Arch. Derm. Forsch. 252, 1--10 (1975) © by Springer-Verlag 1975
The Histoid Variety of Lepromatous Leprosy* Clovis Bopp and Lucio Bakos Discipline of Dermatology, Department of Internal Medicine Federal University of Rio Grande do Sul (Head: Professor Clovis Bopp) Porto Alegre (Brazil) Received August 1, 1974
Summary. Three cases of the so-called "histoid variety" of lepromatous leprosy are reported. This variety has definite clinical features, associated with characteristic histological and bacteriological findings. Some of the features presented by our patients are similar to those described originally by Wade, especially the resistance to treatment. Considering the discrepancies existing among the authors which studied the subject, our opinion is that further studies should be done in order to elucidate the controversial points. Zusammen/assung. Drei Patienten mit der sog. histiozyt~ren Sonderform der lepromatSsen Lepra werden besehrieben. Diese Sonderform zeichnet sich durch bestimmte klinische Symptome sowie charakteristisehe histologische und bakteriologische Befunde aus. Eine Reihe yon Symptomen, die wir bei unseren Patienten beobachteten, gleiehen den urspr~nglieh yon Wade beschriebenen Krankheitszeichen. Das gilt besonders auch hinsichtlich der Therapieresistenz. Die divergierenden Ansichten einzelner Autoren sollten Anla$ zu weiteren Untersuchungen sein. I n 1963, W a d e (8) described the histoid variety of lepromatous leprosy, whose most striking feature was the existence of lesions more closely resembling t u m o u r s composed of a single tissue of spindle-shaped cells rather t h a n the inflammatory granuloma of the ordinary leproma. This variety is most likely to occur in old cases which for years h a d progressed as ordinary lepromatous leprosy, already treated and clinically healed. Some of t h e m had even reached bacteriological negativity. At relapse, these cases presented v e r y peculiar clinical features such as: a) Well defined subcutaneous nodules of variable size, some of t h e m even reaching 5 cm in diameter; b) Cutaneous nodules, arising either from the upper dermis or from the " m i r g a t i o n " to the corium of the subcutaneous nodules. These lesions are elevated, pinkish or norma]-skin-coloured, p r o t u b e r a n t and even pedunculated, ranging from 0.2 to 2.0 cm in diameter. The hardness and the smooth and shiny surface of some of t h e m make t h e m similar to y o u n g keloids. T h e y would arise on an a p p a r e n t l y normal and bacteriologically negative skin, some of t h e m undergoing central necrosis, forming a crateriform ulceration; c) Strictly limited tuberous plaques, developing on points of pressure, especially the elbows or anywhere else. After W a d e ' s article, several authors reported cases in which the histoid lesions appeared "de novo", t h a t means, without a n y previous lesions or treatment, thus without the possibility of being relapsing cases. * Herrn Prof. Dr. H. GStz zum 60. Geburtstag gewidmet. i
Arch. Derm. Forsch., B4. 252
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According to Wade, the most characteristic histological features are found in young, active subcutaneous nodules, in which the intertwining of strands of spindle-shaped cells--histiocytes and not fibrocy~es--resemble closely some histiocytomas or nodular subepidermal fibrosis. They are usually surrounded by a pseudocapsule, derived from the expansile growth of the nodule and its pressure on the neighbouring connective tissue. The pseudocapsule and the spindle-shaped histiocytes would be seen less often in the cutaneous tubercles and plaques. While young subcutaneous lesions contain very few collagen fibers, these are seen in larger amounts in older ones, although never diffusely dispersed throughout the "parenchyma". Nerve branches were not seen inside the nodule, and: the author, in certain infrequent cases, observed "mixed" structures in wl~ich, in the same section, a typical histoid pattern was surrounded in part by an ordinary lepromatous granuloma. The absence of g]obus formation, according to the author, constitutes one of the most striking features in sections stained for acid-fast organisms, even though bacilli were present in considerable number, at times more abundant than in ordinary lepromas. They would be arranged following the long axis of the elongated histiocyte. I n size, the bacilli would be notably larger than those in the ordinary ]epromatous infiltrate. Wade also observed with certain frequency the occurrence of a "contamination" of some subcutaneous histoid nodules by rare and small tuberculoid foci within the lesion or in the encircling fibrous pseudocapsule, almost free from bacilli, in sharp contrast with their abundance in the surrounding histoid structures. According to him, such patients do not undergo the erythema nodosum leprosum type of reaction. Wade identified as histoid cases Figs.25 and 29 of the Atlas de Leprologia of Orestes ])iniz. The publication of his article was followed by the papers of Melamed (2) and Jonqui~res (1), from Argentina, S~nchez (7) from Mexico, Pettit et al. (4) from Malaysia and Price and Pitzherbert (5) from Abyssinia. l~odrigucz (6), from the Philippines, observed 28 relapsing patients presenting histoid lesions added with 7 nonrelapsing ones, in which the nodules appeared primitively, without any previous treatment. Pereira Junior (3), in his thesis (1970), presents four more cases of histoid leprosy, doing a critical study of this variety.
Case Reports Case i. (L. V. L.) Male, caucasian, aged 45 years, farmer. This patient had been under treatment since 1960 with I)DS and diphenyl-thiourea for a maeular form of lepromatous leprosy, obtaining clinical negativity. In March, 1970, still under treatment, he relapsed and was admitted to the hospital, presenting generalized tuberous lesions, with a smooth and shiny surface, located mostly on the trunk but also on the limbs (Fig. 1). Cutaneous plaques were also found, formed by the confluence of these lesions. Some subcutaneous nodules were seen near the joints. All these lesions were arising from apparently normal skin. Anaesthesia was found only in the hands, both presenting claw fingers. Wasting of thenar, hypothenar and intrinsic muscles was seen on the right hand. Both ulnar nerves were thickened. The face was normal, without infiltration or madarosis. The nasal septum was perforated.
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Fig. 1. Case 1 (L. V. L.) Cutaneous nodules, arismg from apparently normal skin
Acid-fast bacilli and globi w e r e found in smears from the nasal mucosa, from the lesions and from the clinically normal surrounding skin. Laboratory investigation showed normal V D R L test, WBC, RBC, serum proteins, sedimentation rate and urinalysis. Latex, C-reactive protein a n d L. E. cell preparations were negative. Lepromin, tuberculin and Montenegro tests were also negative. Since his admission, the patient has been regularly treated for the last four years with alternate series of DDS, Clofazimine, Doxicycline and diphenyl-thiourea, with periods of improvement and relapse. Upon last examination, the lesions were markedly worsened and the face was infiltrated. Skin smears were repeatedly positive for acid-fast bacilli and his last M.I. was 80/o. Case 2. (V. J. O.) Male, mulatto, aged 37 years, farmer. His disease started in 1968 with progressive numbness of hands a n d feet and swelling of the lower limbs. Three months prior to consultation he noticed the growing of several nodular lesions on the face and limbs. On examination (June, 1970), several papular and nodular lesions, arising from normal skin, could be observed on the forehead, left cheek, neck, b o t h shoulders, upper limbs, right lumbar region, buttocks a n d thighs. A plaque of 3 cm in diameter was formed on the cheek by the confluence of a few nodules (Fig.2). Infiltration on the face and madarosis were absent. Three nodular subcutaneous lesions were observed on the left arm (Fig. 3), the largest one measuring 3 cm in diameter. The patient h a d sensory impairment of pain and t e m p e r a t u r e in b o t h legs, right forearm a n d left foot. As in case 1, A F B a n d globi were also found in nasal scrapings a n d in smears from b o t h the histoid lesions and the surrounding skin. A positive tuberculin test (1 : 1000) was observed, showing a papule with 13 m m of induration. Sporothrichin a n d eandidin intradermM tests were b o t h positive, b u t lepromin and Montenegro tests were negative. V D R L reaction, latex, L. E. cell preparations a n d C-reactive protein were negative. Sedimentation rate, WBC, RBC, serum proteins and urinalysis were normal. I n four years of regular treatment, the patient received successively Promin, diphenylthiourea, DDS and Clofazimine. He underwent two reactional episodes of e r y t h e m a nodosum leprosum and one episode of e r y t h e m a multiforme. A t the last clinical examination, the histoid lesion were markedly improved. Nasal smears were negative, although skin sites remained positive, with a B. I. of 1.5 and a M.I. of 0. 1"
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Fig.2. Case 2 (V. J. 0.) Nodular lesions of the face, forming a plaque on left cheek. Note absence of infiltration or madarosis
Fig. 3. Case 2 (V. J. 0.) Subcutaneous nodular lesion
Case 3. (F. W. 1~.) Male, caucasian, aged 34 years. His disease started in 1973 with nodules on the left leg, in association with numbness of the hands and feet. At the first consultation, the patient showed a large number of solid nodular lesions, pink or dull-red coloured, of various sizes, at times pedunculated, dispersed throughout the integument, including the scrotum, but in larger number on the upper limbs and buttocks, arising from apparently normal skin. Subcutaneous lesions were palpable on the arms and thighs. Of particular interest in this patient was the association of histoid leprosy with widespread lesions of "tinea corporis", "tinea versicolor" and almost complete destruction of the nails of both hands by ringworm infection.
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Fig. 4. Subcutaneous histoid nodule. Intertwining of strands of spindle-shaped histioeytes. (H. and E. × 150)
Cervical and inguinal lymph nodes were enlarged. Both ulnar nerves were thickened. Acid-fast bacilli and globi were found in large number in nasal smears. B.I. was 4.4 and M.I. was 930/0. Lepromin, tuberculin, sporothrichin and Montenegro tests were negative. VDRL and FTA-ABS reactions were bogh negative. L. E. cells were not found, but latex and C-reactive protein were positive. WBC, t~BC, globular sedimentation rate and urinalysis were normal, as in the other cases. For a little more than one month, the patient received 900 mg. of Rifampiein daily, showing some flattening of the cutaneous nodules. On this occasion, his B.I. was 4.3 and M.I. was 390/0. AFB were absent from nasal smears.
Histopathology of the Lesions Several biopsies were t a k e n from our patients, most of t h e m showing the t y p i c a l features of histoid leprosy as described b y Wade. The specimens included b o t h c u t a n e o u s a n d s u b c u t a n e o u s nodules. The most striking feature of these lesions was the i n t e r t w i n i n g of cellular s t r a n d s composed b y spindle-shaped histiocytes, closely resembling fibrocy~es (Fig.4). I n some cases small a m o u n t s of collagen fibers were observed within the cellular whorls, best evidenced b y Mallory a n d V a n Gieson stainings. These features were more p r o m i n e n t in s u b c u t a n e o u s lesions a n d in the nodules with a deeply-seated dermal infiltrate. I n some of the superficial cutaneous lepromas, the histoid nodule was s u r r o u n d e d b y areas of o r d i n a r y lepromatous f o a m y cells (Fig. 5).
C. Bopp and L. Bakos
:Fig.5. Collagen band and foamy histioeytes in the upper dermis of a cutaneous histoid nodule. (H.-E. x 150) The collagen band of Unna was always spared, although extremely flattened in certain lesions, probably due to the upward growth of the infiltrate. This expansion also led to the formation of a pseudocapsule, by pushing aside the neighbouring connective tissue elements. This was more conspicuously seen in the deepest nodules, especially in the subcutaneous, being less evident in the superficial ones. On rare occasions, small nerve branches were found within the foamy cells surrounding the histoid nodule, although never within the spindle-shaped histiocytes. Acid-fast bacilli were always abundant in the active spindle-cell parenchyma, isolated or forming elongated clumps in these histiocytes. Typical globi formation was seen only in the ordinary lepromatous infiltrate. Most of the organisms were arranged following the largest axis of the elongated cells (Fig. 6). In most sections the bacilli were larger than those seen in the ordinary lepromas, but some variation in their size was evidenced according to the lesion. Clinically normal skin of all patients always showed small clumps of typical foamy cells around blood vessels and adnexa] structures, with regular amounts of organisms. A biopsy was taken from a small nodule formed at the site of a positive tuberculin test (Case 2), 18 days after the inoculation, evidencing a small granuloma with Langhans' giant cells, virtually free from bacilli (Fig. 7). A supra-clavicular lymph node from Case 3 showed massive sinusal infiltration by foamy cells, with a regular amount of acid-fast organisms.
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Fig. 6. Elongated clumps of bacilli in histoid nodule. (Ziehl-Nielsen × 600)
Fig.7. Case 2. Site of tuberculin test. Tuberculoid granuloma with Langhans' giant cell. (H.-E. × 150)
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C. Bopp and L. Bakes Comments
Among the polymorphous manifestations of lepromatous leprosy, Wade outlined the "histoid variety" with its own clinical, histological and evolutive features. The reports that followed the original article, although in partial agreement with the features there described, were not sufficiently uniform to be accepted unanimously. This is due to the fact that "pure" cases, that is, cases exactly similar to those described by Wade, are quite rare. Some authors solely point out the finding of histoid features in some forms of ordinary lepromatous leprosy. Other authors report "mixed" cases, that is, the association of both ]epromatous and borderline leprosy with histoid lesions. Therefore, further studies are necessary, in order to consolidate the nosologic validity of this variety. The features presented by our patients did not follow very closely the original description. Only one ease was a relapse, the other two being nonrelapsed ones. As already observed by Wade, in all cases the face did not show the typical leprotic infiltration of the earlobes and eyebrows. Subcutaneous nodules--rarely observed in ordinary ]epromatous cases--were located close to the joints, beneath an apparently normal skin. Cutaneous and subcutaneous nodules, the essential clinical features in histoid leprosy, were observed in all our patients. These lesions appeared as round or oval elevations, with a shiny surface, at times with an umbilicated centre, arising from an apparently normal skin. In all the eases, acid-fast bacilli were found in these areas of "healthy" skin, in contrast with the negative findings of Wade, under the same conditions. Apart from slight sensory impairment and lymph node involvement, no sign of other organ involvement was noticed. As in other reports, two of our patients developed resistance to treatment (Case 1 and 2), for after four years of regular treatment they were still bacteriologically positive, one of them even with clinical worsening. From Case 3, the patient treated with Rifampiein, no conclusions can be drawn from short-time observation. The peculiar resistance of the relapsed cases to specific drugs was demonstrated in part by Pettit et al., by inoculating DDS-resistant bacilli into the footpad of mice treated with Dapsone. Some of these bacilli proceeded from patients presenting lesions histologically resembling histoid lesions. Based on those findings, Rodriguez postulated a theory in which this clinical variety of leprosy--according to him never occurring in the presulfonic era or even in the first following decade--would be the result of the activity of a bacterial population composed of sulfone-resistant organisms, mutations from M. leprae, the "histoid bacilli". lie assumed that treatment with su]fone would destroy or at least inhibit multiplication of DDS-sensitive M. leprae, allowing the growth of that resistant strain. Histoid lesions, as seen in relapsed patients, would be the result of activity of hidden loci of "histoid bacilli", surviving destruction of drug-sensitive organisms, responsible for the ordinary lepromatous lesions.
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The varying proportions of mutant bacteria would be responsible for the different clinical manifestations and the varying degrees of infectivity of the host. Thus, being this histoid population of great proportions in the host, he could infect a healthy organism, giving origin to nonrelapscd cases. In Rodrlguez's relapsed histoid patients, treatment with sulfone neither promoted clinical improvement nor prevented the appearance of new lesions. In his nonrelapsing cases the histoid lepromas subsided after treatment, with improvement of other ]epromatous lesions. One of our patients underwent three episodes of acute ENL; this goes against Wade's observations but is an event already reported by other authors in histoid leprosy. Of particular interest in our cases was the finding of massive infection by ringworm of glabrous skin and fingernails, associated with tinea versicolor, in our Case 3. Histological features of our biopsies generally resembled Wade's findings. The intertwining of strands of spindle-shaped histioeytes was mostly observed in subcutaneous nodules, partially limited by a pseudoeapsule of connective tissue, formed by the expansion of the histoid ]eproma. The finding of foamy cells around the histoid infiltrate was not rare, especially in the most superficial lesions. Acid-fast bacilli were abundant, mostly arranged as elongated clumps in the spindle cells. Globi were found only within the foamy cell infiltrate. Case 2 had a strongly positive sporothrichin dermal test, whose area was biopsied 18 days afterwards, showing an ordinary infiltrate composed of foamy cells, intermingled with some lymphocytes, plasma cells, eosinophils and neutrophils. AFB were normally found. In the same patient, a biopsy was also done 18 days afterwards, in the area of a strongly positive tuberculin test, showing this time granulomas with Langhans' giant cells, lymphoeytes and a reduced number of organisms. This finding is as surprising as Wade's tuberculoid "contamination" of certain histoid lesions. The finding of these tuberculoid loci would lead us to admit the existence of some degree of resistence of the host, thus suggesting a good prognosis. This first impression, however, is destroyed by the well-known resistance to treatment of these cases, confirming the bad prognosis already stated by Wade. Another interesting pathological finding in our eases is the massive infiltration of lymph node sinuses by foamy cells, containing acid-fast bacilli. In the course of this review, a few patients whose clinical lesions resembled closely histoid ]epromas were observed, but whose histology, however, revealed only an ordinary foamy infiltrate, totally dispossessed of spindle cells. These eases, were obviously not included in this article because, in our opinion, the so-called "histoid variety" is a particular clinical and pathological variant of lepromatons leprosy, thus being identified only when the patient presents definite clinical features associated with characteristic histological and bacteriological findings. References 1. Jonqai~res, E. D. L. : Quoted in t~odriguez, J.N. (1969) The histoid leproma. Int. J. Leprosy 37, 1--21 (1964)
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2. Melamed, A. J.: Quoted in Rodrlguez, J. N. (1969) The histoid leproma. Int. J. Leprosy 37, 1--21 (1964) 3. Fereira, A. C., Jr. : Novas dimens5es da hansenlase Virchowiana. Thesis, l~io de Janeiro 1970 4. Pettit, J. H. S.: Studies on sulfone resistance in leprosy. Int. J. Leprosy 84, 375--390 (1966) 5. Price, E. W., Fitzherbert, H.: Histoid (high-resistance) lepromatous leprosy. Int. J. Leprosy 84, 367--374 (1966) 6. Rodriguez, J. N.: The histoid leproma. Int. J. Leprosy 87, 1--21 (1969) 7. S£nchez, J.: Quoted in godriguez, J. N. (1969). The histoid leproma. Inter. J. Leprosy 87, 1--21 (1965) 8. Wade, H. W.: The histoid variety of lepromatous leprosy. Int. J. Leprosy 81, 139--142 (1963) Profi Dr. C. Bopp Discipline of Dermatology Dept. of Internal Medicine, Federal Univ. of I~io Grande do Sul Porto Alegre 90000 Brazil
The Histoid Variety of Lepromatous Leprosy* Clovis Bopp and Lucio Bakos Discipline of Dermatology, Department of Internal Medicine Federal University of Rio Grande do Sul (Head: Professor Clovis Bopp) Porto Alegre (Brazil) Received August 1, 1974
Summary. Three cases of the so-called "histoid variety" of lepromatous leprosy are reported. This variety has definite clinical features, associated with characteristic histological and bacteriological findings. Some of the features presented by our patients are similar to those described originally by Wade, especially the resistance to treatment. Considering the discrepancies existing among the authors which studied the subject, our opinion is that further studies should be done in order to elucidate the controversial points. Zusammen/assung. Drei Patienten mit der sog. histiozyt~ren Sonderform der lepromatSsen Lepra werden besehrieben. Diese Sonderform zeichnet sich durch bestimmte klinische Symptome sowie charakteristisehe histologische und bakteriologische Befunde aus. Eine Reihe yon Symptomen, die wir bei unseren Patienten beobachteten, gleiehen den urspr~nglieh yon Wade beschriebenen Krankheitszeichen. Das gilt besonders auch hinsichtlich der Therapieresistenz. Die divergierenden Ansichten einzelner Autoren sollten Anla$ zu weiteren Untersuchungen sein. I n 1963, W a d e (8) described the histoid variety of lepromatous leprosy, whose most striking feature was the existence of lesions more closely resembling t u m o u r s composed of a single tissue of spindle-shaped cells rather t h a n the inflammatory granuloma of the ordinary leproma. This variety is most likely to occur in old cases which for years h a d progressed as ordinary lepromatous leprosy, already treated and clinically healed. Some of t h e m had even reached bacteriological negativity. At relapse, these cases presented v e r y peculiar clinical features such as: a) Well defined subcutaneous nodules of variable size, some of t h e m even reaching 5 cm in diameter; b) Cutaneous nodules, arising either from the upper dermis or from the " m i r g a t i o n " to the corium of the subcutaneous nodules. These lesions are elevated, pinkish or norma]-skin-coloured, p r o t u b e r a n t and even pedunculated, ranging from 0.2 to 2.0 cm in diameter. The hardness and the smooth and shiny surface of some of t h e m make t h e m similar to y o u n g keloids. T h e y would arise on an a p p a r e n t l y normal and bacteriologically negative skin, some of t h e m undergoing central necrosis, forming a crateriform ulceration; c) Strictly limited tuberous plaques, developing on points of pressure, especially the elbows or anywhere else. After W a d e ' s article, several authors reported cases in which the histoid lesions appeared "de novo", t h a t means, without a n y previous lesions or treatment, thus without the possibility of being relapsing cases. * Herrn Prof. Dr. H. GStz zum 60. Geburtstag gewidmet. i
Arch. Derm. Forsch., B4. 252
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According to Wade, the most characteristic histological features are found in young, active subcutaneous nodules, in which the intertwining of strands of spindle-shaped cells--histiocytes and not fibrocy~es--resemble closely some histiocytomas or nodular subepidermal fibrosis. They are usually surrounded by a pseudocapsule, derived from the expansile growth of the nodule and its pressure on the neighbouring connective tissue. The pseudocapsule and the spindle-shaped histiocytes would be seen less often in the cutaneous tubercles and plaques. While young subcutaneous lesions contain very few collagen fibers, these are seen in larger amounts in older ones, although never diffusely dispersed throughout the "parenchyma". Nerve branches were not seen inside the nodule, and: the author, in certain infrequent cases, observed "mixed" structures in wl~ich, in the same section, a typical histoid pattern was surrounded in part by an ordinary lepromatous granuloma. The absence of g]obus formation, according to the author, constitutes one of the most striking features in sections stained for acid-fast organisms, even though bacilli were present in considerable number, at times more abundant than in ordinary lepromas. They would be arranged following the long axis of the elongated histiocyte. I n size, the bacilli would be notably larger than those in the ordinary ]epromatous infiltrate. Wade also observed with certain frequency the occurrence of a "contamination" of some subcutaneous histoid nodules by rare and small tuberculoid foci within the lesion or in the encircling fibrous pseudocapsule, almost free from bacilli, in sharp contrast with their abundance in the surrounding histoid structures. According to him, such patients do not undergo the erythema nodosum leprosum type of reaction. Wade identified as histoid cases Figs.25 and 29 of the Atlas de Leprologia of Orestes ])iniz. The publication of his article was followed by the papers of Melamed (2) and Jonqui~res (1), from Argentina, S~nchez (7) from Mexico, Pettit et al. (4) from Malaysia and Price and Pitzherbert (5) from Abyssinia. l~odrigucz (6), from the Philippines, observed 28 relapsing patients presenting histoid lesions added with 7 nonrelapsing ones, in which the nodules appeared primitively, without any previous treatment. Pereira Junior (3), in his thesis (1970), presents four more cases of histoid leprosy, doing a critical study of this variety.
Case Reports Case i. (L. V. L.) Male, caucasian, aged 45 years, farmer. This patient had been under treatment since 1960 with I)DS and diphenyl-thiourea for a maeular form of lepromatous leprosy, obtaining clinical negativity. In March, 1970, still under treatment, he relapsed and was admitted to the hospital, presenting generalized tuberous lesions, with a smooth and shiny surface, located mostly on the trunk but also on the limbs (Fig. 1). Cutaneous plaques were also found, formed by the confluence of these lesions. Some subcutaneous nodules were seen near the joints. All these lesions were arising from apparently normal skin. Anaesthesia was found only in the hands, both presenting claw fingers. Wasting of thenar, hypothenar and intrinsic muscles was seen on the right hand. Both ulnar nerves were thickened. The face was normal, without infiltration or madarosis. The nasal septum was perforated.
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Fig. 1. Case 1 (L. V. L.) Cutaneous nodules, arismg from apparently normal skin
Acid-fast bacilli and globi w e r e found in smears from the nasal mucosa, from the lesions and from the clinically normal surrounding skin. Laboratory investigation showed normal V D R L test, WBC, RBC, serum proteins, sedimentation rate and urinalysis. Latex, C-reactive protein a n d L. E. cell preparations were negative. Lepromin, tuberculin and Montenegro tests were also negative. Since his admission, the patient has been regularly treated for the last four years with alternate series of DDS, Clofazimine, Doxicycline and diphenyl-thiourea, with periods of improvement and relapse. Upon last examination, the lesions were markedly worsened and the face was infiltrated. Skin smears were repeatedly positive for acid-fast bacilli and his last M.I. was 80/o. Case 2. (V. J. O.) Male, mulatto, aged 37 years, farmer. His disease started in 1968 with progressive numbness of hands a n d feet and swelling of the lower limbs. Three months prior to consultation he noticed the growing of several nodular lesions on the face and limbs. On examination (June, 1970), several papular and nodular lesions, arising from normal skin, could be observed on the forehead, left cheek, neck, b o t h shoulders, upper limbs, right lumbar region, buttocks a n d thighs. A plaque of 3 cm in diameter was formed on the cheek by the confluence of a few nodules (Fig.2). Infiltration on the face and madarosis were absent. Three nodular subcutaneous lesions were observed on the left arm (Fig. 3), the largest one measuring 3 cm in diameter. The patient h a d sensory impairment of pain and t e m p e r a t u r e in b o t h legs, right forearm a n d left foot. As in case 1, A F B a n d globi were also found in nasal scrapings a n d in smears from b o t h the histoid lesions and the surrounding skin. A positive tuberculin test (1 : 1000) was observed, showing a papule with 13 m m of induration. Sporothrichin a n d eandidin intradermM tests were b o t h positive, b u t lepromin and Montenegro tests were negative. V D R L reaction, latex, L. E. cell preparations a n d C-reactive protein were negative. Sedimentation rate, WBC, RBC, serum proteins and urinalysis were normal. I n four years of regular treatment, the patient received successively Promin, diphenylthiourea, DDS and Clofazimine. He underwent two reactional episodes of e r y t h e m a nodosum leprosum and one episode of e r y t h e m a multiforme. A t the last clinical examination, the histoid lesion were markedly improved. Nasal smears were negative, although skin sites remained positive, with a B. I. of 1.5 and a M.I. of 0. 1"
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Fig.2. Case 2 (V. J. 0.) Nodular lesions of the face, forming a plaque on left cheek. Note absence of infiltration or madarosis
Fig. 3. Case 2 (V. J. 0.) Subcutaneous nodular lesion
Case 3. (F. W. 1~.) Male, caucasian, aged 34 years. His disease started in 1973 with nodules on the left leg, in association with numbness of the hands and feet. At the first consultation, the patient showed a large number of solid nodular lesions, pink or dull-red coloured, of various sizes, at times pedunculated, dispersed throughout the integument, including the scrotum, but in larger number on the upper limbs and buttocks, arising from apparently normal skin. Subcutaneous lesions were palpable on the arms and thighs. Of particular interest in this patient was the association of histoid leprosy with widespread lesions of "tinea corporis", "tinea versicolor" and almost complete destruction of the nails of both hands by ringworm infection.
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Fig. 4. Subcutaneous histoid nodule. Intertwining of strands of spindle-shaped histioeytes. (H. and E. × 150)
Cervical and inguinal lymph nodes were enlarged. Both ulnar nerves were thickened. Acid-fast bacilli and globi were found in large number in nasal smears. B.I. was 4.4 and M.I. was 930/0. Lepromin, tuberculin, sporothrichin and Montenegro tests were negative. VDRL and FTA-ABS reactions were bogh negative. L. E. cells were not found, but latex and C-reactive protein were positive. WBC, t~BC, globular sedimentation rate and urinalysis were normal, as in the other cases. For a little more than one month, the patient received 900 mg. of Rifampiein daily, showing some flattening of the cutaneous nodules. On this occasion, his B.I. was 4.3 and M.I. was 390/0. AFB were absent from nasal smears.
Histopathology of the Lesions Several biopsies were t a k e n from our patients, most of t h e m showing the t y p i c a l features of histoid leprosy as described b y Wade. The specimens included b o t h c u t a n e o u s a n d s u b c u t a n e o u s nodules. The most striking feature of these lesions was the i n t e r t w i n i n g of cellular s t r a n d s composed b y spindle-shaped histiocytes, closely resembling fibrocy~es (Fig.4). I n some cases small a m o u n t s of collagen fibers were observed within the cellular whorls, best evidenced b y Mallory a n d V a n Gieson stainings. These features were more p r o m i n e n t in s u b c u t a n e o u s lesions a n d in the nodules with a deeply-seated dermal infiltrate. I n some of the superficial cutaneous lepromas, the histoid nodule was s u r r o u n d e d b y areas of o r d i n a r y lepromatous f o a m y cells (Fig. 5).
C. Bopp and L. Bakos
:Fig.5. Collagen band and foamy histioeytes in the upper dermis of a cutaneous histoid nodule. (H.-E. x 150) The collagen band of Unna was always spared, although extremely flattened in certain lesions, probably due to the upward growth of the infiltrate. This expansion also led to the formation of a pseudocapsule, by pushing aside the neighbouring connective tissue elements. This was more conspicuously seen in the deepest nodules, especially in the subcutaneous, being less evident in the superficial ones. On rare occasions, small nerve branches were found within the foamy cells surrounding the histoid nodule, although never within the spindle-shaped histiocytes. Acid-fast bacilli were always abundant in the active spindle-cell parenchyma, isolated or forming elongated clumps in these histiocytes. Typical globi formation was seen only in the ordinary lepromatous infiltrate. Most of the organisms were arranged following the largest axis of the elongated cells (Fig. 6). In most sections the bacilli were larger than those seen in the ordinary lepromas, but some variation in their size was evidenced according to the lesion. Clinically normal skin of all patients always showed small clumps of typical foamy cells around blood vessels and adnexa] structures, with regular amounts of organisms. A biopsy was taken from a small nodule formed at the site of a positive tuberculin test (Case 2), 18 days after the inoculation, evidencing a small granuloma with Langhans' giant cells, virtually free from bacilli (Fig. 7). A supra-clavicular lymph node from Case 3 showed massive sinusal infiltration by foamy cells, with a regular amount of acid-fast organisms.
Histoid Variety of Lepromatous Leprosy
7
Fig. 6. Elongated clumps of bacilli in histoid nodule. (Ziehl-Nielsen × 600)
Fig.7. Case 2. Site of tuberculin test. Tuberculoid granuloma with Langhans' giant cell. (H.-E. × 150)
8
C. Bopp and L. Bakes Comments
Among the polymorphous manifestations of lepromatous leprosy, Wade outlined the "histoid variety" with its own clinical, histological and evolutive features. The reports that followed the original article, although in partial agreement with the features there described, were not sufficiently uniform to be accepted unanimously. This is due to the fact that "pure" cases, that is, cases exactly similar to those described by Wade, are quite rare. Some authors solely point out the finding of histoid features in some forms of ordinary lepromatous leprosy. Other authors report "mixed" cases, that is, the association of both ]epromatous and borderline leprosy with histoid lesions. Therefore, further studies are necessary, in order to consolidate the nosologic validity of this variety. The features presented by our patients did not follow very closely the original description. Only one ease was a relapse, the other two being nonrelapsed ones. As already observed by Wade, in all cases the face did not show the typical leprotic infiltration of the earlobes and eyebrows. Subcutaneous nodules--rarely observed in ordinary ]epromatous cases--were located close to the joints, beneath an apparently normal skin. Cutaneous and subcutaneous nodules, the essential clinical features in histoid leprosy, were observed in all our patients. These lesions appeared as round or oval elevations, with a shiny surface, at times with an umbilicated centre, arising from an apparently normal skin. In all the eases, acid-fast bacilli were found in these areas of "healthy" skin, in contrast with the negative findings of Wade, under the same conditions. Apart from slight sensory impairment and lymph node involvement, no sign of other organ involvement was noticed. As in other reports, two of our patients developed resistance to treatment (Case 1 and 2), for after four years of regular treatment they were still bacteriologically positive, one of them even with clinical worsening. From Case 3, the patient treated with Rifampiein, no conclusions can be drawn from short-time observation. The peculiar resistance of the relapsed cases to specific drugs was demonstrated in part by Pettit et al., by inoculating DDS-resistant bacilli into the footpad of mice treated with Dapsone. Some of these bacilli proceeded from patients presenting lesions histologically resembling histoid lesions. Based on those findings, Rodriguez postulated a theory in which this clinical variety of leprosy--according to him never occurring in the presulfonic era or even in the first following decade--would be the result of the activity of a bacterial population composed of sulfone-resistant organisms, mutations from M. leprae, the "histoid bacilli". lie assumed that treatment with su]fone would destroy or at least inhibit multiplication of DDS-sensitive M. leprae, allowing the growth of that resistant strain. Histoid lesions, as seen in relapsed patients, would be the result of activity of hidden loci of "histoid bacilli", surviving destruction of drug-sensitive organisms, responsible for the ordinary lepromatous lesions.
Histoid Variety of Lepromatous Leprosy
9
The varying proportions of mutant bacteria would be responsible for the different clinical manifestations and the varying degrees of infectivity of the host. Thus, being this histoid population of great proportions in the host, he could infect a healthy organism, giving origin to nonrelapscd cases. In Rodrlguez's relapsed histoid patients, treatment with sulfone neither promoted clinical improvement nor prevented the appearance of new lesions. In his nonrelapsing cases the histoid lepromas subsided after treatment, with improvement of other ]epromatous lesions. One of our patients underwent three episodes of acute ENL; this goes against Wade's observations but is an event already reported by other authors in histoid leprosy. Of particular interest in our cases was the finding of massive infection by ringworm of glabrous skin and fingernails, associated with tinea versicolor, in our Case 3. Histological features of our biopsies generally resembled Wade's findings. The intertwining of strands of spindle-shaped histioeytes was mostly observed in subcutaneous nodules, partially limited by a pseudoeapsule of connective tissue, formed by the expansion of the histoid ]eproma. The finding of foamy cells around the histoid infiltrate was not rare, especially in the most superficial lesions. Acid-fast bacilli were abundant, mostly arranged as elongated clumps in the spindle cells. Globi were found only within the foamy cell infiltrate. Case 2 had a strongly positive sporothrichin dermal test, whose area was biopsied 18 days afterwards, showing an ordinary infiltrate composed of foamy cells, intermingled with some lymphocytes, plasma cells, eosinophils and neutrophils. AFB were normally found. In the same patient, a biopsy was also done 18 days afterwards, in the area of a strongly positive tuberculin test, showing this time granulomas with Langhans' giant cells, lymphoeytes and a reduced number of organisms. This finding is as surprising as Wade's tuberculoid "contamination" of certain histoid lesions. The finding of these tuberculoid loci would lead us to admit the existence of some degree of resistence of the host, thus suggesting a good prognosis. This first impression, however, is destroyed by the well-known resistance to treatment of these cases, confirming the bad prognosis already stated by Wade. Another interesting pathological finding in our eases is the massive infiltration of lymph node sinuses by foamy cells, containing acid-fast bacilli. In the course of this review, a few patients whose clinical lesions resembled closely histoid ]epromas were observed, but whose histology, however, revealed only an ordinary foamy infiltrate, totally dispossessed of spindle cells. These eases, were obviously not included in this article because, in our opinion, the so-called "histoid variety" is a particular clinical and pathological variant of lepromatons leprosy, thus being identified only when the patient presents definite clinical features associated with characteristic histological and bacteriological findings. References 1. Jonqai~res, E. D. L. : Quoted in t~odriguez, J.N. (1969) The histoid leproma. Int. J. Leprosy 37, 1--21 (1964)
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2. Melamed, A. J.: Quoted in Rodrlguez, J. N. (1969) The histoid leproma. Int. J. Leprosy 37, 1--21 (1964) 3. Fereira, A. C., Jr. : Novas dimens5es da hansenlase Virchowiana. Thesis, l~io de Janeiro 1970 4. Pettit, J. H. S.: Studies on sulfone resistance in leprosy. Int. J. Leprosy 84, 375--390 (1966) 5. Price, E. W., Fitzherbert, H.: Histoid (high-resistance) lepromatous leprosy. Int. J. Leprosy 84, 367--374 (1966) 6. Rodriguez, J. N.: The histoid leproma. Int. J. Leprosy 87, 1--21 (1969) 7. S£nchez, J.: Quoted in godriguez, J. N. (1969). The histoid leproma. Inter. J. Leprosy 87, 1--21 (1965) 8. Wade, H. W.: The histoid variety of lepromatous leprosy. Int. J. Leprosy 81, 139--142 (1963) Profi Dr. C. Bopp Discipline of Dermatology Dept. of Internal Medicine, Federal Univ. of I~io Grande do Sul Porto Alegre 90000 Brazil
