Necrotizing and suppurative lymphadenitis in Leishmania

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1 Tropical Medicine and International Health VOLUME I NO. 2 PP APRIL 1996 Necrotizing and suppurative lymphadenitis in Leishmania major infections A. Gaafar r, A. Ismai13, A. Y. El Kadaro4, Elsir Hashim, E. A. G. Khalil and A. M. El Hassan3 lnstitute of Tropical Medicine, MRC, Khartoum Center for Medical Parasitology (CMP) at the University of Copenhagen Institute of Endemic Diseases, University of Khartoum Tropical Diseases Hospital, Omdurman Paediatrics Department, Faculty of Medicine, University of Khartoum Pathology Department, Faculty of Medicine, University of Khartoum Summary The pathology of lymph nodes and subcutaneous nodules in 6 patients with cutaneous leishmaniasis (Oriental sore) due to Leishmania major is described in this paper. In 3 patients enlarged epitrochlear lymph nodes were found to be associated with primary skin lesions in the forearm. The lymph node in one patient showed a necrotizing granulomatous reaction that simulated tuberculous lymphadenitis. Leishmania parasites were, however, found in sections of the node, and staining for mycobacteria was negative. The second patient presented with an abscess and a discharging sinus in the epitrochlear region. Parasites were found in smears of the pus and cultures for bacteria were negative. The lesion healed with antimonial therapy. In the third patient the lesion resembled cat-scratch disease and showed stellate abscesses and granulomas. Leishmania parasites were also identified in the sections. Sections of a subcutaneous nodule from the fourth patient showed a necrotizing granuloma. The lesion healed spontaneously and the patient became leishmanin-positive. In two other patients fine needle aspiration of the subcutaneous nodules showed parasites, granuloma and necrosis. We concluded that L. major disseminates from the primary cutaneous lesion via the lymphatics to the subcutaneous tissues and the regional lymph nodes. The subcutaneous nodules and lymphadenopathy may persist long after the primary lesion had healed. The primary lesion is sometimes inconspicuous. Necrotizing and suppurative lymphadenitis due to L. major have to be distinguished from other causes of necrosis and suppuration such as tuberculosis and cat-scratch disease. keywords pathology, subcutaneous nodules, lymph nodes, Leishmania major correspondence Professor A. M. El Hassan, PO Box 3 5 I 6, Khartoum, Sudan Introduction Leishmania major is the cause of cutaneous leishmaniasis in several countries in the Middle East including the Sudan (Elsafi & Peters 1992; Kadaro et al. 1993). In addition to various clinical forms of the primary infection in the skin, the parasite disseminates through lymphatics causing sporotrichoid-like lesion in the subcutaneous tissues (Algindan et al. 1989; Gaafar et al. 1994). The disease may also be associated with lymphadenopathy involving nodes draining the primary cutaneous lesions. The pathology of these nodes shows hyperplastic changes involving the B- and T-cell zones Blackwell Science Ltd

2 Tropical Medicine and International Health VOLUME I NO. 2 PI APRIL 1996 ~ A Gaafar et of. Lymphadenitis in Leishmania major infections and there may be epithelioid granulomas with or without necrosis (Algindan et al. 1989). These changes may be a diagnostic problem to the pathologist, particularly when the parasites are scanty. Lymphadenopathy and subcutaneous nodules may persist long after the primary skin lesion has healed and patients may present with lymphadenopathy in the absence of active cutaneous lesions or a conspicuous scar of a healed lesion. Rarely, subcutaneous nodules develop in the absence of a primary skin lesion. This paper describes the pathology of lymph nodes in L. major infection, with particular reference to necrotizing and suppurative forms which need to be distinguished from other causes of granulomatous lymphadenitis. For comparison the pathology of lymph nodes in visceral leishmaniasis, where up to 70% of patients may have generalized lymphadenopathy, is also described (Siddig Ali et al. 1989). Material and methods Patients were seen in the Tropical Diseases Hospital in Omdurman or Soba University Teaching Hospital, Khartoum, Sudan. After informed consent, lymph nodes were removed under local anaesthesia from patients with cutaneous leishmaniasis, fixed in neutral formalin and processed for light microscopy. Five-micron (pm) paraffin sections were stained with haematoxylin and eosin and for reticulin. Seven enlarged epitrochlear lymph nodes from proven cases of visceral leishmaniasis were removed and the pathology was compared with that of nodes from patients with cutaneous leishmaniasis. In two patients fine needle aspiration of subcutaneous nodules was stained with May-Grunwald-Giemsa and examined for parasites and cellular composition. Results Case reports Patient I A male aged 41 years reported with a 4-cm volcanic ulcer of one month duration in the left forearm. The left epitrochlear lymph node was palpable (3 x z cm), mobile and non-tender. He had subcutaneous nodules extending from the primary cutaneous lesion to the epitrochlear node. Other nodes, liver and spleen were not palpable. Haematological investigations revealed no abnormality and a chest radiograph was normal. Parasites were demonstrated in a biopsy of the cutaneous lesion. In a haematoxylin and eosin stained section of the epitrochlear lymph node, the architecture of the node was preserved. Scattered in the node were several large areas of necrosis surrounded by epithelioid and Langhans giant cells (Figure I). Some of the epithelioid cells contained amastigotes (Figure 2). The latter were also seen in the necrotic foci. Non-caseating epithelioid granulomas were seen in other areas of the node, in the capsule and in the surrounding fat. In the latter situation, the epithelioid cells surrounded afferent lymphatics. The rest of the node, which was not involved by the granuloma, showed follicular hyperplasia and expansion of the paracortex. A striking feature was the presence of many plasma cells, particularly in the vicinity of the caseating granulomas. Ziehl-Neelsen stain did not show acid fast bacilli. The patient was treated with sodium stibogluconate at 10 mg/kg/day intravenously for 21 days. His skin lesions healed completely in one month and remained well at 6 months follow-up. Patient 2 A 17-year-old male presented with a stiff right elbow and a discharging sinus in the skin over the right epitrochlear region. On examination, he had a nodulo-ulcerative lesion in the forearm. The elbow was held in flexion and could not be extended pas. sively because of spasm in the flexor muscles and pain. There was a swelling measuring 5 x 7 cm over the right epitrochlear region discharging pus through a sinus. He had no fever or other constitutional disturbance. The white cell count and the haemoglobin were normal. Smears from the primary skin lesion in the forearm and the discharge from the lesion in the elbow showed amastigotes within macrophages and neutrophils. Culture of the pus from the elbow for bacteria was sterile. The patient was treated with intravenous sodium stibogluconate at 10 mg/kg/day for 30 days. No antibiotic treatment was given. The primary lesion in the forearm healed completely, the swelling in the epitrochlear region subsided, the sinus closed and the arm regained its function Blackwell Science Ltd

3 Tropical Medicine and International Health VOLUME 1 NO. 2 Pl' APRIL 1996 A Gaafar et 01 Lymphadenitis in Leishmania major infections 13 m x n Y Blackwell Science Ltd

4 Tropical Medicine and International Health VOLUME I NO. 2 PP APRIL 1996 ~- - A Gaafar et ol Lymphadenitis in Leishmania major infections f! M a Blackwell Science Ltd

5 Figure 3 Patient 3. Section of the epitrochlear lymph node showing a stellate shaped area of necrosis containing some neutrophils. Two epithelioid granulomas are seen. In other areas there were frank stellate abscesses. H & E. x 400. li P w N P 4

6 Tropical Medicine and International Health VOLUME 1 NO. 2 PP APRIL 1996 A Gaafar et a/. Lymphadenitis in Leishmania major infections Patient 3 A zo-year-old male was admitted with multiple nodulo-ulcerative cutaneous lesions of z months duration in the right forearm and leg. There were two subcutaneous nodules proximal to the lesion in the forearm. The right epitrochlear lymph node was enlarged and non-tender. A slit smear from one of the lesions in the forearm showed amastigotes. In sections of the epitrochlear node there were scattered small epithelioid granulomas and stellate areas of necrosis and abscesses rimmed by palisading epithelioid cells and macrophages. The patient was treated with sodium stibogluconate at 10 mg/kg/day for 21 days. The skin lesion healed completely and the subcutaneous nodules decreased markedly in size. Two months later the subcutaneous nodules disappeared spontaneously and the leishmanin test was positive. Patients 5 and 6 Two females aged 23 years and 25 years respectively presented with nodulo-ulcerative lesions of cutaneous leishmaniasis in the forearm associated with subcutaneous nodules proximal to the primary lesions. Fine needle aspiration from both patients showed similar changes. There was a mixture of lymphocytes, plasma cells, neutrophils and macrophages. Some of the latter contained amastigotes. There were scattered foci of necrosis and epithelioid granulomas. Lymph nodes in visceral leishmaniasis Patient 4 A yyear-old female from Khartoum was seen in another hospital with nodules in the left forearm and arm of about 8 months duration. She had enlarged axillary lymph nodes. One of the nodules in the forearm was removed and histopathology revealed a necrotizing granuloma; no parasites were identified in the sections. No definite diagnosis was made but the possibility of tuberculosis was suggested. A reaction to BCG inoculation was ruled out since the child had had her BCG vaccination 8 years previously and the inoculation site healed completely without any complications. When she was referred to us, a careful history revealed that the child had had a small ulcer in the left forearm which healed within a few weeks. The patient could not recall whether the nodules in the forearm and arm were present at the time of the ulcer or occurred after the ulcer had healed. On examination there was an inconspicuous scar measuring 1.5 cm in the left forearm. Proximal to the scar there were z subcutaneous nodules in the forearm and one in the medial aspect of the arm. The epitrochlear, axillary and other lymph nodes were not palpable. Examination of the other systems revealed no abnormality. In view of the recent epidemic of cutaneous leishmaniasis in Khartoum, which is now becoming endemic, a provisional diagnosis of cutaneous leishmaniasis was made. The lymph nodes showed effacement of the architecture. In some nodes there were only ill-defined primary follicles but there were no germinal centres. The lymphocytes in the paracortex were variable in numbers, increased in some and diminished in others. The decrease was usually in nodes showing a heavy parasite load. Parasites were detected in macrophages within the sinuses and in the paracortex and medullary cords. There was a marked plasma cell infiltration in the medulla. There were no granulomas. The capsule, periglandular fat and afferent lymphatics were free of inflammation. Discussion The first case could easily have been misdiagnosed as tuberculosis. Indeed, this was the initial diagnosis made by two pathologists independently when the node was examined under low power magnification. The correct diagnosis was made when the section was examined under high magnification and amastigotes were seen. The presence of granuloma around the afferent lymphatics, the capsule and the marginal sinus is consistent with the pathology of an agent carried in the afferent lymphatics to the node, such as Leishmania parasites in this case. This is unlikely to be seen if the cause of the granuloma was brought to the nodes through the blood stream. In visceral leishmaniasis, Leishmania parasites reach Blackwell Science Ltd

7 Tropical Medicine and International Health VOLUME I NO. 2 PI' APRIL 1996 A Gaafar et ol. Lymphadenitis in Leishmania major infections the lymph node through the blood and the parasites are confined to the mononuclear phagocytes within the node; consequently, the afferent lymphatics and the periglandular fat are free of parasites and inflammation. Granuloma in the periglandular fat and around afferent lymphatics is therefore a useful diagnostic sign in lymphatic leishmaniasis associated with a localized cutaneous lesion. The second and third patients illustrate the fact that suppuration can occur in lymph nodes infected with L. major parasites. In the second patient, the suppuration was extensive and resulted in a large abscess that discharged through the skin. Parasites were found in the pus and on culture there was no bacterial growth. The lesions healed completely with anti-leishmania1 therapy. All this suggested that the elbow lesion was of leishmanial origin. The pathology in the third patient is remarkably similar to cat-scratch disease. Other necrotizing and suppurative granulomas that simulate lymphadenitis due to L. major are Iymphogranuloma venereum, Yersini, lymphadenitis, histoplasmosis, tularaemia (Lee & Anderson 1980) and tuberculosis, which can be excluded by the clinical features and appropriate laboratory tests. The presence of a primary skin lesion in which parasites are found points to the leishmanial aetiology of the granulomatous reaction in the draining lymph nodes. In these cases, the diagnosis can be made by demonstration of the Leishmania antigen by immunofluorescence or immunoperoxidase (Algindan et al. 1989). The fourth patient had sporotrichoid cutaneous leishmaniasis which occurs with a frequency of 22% in patients with cutaneous leishmaniasis in the Sudan (Gaafar et al. 1994). The other differential diagnosis in this patient is sporotrichosis which is rare in the country; only two cases have so far been reported (Gumaa 1979). Furthermore, in this patient histological examination and culture failed to demonstrate the fungus. Positive leishmanin after spontaneous regression of the subcutaneous nodules supports the diagnosis of cutaneous leishmaniasis. It is known that necrosis in subcutaneous nodules is a common finding in L. major infection as was the case in this patient. Patients 5 and 6 also had sporotrichoid cutaneous leishmaniasis. The diagnosis was made by fine needle aspiration which is less invasive and a quicker diagnostic tool than surgical excision. In both cases necrosis was found in the lesion. The patients recovered completely after specific anti-leishmania1 therapy. The pathology of the lymph node in visceral leishmaniasis is completely different from that of cutaneous leishmaniasis. In the latter there is evidence of intense antigen stimulation involving both B- and T-cell zones. There is also granuloma formation. These features are lacking in visceral leishmaniasis. In conclusion, L. major is a cause of necrotizing and suppurative lymphadenitis. The changes may simulate other causes of granulomatous inflammation, particularly tuberculosis and cat-scratch disease. The diagnosis of leishmanial lymphadenitis is made by demonstrating parasites. The pathology of subcutaneous nodules often shows necrosis and suppuration and may also cause diagnostic problems when the parasites cannot be identified in the sections with certainty. References Algindan Y, Kubba R, El Hassan AM eta[. (1989) Dissemination in cutaneous leishmaniasis. 3 Lymph node involvement. International Journal of Dermatology 28, Elsafi SH & Peters W (1991) Studies on Leishmaniasis in the Sudan I. Epidemic of cutaneous leishmaniasis in Khartoum. Transactions of the Royal Society of Tropical Medicine and Hygiene 85, Gaafar A, Fad1 A, El Hassan AM et al. (1994) Sporotrichoid cutaneous leishmaniasis caused by L. major of different zymodemes in the Sudan and Saudi Arabia. Transactions of the Royal Society of Tropical Medicine and Hygiene 88, Gumaa SA (1979) Sporotrichosis in the Sudan. Transactions of the Royal Society of Tropical Medicine and Hygiene 72, Kadarb AY, Ghalib HW, Ali MS et al. (1993) Prevalence of cutaneous leishmaniasis along the Nile river north of Khartoum (Sudan) in the aftermath of an epidemic in American Journal of Tropical Medicine and Hygience 48, Kubba R, El Hassan AM, Algindan Y (1987) Dissemination in cutaneous leishmaniasis. I Subcutaneous nodules. International Journal of Dermatology 26, Blackwell Science Ltd

8 Tropical Medicine and International Health VOLUME T NO APRIL 1996 A Gaafar et ol. Lymphadenitis in Leishmania major infections Lee FAD & Andersen GAR (1980) Lymphoreticular tissues. In: Muir s Textbook of Pathology (GAR Anderson ed.) T 7th edn. Edward Arnold, London. PP Siddig Ali MS, Gaafar A, Ghalih HW et al. (ry89) Kala-azar in the Sudan: clinical and immunological manifestations. Sudan Medical Journal 27, Blackwell Science Ltd