Methods

A retrospective review of our records during the period from July 1988 to June 1992 was undertaken. Out of 1884 lymph node biopsy cases, 22 cases with necrotizing lymphadenitis were identified. Nineteen of these cases showed areas of necrosis without granulocytes. Nine cases were excluded, two associated with lymphoma and one with tuberculosis. The other six cases were referral cases from remote hospitals and no clinical records were available for review.

In addition to the hematoxylin and eosin (H&E), special stains for acid fast bacillus, PAS, reticulin and PTAH were performed. Clinical and laboratory data were retrieved for 13 of these cases who were admitted and managed at Riyadh Central Hospital.

Results

Clinical Data: The mean age of the patients was 27.5 years (range 14 to 36 years) with seven females to six males (F/M ratio 1.16:1). There were three Saudis, six from the Indian subcontinent, two Sudanese, one Indonesian and one Filipino. Patients were of diverse occupations. The most common presenting symptom was cervical lymphadenopathy which was observed in 77% of the cases (10/13) followed by fever in 61.5% (8/13). In four cases (31%), cervical lymphadenopathy was the sole presenting complaint while in six others (46%), there was associated fever. In four of these patients, the lymphadenopathy was painful. One patient presented with malaise, fever and weight loss and others with sweats and vomiting only. The sites of lymph node involvement are outlined in Table 1. One patient was diagnosed to have mixed connective tissue disease (MCTD) two years earlier; otherwise, past medical history was noncontributory.

Laboratory: The white cell count was low (<4x10/dL) in five (38.5%) patients at presentation and two others subsequently developed leukopenia (53.7%). ESR was available in nine patients, four of whom had elevated figures (up to 80 mm/hr). Connective tissue disease screen was done in six patients and was positive in one (known to have MCTD two years earlier). Bacterial cultures were negative in the nine patients in whom they were done. Serology was negative except in one patient who had a positive titer for Epstein-Barr virus (1:60) on admission. The titer did not show a rise subsequently and the monospot test was negative. None of our patients had positive antibodies to toxoplasma. One patient had elevated liver enzymes (ALT 85 mmol/L). These laboratory changes were transient.

Table 1. Distribution of lymph nodes by site.

Histologic Observation: Areas of necrosis without granulocytes were identified in all 13 cases. The lymph node architecture was partially preserved. The extension of the necrosis varied from focal to broad, in some cases involving the entire nodal structure. The necrosis involved the cortex, paracortex and medullary region of the lymph node without predilection for any specific area. Karyorrhexis was present in the necrotic area with scattered fibrin deposition. Some plasma cell collection or large mononuclear cells were present at the periphery of the lesion (Figures 1 & 2). In two cases, vascular occlusion by organized thrombi was present. In one of them, vasculitis with lymphocytic infiltration of the wall was noted. The germinal centers were decreased in number but were present in 10 cases (58.8%). Fibrin thrombi were observed in the capillaries in 10 cases (76.9%). This was easily seen with PTAH stain (Figure 3). In five cases (38.5%), plasma cells were easily seen. The paracortical areas were expanded and most of the time the capsules were minimally involved in the inflammatory process. Zeihl-Neilson staining for acid-fast bacilli was done in every case and found to be negative.

Follow-up Information: The patients were followed up without any treatment for a period ranging from six months to four years from the time of diagnosis. Unfortunately, four patients were lost to follow-up. In the nine patients followed up, the lymphadenopathy and other symptoms subsided.

Discussion

Kikuchi disease or histiocytic necrotizing lymphadenitis without granulocytic infiltration is a clinicopathologic entity of unknown etiology. The predilection for patients in their second to fourth decades of life coincides with other studies.^6,7 The reported female-to-male ratio is 4:1 but in this series it is lower, probably because of the predominantly male expatriate labor force in Saudi Arabia. The cervical group of lymph nodes is most often affected and those nodes may or may not be painful. To the clinician, this presentation, especially when associated with constitutional symptoms, implies a diagnosis of tuberculous lymphadenitis or malignant lymphoma. Isolated involvement of retroperitoneal lymph nodes⁸ and mediastinal lymph nodes⁹ have been reported previously but our case is the first to present with isolated bilateral hilar lymphadenopathy. Fever is the most common constitutional symptom (61.5%) although even those with fever appear generally well. Leukopenia is a well recognized feature of the disease, occurring in 53.7% of our patients. ESR, although elevated in a number of patients, is not a reliable indicator of disease activity. Serology helps to exclude other diseases with lymphadenopathy such as toxoplasmosis, CMV and E-BV infection. Liver dysfunction has only recently been described¹⁰ and it is usually mild and transient.

The pathologic characteristic of the disease is the presence of well-defined necrosis without granulocytic cells. Karyorrhexis of the necrotic cells is prominent and it is usually located in the paracortical area of the lymph node. However, other areas can be involved, as observed in 80% of our cases. The proliferative cells are predominantly histiocytes and immunoblasts. The germinal centers are usually inconspicuous, as observed in 58.8% of the cases. However, it also could be prominent, as reported in the literature.¹¹ Since the lymph nodes show an inconspicuous germinal center with a monotonous configuration associated with reactive immunoblasts, the lesion may be mistaken for a malignant lymphoma. An interesting pattern in our cases is the presence of fibrin thrombi in the lumen of the capillaries (76.9%) which were more distinctly seen with PTAH stain (Figure 3). In two of our cases, there were clear vascular arteriolar occlusions, one of them associated with vasculitis with a lymphocytic infiltration of the endothelium and muscular coat of the blood vessels. In most of the cases, the fibrin thrombi could be the result of necrotic changes but could also be secondary to the lesion in the blood vessel wall due to viral or immune complex deposits with subsequent fibrin thrombi and therefore, ischemic necrosis. The exact nature and role of these findings deserve further investigation. The etiology of the disease is not well established. The presence of tubuloreticular structures in the cellular infiltrate on electron-microscopy¹² suggests hyperimmune lymphadenitis as in SLE. Indeed, associations have been noted with SLE either before or after full expression of the disease.¹³Associations have also been noted with Still disease,^14,15 Yersinia,¹⁶ and Toxoplasma,¹⁷ among other organisms. Various stimuli may be responsible — infective, chemical, physical or autoimmune. The disease is self-limiting, averaging four months to resolve, and recurrence has been described.¹⁸ There has been a report of a fatal case of Kikuchi disease,¹⁹ the cause of death being myocardial damage. It is postulated that myocardial damage is a result of cytokines or an overwhelming effect of catecholamines on the heart or the result of unidentified microbial agents.

We suggest that Kikuchi disease be considered as one of the differential diagnoses in young patients presenting with cervical lymphadenopathy and fever of unknown origin.

References