18 F-Fluorodeoxyglucose positron emission tomography-computed tomography imaging in HIV-infected patients with lymphadenopathy,with or without fever and/or splenomegaly

Abstract

We audited whether ¹⁸F-Fluorodeoxyglucose positron emission tomography-computed tomography (¹⁸FDG PET-CT) imaging could discriminate between different diagnoses in HIV-infected patients presenting with lymphadenopathy, with or without fever and/or splenomegaly. Maximum standardised uptake (SUV_max) values were similar in lymphoma and mycobacterial and fungal infections and were lower but similar in those with human herpesvirus (HHV) 8-associated disease and HIV-associated reactive lymphadenopathy. Nodal ¹⁸FDG avidity, with SUV_max ≥10, excluded diagnoses of HHV 8-associated disease and miscellaneous conditions, and HIV-associated reactive lymphadenopathy was additionally excluded in those who had undetectable plasma HIV viral loads. This audit suggests ¹⁸FDG PET-CT imaging did not permit discrimination between specific diagnoses but has utility in identifying lymph nodes with increased avidity that could be targeted for biopsy and in ruling out significant pathology.

Keywords

Fever lymphoma infection lymph node biopsy HIV infection pyrexia of undetermined origin Kaposi sarcoma Castleman disease

Introduction

The immunosuppressed HIV-infected patient can present with lymphadenopathy, with or without a fever and/or splenomegaly.¹ The differential diagnosis for this presentation is wide and includes Hodgkin and non-Hodgkin lymphoma, human herpesvirus 8 (HHV 8)-associated disease, including Kaposi sarcoma (KS) and multicentric Castleman disease (MCD), Mycobacterium tuberculosis, disseminated Mycobacterium avium complex, leishmaniasis and histoplasmosis,^1–3 as well as other conditions such as metastatic carcinoma and HIV-associated ‘reactive’ lymphadenopathy. Definitive diagnosis often requires tissue sampling with histology and/or microbiological culture in addition to traditional investigations. ¹⁸F-Fluorodeoxyglucose positron emission tomography-computed tomography (¹⁸FDG PET-CT) hybrid imaging, already widely used in the diagnosis, staging and monitoring of malignancies, particularly lymphoma, is increasingly used to image infectious and inflammatory disorders in both immune-competent and immune-suppressed individuals.^1,4–11 We audited whether ¹⁸FDG PET-CT could aid in discriminating between diagnoses in HIV-infected patients presenting with lymphadenopathy, with or without fever and/or splenomegaly.

Methods

Consecutive patients who presented with lymphadenopathy, with or without fever and/or splenomegaly, at the HIV service at Mortimer Market Centre and University College Hospitals (UCLH) London between January 2008 and December 2016 and who underwent ¹⁸FDG PET-CT scanning as part of routine clinical investigation were identified from the UCLH Clinical Data Repository (CDR) system. Information collected from the CDR and the patients’ clinical case notes included their presenting symptoms and signs, the maximum standardised uptake value (SUV_max) in node(s) or other tissue on ¹⁸FDG PET-CT imaging, CD4 cell count, plasma HIV load and whether the patient was receiving antiretroviral therapy (ART) at the time of diagnosis. The diagnosis of lymphoma, HHV 8-associated disease and HIV-associated reactive lymphadenopathy was made histologically, while that of mycobacterial and fungal infections was made by microbiological culture, as previously described.¹² In each patient, ¹⁸FDG PET-CT scanning was done prior to tissue sampling, and before the results of microbiological culture were available. Patients in whom a tissue diagnosis of malignancy had been made and who subsequently underwent ¹⁸FDG PET-CT scanning for staging were excluded, as were those with undifferentiated fever, or pyrexia of undetermined origin (PUO). Results were analysed using Mann-Whitney and Kruskal-Wallis tests to compare SUV_max values among different patient groups. GraphPad Prism Version 6.0h (GraphPad software, Inc., La Jolla, CA, USA) was used for statistical analysis; p <0.05 was regarded as statistically significant.

Results

A total of 120 patients (88 men) presented with lymphadenopathy, with or without fever and/or splenomegaly and underwent ¹⁸FDG PET-CT. Figure 1 shows the clinical features at presentation. Patients were aged 42 years (33–48) (median [interquartile range: IQR]). Forty-five patients were receiving ART and had an undetectable plasma HIV load (<50 copies/ml) (median [IQR] CD4 cell count = 400 [200–520] cells/µl), while 17 others were receiving ART but had detectable viral loads (median [IQR] =1700 [110–2850] copies/ml, CD4 cell count = 200 [155–340] cells/µl). Fifty-eight patients were not receiving ART and had detectable viral loads (median [IQR] HIV plasma load = 155,000 [15,250–550,000] copies/ml, and median [IQR] CD4 cell count = 185 [80–360] cells/µl).

Figure 1.

Clinical features at presentation among 120 HIV-infected patients who underwent ¹⁸FDG PET-CT imaging.

The final diagnosis was HIV-related reactive lymphadenopathy in 43 patients, lymphoma in 27 (Hodgkin lymphoma in 13, diffuse large B-cell in 7, Burkitt in 3, plasmablastic in 3 and T-cell in 1), HHV 8-associated disease in 19 (KS in 5, MCD in 7 and KS with MCD in 7), mycobacterial infection in 14 (M. tuberculosis in 8, M. avium complex in 6) and fungal infections in 4 (Cryptococcus neoformans in 3, histoplasmosis in 1). Thirteen patients had a wide range of miscellaneous conditions: these were adult-onset Still’s disease, sclerosing peritonitis, intra-abdominal sepsis, metastatic adenocarcinoma, reflux oesophagitis/benign colonic polyp, lobar pneumonia, visceral leishmaniasis, necrotizing granulomatosis, nodular hepatic fibrosis secondary to schistosomiasis, toxoplasmosis, and nodular hepatic fibrosis/portal hypertension with thyrotoxicosis/thyroiditis, each in one patient, and self-limiting febrile episodes with lymphadenopathy in two patients.

SUV_max values were similar in lymphoma and mycobacterial and fungal infections and were lower but similar in those with HHV 8-associated disease and HIV-associated reactive lymphadenopathy. Individuals with miscellaneous (largely non-infectious and non-malignant conditions) had low SUV_max values (Table 1). Across all diagnoses, there were statistically significant differences in median SUV_max when lymphoma was compared with HIV-associated reactive lymphadenopathy (p = 0.0007) and with HHV 8-associated diseases (p = 0.0008) and when mycobacterial infection was compared with HIV reactive and HHV 8-associated diseases (p = 0.004 and p < 0.0001, respectively). No statistically significant differences were found between the other groups of diagnoses. Within each diagnostic group, median SUV_max showed no significant differences in those with detectable and those with undetectable viral loads (Table 1). Among all patients, nodal FDG avidity, with SUV_max ≥10, excluded diagnoses of HHV 8-associated disease and miscellaneous conditions, and HIV-associated reactive lymphadenopathy was additionally excluded in those in receipt of ART who had undetectable plasma viral loads. Reversal of the liver:spleen ¹⁸FDG avidity ratio was observed more commonly among those with detectable viral loads but did not aid discrimination between diagnoses.

Table 1.

Median SUV_max and diagnosis in 120 patients who underwent ¹⁸FDG PET-CT imaging.

Diagnosis (n)	SUV_max, median (IQR)
HIV-associated reactive lymphadenopathy (43)	5.6 (3.3–9.4)
Undetectable viral load (9)	3.7 (3.0–6.3)
Detectable viral load (34)	6.0 (3.3–9.7)
Lymphoma (27)	12.0 (6.5–14.0)
Undetectable viral load (17)	12.5 (6.8–18.1)
Detectable viral load (10)	12.0 (5.5–13.3)
HHV 8-associated disease (KS/MCD) (19)	5.7 (4.5–7.5)
Undetectable viral load (5)	5.7 (3.5–7.1)
Detectable viral load (14)	5.9 (4.3–8.9)
Mycobacterial infection (14)	10.9 (9.1–13.9)
Undetectable viral load (2)	8.7
Detectable viral load (12)	12.3 (9.2–14.6)
Fungal infection (4)	13.3 (6.4–20.6)
Undetectable viral load (3)	13.5 (4.2–23.0)
Detectable viral load (1)	13.2
Miscellaneous conditions (13)	2.0 (2.0–6.1)
Undetectable viral load (9)	2.0 (2.0–7.1)
Detectable viral load (4)	2.0 (2.0–2.5)

IQR: interquartile range; KS: Kaposi sarcoma; MCD: multicentric Castleman disease; HIV: human immunodeficiency virus; ¹⁸FDG PET-CT: ¹⁸F-Fluorodeoxyglucose positron emission tomography-computed tomography; SUV_max: maximum standardised uptake.

Discussion

This audit shows similar avidity of ¹⁸FDG uptake, measured by SUV_max, in patients with lymphoma, mycobacterial infection and fungal infection; accordingly, ¹⁸FDG-PET-CT imaging did not provide diagnostic information enabling discrimination between these diagnoses. A SUV_max ≥10 enabled HHV 8-associated disease and miscellaneous conditions to be excluded in all patients, and additionally, in those in receipt of ART who had undetectable plasma viral loads HIV-associated reactive lymphadenopathy could be excluded. This observation requires validation in prospective studies before it is used in diagnostic algorithms. In HIV-infected patients, different pathology may occur concurrently. This audit did not identify any features on ¹⁸FDG PET-CT imaging that suggested coexistence of dual or multiple pathology. The utility of ¹⁸FDG PET-CT imaging was in identifying lymph nodes with increased avidity that could be targeted for biopsy and in excluding significant pathology. The limitations of this audit are first, it is from a single centre and second, the sample size is small. Additionally, patients with undifferentiated PUO, and those with an established tissue diagnosis of malignancy prior to ¹⁸FDG PET-CT scanning were excluded.

Footnotes

Acknowledgements

We thank Drs N Ranganathan, A Haroon, and G Whitlock for help with data collection.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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