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Infectious Lymphadenitis in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Rare, But Important, Complication Deborah A. Bowen, Kari G. Rabe, Susan M. Schwager, Susan L. Slager, Timothy G. Call, David S. Viswanatha, and Clive S. Zent

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doi: 10.3109/10428194.2014.914202 Abstract The differential diagnosis of rapidly progressive or symptomatic lymphadenopathy in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) includes infectious lymphadenitis. We studied 286 (9%) of 3040 CLL patients seen between 2003-2012 at Mayo Clinic Rochester who had 356 diagnostic lymph node biopsies to evaluate rapidly progressive or symptomatic lymphadenopathy. Most (85.4%) biopsies showed progressive CLL, 8.9% a second lymphoid malignancy, 3.9% infectious lymphadenitis, 1.1% reactive adenitis, and 0.6% non-hematological malignancies. Of the 12 patients (14 biopsies) with infectious lymphadenitis, five patients had never been treated for their CLL, and seven had a specific microbiological diagnosis (herpes simplex n=3, Cryptococcus neoformans n=1, Mycobacterium n=1, coagulase negative Staphylococcus n=2). We conclude that infectious lymphadenitis is a rare complication of CLL with clinical characteristics similar to progressive CLL and transformation to a more aggressive lymphoma. Early recognition and antimicrobial therapy treatment of infectious lymphadenitis can be highly effective in these patients.

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Infectious Lymphadenitis in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Rare, But Important, Complication

Timothy G. Call1, David S. Viswanatha3, and Clive S. Zent1

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Division of Hematology, 2Department of Health Sciences Research, and 3Department of

Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA

Corresponding Author: Clive S. Zent, MD, James P. Wilmot Cancer Center, University of Rochester, 601 Elmwood Avenue, Box 704, Rochester, NY 14642 USA. E-mail: [email protected] Tel: 585 276-6891 Fax: 585 276-0350

Abstract

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Short title: Infectious Lymphadenitis in CLL

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The differential diagnosis of rapidly progressive or symptomatic lymphadenopathy in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) includes infectious lymphadenitis. We studied 286 (9%) of 3040 CLL patients seen between 2003-2012 at Mayo Clinic Rochester who had 356 diagnostic lymph node biopsies to evaluate rapidly progressive or symptomatic lymphadenopathy. Most (85.4%) biopsies showed progressive CLL, 8.9% a second lymphoid malignancy, 3.9% infectious lymphadenitis, 1.1% reactive adenitis, and 0.6% non-hematological malignancies. Of the 12 patients (14 biopsies) with infectious lymphadenitis, five patients had never been treated for their CLL, and seven had a specific microbiological diagnosis (herpes simplex n=3, Cryptococcus neoformans n=1, Mycobacterium n=1, coagulase negative Staphylococcus n=2). We conclude that infectious lymphadenitis is a rare complication of CLL with clinical characteristics similar to progressive CLL and transformation to a more aggressive lymphoma. Early recognition and antimicrobial therapy treatment of infectious lymphadenitis can be highly effective in these patients. Key words Chronic lymphocytic leukemia, small lymphocytic lymphoma, CLL, lymphadenopathy, infection, lymphadenitis, Cryptococcus, Mycobacterium avium, herpes simplex

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Deborah A. Bowen1, Kari G. Rabe2, Susan M. Schwager1, Susan L. Slager2,

Introduction

Rapidly progressive or symptomatic lymphadenopathy in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) has an extensive differential diagnosis. Potential causes include rapid progression of CLL, development of a more aggressive lymphoma

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(Richter’s transformation), other second malignancies, physiological responses to immune activation (reactive lymphadenopathy), and lymph

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etiology of rapidly progressive or symptomatic lymphadenopathy in patients with CLL can be important for management and frequently requires a lymph node biopsy.

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CLL patients are immunocompromised by their disease and from its treatment, leading to an increased risk of infectious complications [1]. However, there is limited data on the clinical presentation and

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consequences of infectious lymphadenitis in patients with CLL. We thus analyzed a large CLL patient cohort to identify individuals presenting with rapidly progressive or symptomatic lymphadenopathy who underwent a lymph node biopsy which was diagnostic for infectious lymphadenitis. These patients were then studied to determine the frequency, clinical

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node infections (infectious lymphadenitis). An accurate diagnosis of the

presentation, etiology, and outcome of infectious lymphadenitis in CLL. Methods

We conducted an observational study of 3040 patients with a

diagnosis of CLL seen at least once in the Division of Hematology at Mayo Clinic Rochester from January 1, 2003 to December 31, 2012, with approval of the Institutional Review Board and according to the principals

of the Helsinki Accord. All patients had a confirmed diagnosis of CLL by standard criteria [2,3]. Prognostic parameters were evaluated by analysis of peripheral blood CLL cells. Cells were evaluated by interphase fluorescent in situ hybridization (FISH) for common recurrent genetic

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defects as previously described [4] and results reported using the hierarchical method [5]. The CLL cell IGHV gene was evaluated for

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predictive of a lower risk disease by Sanger sequencing as previously described [6]. CLL cells were examined by flow cytometric methods for expression of the higher levels of ZAP70 (≥ 20%) and CD38 (≥ 30%)

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expression that are associated with higher risk CLL as previously described [6,7]. The Mayo Clinic CLL database was used to identify all patients with rapidly progressive or symptomatic lymphadenopathy who

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underwent a diagnostic lymph node biopsy. The presentation and outcome of all these patients were then reviewed in detail using the electronic clinical, pathology, and imaging records. A consultant pathologist (D.S.V.) reviewed all lymph node biopsies with a diagnosis of infectious lymphadenitis.

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somatic hypermutation (≥ 2% difference from germline sequence)

Results

Two hundred eighty-six (9%) patients with rapidly progressive or

symptomatic lymphadenopathy had 356 diagnostic lymph node biopsies (median number of biopsies=1, range 1-4). The majority of these biopsies (n=304, 85.4%) showed progressive CLL. Fifty-two (14.6%) biopsies showed an additional disease process: 32 (9%) a second lymphoid

malignancy (25 diffuse large B-cell lymphomas, 3 Hodgkin lymphomas, 2 follicular B-cell lymphomas, 1 mantle cell lymphoma, and 1 peripheral Tcell lymphoma), 14 (3.9%) infectious lymphadenitis, 4 (1.1%) reactive adenitis, and 2 (0.6%) non-hematological malignancies (1 lung

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adenocarcinoma, 1 melanoma). Twelve patients had 14 biopsies (9 excision and 5 fine needle

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was identified in 8 biopsies (7 patients). The patients’ clinical

characteristics are detailed in Table I. Five patients had not been previously treated for progressive CLL. Two of these patients presented

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with rapidly progressive symptomatic infectious lymphadenitis, and their CLL was an incidental diagnosis on the biopsy done to determine the etiology of their lymphadenitis. Seven patients had received treatment for

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progressive CLL prior to developing infectious lymphadenitis. However, only three of these had been treated in the two years preceding their diagnosis of infectious lymphadenitis (2 purine analogue containing chemoimmunotherapy, 1 alemtuzumab). All 12 patients presented with both rapidly progressive and symptomatic lymphadenitis. Eleven patients

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aspiration) diagnostic for infectious lymphadenitis, and a specific infection

had no clinically obvious source of infection in the area draining to the enlarged lymph nodes. One patient had an oral ulcer that preceded the development of cervical lymphadenopathy by two weeks and responded to treatment with valacyclovir. The subsequent lymph node biopsy did not yield a microbiological cause of the infectious lymphadenitis. Two

patients had a second lymph node biopsy to evaluate recurrent lymphadenitis during the study period. Herpes simplex virus (HSV) infection was detected in four biopsies performed in three patients by immunohistochemical (IHC) or in situ

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hybridization methods. In all four specimens, the histological evaluation showed suppurative necrosis. The patient with recurrent HSV

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with alemtuzumab and everolimus and the second episode three months after starting therapy with ofatumumab. The other two patients had also received therapy for progressive CLL prior to developing HSV

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lymphadenitis. One patient had been treated five years previously with rituximab, cyclophosphamide, vincristine, and prednisone, and the other had pentostatin, cyclophosphamide and rituximab (PCR) 4.5 years

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previously. All episodes of HSV lymphadenitis responded well to valacyclovir therapy.

The patient with recurrent Mycobacterium avium lymphadenitis had not been treated for his CLL. He initially presented with a single rapidly progressive and symptomatic lymph node and excision biopsy

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lymphadenitis had the first episode 20 months after completing therapy

showed granulomatous inflammation with focal necrosis, but no organisms were cultured. The patient received no further treatment. A year later, the patient presented again with more extensive rapidly progressive and symptomatic lymphadenopathy with purulent drainage to the skin through a sinus tract. An excision biopsy showed prominent necrotizing granulomatous inflammation with acid-fast bacilli and a

positive culture for Mycobacterium avium. His residual lymphadenopathy responded well to three months of treatment with rifampicin, ethambutol, and azithromycin. One year later (and outside of the time interval reported in this study), he had a third episode of rapidly progressive and

Mycobacterium avium lymphadenitis.

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symptomatic lymphadenopathy, and excision biopsy showed recurrent

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presented with rapidly progressive tender lymphadenopathy in the abdomen, chest and neck. He had been treated for his CLL with fludarabine, cyclophosphamide and rituximab and PCR in the previous

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year. A right supraclavicular excision lymph node biopsy showed nonnecrotic granulomas with foreign body type giant cells. The visible fungal organisms were positive for Cryptococcus by in-situ hybridization, and

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Cryptococcus neoformans was cultured from the specimen. He was treated with liposomal amphotericin B and 5-fluorocytosine but died of disseminated Cryptococcus infection one month after initial presentation. Two patients with an excisional lymph node biopsy showing evidence of infection or inflammation (reactive follicular germinal centers

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The patient with Cryptoccocus neoformans lymphadenitis

and increased paraimmunoblasts) had lymph node cultures positive for coagulase negative Staphylococcus. One of these patients responded to therapy with cephalexin, and the other did not require any additional therapy after resection of the single involved lymph node. Five patients had biopsies (3 excision and 2 fine needle

aspiration) showing histological evidence suggestive of infection (e.g.

abscess formation, granulomatous inflammation, necrosis and fibrosis) without identification of a causative organism on lymph node examination or culture. All of these had patients had been treated with antimicrobials (4 cephalexin, 1 levofloxacin, 1 valacyclovir) prior to their lymph node

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biopsies, and all had complete resolution of their lymphadenitis. Five (36%) of the14 lymph node biopsies in patients with infectious

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biopsies were diagnostic for HSV infection, including one that showed HSV reactivation. The other two biopsies showed focal granulomatous and reactive changes but did not identify an infectious etiology by

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histological methods or culture. However, both patients had rapid

Discussion

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responses to empiric antimicrobial therapy.

Infectious lymphadenitis is a rare but treatable complication of CLL, which can be clinically indistinguishable from transformation to a more aggressive lymphoma. In this study, we demonstrated that 12/286

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lymphadenitis were performed by fine needle aspiration. Three of these

(4.2%) patients who had lymph node biopsies to investigate rapidly progressive or symptomatic lymphadenopathy had infectious lymphadenitis. In five of these patients, the identification of the causative organism resulted in appropriate treatment. The most common identified etiology of infectious lymphadenitis

was HSV reactivation. Patients with CLL are at increased risk of HSV

lymphadenitis that can vary in severity and can be difficult to distinguish from other causes of rapidly progressive or symptomatic adenopathy, including diffuse large B-cell lymphoma [8-10]. HSV reactivation caused recurrent infectious lymphadenitis in one of our patients, a problem which

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has been previously reported in a CLL patient [11]. However, because recurrent HSV lymphadenitis is a very rare complication of CLL, the role

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The two patients with opportunistic infections (Cryptococcus neoformans and Mycobacterium avium) involving their lymph nodes provide a good rationale for excision biopsies to evaluate rapidly

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progressive or symptomatic lymphadenopathy in patients with CLL. These biopsies yielded both histological and microbiological information which was essential for appropriate treatment of these infections.

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Cryptococcus is a well described opportunistic infection in patients with lymphoproliferative disorders including CLL, and the risk is increased in patients treated with purine analogues or alemtuzumab [12]. The most common presentation in immunocompromised patients is meningitis [12]. Cryptococcus lymphadenitis is well described in patients with HIV

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of prophylactic anti-herpes virus therapy in these patients is unknown.

infection [13], and there is one case report of isolated mediastinal Cryptococcus lymphadenitis developing in a patient with enteropathyassociated T-cell lymphoma [14]. However, to the best of our knowledge, there are no published reports of Cryptococcus lymphadenitis in patients with CLL.

Mycobacterium avium infection of a lymph node has previously been reported in two patients after treatment for their CLL (1 alemtuzumab, 1 cyclophosphamide, vincristine and prednisone) [15,16]. Here we report recurrent Mycobacterium avium lymphadenitis in a patient

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who had not been treated for his CLL and did not have any non-CLL related immunosuppressive disease or treatment. This suggests that

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complication.

The relevance of the culture of coagulase negative

Staphylococcus in two patients with inflammatory changes in their lymph

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nodes is uncertain. In a study of a large number of lymph nodes (n=1688) resected from patients with a clinical suspicion of infectious lymphadenitis, molecular markers of coagulase negative staphylococcus

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were detected in 20 (1.1%) lymph nodes, and coagulase negative staphylococci were cultured from 19 (1.1%) lymph nodes [17]. However, even though coagulase negative Staphylococcus can cause systemic infections in immunocompromised patients [18], detection of these organisms in a lymph node by molecular methods or culture does not

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immunosuppression related to CLL is sufficient to cause this

prove causality. Although the histological findings are strongly supportive of some infectious mechanism, we cannot determine whether coagulasenegative Staphylococcus had an etiological role in the lymphadenitis in these patients.

Five patients with histological evidence of infection did not have a

microbiological diagnosis. These patients received empiric antimicrobial

therapy prior to their biopsies, which could have contributed to their negative studies for infection. Although the histological findings were also compatible with non-infectious granulomatous conditions such as sarcoidosis in some of these patients, the clinical presentation and rapid

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response to empirical antimicrobial therapy strongly favored the diagnosis of infectious lymphadenitis. Our data thus suggest that a

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infectious lymphadenitis treated with empiric antimicrobial therapy have good clinical responses. These patients could benefit from a closely monitored therapeutic trial of empiric antimicrobial therapy for presumed

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infectious lymphadenitis, and lymph node biopsies would then only be indicated in non-responsive patients.

Fine needle aspiration biopsies are generally less expensive and

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lower risk than excision biopsies. In CLL patients with rapidly progressive lymphadenopathy, an excision or wide-incision biopsy provides considerably more material for diagnostic analysis and allows the pathologist to evaluate lymph node architecture. These data can be critical in differentiating between progressive CLL and transformed

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subgroup of CLL patients with clinical and histological evidence of

lymphomas [19]. In this study, an infectious etiology was not diagnosed in two out of five (40%) lymph nodes biopsies with fine needle aspiration compared to four out of nine (44%) excision biopsies. However, the only infectious diagnosis made by fine needle aspiration biopsies was HSV. These data do not allow for any conclusions about the relative merits of fine needle aspiration compared to excision biopsy in the diagnosis of

infectious lymphadenitis in patients with CLL. Based on our finding that 85.4% of lymph node biopsies done in patients for rapidly progressive or symptomatic lymphadenopathy showed only progressive CLL and 9% were diagnostic for a second lymphoid malignancy (compared to only

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3.9% with infectious lymphadenitis), we strongly recommend that excision biopsy should remain the method of choice for evaluation of

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CLL.

This study evaluated infectious lymphadenitis complicating CLL in a large and well-characterized CLL cohort using data collected

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prospectively. However, the rate of infectious lymphadenitis in this population could be higher than that reported in this study because patients with mild infections causing mild infectious or reactive

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lymphadenitis will often not seek medical attention, and, among those that are evaluated, many could respond well to empiric antibiotic therapy without a specific diagnosis.

In conclusion, our study shows that infectious lymphadenitis is a rare, but important, complication of CLL. Infectious lymphadenitis needs

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rapidly progressive or symptomatic lymphadenopathy in patients with

to be considered in the differential diagnosis of CLL patients presenting with rapidly progressive and symptomatic lymphadenitis because management is clearly different from that of progressive or transformed CLL, and appropriate anti-microbial therapy can be highly effective.

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Acknowledgments Funding for this study was provided in part by the Predolin Foundation.

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Table I Characteristics of the 12 CLL Patients with Infectious Lymphadenitis N (%) Age (years, median and range) CLL diagnosis First biopsy

61 (49-75) 71.5 (54-84) 9 (75) 3.4 (0-36)

CD38 expression Positive (≥30%) Negative (

small lymphocytic lymphoma: a rare, but important, complication.

The differential diagnosis of rapidly progressive or symptomatic lymphadenopathy in patients with chronic lymphocytic leukemia/small lymphocytic lymph...
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