Cervical lymphadenopathy of Togolese children in a tropical context: clinicopathological study

Introduction

Cervical lymphadenopathy in children is a frequent reason for consultation. It is a diagnostic challenge owing to its extensive differential diagnosis and requires rigorous diagnostic investigation to resolve.^1,2 In many, a complete clinical examination may establish the origin of the lymphadenopathy before the histological analysis, but requires knowledge of possible aetiology.^3,4 Differences in regional causes for lymphadenopathy have been described.^3,5 In Africa, particularly in Togo, limited knowledge of cervical adenopathy in children is available. The aim of our study was to document the epidemiology and aetiology in Togolese children aged < 15 years.

Methods

This was a retrospective file review. Patients aged <15 years were diagnosed from 2003 to 2017 at the Department of Anatomical Pathology of the Sylvanus Olympio Teaching Hospital of Lomé. During this period, lymph node specimens were registered, prepared in paraffin-embedded sections (at 56–60℃) and stained with haematoxylin and eosin (H&E). Our laboratory does not have the facilities to perform immunohistochemistry techniques. Confirmation of HIV was done by indirect enzyme-linked immunosorbent assay (ELISA) tests. All specimens were accompanied by the relevant patient clinical data. The study parameters included laterality of the nodes, sex, age and possible aetiology. Lymphomas were classified according to World Health Organization (WHO) classification. ⁵ This study was approved by the head of the laboratory department of Sylvanus Olympio Teaching Hospital (reference no. 17/2019/LAP/CHUSO). Data were anonymised to preserve patient confidentiality.

Results

Our study included 221 cases of cervical lymphadenopathy in children (118 [53.4%] boys; mean age at diagnosis = 9.8 ± 0.3 years; age range = 2 months–14 years). A total of 112 (50.7%) cases were unilateral, 95 (43.0%) were bilateral and 14 (6.3%) were not specified. HIV was confirmed in 69 (31.2%) children. Histology demonstrated infection (n = 128, 57.9%), tumour (n = 85, 38.5%) and other causes (n = 8, 1.6%). Infectious aetiology (Table 1) was identified in 96 (75.0%) children, in whom tuberculosis (TB) was predominant (46 boys, 38 girls), with 78 cases of caseo-follicular TB and six cases of pure caseous TB. Other specific aetiology is tabulated (Table 1). Primary tumours were diagnosed in 82 (86.3%) cases and metastatic lymphadenopathy in 3 (13.7%) cases (Table 2). The primary tumours included lymphoma (n = 74) and leukaemia (n = 8), the latter being all acute lymphocytic leukaemia. Lymphomas were diagnosed at an average age of 10.5 years (age range = 2–14 years) in 40 (54.1%) boys and 34 (45.9%) girls. Non-Hodgkin lymphoma was diagnosed in 58 (78.4%) cases and Hodgkin's lymphoma in 16 (21.6%) cases. Of the former, the predominant type was Burkitt's lymphoma (n = 44/58, 75.9%). The remaining non-Hodgkin lymphomas are shown in Table 2. Application of the international clinical formulation to diagnosis showed that it was lymphoma in 44 (75.8%) cases, intermediate in 11 (19.0%) cases and low in 3 (5.2%) cases. Cases of Hodgkin lymphoma were predominantly lymphocyte depleted (n = 8), followed by the nodular sclerosing (n = 5) and the mixed cellular (n = 3) types. The three cases of cervical lymph node metastasis were alveolar rhabdomyosarcoma (n = 2) and undifferentiated carcinoma (n = 1). The primary source of the rhabdomyosarcomata was the mandibular region and the primary site of the carcinoma was localised to the pharyngeal region. The remaining cases were diagnosed as histiocytosis (n = 3), sarcoidosis (n = 3) and lupus (n = 2). Amongst HIV-positive cases, the aetiology was TB, sarcoidosis (n = 2) and lupus (n = 1). Six cases of Burkitt's lymphoma were the only malignancies associated with HIV in the cohort.

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Table 1.

Distribution of infectious aetiology.

Type of aetiology	Cases
Tuberculosis	84 (65.6)
Histoplasmosis	9 (7.0)
Toxoplasmosis	2 (1.6)
Leishmaniasis	1 (0.8)
Non-specific adenites	32 (25.0)
Total	128 (100)

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Table 2.

Distribution of non-Hodgkin lymphoma.⁵

Histological type	Cases
Burkitt's lymphoma	44 (75.9)
Diffuse large B-cell lymphoma	6 (10.4)
MALT lymphoma	3 (5.2)
Mature T and NK neoplasms	2 (3.4)
High-grade B-cell lymphoma, NOS	2 (3.4)
B-cell lymphoma, unclassifiable	1 (1.7)
Total	58 (100)

Values are given as n (%).

MALT, mucosa-associated lymphoid tissue; NOS, not otherwise specified.

Discussion

Cervical lymphadenopathy in children remains a common problem. The mean age of children in our series is similar to elsewhere,^3,6 as is the slight male predominance.^7,8 Palpation of small and firm nodes is common in children.^1,2 However, the finding of isolated lymphadenopathy, of worrying or multiple and persistent volume, must alert the clinician and lead to a rigorous diagnostic approach. ⁹ It requires logical management, which ranges from simple surveillance with reassurance to a biopsy, excision and intensive treatment. Benign causes are the most common, but non-communicable diseases such as childhood malignancy are increasing, especially in Africa. ¹⁰

However, not all cases of cervical lymphadenopathy in children require a biopsy. Therefore, understanding the indications for invasive investigations are of importance especially in resource-limited settings. ¹¹ Small, mobile and fixed cervical lymphadenopathies do not require an assessment, ⁷ while large, soft, lymphadenopathy with inflammatory, febrile looking skin should be explored. ⁷ Only symptomatic, persistent, fixed lymphadenopathy > 3 cm or general lymphadenopathy > 1 cm needs further investigation. ⁴ Biopsy remains the examination of choice for the confirmation of diagnosis in the absence of less invasive tests ⁵ such as inflammatory markers such as sedimentation rate or C-reactive protein, supplemented with other investigations where necessary.^7,8

Complementary investigations include viral serology such as Epstein-Barr virus (EBV), serology for toxoplasmosis, to tuberculin intradermal reaction and chest radiography and advanced imaging.^1,4 Many of these may, however, not be available in resource-limited settings.

While cervical lymphadenopathy is, in up to 60% of cases, benign, ¹⁰ chronic cervical lymphadenopathy is often of infectious origin, and TB typically remains the highest incidence.^9,10 TB is usually easily diagnosed on TB defining imaging, subdermal testing and cultures. ¹² Fine-needle aspiration, which can be performed on an outpatient basis in a primary healthcare setting, with a rapid, sensitive diagnostic technique may contribute substantially to the effective management of mycobacterial infection in children. ¹³ The implications of rapid, accurate diagnosis include access to appropriate, adequate therapy and less costly further investigations. ¹³ The conventional Ziehl-Neelsen method on smears is widely used and plays a key role in the diagnosis of TB, but it has a poor sensitivity in aspirates because of the small number of mycobacterial cells. Fine-needle aspiration may not be able to detect the pathogen, but detects the presence of epithelioid cellular granulomas and necrosis, which leads to a definitive diagnosis in 73% of cases. ¹⁴ Polymerase chain reaction is very sensitive for the diagnosis of lymph node TB. Although rarely used, it is recommended in cases with negative culture results or for the differential diagnosis between other forms of granulomatous adenitis. ¹⁴

Histological examination is of value for confirmation when there is a tuberculoid granuloma or giant cellular granuloma associated with a caseous necrosis, and occasionally when Koch's bacillus is found, or in the absence of other clinical diagnoses. ¹⁵ Other isolated giant granulomata may be seen with foreign body reactions, sarcoidosis and connective tissue disease.^8,15

Childhood cancers in tropical environments are mainly non-Hodgkin lymphomas of the Burkitt type.^16–18 This is known to be linked to the endemicity of malaria and the EBV. ¹⁶ Burkitt's lymphoma is also more common in the immunocompromised patient.

Polyadenopathy may be characteristic of system diseases such as sarcoidosis and lupus, but may arise with use of some drugs, especially phenytoin and isoniazid. ¹⁹

Cervical lymphadenopathy has been observed after vaccination against diphtheria, tetanus, polio or typhoid fever, all of which are maintained in Togo's active vaccination schedule of children. ²⁰ Mild-looking cervical lymphadenopathy with no obvious aetiological cause should be monitored frequently for at least 2–4 weeks. ²¹

Caution should be exercised in excluding a diagnosis with fine-needle aspiration as it may not lead to a definitive diagnosis in detecting pathogens and malignancies in the presence of epithelioid cell granulomas and necrosis. ¹⁵ An excision biopsy, to obtain sufficient tissue, is the examination of choice to confirm the diagnosis in the case of a suspected malignancy, persistent lymphadenopathy or resistant to antibiotic treatment.^22,23 Treatment depends on the diagnosis with the majority of lymphadenopathies regressing spontaneously without treatment. The persistence of lymphadenopathy after four weeks is an indication for excisional biopsy. ²³ The present study has limitations due to the retrospective methodology. Cases may not have been reported of patients who prefer to contact traditional healers and who consult health centres where histological examinations are not performed. The full extent of laboratory diagnostic potential was not possible in the absence of immunohistochemistry techniques.