24 h Time from diagnosis to evaluation, mos Time from diagnosis to treatment, mos Treatment (N ¼ 29) HDM/SCT MDex or MPred Bortezomib based LDex RCVP Other Second line treatment
63 (33–79) 25 (53) 15/26 6 14 (30) No. (%) 18 (55) 13 (39) 11 (33) 5 (15) 15 (45) Median (range) 109 (16–5411) 0.019 (0.006–0.161) 60 (32–74) 11 (7–21) 0.9 (0.4–4.5) 91 (0–11147) 4 (1–80) 5 (1–77) No. (%) 9 (31) 9 (31) 2 (7) 2 (7) 2 (7) 5 (17) 18 (62)
Other treatment options: Rituximab/Fludarabine; Rituximab/Velcade/ Dexamethasone; Cytoxan/Prednisone/Rituximab, Thalidomide, and single agent Dexamethasone.
1–7 8 9 10
Progression Waldenstro¨m macroglobulinemia (1), lymphoma (4), AL amyloidosis (2) Hemiparalysis of diaphragm, IgG kappa AL amyloidosis Extensive pulmonary lymphadenopathy causing hemoptysis and ICU stay Isolated lymphadenopathy
Treatment Standard HDM/SCT, then dexamethasone Melphalan and dexamethasone Unknown
36.1 mg/L (range 2.2–2520), and the differential free light chain median was 41.9 mg/L (range 0.8–2513.1) (Table 1).
Treatment and outcomes The median time from diagnosis to evaluation at our center was 4 months (range 1–80) and the median time from diagnosis to treatment was 5 months (range 1–77) for the entire cohort. First-line treatment included high dose melphalan and autologous stem cell transplantation (HDM/SCT) in 9 patients (31%) and oral melphalan and dexamethasone or prednisone in 9 (31%). Two patients (7%) received bortezomib-based treatment, two patients (7%) received lenalidomide and dexamethasone, and another two patients (7%) received rituximab, cyclophosphamide, vincristine and prednisone. Other treatment regimens are described in Table 1. Eighteen (62%) patients underwent subsequent second-line treatment due to progression of their underlying plasma cell dyscrasia.
Lymphadenopathy in amyloidosis
DOI: 10.3109/13506129.2014.958610
259
Figure 3. Overall survival from diagnosis by the Kaplan–Meier method of isolated versus systemic lymphadenopathy group.
Of the 14 patients presenting without evidence of other organ involvement at diagnosis, 10 eventually developed evidence of a systemic lymphoplasmacytic process and required systemic chemotherapy. One patient was diagnosed with Waldenstro¨m macroglobulinemia (10%), 4 with lymphoma (40%) and 2 with systemic AL amyloidosis (20%), and they were treated. One patient, reported in a case report previously [18], developed hemiparalysis of the diaphragm with involvement of her phrenic nerve and likely T10 nerve involvement and was subsequently diagnosed with IgG kappa AL amyloidosis and treated with high-dose melphalan and autologous stem cell transplantation. One patient had extensive pulmonary lymphadenopathy causing significant hemoptysis requiring ICU admission, and was subsequently treated with melphalan and dexamethasone. The remaining patients had treatment for isolated lymphadenopathy outside hospital with an unknown regimen. The median overall survival from diagnosis for the whole cohort was 4.5 years. Patients with isolated lymphadenopathy (4 patients) had a longer survival than those presenting with other organ involvement (12.5 years versus 3.6 years, respectively) (Figure 3). Four patients with isolated amyloid lymphadenopathy remain alive without systemic therapy at a median follow-up of 12 years (range 3–16).
Discussion Of 3008 patients evaluated at our center from January 1994 to May 2013, 47 (2%) presented with lymphadenopathy. Most of these (39, 83%) had systemic AL amyloidosis at initial evaluation or developed it during follow up; there was a single case each of AA, wt TTR, V122I TTR and one un-typed amyloidosis. The majority of lymph nodes which were initially biopsied were mediastinal, found on chest radiography performed for either amyloid specific symptoms or unrelated symptoms. Lymph node involvement from AA, wtTTR and V12ITTR amyloidosis is novel and very unusual. However, they were confirmed and typed based on immunohistochemistry on lymph node biopsy specimen and abdominal fat pad
aspiration, immunohistochemistry with gold-labeled antibody and electron microscopy and genetic testing in the case of V122ITTR amyloidosis. Fourteen (30%) had isolated lymph node involvement at the initial evaluation. Over time, 10 developed clear evidence of a systemic lymphoplasmacytic process, or symptomatic disease necessitating treatment, anywhere from 4 to 71 months after initial diagnosis (median, 10 months). With a median follow-up of 11 years (range 3–16), four patients (9%) had isolated lymphadenopathy only, and were observed with no adverse outcomes or signs of vital organ involvement or plasma cell dyscrasia. In three patients, treatment was administered for progressive lymphadenopathy causing local pathology including hemoptysis and diaphragmatic paralysis. Other treatment modalities for patients with progressive localized amyloidosis include surgical debulking, radiation or laser therapies. This work and other works have described these options in tracheobronchial amyloid [5,19] and cervical lymphadenopathy[16]. The median overall survival was 4.5 years for the whole cohort and 12.5 years for the group presenting with isolated lymphadenopathy. Even in the initial cohort of 14 with isolated lymphadenopathy, one patient eventually progressed only after 71 months of close observation. Our data support an approach of thorough initial evaluation for systemic disease, and careful observation for those patients with isolated adenopathy only at presentation, as there is a small group of patients (4 of 47 in this series), similar to other patients with localized amyloidosis of the gastrointestinal tract [20], breast [21], lung [5,19] and skin [22] that will not benefit from systemic therapy and its accompanying toxicities.
Acknowledgements We gratefully acknowledge our colleagues in the Amyloidosis Center at BUSM, and the Clinical Trials Office and staff of the Solomont Center for Cancer and Blood Disorders at Boston Medical Center who assisted with the
260
J. Fu et al.
multidisciplinary evaluation and treatment of these patients with amyloidosis.
Declaration of interest The authors report no conflicts of interest.
References 1. Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. N Engl J Med 2003;349:583–96. 2. Dember LM. Emerging treatment approaches for the systemic amyloidoses. Kidney Int 2005;68:1377–90. 3. Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med 1997;337:898–909. 4. Biewend ML, Menke DM, Calamia KT. The spectrum of localized amyloidosis: a case series of 20 patients and review of the literature. Amyloid 2006;13:135–42. 5. Berk JL, O’Regan A, Skinner M. Pulmonary and tracheobronchial amyloidosis. Semin Respir Crit Care Med 2002;23:155–65. 6. Prokaeva T, Spencer B, Kaut M, Ozonoff A, Doros G, Connors LH, Skinner M, et al. Soft tissue, joint, and bone manifestations of AL amyloidosis: clinical presentation, molecular features, and survival. Arthritis Rheum 2007;56:3858–68. 7. Mackenzie DH. Amyloidosis presenting as lymphadenopathy. Br Med J 1963;2:1449–50. 8. Ko HS, Davidson JW, Pruzanski W. Amyloid lymphadenopathy. Ann Intern Med 1976;85:763–4. 9. Matsuda M, Gono T, Shimojima Y, Yoshida T, Katoh N, Hoshii Y, Yamada T, et al. AL amyloidosis manifesting as systemic lymphadenopathy. Amyloid 2008;15:117–24. 10. Simmonds PD, Cottrell BJ, Mead GM, Wright DH, Whitehouse JM. Lymphadenopathy due to amyloid deposition in non-Hodgkin’s lymphoma. Ann Oncol 1997;8:267–70. 11. Dalton HR, Featherstone T, Athanasou N. Organ limited amyloidosis with lymphadenopathy. Postgrad Med J 1992;68:47–50.
Amyloid, 2014; 21(4): 256–260
12. Kutlay S, Hasan T, Keven K, Nergizoglu G, Ates K, Karatan O. Primary amyloidosis presenting with massive generalized lymphadenopathy. Leuk Lymphoma 2002;43:1501–3. 13. Kumar D, Singh AC, Neehar P, Usha, Tandon R, Tripathi K. Primary amyloidosis presenting with predominant lymphnodal masses. J Assoc Phys India 2005;53:312–13. 14. Vogel MN, Wehrmann M, Horger MS. Massive cervical and abdominal lymphadenopathy caused by localized amyloidosis. J Clin Oncol 2007;25:343–4. 15. Takeshita K, Yamada S, Sato N, Kuwabara K, Kobayashi K, Asano K, Yamaguchi K. An unusual case of mediastinal lymphadenopathy caused by amyloidosis. Intern Med 2000;39: 839–42. 16. Matsuda M, Katoh N, Tazawa K, Shimojima Y, Mishima Y, Sano K, Ikeda S. Surgical removal of amyloid-laden lymph nodes: a possible therapeutic approach in a primary systemic AL amyloidosis patient with focal lymphadenopathy. Amyloid 2011; 18:79–82. 17. Urschel JD, Urschel DM. Mediastinal amyloidosis. Ann Thorac Surg 2000;69:944–6. 18. Berk JL, Wiesman JF, Skinner M, Sanchorawala V. Diaphragm paralysis in primary systemic amyloidosis. Amyloid 2005;12: 193–6. 19. O’Regan A, Fenlon HM, Beamis Jr JF, Steele MP, Skinner M, Berk JL. Tracheobronchial amyloidosis: the Boston University experience from 1984 to 1999. Medicine (Baltimore) 2000;79: 69–79. 20. Cowan AJ, Skinner M, Seldin DC, Berk JL, Lichtenstein DR, O’Hara CJ, Doros G, et al. Amyloidosis of the gastrointestinal tract: a 13-year, single-center, referral experience. Haematologica 2013; 98:141–6. 21. Charlot M, Seldin DC, O’Hara C, Skinner M, Sanchorawala V. Localized amyloidosis of the breast: a case series. Amyloid 2011; 18:72–5. 22. Kaltoft B, Schmidt G, Lauritzen AF, Gimsing P. Primary localised cutaneous amyloidosis – a systematic review. Dan Med J 2013;60: A4727–34.
Copyright of Amyloid is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
ORIGINAL ARTICLE
Lymphadenopathy as a manifestation of amyloidosis: a case series Julie Fu1, David C. Seldin1, John L. Berk1, Fangui Sun1,2, Carl O’Hara1, Haili Cui1, and Vaishali Sanchorawala1 1
Amyloidosis Center, Boston University School of Medicine, Boston, MA, USA and 2School of Public Health, Boston Medical Center, Boston, MA, USA
Abstract
Keywords
Lymphadenopathy as a manifestation of amyloidosis is rare. Of 3008 new patients with amyloidosis evaluated from 1994 to 2013 at a single center, 47 (1.6%) presented with lymph node enlargement leading to a biopsy and the diagnosis. We conducted a retrospective review of the initial presentation, time to progression, and treatment outcomes for these patients. Upon initial evaluation, 14 (30%) had isolated lymphadenopathy while 33 (70%) had evidence of vital organ involvement. Thirty-nine patients (83%) had systemic AL amyloidosis at initial evaluation or developed it on follow up; there was a single case each of AA, wtTTR and V122ITTR and one untyped amyloidosis. Eleven patients (23%) had IgM monoclonal gammopathy and 3 (6%) had histology consistent with lymphoplasmacytic lymphoma. Of the 14 patients with isolated lymphadenopathy, 10 (71%) eventually progressed to other organ disease requiring treatment at a median time of 10 months (range 4–71). This series demonstrates that patients presenting with amyloid lymphadenopathy usually have AL amyloidosis, and should have a thorough evaluation for other organ involvement at diagnosis. If present, treatment should be similar to that of other patients with systemic AL amyloidosis, but if not, patients should be monitored regularly for development of other organ disease over time.
Amyloidosis, lymph nodes, treatment History Received 30 May 2014 Revised 31 July 2014 Accepted 1 August 2014 Published online 10 September 2014
Abbreviations: AA: amyloid protein A; AL: amyloid light chain; BNP: B-type natriuretic peptide; FLC: free light chain; GI: gastrointestinal; wtTTR: wild type transthyretin
Introduction Amyloidosis is a heterogeneous group of protein misfolding disorders in which proteins deposit extracellularly as amyloid fibrils causing organ damage. Amyloidosis can be either systemic or localized. In systemic amyloidosis, deposition occurs in multiple organs distant from the site of production of the precursor protein, while in localized amyloidosis, production and deposition occur in a single tissue organ [1,2]. The most commonly diagnosed type of systemic amyloidosis is light chain (AL) amyloidosis. AL amyloidosis most frequently affects the kidneys and heart, but can also involve the pulmonary system, peripheral and autonomic nervous system, gastro-intestinal tract including the liver, and soft tissues [3]. Localized AL amyloidosis can occur in sites including the tracheobronchial tree, genitourinary tract, breast and skin [4]. We and others have observed amyloidosis presenting as lymphadenopathy [5–8], but this presentation has not been
examined systematically. Additional case reports describe involvement of cervical, axillary, paratracheal, retroperitoneal, mesenteric, inguinal and various combinations of lymph node groups [9–16]. In patients with thoracic involvement and systemic amyloidosis, 75% of patients have been reported to have involvement of the mediastinal or hilar lymph nodes [17]. To better understand the clinical implications of amyloidosis diagnosed in lymph nodes, we retrospectively reviewed all cases with lymphadenopathy as the presenting manifestation of amyloidosis from January 1994 to May 2013 in our tertiary referral center. While this presentation proved to be rare, identification of 47 cases allowed us to delineate the patient characteristics, frequency and type of vital organ involvement, time to progression, treatment outcomes, and survival in this unusual group of patients.
Patients and methods Patients
Address for correspondence: Vaishali Sanchorawala, Section of Hematology/Oncology, School of Public Health, Boston Medical Center, FGH 1007, 820 Harrison Avenue, Boston, MA 02118, USA. Tel: (617) 638-7002. Fax: 617 414 1831. E-mail: Vaishali. [email protected]
Data on 3008 consecutive patients with all forms of amyloidosis seen from January 1994 to May 2013 in the Boston University Amyloidosis Center were reviewed. The Institutional Review Board of Boston University Medical Campus approved data collection and analysis, and written
Lymphadenopathy in amyloidosis
DOI: 10.3109/13506129.2014.958610
informed consent was obtained from each patient, in accordance with the Declaration of Helsinki. Forty-seven patients were identified as having been diagnosed with amyloidosis based upon lymph node biopsy performed because of lymphadenopathy. Biopsies from outside institutions were reviewed, with repeat Congo red staining if necessary for confirmation. Immunohistochemical staining, mass spectrometry, or immunogold electron microscopy was used to type the amyloid deposits. In addition, gene sequencing was performed for cases of ATTR amyloidosis. Patients were evaluated for systemic amyloidosis with extensive testing for a plasma cell dyscrasia, and for involvement of vital organs including heart, kidney, liver, gastrointestinal tract and neurologic system. Data collection Data reviewed for each patient included time from diagnosis to evaluation and organ involvement, including cardiac, pulmonary, renal, neurologic, soft tissue, and hepatic disease. For patients with AL amyloidosis, data included bone marrow biopsy with Congo red staining, CD138 immunohistochemistry, and in situ hybridization for light chain expression, serum free light chain (FLC) measurements, and serum and urine immunofixation electrophoresis. The difference (dFLC) between the involved FLC and the uninvolved FLC at presentation was calculated, where applicable. Serum creatinine, B-type natriuretic peptide (BNP), troponin-I, serum albumin, and alkaline phosphatase levels were collected on almost all patients; troponin-I data were not available until June 2008, BNP was not collected until 2005, thus not all patients had this measurement available. Median overall survival and associated Kaplan–Meier survival curves were calculated for all patients. For patients for whom follow-up information was not available, survival was determined using the social security database.
Results Demographics A total of 47 patients (2%) presented with lymphadenopathy as the presenting manifestation of amyloidosis. There were 25 men (53%). The median age at the time of diagnosis was 63 years (range 33–79).
257
Site of biopsy Diagnostic biopsies were obtained from mediastinal lymph nodes in 14 patients (30%), cervical or supraclavicular nodes in 11 (23%), inguinal nodes in 8 (17%), axillary nodes in 7 (15%), and retroperitoneal, mesenteric, or peripancreatic nodes in 7 (15%) (Figure 1). Organ involvement At diagnosis, 14 (30%) had isolated lymphadenopathy while 33 (70%) had evidence of vital organ involvement in addition to the lymph nodes. At the end of this review (1994–2013), 39 patients (83%) had systemic AL amyloidosis; there was a single case each of AA, wtTTR, V122I TTR and one un-typed amyloidosis (Figure 2). Of those with systemic amyloidosis, the most common organ system involved at diagnosis was cardiac in 18 patients (55%), gastrointestinal tract in 13 (39%), renal in 11 (33%), and pulmonary in 5 (15%). Fifteen patients (45%) had greater than 2 organ systems involved (Table 1). There was no anatomical correlation between the sites of lymph node enlargement and involvement of the other organs. Plasma cell dyscrasia At diagnosis and initial presentation, 29 patients (62%) had evidence of systemic AL amyloidosis; 8 (28%) had kappa, and 21 (72%) had lambda. Of the 47 patients, 11 (23%) had IgM monoclonal protein gammopathy, and there were three cases in which the lymph node histology was consistent with lymphoplasmacytic lymphoma and amyloidosis. At diagnosis, 14 (30%) patients had isolated lymphadenopathy. Of the 14 patients, 7 (50%) had kappa, 5 (36%) had lambda and 2 (14%) were un-typed. Ten of those 14 patients with isolated lymphadenopathy eventually progressed requiring treatment (Table 2). Four patients continued to have isolated lymphadenopathy with a median follow-up time of 12 years (range 3–16). In this group, there was 1 case of kappa, 1 of lambda predominance and 2 patients with unknown type. For the total 47 patients, on bone marrow biopsy: 2 (4%) had55% plasma cells, 33 (70%) had 5–10% plasma cells, and 9 (19%) had 10–20% plasma cells. These data were not available for 3 patients (7%). The median serum free kappa light chain concentration was 26.2 mg/L (range 3–505). The median serum free lambda light chain concentration was
Figure 1. (a) Lymph node stained with Congo red stain (40). (b) Lymph node stained with Congo red stain revealing apple green birefringence under polarization microscopy (40).
258
J. Fu et al.
Amyloid, 2014; 21(4): 256–260
Figure 2. Patient consort diagram.
Table 1. Patient and treatment characteristics.
Table 2. Isolated lymphadenopathy group of 14; 10 progressed.
Characteristic
Patient no.
Median age, y (range) (%) No. male (%) No. with /l isotype No. with non-AL or untyped Isolated lymph node involvement, No. (%) Organ involvement: Cardiac GI Renal Pulmonary 42 organ involvement Baseline laboratory data: BNP, pg/mL Troponin I, ng/mL LVEF (%) IVS (mm) Serum creatinine, mg/dL 24 hour urine protein excretion, mg/24 h Time from diagnosis to evaluation, mos Time from diagnosis to treatment, mos Treatment (N ¼ 29) HDM/SCT MDex or MPred Bortezomib based LDex RCVP Other Second line treatment
63 (33–79) 25 (53) 15/26 6 14 (30) No. (%) 18 (55) 13 (39) 11 (33) 5 (15) 15 (45) Median (range) 109 (16–5411) 0.019 (0.006–0.161) 60 (32–74) 11 (7–21) 0.9 (0.4–4.5) 91 (0–11147) 4 (1–80) 5 (1–77) No. (%) 9 (31) 9 (31) 2 (7) 2 (7) 2 (7) 5 (17) 18 (62)
Other treatment options: Rituximab/Fludarabine; Rituximab/Velcade/ Dexamethasone; Cytoxan/Prednisone/Rituximab, Thalidomide, and single agent Dexamethasone.
1–7 8 9 10
Progression Waldenstro¨m macroglobulinemia (1), lymphoma (4), AL amyloidosis (2) Hemiparalysis of diaphragm, IgG kappa AL amyloidosis Extensive pulmonary lymphadenopathy causing hemoptysis and ICU stay Isolated lymphadenopathy
Treatment Standard HDM/SCT, then dexamethasone Melphalan and dexamethasone Unknown
36.1 mg/L (range 2.2–2520), and the differential free light chain median was 41.9 mg/L (range 0.8–2513.1) (Table 1).
Treatment and outcomes The median time from diagnosis to evaluation at our center was 4 months (range 1–80) and the median time from diagnosis to treatment was 5 months (range 1–77) for the entire cohort. First-line treatment included high dose melphalan and autologous stem cell transplantation (HDM/SCT) in 9 patients (31%) and oral melphalan and dexamethasone or prednisone in 9 (31%). Two patients (7%) received bortezomib-based treatment, two patients (7%) received lenalidomide and dexamethasone, and another two patients (7%) received rituximab, cyclophosphamide, vincristine and prednisone. Other treatment regimens are described in Table 1. Eighteen (62%) patients underwent subsequent second-line treatment due to progression of their underlying plasma cell dyscrasia.
Lymphadenopathy in amyloidosis
DOI: 10.3109/13506129.2014.958610
259
Figure 3. Overall survival from diagnosis by the Kaplan–Meier method of isolated versus systemic lymphadenopathy group.
Of the 14 patients presenting without evidence of other organ involvement at diagnosis, 10 eventually developed evidence of a systemic lymphoplasmacytic process and required systemic chemotherapy. One patient was diagnosed with Waldenstro¨m macroglobulinemia (10%), 4 with lymphoma (40%) and 2 with systemic AL amyloidosis (20%), and they were treated. One patient, reported in a case report previously [18], developed hemiparalysis of the diaphragm with involvement of her phrenic nerve and likely T10 nerve involvement and was subsequently diagnosed with IgG kappa AL amyloidosis and treated with high-dose melphalan and autologous stem cell transplantation. One patient had extensive pulmonary lymphadenopathy causing significant hemoptysis requiring ICU admission, and was subsequently treated with melphalan and dexamethasone. The remaining patients had treatment for isolated lymphadenopathy outside hospital with an unknown regimen. The median overall survival from diagnosis for the whole cohort was 4.5 years. Patients with isolated lymphadenopathy (4 patients) had a longer survival than those presenting with other organ involvement (12.5 years versus 3.6 years, respectively) (Figure 3). Four patients with isolated amyloid lymphadenopathy remain alive without systemic therapy at a median follow-up of 12 years (range 3–16).
Discussion Of 3008 patients evaluated at our center from January 1994 to May 2013, 47 (2%) presented with lymphadenopathy. Most of these (39, 83%) had systemic AL amyloidosis at initial evaluation or developed it during follow up; there was a single case each of AA, wt TTR, V122I TTR and one un-typed amyloidosis. The majority of lymph nodes which were initially biopsied were mediastinal, found on chest radiography performed for either amyloid specific symptoms or unrelated symptoms. Lymph node involvement from AA, wtTTR and V12ITTR amyloidosis is novel and very unusual. However, they were confirmed and typed based on immunohistochemistry on lymph node biopsy specimen and abdominal fat pad
aspiration, immunohistochemistry with gold-labeled antibody and electron microscopy and genetic testing in the case of V122ITTR amyloidosis. Fourteen (30%) had isolated lymph node involvement at the initial evaluation. Over time, 10 developed clear evidence of a systemic lymphoplasmacytic process, or symptomatic disease necessitating treatment, anywhere from 4 to 71 months after initial diagnosis (median, 10 months). With a median follow-up of 11 years (range 3–16), four patients (9%) had isolated lymphadenopathy only, and were observed with no adverse outcomes or signs of vital organ involvement or plasma cell dyscrasia. In three patients, treatment was administered for progressive lymphadenopathy causing local pathology including hemoptysis and diaphragmatic paralysis. Other treatment modalities for patients with progressive localized amyloidosis include surgical debulking, radiation or laser therapies. This work and other works have described these options in tracheobronchial amyloid [5,19] and cervical lymphadenopathy[16]. The median overall survival was 4.5 years for the whole cohort and 12.5 years for the group presenting with isolated lymphadenopathy. Even in the initial cohort of 14 with isolated lymphadenopathy, one patient eventually progressed only after 71 months of close observation. Our data support an approach of thorough initial evaluation for systemic disease, and careful observation for those patients with isolated adenopathy only at presentation, as there is a small group of patients (4 of 47 in this series), similar to other patients with localized amyloidosis of the gastrointestinal tract [20], breast [21], lung [5,19] and skin [22] that will not benefit from systemic therapy and its accompanying toxicities.
Acknowledgements We gratefully acknowledge our colleagues in the Amyloidosis Center at BUSM, and the Clinical Trials Office and staff of the Solomont Center for Cancer and Blood Disorders at Boston Medical Center who assisted with the
260
J. Fu et al.
multidisciplinary evaluation and treatment of these patients with amyloidosis.
Declaration of interest The authors report no conflicts of interest.
References 1. Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. N Engl J Med 2003;349:583–96. 2. Dember LM. Emerging treatment approaches for the systemic amyloidoses. Kidney Int 2005;68:1377–90. 3. Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med 1997;337:898–909. 4. Biewend ML, Menke DM, Calamia KT. The spectrum of localized amyloidosis: a case series of 20 patients and review of the literature. Amyloid 2006;13:135–42. 5. Berk JL, O’Regan A, Skinner M. Pulmonary and tracheobronchial amyloidosis. Semin Respir Crit Care Med 2002;23:155–65. 6. Prokaeva T, Spencer B, Kaut M, Ozonoff A, Doros G, Connors LH, Skinner M, et al. Soft tissue, joint, and bone manifestations of AL amyloidosis: clinical presentation, molecular features, and survival. Arthritis Rheum 2007;56:3858–68. 7. Mackenzie DH. Amyloidosis presenting as lymphadenopathy. Br Med J 1963;2:1449–50. 8. Ko HS, Davidson JW, Pruzanski W. Amyloid lymphadenopathy. Ann Intern Med 1976;85:763–4. 9. Matsuda M, Gono T, Shimojima Y, Yoshida T, Katoh N, Hoshii Y, Yamada T, et al. AL amyloidosis manifesting as systemic lymphadenopathy. Amyloid 2008;15:117–24. 10. Simmonds PD, Cottrell BJ, Mead GM, Wright DH, Whitehouse JM. Lymphadenopathy due to amyloid deposition in non-Hodgkin’s lymphoma. Ann Oncol 1997;8:267–70. 11. Dalton HR, Featherstone T, Athanasou N. Organ limited amyloidosis with lymphadenopathy. Postgrad Med J 1992;68:47–50.
Amyloid, 2014; 21(4): 256–260
12. Kutlay S, Hasan T, Keven K, Nergizoglu G, Ates K, Karatan O. Primary amyloidosis presenting with massive generalized lymphadenopathy. Leuk Lymphoma 2002;43:1501–3. 13. Kumar D, Singh AC, Neehar P, Usha, Tandon R, Tripathi K. Primary amyloidosis presenting with predominant lymphnodal masses. J Assoc Phys India 2005;53:312–13. 14. Vogel MN, Wehrmann M, Horger MS. Massive cervical and abdominal lymphadenopathy caused by localized amyloidosis. J Clin Oncol 2007;25:343–4. 15. Takeshita K, Yamada S, Sato N, Kuwabara K, Kobayashi K, Asano K, Yamaguchi K. An unusual case of mediastinal lymphadenopathy caused by amyloidosis. Intern Med 2000;39: 839–42. 16. Matsuda M, Katoh N, Tazawa K, Shimojima Y, Mishima Y, Sano K, Ikeda S. Surgical removal of amyloid-laden lymph nodes: a possible therapeutic approach in a primary systemic AL amyloidosis patient with focal lymphadenopathy. Amyloid 2011; 18:79–82. 17. Urschel JD, Urschel DM. Mediastinal amyloidosis. Ann Thorac Surg 2000;69:944–6. 18. Berk JL, Wiesman JF, Skinner M, Sanchorawala V. Diaphragm paralysis in primary systemic amyloidosis. Amyloid 2005;12: 193–6. 19. O’Regan A, Fenlon HM, Beamis Jr JF, Steele MP, Skinner M, Berk JL. Tracheobronchial amyloidosis: the Boston University experience from 1984 to 1999. Medicine (Baltimore) 2000;79: 69–79. 20. Cowan AJ, Skinner M, Seldin DC, Berk JL, Lichtenstein DR, O’Hara CJ, Doros G, et al. Amyloidosis of the gastrointestinal tract: a 13-year, single-center, referral experience. Haematologica 2013; 98:141–6. 21. Charlot M, Seldin DC, O’Hara C, Skinner M, Sanchorawala V. Localized amyloidosis of the breast: a case series. Amyloid 2011; 18:72–5. 22. Kaltoft B, Schmidt G, Lauritzen AF, Gimsing P. Primary localised cutaneous amyloidosis – a systematic review. Dan Med J 2013;60: A4727–34.
Copyright of Amyloid is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
