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Review Article

Professor A. H. Fahal, MBBS, FRCS,FRCSI,FRCSG, MD, MS, FRCP(London)
Professor of Surgery
Mycetoma Research Centre
University of Khartoum
E.mail:           

                                       
Introduction
Epidemiology and Aetiology
The causative organisms
Clinical presentation
Site of mycetoma
Differential diagnosis
Diagnosis of mycetoma
Radiology
Management
Eumycetoma Medical Treatment
Treatment of actinomycetoma
Surgery for mycetoma
References
 

Introduction:

Mycetoma is a chronic, specific, granulomatous, progressive inflammatory disease; it usually involves the subcutaneous tissue after a traumatic inoculation of the causative organism. Mycetoma may be caused by true fungi or by higher bacteria and hence it is usually classified into eumycetoma and actinomycetoma respectively (1).  Tumefaction and formation of sinus tracts characterize mycetoma. The sinuses usually discharge purulent and seropurulent exudate containing grains. It may spread to involve the skin and the deep structures resulting in destruction, deformity and loss of function, very occasionally it could be fatal (2,3).
         

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Epidemiology :

The true incidence and the geographical distribution of mycetoma throughout the world is not exactly known due to the nature of the disease which is usually painless, slowly progressive which may lead to the late presentation of the majority of patients. Mycetoma has a worldwide distribution but this is extremely uneven. It is endemic in tropical and subtropical regions. The African continent seems to have the highest prevalence (4).  It prevails in what is known as the mycetoma belt stretching between the latitudes of 15 south and 30 north (5). The belt includes Sudan, Somalia, Senegal, India, Yemen, Mexico, Venezuela, Columbia, Argentina and others.

The geographical distribution of the individual mycetoma organism shows considerable variations, which can be convincingly explained on an environmental basis. Areas where mycetoma prevails are relatively arid zones with a short rainy season with a relative humidity.

The organisms are usually present in the soil in the form of grains. The infecting agent is implanted into the host tissue through a breach in the skin produced by trauma caused by sharp objects such as thorn pricks, stone or splinters.
 

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The Causative Organisms:

A variety of eumycetes and actinomycetes are incriminated in the causation of mycetoma. Not less than 18 organisms have were reported from different parts of the world  (Table)

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Clinical Presentation:

Male predominance is a constant finding in mycetoma with a sex ratio of 3.7:1. This is commonly attributed to the greater risk of exposure to organisms in the soil during the outdoor activities. No age is exempted but mycetoma commonly affects adults between 20-40 years of age and these are the earning members of the society especially in under developed countries.  However, in endemic regions children and elderly people may also be affected (3,5). Mycetoma is seen more conventionally in cultivators, field laborers and in herdsmen who come in contact with the land in endemic areas people of other occupations are affected.

The clinical presentation of mycetoma is almost identical irrespective of the causal organism. However, the rate of progress is more rapid with actinomycetoma than with eumycetoma. In eumycetoma, the lesion grows slowly with clear defined margins and remains encapsulated for a long period, whereas, in actinomycetoma the lesion is more inflammatory, more destructive and invades the bone at an earlier period (1,5). The characteristic triad, of a subcutaneous mass, sinus and the presence of discharge containing grains are pathognomic of mycetoma. It presents as a slowly progressive painless subcutaneous swelling at the site of previous trauma. The swelling is usually firm and rounded but it may be soft, lobulated, rarely cystic and it is often mobile. Multiple secondary nodules then evolve as well, the nodules may suppurate and drain through multiple sinus tracts and these sinuses may close transiently after discharge during the active phase of the disease. Fresh adjacent sinuses may open while some of the old ones may heal completely. They are connected with each other, with deep sterile abscesses and with the skin surface. The discharge is usually serous, serosanguinous or purulent. During the active phase of the disease the sinuses discharge grains (fungal colonies) the colour of which depends on the causative organism. The grains can be black, yellow, white or red and they are of variable size and consistency. The black grains are usually due to M. mycetomatis, the red ones are due to A. pelletierii and the white grains can be due to A. madurae. Pus, exudate, the dressing gauze and biopsy material should be examined for the presence of the grains (Fig 1,2).

Mycetoma is usually painless in nature, it was suggested that the mycetoma produces substances that have an anaesthetic action (3). At a late stage of the disease the pain may become negligible due to nerve damage by the tense fibrous tissue reaction, endarteritis obliterans or poor vascularisation of the nerve (3). Pain may be produced by the expansion of the bone with the mycetoma granuloma and grains or it may be due to secondary bacterial infection (6).

As the mycetoma granuloma increases in size the skin over it becomes attached and stretched. The skin may become smooth, shiny and areas of hypo or hyper-pigmentation may develop. In some of the mycetoma patients there may be areas of local hyperhidrosis confined only to the mycetoma lesion and the skin around it. Mycetoma eventually invades the subcutaneous tissue, fat, muscles and bone. This is usually gradual and delayed in eumycetoma while in actinomycetoma, it is earlier and extensive especially in infections induced by A. pelletierii (3). For unknown reasons, the tendons and the nerves are curiously spared until very late in the disease process, this may explain the rarity of neurological and trophic changes even in patients with long standing mycetoma. The absence of trophic changes may also be explained by the adequate blood supply in the mycetoma area.

In the majority of patients the regional lymph nodes are small and shotty. An enlarged regional lymph node is not uncommon and this may be due to secondary bacterial infection, genuine lymphatic spread of mycetoma or it may be due to immune complex deposition as part of a local immune response to mycetoma infection (7)(Fig3).

The infection remains localised and the constitutional disturbances are rare but when they do occur they are generally due to secondary bacterial infection of the open sinus tracts, fistula formation in some patients or generalised immuno-suppression. Cachexia and anaemia may be seen in late mycetoma. This is often due to malnutrition, sepsis and mental depression. Mycetoma can produce many disabilities, distortion and deformity. It can be fatal especially with cranial mycetoma (8,9,10,11).

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Site of Mycetoma:

The commonest site for mycetoma is the foot (79.2%), most of the lesions are seen on the dorsal aspect of the forefoot and for unexplainable reasons the left foot is affected more. The hand ranks as the second commonest site (6.6%), the right hand is more affected. This may imply a traumatic basis of the infection in this site. In endemic areas other parts of the body may be involved but less frequently and these include the knee, arm, leg, head and neck, thigh and the perineum. Rare sites such as the chest and abdominal walls, fascial bones, mandible, paranasal sinuses, eyelid, vulva, orbit, scrotum and surgical incisions may be affected (Fig 4).
 

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Differential Diagnosis:

The differential diagnosis of mycetoma includes many of the soft tissue tumours such as Kaposi's sarcoma, fibroma, malignant melanoma or fibrolipoma as well as thorn granuloma. The radiological features of advanced mycetoma may be comparable to osteogenic sarcoma and bone tuberculosis (1,3) Primary osseous mycetoma is to be differentiated from chronic osteomyelitis, osteoclastoma, bone cysts and from syphilitic osteitis.
 

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Diagnosis of Mycetoma:

Radiology:
 

A series of radiological changes are seen in mycetoma. This is due to the fact that all mycetoma agents are osteophilic and it may be due to the effect of the granuloma on both the affected bone and its blood supply. In the early stage, there is a soft tissue granuloma, which is shown as a dense shadow or as scattered multiple soft tissue shadows. Calcification and obliteration of the fascial planes may sometimes be seen As the disease progresses, the cortex may be compressed from outside by the granuloma leading to bone scalloping, this is followed by a variable amount of periosteal reaction. Periosteal new bone spicules are laid down at right angle to the cortex to create a sun-ray appearance and Codman triangle, an appearance that may be undistinguishable from that due to osteogenic sarcoma.  Late in the disease, there may be multiple punched out cavities through the normal density of the bone. These cavities are large in size, few in number with well-defined margins in eumycetoma. Whereas, the bone cavities in actinomycetoma are usually smaller in size, numerous and have no definite margins (1,3). The cavities are produced by the replacement of the osseous tissue by the grains. Their size is due to the size of the grains of the causative organism (Fig 5). The cavities are usually filled with solid masses of grains and fibrous tissue, which provides bone support. This may explain the rarity of pathological fractures in mycetoma.  The bony changes in the skull are unique: they are purely sclerotic with dense bone formation and loss of trabeculation.

Osteoporosis at and distal to the affected part is well observed in mycetoma and this may be due to disuse atrophy or due to the compression of the bone and its blood supply by the mycetoma granuloma. Chemotherapy causes radiological improvement consisting of remoulding, absorption of the sclerotic bone and reappearance of the normal trabecular pattern (1,3).

Ultrasonic imaging of mycetoma:

The mycetoma grains, its capsule and the accompanying inflammatory granuloma have characteristic ultrasonic appearances. Ultrasound imaging can differentiate between eumycetoma and actinomycetoma and between mycetoma and other non-mycetoma lesions. In eumycetoma lesions, the grains produce numerous sharp bright hyperreflective echoes, which are consistent with the black grains. The grain cement substance is most probably the origin of these sharp echoes. Also there are multiple thick walled cavities with absent acoustic enhancement. In actinomycetoma lesion the findings are similar but the grains are less distinct. This may due to their smaller size and consistency, individual embedding of the grains or the absence of the cement substances in few of them (Fig 6).

The ultrasonic diagnosis of mycetoma is more precise and accurate in lesions with no sinuses. The size and extent of the lesion can be accurately determined ultrasonically and this is useful in planning surgical incisions and procedures  (13).

Fine needle Aspiration Cytology of Mycetoma:

Mycetoma can be accurately diagnosed by Fine Needle Aspiration (FNA) cytology. Mycetoma lesion has a distinct appearance in a cytology smear characterised by the presence of polymorphous inflammatory cells consisting of an admixture of neutrophils, lymphocytes, plasma cells, histiocytes, macrophages and foreign body giant cells and grains. In sections, the grain is closely surrounded by and occasionally infiltrated by neutrophils causing its fragmentation. Outside the neutrophil zone, monocytic cells and giant cells are seen. This is surrounded by granulation tissue rich in fibroblasts and blood vessels. FNA allows morphological identification of mycetoma and its classification into eumycetoma and actinomycetoma, this is important as the treatment depends mainly on the aetiological agents.

The technique is simple, cheap, rapid, sensitive and can be tolerated by patients. It can be used not only in routine diagnosis but can be used as an effective mean in collection of material for culture and immunological studies. Due to the simplicity of the technique it can be used in epidemiological survey of mycetoma and for detection of early cases in which the radiological and serological techniques may not be helpful (14).

Culture:

A large variety of microorganisms are capable of producing mycetoma. They can be identified by their textural description, morphological and biological activities in pure culture. The biological activity may include, acid fastness, optimal temperature, proteolytic activity, utilization of sugars and nitrogenous compounds (15). The grains are the source of the culture and they should be alive and free of contaminants. Many culture media are in use e.g. Sabouraud, blood agar and Malt extract agar.  The culture technique is cumbersome, time consuming and chance contamination may give a false positive result. It also requires experience to identify the causative organisms.

The histological technique:

Stained sections usually show the grain morphology and the tissue reaction to the organisms (16). The technique is attractive in that it requires neither aseptic procedure nor the rigid time schedule required for culture, however it lacks the precision of culture.

Serodiagnosis in mycetoma:

In the absence of the classical triad of mycetoma, the demonstration of significant antibodies titers against the causative organism may be of diagnostic value. Serodiagnosis is of a great help in identification and classification of the various organisms, which is an essential prerequisite for medical treatment, and is mandatory for the follow-up of these patients. It has many advantages over the culture and histopathological techniques, as both require surgical biopsy, which may enhance the spread of the organism. The common serodiagnostic tests for mycetoma are the immunodiffusion (ID) and counter-immuno-electrophoresis (CIE) (17,18). The (ID) test is not sensitive enough and unless antigens are quite pure, it can be negative in early cases. (CIE) test remains reliable, simple, economical, rapid and a sensitive test. It is useful for routine diagnosis of early cases of mycetoma and for checking the sera that are weakly positive by (ID) test. It distinguishes between eumycetoma and actinomycetoma and between Actinomycetes themselves, but cross reactivity between A. madurae and A. pelletierii is quite common. However it is time consuming and the preparation of the antigens take a considerable time. Recently the indirect fluorescent antibody test was used in diagnosing mycetoma and was found to be specific and sensitive (19).

Enzyme linked immunosorbent assay (ELISA) was used in the diagnosis of mycetoma (20). It appeared to be a sensitive test for the detection of antibodies, however the high sensitivity of the test makes the cross reactivity unavoidable. ELISA may be a useful tool in community studies as sero-epidemiological survey could give valuable information on the distribution and prevalence of exposure to mycetoma (20).

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Management:

The treatment of mycetoma depends mainly on its aetiological agent and the extent of the disease. Until recently the only available treatment for mycetoma was amputation or mutilating surgical excision of the affected part. Local excision for localised lesion is not commonly performed as most of the patients present late with advanced disease. No case of self-cure has ever been reported in the medical literature.

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Eumycetoma Medical Treatment:

In many centres, surgery is the most acceptable line of treatment for eumycetoma cases. Usually it is in the form of aggressive surgical excision, debulking surgery or amputation in advanced disease  (25).

Reports of medical treatment in eumycetoma are few. A number of studies showed that ketoconazole could cure eumycetoma patients.  The dose is 300-400 mg daily.  The cure rate seemed to be dose dependent. Treatment of these patients may continue for periods ranging from few to many years (26).        

Recently Itraconazole was tried in the treatment of patients with eumycetoma, it had a high success and low recurrence rate. Patients showed good clinical response to 400 mg itraconazole daily. Surgical exploration revealed that, in all patients the lesions became well localized, encapsulated with thick capsule and were then easily removed surgically. There seems, no longer any justification for mutilating surgery or amputation prior to giving medical treatment. One disadvantage of these drugs is however, their current high cost, which may limit their availability to patients in poor countries.

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Treatment of Actinomycetoma:

Actinomycetoma is amenable to medical treatment with antibiotics and other chemotherapeutic agents. Combined drug therapy is always preferred to a single drug to avoid drug resistance and to eradicate residual infection. The common drugs in use include combination of streptomycin sulphate (14 mg/kg daily), diaminodiphenyl sulphone (dapsone) (1.5 mg/kg twice daily). If there is no response for few months or if there is persistent side effect then dapsone is replaced by Co-trimoxazole (14 mg/kg twice daily). An excellent therapeutic response to amikacin sulphate alone or in combination with Co-trimoxazole has been reported in the treatment of actinomycetoma (21,22,23,24).

In resistant cases other drugs such as rifampicin, sulfadoxine-pyrimethamine (fansidar) and sulphonamides had been tried, these proved to be effective in some cases and they remain a good second line therapy. Treatment must be continued until the patient is cured.

Many authors advocate giving mycetoma patients treatment for long periods and in higher doses as the microorganisms are locked in fibrous tissue with poor vasculature (21). The mean duration of treatment is usually more than one year. Medical treatment should be given pre and post operatively as it facilitates surgery, accelerates healing and reduces the chance of relapse. Medical treatment is useful in all stages of actinomycetoma even in large lesions with lymphatic spread, as well as in cases with a great deal of bone damage.  The cure rate varies between 60% and 90%. Recurrence is more common after an incomplete course of medical treatment and there is a good chance for the organism to develop drug resistance. Local administration of mycetoma chemotherapeutic agents was used but the results were not impressive.

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Surgery for Mycetoma:

Surgery in mycetoma is indicated when the disease process is limited and localised and for cases resistant to medical treatment or patients with bony involvement not responding to repeated long term conservative therapy.

The goal of surgery is the complete removal of the lesion or the reduction of size followed by medical treatment. Eumycetoma is well encapsulated and great care must be exercised not to rupture the capsule, which may lead to recurrence by transferring the fungal element into other parts of the operative field. Actinomycetoma has an ill-defined border; therefore a margin of healthy tissue should always be excised with the lesion. Simple bone curettage and soft tissue excision is recommended for localised bony lesions. A bloodless operative field using a tourniquet is mandatory to identify margins of the lesion. It is advisable to flood the wound at the end of surgery with tincture of iodine especially if there is doubt about the completeness of the excision or contamination of the surgical field (22). The wound can be closed primarily or by delayed primary sutures and in many cases skin grafts may be required. The open postoperative wounds are usually dressed with 2% iodine in glycerin. Glycerin is commonly used as it facilities the diffusion of the iodine into the tissue. Many dressing solutions are in use such as normal saline, Eusol solution but no one has advantage over the others.

 In advanced cases of mycetoma not responding to medical treatment for a prolonged period nothing short of amputation is likely to succeed. The amputation rate ranges from 25% to 50%. Extensive repeated excisions of the diseased tissue, including bone may be carried out several times to avoid the social consequences of amputation, This debulking procedure must be coupled with chemotherapy. In less advanced cases less mutilating surgery is advised for example, toe, mid tarsal or Syme's amputation. However, in many cases of inadequate surgery recurrence is inevitable.

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References:

1-Fahal AH, Hassan MA, Mycetoma. British Journal of Surgery.
1992; 79: 1138-1141

2-Abbott PH, Mycetoma in the Sudan. Transactions of the Royal Society of  Tropical Medicine and Hygiene. 1956; 50: 11-24.    

3-Mahgoub ES, Murray IG, Mycetoma. London, William Heinemann, Medical Books Ltd.  1973,  pp. 1-50.

4-Gonzalez-Ochoa A. Mycetoma in: Clinical Tropical Dermatology. Edited by Canizares O. Oxford, Blackwell Scientific. 1975; pp 24-29.

5-Magana M. Mycetoma. International Journal of Dermatology.
1984; 23(4): 221-236.

6-Gumaa SA. Mycetoma. Post-Graduate Doctor. 1983; 6: 15-20.

7-Fahal AH, Suliman SH. The clinical presentation of mycetoma.  Sudan Medical Journal.  1994; 32: 46-65.

8-Fahal AH, EL Sheik H, EL Hassan AM.      Pathological  fracture in mycetoma.   Transactions of Tropical Medicine and Hygiene - 1996; 90:  675-676.

9-Fahal AH, EL Hassan AM, Abella AO, Sheik HE.        Cystic mycetoma: An unusual clinical presentation of  Madurella mycetomatis.  Transactions of the Royal Society of Tropical  Medicine and Hygiene. 1998; 92: 66-67

10-Fahal AH, Yagi HI, EL Hassan AM.         Mycetoma induced palatal deficiency and pharyngeal plexus           Dysfunction.  Transactions of Tropical Medicine and Hygiene –  1996;90: 676-677

11-Gumaa SA, Mahgoub ES, EL Sid MA.  Mycetoma of the head and neck. American Journal of Tropical Medicine and  Hygiene  1986; 35(3): 596-600.

12-EL Hassan AM, Mahgoub ES. Lymph nodes involvement in mycetoma.   Transaction of the Royal Society of Tropical Medicine and Hygiene.   1972; 66: 165-169.

13-Fahal AH, EL Sheikh HA, EL Lider MA, Homeida MA, EL Arabi YE, and Mahgoub ES,  Ultrasonic imaging in mycetoma.  British Journal of Surgery  1997; 78: 765-766.

14-EL Hag IA, Fahal AH, Khalil EAG, Fine needle aspiration cytology of mycetoma. Acta Cytologica.  1996; 40(3):461-464.

15-Mahgoub ES. Mycetoma. Seminars of Dermatology. 1985; 4: 230-239.

16-EL Hassan AM, Fahal AH, EL Hag IA, Khalil EAG.          The pathology of mycetoma: Light microscopic and ultrastructural features. Sudan Medial Journal.  1994; 32: 23-54.

17-Gumaa SA, Mahgoub ES. Evaluation of the complement fixation test in the diagnosis of Actinomycetoma. Journal of Tropical Medicine and Hygiene. 1973; 76: 140-142.

18-     Gumaa SA, Mahgoub ES. Counter-immuno-electrophoresis in the diagnosis of mycetoma and its sensitivity as compared to immuno-diffusion. Sabouraudia. 1975; 13: 309-315.

19-Joshi KR, Singhvi S. Serodiagnosis of mycetoma.Transaction of the Royal Society of Tropical Medicine  and Hygiene.   1988; 82: 334.

20-Taha A.  A serological survey of antibodies to Streptomyces somaliensis and  Actinomadura madurae in the Sudan using enzyme linked immunosorbent (ELISA). Transaction of the Royal Society of Tropical Medicine  and Hygiene.. 1983; 77(1): 49-50.

21-Mahgoub ES.       Medical management of mycetoma. Bulletin of World Health Organization. 1976; 54: 303-310.   

22-Mahgoub ES .Medical treatment of mycetoma in the Sudan. Sudan. Medical Journal. 1994;32 (supp): 88-97.  

23-Mahgoub ES Treatment of actinomycetoma with sulphamethoxazole plus trimethoprim. American Journal of Tropical Medicine and Hygiene. 1972; 21(3): 332-335.

24-Welsh O, Saucceda E, Gonzalez J, Ocampo J. Amikacin alone and in combination with trimethoprim and sulfamethoxazole in the treatment of actinomycotic mycetoma. Journal of American Academy of Dermatology 1987; 17(3): 444-448.   

25-Fahal AH, Hassan MA, Sanhouri M. Surgical treatment of mycetoma.  Sudan Medical Journal.   1994; 32: 98-104.  

26-Mahgoub, ES, Gumaa SA. ketoconazole in the treatment of eumycetoma due to Madurella mycetomi. Transaction of the Royal Society of Tropical Medicine and Hygiene.   1984; 78: 376-379