Leprosy and sarcoidosis share several clinical, histopathological and immunological profiles and, indeed, several reports that leprosy cases were misdiagnosed as sarcoidosis are present. We ourselves have recently experienced a case of multibacillary leprosy in the mainland of Japan, who was initially interpreted as sarcoidosis and treated with prednisolone. In this review, epidemiological, clinical, histopathological and immunological features of leprosy and sarcoidosis are compared and their similarities and contrasts are discussed, and reports of the misdiagnosed cases are reviewed. We should keep in mind the fact that there are some leprosy cases misdiagnosed as sarcoidosis, especially in developed countries.

Leprosy, Sarcoidosis, Misdiagnosis

Nishiguchi M, Furukawa F, Kanazawa N (2016) Leprosy versus Sarcoidosis: Different Diagnosis and Review of Misdiagnosed Cases. J Dermatolog Clin Res 4(5): 1087.

ACE: Angiotensin-Converting Enzyme; AFB: Acid-Fast Bacilli; BB: Mid-Borderline; BL: Borderline Lepromatous; BT: Borderline Tuberculoid; LL: Lepromatous type; LN: Lymph Nodes; M: Mycobacterium; MB: Multibacillary; PB: Paucibacillary; PCR: Polymerase Chain Reaction; PGL: Phenolic Glycolipid; PSL: Prednisolone; Th: T helper; TT: Tuberculoid Type

Leprosy and sarcoidosis share several clinical, histopathological and immunological profiles and, indeed, several leprosy cases have been reported to be misdiagnosed as sarcoidosis [1-6]. We ourselves have recently experienced a case of multibacillary leprosy in the mainland of Japan, who was initially interpreted as sarcoidosis and treated with prednisolone (PSL) (Nishiguchi M, et al, manuscript in press). In this review, the epidemiological, clinical, histopathological and immunological features of leprosy and sarcoidosis are compared and their similarities and contrasts are discussed. Reports of the misdiagnosed cases are also reviewed.

Leprosy is caused by a chronic infection of acid-fast bacilli (AFB) Mycobacterium (M). leprae, which invade macrophages and Schwann cells. Transmission of the bacilli is mediated through droplets from the nose and upper respiratory tracts. It has been claimed that some specific conditions, such as frequent contact with a large amount of M. leprae in infancy or early childhood before the full development of immunity, are required to establish the infection of M. leprae and it often takes several to decades of years until the onset of leprosy. Since M. leprae has only a quite weak infectivity, leprosy can only develop in individuals who are immunodeficient for M. leprae [7].

As the optimum temperature for growth of M. leprae is around 31 degrees centigrade, M. leprae prefers to invade the body areas with lower temperatures, such as auricles, cheeks, back of hands, extensor side of the upper and lower extremities and dorsum of foot.

Leprosy shows a variety of symptoms, such as skin rash, impaired sensation, motor paralysis and muscle weakness. Laboratory examinations required for diagnosis of leprosy include pathological examination, skin smear test, and detection of M. leprae-specific DNA with polymerase chain reaction (PCR). Measurement of serum anti-phenolic glycolipid (PGL)-1 antibody is not required, but useful. Pathologically, non-caseating epithelioid cell granulomas and foam cells are observed by Hematoxylin-Eosin stain and AFB are demonstrated by modified Ziehl-Neelsen stain (Fite stain). Diagnosis of leprosy is synthetically given by a combination of skin rash with imperceptions, peripheral nerve hypertrophy, dyskinesia, detection of M. leprae and pathological features.

After confirmation of the diagnosis of leprosy, its subtype of PB (paucibacillary) or MB (multibacillary) of WHO classification should be determined by counting Bacteriological Index. In Ridley & Jopling classification, leprosy is divided into the lepromatous type (LL), tuberculoid type (TT) and borderline groups. The LL type is characterized by extensive, bilateral, symmetrically distributed skin and nerve lesions. The TT type show less involvement of skin and nerve. Borderline groups are present between the two polar forms and are classified into BT (borderline tuberculoid), BL (borderline lepromatous) and BB (mid-borderline) types. These subtypes are closely related to the host’s immunoreactivity to M. leprae. In the TT type, active cellular immunity and T helper (Th) 1 reactions are remarkable with impaired humoral immunity and Th2 reactions, and vice versa in the LL type. Notably, circulating immune complexes and anti-single stranded DNA antibodies were detected in significant number of patients with leprosy of the LL type with slightly-high levels, without significant association between them [8].

The multidrug therapy (MDT), including oral diaminodiphenyl sulfone, rifampicin and clofazimine, is generally applied according to recommendation of the World Health Organization. It should be continued for 6 months or 1-3 years to treat PB or MB cases, respectively [9]. To prevent functional and external sequelae, early diagnosis for early treatment is of great importance.

Although leprosy is rarely encountered in developed countries, around 13 million patients in India and 3 million patients in Brazil are still suffered from leprosy and it is one of the poorly-controlled infectious diseases in the developing countries.

Sarcoidosis is a systemic granulomatous disease of unknown etiology, which mainly affects the skin, LN, lungs and eyes. However, virtually, any organ can be affected. To diagnose sarcoidosis, required is the pathological proof of non-necrotizing epithelioid cell granulomas, in addition to the clinical and laboratory findings. Clinical courses of cases with sarcoidosis are diverse. Although many cases of sarcoidosis show spontaneous remission, 10 to 30% of them are chronically progressive and result in fibrosis. The pathogenesis of sarcoidosis is unclear. However, environmental (infectious or non-infectious) factors affect individuals with genetic predispositions to cause chronic inflammatory responses, leading to the disease onset. Recently, especially in Japan, a role of latent infection of Propionibacterium acnes has been considered most important in the pathogenesis of sarcoidosis and an increasing number of proofs have been collected [10]. Immunologically, locally active cellular immunity with systemically impaired cellular immunity, indicated by negative Tuberculin test, is remarkable. Hyper gamma globulinemia is usually accompanied and anti-nuclear antibodies and rheumatoid factor is detected in significant number of patients [11].

Clinical symptoms are highly divergent, including eyes (blurred vision and myodesopsia), skin (facial nodules and nodular erythemas), heart (atrioventricular block), and nervous system (headache and paralysis) lesions. Laboratory findings include non-caseating epithelioid cell granulomas in pathology, bilateral hilar lymphadenopathy in chest roentgenogram, increased numbers of total cells and lymphocytes and an elevated CD4/8 ratio in bronchoalveolar lavage, negative tuberculin test, and an elevated serum angiotensin-converting enzyme (ACE) level. Focally up regulated Th1 response with granuloma formation, while systemically impaired cellular immunity with negative Tuberculin test, is characteristic and the pathophysiology is still fully unknown. Therefore, on diagnosing sarcoidosis, not only these clinical and laboratory findings, but thorough exclusion of other diseases is essential.

Corticosteroid is the first selected for treating sarcoidosis. However, some alternative treatment should be required for cases, in whom the disease is resistant for corticosteroid or corticosteroid is difficult to be continued. While spontaneous remission can be seen during the disease course, some cases develop organ failure due to fibrosis, which becomes intractable and shows poor prognosis [12].

Leprosy and sarcoidosis share several clinical and laboratory profiles. Comparison of their features is summarized in Table (1). Sarcoidosis is more frequently recognized in female, while leprosy is similarly recognized in men and women. All age groups are at risk for the onset of leprosy, although sarcoidosis develops most commonly in 20 to 40 years of age [13]. Skin lesions are observed in all cases of leprosy, whilst it is affected in 20-60% cases of sarcoidosis [13]. Skin lesions of sarcoidosis are classified into erythema nodosum, scar infiltration and cutaneous sarcoidosis, which is further classified into nodular type, plaque type, subcutaneous type, lichenoid type, ichthyosiform type, ulceration type, lupus pernio and others. Frequency of each subtype is 38% in nodular type, 26% in plaque type, 25% in subcutaneous type, and only 11% in the others. Although nerve involvement is observed in around 5% cases of sarcoidosis, peripheral nerve involvement is relatively rare and is observed only in 6-18% of them [14]. In case of leprosy, peripheral nerve dysfunction is commonly observed because M. leprae invade peripheral nerves. Bone/joint lesions are observed in 1 to 13% cases of sarcoidosis [15], whilst they are more frequently observed in leprosy [16]. Eye lesions are mostly uveitis in sarcoidosis. However, in leprosy, they are divided into two types: lesions of eyelids and cornea caused by facial nerve palsy, and lesions of cornea, episclera, iris and ciliary body caused by bacterial invasion or accompanying inflammation. Regarding frequencies, eye lesions are observed in 50 to 70% of sarcoidosis, and in 15 to 20% of leprosy [15]. In sarcoidosis, swelling of superficial lymph nodes (LN) with granuloma formation is observed mainly in axillary and inguinal areas. Swollen superficial LN can be recognized with AFB in LL type, but not in TT type leprosy [17]. Hepatosplenomegaly is observed in 13% of sarcoidosis [18], though it is almost absent in leprosy [16]. Tuberculin test is negative in 70% of sarcoidosis, though it is mostly positive in leprosy [17]. Serum and urine calcium levels are elevated in 18% and 40% of sarcoidosis, respectively, though they are within normal levels in leprosy [17]. Serum ACE level is elevated in 60% of sarcoidosis, and in 30 to 40% of leprosy [19]. In sarcoidosis, granuloma formation is observed in multiple organs, whilst it is confined to the skin and nerves in leprosy. In sarcoidosis, “naked granulomas” with scanty lymphocytic cell infiltration around epithelioid cell granulomasare characteristic. In tuberculoid leprosy, noncaseating epithelioid cell granulomas are remarkable, which are difficult to be distinguished from sarcoidosis. In lepromatous leprosy, a huge number of foamy macrophages called foam cells are observed. Diagnosis of leprosy is given by a demonstration of AFB with Fite staining, and the subtype of PB or MB should be determined by the number of bacilli.

We ourselves have recently experienced a case of multibacillary leprosy in the mainland of Japan, who was initially 

Table 1: Comparison of tuberculoid/lepromatous type leprosy and sarcoidosis.

Table 2: Summary of leprosy cases initially misdiagnosed as sarcoidosis.

interpreted as sarcoidosis and treated with PSL. So far, at least 6 cases of leprosy misdiagnosed as sarcoidosis have been reported [1-6]. Major features of these cases and our own case are summarized in Table (2). Although early diagnosis for early treatment is essential to prevent functional and external sequelae, there was a case that had been misdiagnosed for more than 10 years. The most characteristic feature shared among them is that none of Fite stain, PCR or skin smear test has been performed and the diagnosis of sarcoidosis has somewhat positively been given based on their clinical and laboratory findings, such as presence of non-caseating granuloma on pathology and high serum ACE levels. As the clinical manifestations of sarcoidosis are highly divergent, lepromatous annular erythema can be considered as the plaque type cutaneous sarcoidosis and neurological symptoms can be considered as rare peripheral neuropathy with sarcoidosis. Furthermore, leprosy cannot be excluded because f the high serum ACE level and eye lesions (Table 1). It should be essential, before determining the diagnosis of sarcoidosis, complete exclusion of M. leprae, as well as other pathogenic microorganisms, by Fite staining of lesion skin sections, examination of sequential 5-6 sections [5], skin smear test, and PCR. We should keep in mind the fact that there are some leprosy cases misdiagnosed as sarcoidosis in developed countries.

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