Objectives: Our aim was to review our single center experience regarding histopathologic features arising from enlarged lymph nodes following solid- organ transplant.

Materials and Methods: In 2148 people who had solid-organ transplant from 1985 to 2013, there were 34 patients (1.58%) who developed lympha­denopathy. A retrospective review was performed to evaluate demographic, clinical, and histo­pathologic features of medical and pathologic records.

Results: Nonneoplastic lesions were more common, comprising 70.5% (n = 24) all cases which included nonspecific reactive lymphoid hyperplasia in 8 patients (33.3%), tuberculous lymphadenitis in 6 patients (25%), amyloid lymphadenopathy in 4 patients (16.6%), dermatopathic lymphadenopathy in 2 patients (8.3%), Kikuchi-Fujimoto disease in 1 patient (4.16%), hemangioma in 1 patient (4.16%), plasmacytic form of Castleman disease and amyloid lymphadenopathy in 1 patient (4.16%), and sea blue histiocytosis in 1 patient (4.16%). Neoplastic lesions comprised 29.41% (n = 10) cases which included posttransplant lymphoproliferative disorder in 6 patients (60%), Kaposi sarcoma in 2 patients (20%), posttransplant lymphoproliferative disorder and Kaposi sarcoma in 1 patient (10%), and metastatic carcinoma in 1 patient (10%).

Conclusions: Detecting enlarged lymph nodes in solid-organ transplant recipients is an infrequent occurrence. Infectious diseases, posttransplant lymphoproliferative disorder, and malignancies related to transplant should be considered in the differential diagnosis when enlarged lymph nodes in solid-organ transplant recipients are encountered.

Key words : Biopsy, Kaposi sarcoma, Lymphadenopathy, Posttransplant lymphoproliferative disorder, Tuberculosis

Introduction

Organ transplant is a life saving option for individuals with end-stage organ disease, and more than 28 000 solid-organ transplants are performed yearly in the United States.¹ However, solid-organ transplant patients must receive intensive long-term immuno­suppressive therapy to prevent rejection of the transplant, putting them at high risk of developing de novo malignancies and opportunistic infections. In addition, recurrent diseases are some of the main entities leading to late graft loss.

Clinically, lymphadenopathy may be peripheral or visceral. Peripheral lymphadenopathies are detected easily by routine physical examination and biopsied often because they are accessible easily for lympha­denectomy, which is a minor surgical procedure. In contrast, visceral lymphadenopathy requires laparotomy or sophisticated imaging techniques for detection. Among the peripheral nodes, those in the upper part of the body (cervical, supraclavicular, or axillary) are biopsied preferentially than lower limb nodes (popliteal, inguinal, or femoral) because the former are more likely to yield definitive diagnosis, whereas the latter often are characterized by nonspecific reactive or chronic inflammatory and fibrotic changes.² However, there is a paucity of information about the spectrum of diseases affecting lymph nodes from this region.

Enlarged lymph nodes often are biopsied in transplant recipients to determine whether the adenopathy is due to reactive lymphoid hyperplasia, infection, lymphoma, or Kaposi sarcoma. It is important to distinguish between these entities because treatments differ and adverse events may arise from delayed diagnosis of infectious or malignant etiologies. However, it often is challenging to determine the cause of enlarged peripheral lymph nodes on clinical examination, and clinicians often are faced with the decision to biopsy enlarged lymph nodes and the urgency of this procedure.

The aim of this study was to highlight some of the nonneoplastic and neoplastic conditions that may be seen more commonly in lymph node biopsies from transplant recipients, bearing in mind that some of these conditions may occur concurrently. In addition, lymphoproliferative disorders are mentioned even though these are predominantly extranodal in transplant recipients. We examined the etiology of lymphadenopathy in these biopsies and tried to determine clinical factors that may serve as predictive markers for diagnosis.

Materials and Methods

All 2148 solid-organ transplant (1740 kidney, 408 liver) recipients who underwent transplant between 1985 and 2013 were included in the study. In these patients, there were 34 patients (1.58%) who had lymph node biopsy at the same center.

Basic demographic data, age, sex, Epstein-Barr virus status, immunosuppressive therapy, time from transplant to lymph node biopsy, B symptoms (fever, weight loss, and night sweats), purified protein derivative (PPD) status, medical history, and location of lymphadenopathy were abstracted from the electronic medical records. Follow-up information was obtained from medical records or by direct communication with patients or families.

In this study, we included lymph node biopsies which were taken from the head and neck, axilla, thorax, abdomen, pelvis, and inguinal region. In some patients, multiple lymphadenopathies were observed at different locations. The size of lymph nodes was determined based on either radiographic or pathologic measurements.

Clinical symptoms were recorded such as painful lymphadenopathy, palpable lymphadenopathy, documented fever > 37.7°C, and unintentional weight loss ≥ 10% total body weight within 1 year. Type of biopsy (fine needle aspiration biopsy [FNAB], core needle (Tru-Cut) biopsy, or surgical excision) and pathologic and microbiologic diagnoses were documented.

The study was approved by the Ethical Review Committee of the institute.

Data analysis was performed with statistical software (SPSS for Windows, Version 16.0, SPSS Inc., Chicago, IL, USA). Average data were reported as mean ± SD. Comparisons between groups were made with Mann-Whitney and Kruskal-Wallis tests. Categorical data were compared with Fisher exact test and chi-square test. Statistical significance was defined by P ≤ .05.

Results

The frequency of lymphadenopathy was greater in kidney recipients (30 of 1740 patients [1.72%]) than liver recipients (4 of 408 patients [0.98%]). Of 34 patients, 23 patients (67.6%) were male and 11 patients (32.3%) were female.

Mean age at transplant was 31 ± 13 years (range, 0.5 to 55 y). Mean age at the time of lymph node biopsy was 36.64 ± 14.15 years (range, 1 to 59 y) and the mean interval to lymph node biopsy after transplant was 70.14 ± 86.3 months (range, 1 to 274 mo). There were 3 patients (8.8%) who were younger than 19 years at the time of lymph node biopsy.

There were 23 patients (67.6%) who had living-related-donor transplant and 11 patients (32.35%) who had deceased-donor transplant. Indications for transplant varied (Table 1).

There were 15 patients who had progressive dysfunction of the renal allograft at a mean 31.6 ± 55.5 months (range, 1 to 195 mo) after renal transplant, and 5 of these 15 patients had kidney retransplant. A patient with oxalosis also underwent kidney transplant at 4 months after liver transplant.

All liver transplant and 4 kidney transplant recipients received tacrolimus and 24 kidney transplant recipients received cyclosporine as immuno­suppressive drugs. Additionally, all aforementioned 34 patients received corticosteroids. The remaining 2 patients received only corticosteroids.

At lymph node biopsy, all patients had immuno­suppressive therapy for a mean 5.8 ± 7.19 years (range, 0.5 - 22.8 y).

Lymphadenopathy was detected incidentally during transplant (n = 7) or graft nephrectomy (n = 5) in 12 of 34 patients. In the remaining 22 patients, lymphadenopathy was detected by physical (n = 12) and radiographic examination (n = 10). The exam­ination of 7 patients who had lymphadenopathy that was detected during kidney transplant showed amyloidosis in 3 patients, hemangioma in 1 patient, sea blue histiocytosis in 1 patient, Castleman disease and amyloidosis in 1 patient, and granulomatous inflammation in 1 patient. Patients with a diagnosis of tuberculosis did not have a history of tuberculosis and/or positive PPD before the recent diagnosis. Patient demographics and characteristics were summarized (Table 2).

The distribution of lymphadenopathy that was biopsied showed that the most common region of lymphadenopathy was the pelvic area (Table 3). In this study, 41.7% patients (n = 14) had generalized lymphadenopathy. Excisional biopsy was performed in 76.4% patients (n = 26), Tru-Cut biopsy in 20.5% patients (n = 7), and FNAB in 2.9% patients (n = 1).

During follow-up, 22 of these 34 patients were alive and 12 patients were dead at a mean 41.25 ± 41 months after lymph nodes biopsy (range, 1 to 140 months).

Histopathologic examination showed that 24 of 34 cases were nonneoplastic and 10 cases were neoplastic. Histopathologic features of the 34 cases were shown (Table 4).

The PTLD was the most common malignancy, occurring in 7 patients and accounting for 70% of all malignancies in our study. Histologic diagnosis was monomorphic B-cell PTLD (diffuse large B-cell lymphoma) in 4 patients (57.4%), early lesion PTLD in 2 patients (28.5%), and monomorphic T-cell PTLD in 1 patient (14.2%). Epstein-Barr virus was positive in 4 histologic specimens.

For patients diagnosed with PTLD, mean age at transplant was 26.21 ± 15.56 years (range, 0.5 to 51 y). Mean age at lymph node biopsy was 32.5 ± 19.54 years (range, 1 - 52 y) and the mean interval to lymph node biopsy after transplant was 75.2 ± 101.54 months (range, 5 - 250 mo). The frequency of nodal PTLD was greater in liver transplant patients (3 of 408 patients [0.73%]) than kidney transplant patients (4 of 1740 patients [0.22%]). There were 4 patients who had deceased-donor transplant and 3 patients who had living-related-donor transplant. Graft loss was experienced by only 1 renal transplant patient. The mean short-axis lymph node size was 2.37 ± 0.77 cm (range, 1.5 - 3.5 cm) in all cases with PTLD.

In 3 of the 34 lymph node biopsies, Kaposi sarcoma was observed. In 3 patients who had Kaposi sarcoma (8.8%), immunosuppressive therapy was based on cyclosporine. Most Kaposi sarcoma cases were seen in male patients. Mean age at lymph node biopsy was 25 ± 3.6 years (range, 22 - 29 y) and the mean interval to lymph node biopsy after transplant was 23.6 ± 5.1 months (range, 18 - 28 mo) for these 3 cases. Furthermore, gastrointestinal system involvement was observed in 2 of these patients who were diagnosed with Kaposi sarcoma. All of the patients died at a mean 12.6 ± 13.8 months after the diagnosis of Kaposi sarcoma (range, 1 - 28 mo). Additionally, as a result of the postmortem examination, which was performed only in 1 of these 3 patients, early-lesion PTLD (plasmacytic hyperplasia) was observed in a different lymph node.

In 1 of the 4 liver transplant recipients, thyroid papillary carcinoma was detected in the right supraclavicular lymph node 5 years after transplant. She was treated with total thyroidectomy and radioactive iodine therapy and she is alive during follow-up.

Among the nonneoplastic etiologies, nonspecific reactive hyperplasia was most common and tuberculous lymphadenitis was second most common. There were 6 patients who were diagnosed with tuberculosis; 4 of the patients had living-related-donor transplant and 2 patients had deceased-donor transplant. In 2 patients who were diagnosed with tuberculous lymphadenitis, graft loss occurred and 1 patient was retransplanted. There were 2 patients who had tuberculosis history; the PPD values of these patients were 13 mm and anergic. Hepatitis C virus (HCV) seropositivity was observed in 2 patients who were diagnosed with tuberculous lymphadenitis. Enlarged lymph nodes were located in the head and neck and intrathoracic regions. In 2 cases, lymphadenopathy was observed in multiple locations. There were 4 patients who were diagnosed with tuberculous lymphadenitis who were alive, and 2 patients died at 2 and 140 months after diagnosis.

In this nonneoplastic group, there were 5 amyloidosis cases, including 1 patient who had associated Castleman disease. Of these 5 patients with amyloidosis, 2 patients lost their grafts. There were 4 of 5 patients who had tuberculosis history, and 3 of these 4 patients had negative PPD values measured. In 2 patients with amyloid A(AA), the cause of end-stage renal disease was renal amyloidosis secondary to familial Mediterranean fever in 1 patient and juvenile rheumatoid arthritis in 1 patient. The cause of renal amyloidosis was unknown in 2 patients; 1 patient had a history of tuberculosis (PPD was negative) and the other 1 patient had Castleman disease and nephrolithiasis, which leads us to think that these diseases could be linked with AA type amyloidosis. At follow-up, 1 patient who was diagnosed with amyloidosis was alive and 4 patients were deceased.

Dermatopathic lymphadenopathy was observed in 2 patients, including 1 patient who had liver and kidney transplant due to oxalosis and 1 patient who had kidney transplant due to nephrolithiasis. Itchy skin lesions were observed in both patients.

Castleman disease, Kikuchi-Fujimoto disease, sea blue histiocytosis, and nodal hemangioma were observed incidentally in lymph node biopsies. In statistical analysis, fever, weight loss, night sweats, generalized lymphadenopathy, graft loss, sex, age, and lymph node size were not associated with lymphadenopathy etiology.

Discussion

We reviewed the records of 34 solid-organ transplant recipients with lymphadenopathy over a 28-year period to determine the prevalence of various etiologies of lymphadenopathy.

We found that readily available clinical characteristics could help distinguish patients at high risk for malignant or infectious etiologies from those with reactive lymphadenopathy. These results may aid clinicians in deciding the need and urgency for lymph node biopsy in renal and liver transplant recipients.

The development of neoplastic pathologies in lymphadenopathy could be explained by intense immunosuppressive therapy during acute rejection episodes in patients with graft loss.

The non-Hodgkin lymphoma is one of the most common malignancies diagnosed after transplant. Risk of non-Hodgkin lymphoma in transplant recipients is 3- to 21-fold higher than the general population and 120-fold higher in children who receive transplants.³ In our series, most malignancies were categorized as PTLD, which typically occurs with advanced disease and frequent extranodal involvement.⁴ Our previous study showed that 33% patients were diagnosed with nodal PTLD.⁵

The risk of Kaposi sarcoma in transplant recipients parallels Human herpesvirus 8 (HHV-8) seroprevalence in different countries and regions. The reported incidence of Kaposi sarcoma in solid-organ transplant recipients varies from 0.5% in transplant recipients from North America, Asia, and northern Europe to 28% in HHV-8-seropositive transplant recipients from the Middle East. In 25% cases, Kaposi sarcoma has visceral involvement and may involve the lymph nodes, lungs, gastrointestinal tract, and liver.⁶ In our study, most Kaposi sarcoma cases were diagnosed in the first 2 years after receiving a renal allograft, which is compatible with previous studies.⁷

A study that evaluated radiographic images of enlarged lymph nodes in the abdominal region in liver transplant patients showed that 26% lymph­adenopathies were reactive.⁸ Nonspecific reactive lymphoid hyperplasia accounted for 23.5% biopsies in our study, similar to the previous study.⁸

Posttransplant tuberculosis is a life-threatening opportunistic infection that is encountered, but the diagnosis often is delayed. Mycobacterial infection occurred approximately 20 to 74 times more frequently in renal transplant patients than the general population.⁹ In Turkey, tuberculosis is observed in 26.2 per 100 000 population. Posttransplant tuberculosis is observed in 3.5% of our transplant population. In the current study, 17.6% lymphadenopathy patients had tuberculous lymphadenitis. There were 6 cases of tuberculous lymphadenitis in this study, including positive PPD documented in 33.6% patients (n = 2), most of whom were treated for latent tuberculosis infections after this diagnosis was made. In an earlier population-based study, chronic obstructive pulmonary disease, HCV infection, and cyclosporine-based immunosuppressants were independent risk factors for subsequent tuberculosis in renal transplant recipients.⁹ In the current study, 2 patients had tuberculosis history; the PPD value in 1 of the patients was 13 mm, and the other patient was anergic to the PPD test. The HCV seropositivity was observed in 2 patients who were diagnosed with tuberculous lymphadenitis. Most of our patients (5 of 6 patients) who were diagnosed with tuberculous lymph­adenopathy were using cyclosporine as an immuno­suppressive therapy, which is consistent with the literature. In 2 of our patients who were diagnosed with tuberculous lymphadenitis, graft loss occurred, and 1 of them was retransplanted. There were 2 patients (33%) who developed tuberculosis in the first year after transplant. Optimal immunosuppressive agent use, monitoring of individuals at high risk for tuberculosis, and appropriate treatment are required to treat tuberculosis infection in solid-organ transplant patients.

Previously, we showed that the incidence of amyloid lymphadenopathy was 22% in uremic patients,¹⁰ but in the current study, this incidence was 14.7%.

Symptoms such as night sweats, weight loss, and generalized lymphadenopathy, which may be indicators of malignancy in immunocompetent individuals, were not different for immunosuppressed patients. These symptoms may be observed in some benign cases such as tuberculosis and amyloidosis (familial Mediterranean fever). This similarity may cause difficulties in evaluating lymphadenopathy cases at transplant.

There is no comprehensive study about the etiology of lymphadenopathy in solid-organ transplant patients. In the literature, multivariate analysis in individuals whose immune systems were suppressed, such as HIV-infected persons, showed an association between nonreactive etiology and factors such as increasing age, antiretroviral use, presence of fever, weight loss, and lymph node size.11 However, in our study on solid-organ transplant patients, we could not identify any association between nonreactive etiology of lymphadenopathy and these factors.

A limitation of this study was that the study included retrospective data which probably disregarded clinical features of lymphadenopathy such as duration and consistency. These features may have contributed valuable data to a prediction tool, but they could not be documented reliably from charts.

In summary, lymphadenopathy in solid-organ transplant recipients in areas endemic with tuberculosis is likely reactive or malignant. Readily available clinical factors such as immunosuppressive drug use, larger size, presence of fever, or weight loss may direct clinicians to decide about the urgency of lymph node biopsy in this setting.

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