diffuse leprosy of lucio and latapı´: a histologic study · diffuse leprosy of lucio and...

Diffuse leprosy of Lucio and Latapı: a histologic

study

FRANCISCO VARGAS-OCAMPO

Instituto de Diagnostico y Referencia Epidemiologicos (InDRE).

Mexico, D.F., Mexico

Accepted for publication 28 August 2007

Summary

Background and purpose Ladislao de la Pascua described the spotted or lazarine

leprosy for first time in 1844. Later on, Lucio and Alvarado studied and published it with

the same names in 1852. Latapı re-discovered it in 1938 and reported it as ‘Spotted’

leprosy of Lucio in 1948. Frenken named it diffuse leprosy of Lucio and Latapı in 1963.

Latapı and Chevez-Zamora explained that the fundamental condition of this variety of

leprosy was a diffuse generalised cutaneous infiltration, naming it pure and primitive

diffuse lepromatosis, upon which necrotising lesions develop, calling these lesions

Fenomeno de Lucio or erythema necrotisans. A great number of histopathological

reports have addressed the study of Lucio’s phenomenon, and few about the histologic

changes that take place in the course of diffuse lepromatous leprosy. The purpose of this

work is to report the histologic findings observed in the study of l70 cutaneous biopsies

of diffuse leprosy of Lucio and Latapı and 30 of Lucio’s phenomenon.

Methods This is a retrospective study, which included the examination of 200 biopsy

skin specimens from 199 patients with diffuse leprosy at different course of the

disease. These cases were diagnosed in Mexico from 1970 to 2004.

Results The histologic examination revealed a vascular pattern affecting all cutaneous

vessels, characterised by five outstanding features: a) colonisation of endothelial cells

by acid-fast bacilli, b) endothelial proliferation and marked thickening of vessel walls

to the point of obliteration, c) angiogenesis, d) vascular ectasia, and e) thrombosis.

Necrotising lesions seen in diffuse lepromatous leprosy displayed two

histopathological patterns: one of them, non-inflammatory occlusive vasculopathy

and, the other one, occlusive vasculopathy, leukocytoclastic vasculitis, large

neutrophilic infiltrate and lobular panniculitis. The first appeared as a result of the

course of the occlusive vasculopathy produced by the colonisation of endothelial cells

by Mycobacterium leprae. The second, as a result of a previous occlusive vasculopathy

plus a leprosy reaction which is considered here as variant of ENL.

Conclusions Endothelial cell injury appears to be the main event in the pathogenesis

of diffuse leprosy of Lucio and Latapı. Once M. leprae has entered the endothelial

cell, the micro-organism damages the blood vessels, leading to the specific changes

seen in this variety of lepromatous leprosy.

Correspondence to: F. Vargas-Ocampo, Laboratorio de dermatopatologıa, InDRE Carpio 470, Mexico, D.F.,11340. Mexico (e-mail: [email protected])

Lepr Rev (2007) 78, 248–260

0305-7518//064053+13 $1.00 q Lepra 248

Introduction

In 1844, Ladislao de la Pascua, when Director of the ‘Hospital de los Lazarinos’ in Mexico

City, described three clinical forms of leprosy, tuberculous (nodular), anaesthetic and a third

characterised by the production of painful red spots that went on to ulcerate. These patients

were known in Mexico as ‘Lazarinos’.1 Later on, Rafael Lucio, in collaboration with Ignacio

Alvarado, published in 1852 a paper entitled ‘Opusculo de la Enfermedad de San Lazaro o

Elefanciasis de los Griegos’,2 in which Lucio described his observations, made during 8 years

at the same ‘Hospital de los Lazarinos’ in Mexico City, of which he was Director after de la

Pascua. He also distinguished three clinical forms of leprosy: tuberculous (nodular),

anaesthetic, and spotted (manchada), and paid special attention to the spotty form,

characterised by the presence of red and painful spots undergoing necrosis, and which was

striking because the skin underwent characteristic changes according to the stage of the

condition. This landmark paper by Lucio and Alvarado was gradually forgotten and this

variety of leprosy was completely unknown among leprologists outside Mexico until Latapı

and Chevez-Zamora3 brought it to attention at the 5th International Congress of Leprosy held

in Havana in 1948. That the authors explained that the underlying condition of this clinical

form, unnoticed by Lucio and Alvarado, was generalised diffuse cutaneous infiltration, which

Latapı and Chevez-Zamora named ‘pure and primitive diffuse lepromatosis’, upon which

secondary cutaneous outbreaks developed. These outbreaks were regarded as a form of lepra

reaction produced by multiple, acute, necrotising vasculitis for which Latapı proposed the

name of ‘Fenomeno de Lucio or erythema necrotisans’. Before Latapı and Chevez-Zamora’s

report, Martinez Baez had studied spotted lesions of five patients in 1941,1,3 – 6,20 noting the

basic lepromatous structure, acute vasculitis with nuclear dust, and thickening and occlusion

of the larger vessels producing necrosis. He described for the first time the histological

changes that occurred in what Latapı would later name Lucio’s phenomenon.

About 1943, Latapı distinguished the pure and primitive diffuse leprosy that always

begins as diffuse leprosy, and the secondary diffuse leprosy, which arises from an

indeterminate form; both display the same clinical aspect and the same histologic changes

during their course.5,7 In 1963, Frenken included both under the name of diffuse leprosy of

Lucio and Latapı, having as fundamental characteristic, that the generalised infiltration never

develops nodules.1,5,7

Diffuse leprosy of Lucio and Latapı is characterised by a diffuse cutaneous infiltration,

without nodules, succulent or atrophic according to the stage of progression. Dysesthesia,

anhidrosis, alopecia, destructive rhinitis and telangiectasia, and a special variant of lepra

reaction named Lucio’s phenomenon or erythema necrotisans (erythema necroticans).

Histologically it has been reported that the finding of heavy endothelial parasitisation by

Mycobacterium leprae is a peculiar feature to diffuse leprosy.4,5,8 – 12

Lucio’s phenomenon is clinically characterised by crops of wine-red irregular spots

(manchas) with burning sensation, sharply delineated, and capricious centre, which turn

purpuric and become necrotic leaving atrophic stellar scars. Histopathologically Lucio’s

phenomenon has been reported to have two types of patterns. One of them involves

leukocytoclastic vasculitis as the underlying pathologic change,5,13,14 and the other,

endothelial cell proliferation, thrombosis, a mild mononuclear cell infiltrate and ischemic

necrosis.15,16 The first pattern is thought to be due to an immune complex disease caused by

leprae or skin antigens.17 In the second pattern, vascular damage is thought to be due to direct

invasion of M. leprae.15,16

Diffuse leprosy of Lucio and Latapı 249

Diffuse leprosy is considered to be the most anergic of the all-immunological spectrum of

leprosy.18 In a study on lepromin responsiveness, Leiker reported that not all lepromatous

patients are completely anergic to lepromin, as a weak response to lepromin had been

observed in many such cases and it seemed that the diffuse lepromatous variety was the only

truly anergic type of leprosy.19 Lucio and other authors believed that this variety of the

disease was exclusive to Mexico. Yet it is found not only in Mexico, but also in other

countries.8,13,21 – 24 The purpose of this study is to describe histological changes seen in 170

cutaneous biopsies of diffuse leprosy of Lucio and Latapı and 30 of Lucio’s phenomenon.

Materials and methods

This is a retrospective study, which included the examination of 200 biopsy specimens of

diffuse leprosy of Lucio and Latapı obtained from 199 patients. In one patient two biopsy

specimens were taken, one was from infiltrated skin and other from a necrotic skin lesion. The

cases were diagnosed between 1970 and 2004 at the Laboratory of Dermatopathology of the

Institute for Epidemiologic Diagnosis and Reference (InDRE) in Mexico City. Twenty-six

cases were from the archive of the InDRE; 174, were included in a previous report by the

National Leprosy Control Programme.25 Biopsies selected for this study were those that were

taken from patients who had two or more physical signs of diffuse lepromatous leprosy

without nodules (DLL). The clinical data were obtained from the histology request forms.

Specimens were dispatched in glass or plastic vials containing 10% formalin solution from

different provinces of the country to the InDRE in Mexico City where all histological

processing was carried out. Specimens were processed routinely and stained with

haematoxylin and eosin; the first 125 specimens with Fite-Faraco stain, and the other 75

specimens with a modified Fite-Faraco stain using carbol-fuchsin solution to stain acid-fast

bacilli, Weigert’s iron haematoxylin to stain nuclei, and metanil yellow solution to stain other

tissue elements.26 The leprosy programme uses the Madrid classification,27 which considers

two polar types: lepromatous and tuberculoid; and two groups: indeterminate and

dimorphous. This classification does not include the variety diffuse lepromatous leprosy.

Results

The series was composed of 128 males and 71 females, with a male to female ratio 1·8:1; the

ages ranged from 12 to 88 years, with a median age of 37 years and an average of 28.8 years.

The elapsed time from the appearance of the first sign or symptom referable to leprosy ranged

from 1 week to 12 years, with a median of 3 years and an average of 4.2 years. Out of the 200

cases, 181 (90·5%) were from Pacific Coast states of Mexico and 19 (9·5%) from other states

of Mexico.

The biopsy specimens were obtained at different times in the course of the illness, and

included those that showed apparently normal skin and those with necrotising lesions; 170

were from patients with diffuse leprosy without necrotising lesions, and 30 were from patients

with diffuse leprosy with Lucio’s phenomenon. All patients had physical signs of DLL),

mainly diffuse infiltration of the skin, impairment of sensation (numbness of the dorsal aspects

of the extremities, hypaesthesia, or aesthesia), alopecia of eyebrows and eyelashes, anhidrosis,

and destructive rhinitis. All the biopsy specimens were obtained from skin with sensory

F. Vargas-Ocampo250

impairment associated with another or other physical signs of DLL: 32 from apparently normal

skin, 82 from skin with diffuse infiltration, 13 from atrophic skin, 9 from hypochromic macules,

7 from erythematous macules, and 30 from skin with Lucio’s phenomenon, data on 27 cases

were missing. Biopsy sites were: 141 from the limbs, 33 from the ear lobe, 12 from the trunk,

data on 14 cases were missing. As the clinical diagnosis made by physicians of the control

programme did not include diffuse leprosy, 86 of the request forms for histological study only

had the clinical diagnosis ‘lepromatous’. Nonetheless, 62 had the clinical diagnosis of DLL and

8 the clinical diagnosis of pure and primitive diffuse lepromatosis (PPDL), because, these

specific diagnoses were made by physicians with several years working in the programme.

There were other clinical diagnoses: 7 of indeterminate leprosy, 4 of dimorphous leprosy 1 of

tuberculoid leprosy, 30 of Lucio phenomenon, and 2 were without clinical diagnosis. The

physical signs of leprosy reported by medical staff in the request forms for histological exam,

apart from the lesions of Lucio’s phenomenon, correspond closely with DLL, thus, none of the

199 patients had nodular lesions. The 199 (100%) presented impairment of sensation

(hypaesthesia or anaesthesia or numbness of the extremities), 132 diffuse cutaneous infiltration

with absence of nodules, 36 apparently normal skin, 15 atrophic skin, 9 hypochromic macules,

7 erythematous macules, 87 anhidrosis, 126 alopecia of eyebrows, and 63 destructive rhinitis.

The histopathological features were divided into five stages: (1) early, (2) bacillary

dissemination, (3) well-developed, (4) necrosis by vascular occlusion and (5) necrosis by

vascular occlusion plus leprosy reaction. The changes observed during these different

histologic stages are described below.

STAGE 1 . EARLY

Fifty-three biopsies comprised 33 males and 20 females (M:F ratio 1·7:1), age range 15 to 88

years, (median 43 years and mean 43). The delay from the appearance of the first sign referable

to leprosy was 2 months to 17 years (median 1 year, mean 1.4 years). The skin where the

specimens were taken was: diffuse infiltration 36, apparently normal with dysesthesia 3,

atrophic 2, hypocromic macule 1, erythematous macule 2, no information 9. Biopsy sites were:

inferior extremity 18, upper extremity 19, thorax 4, and ear lobe 9, no information 3.

Histology

Blood vessels looked dilated with a thick wall lined with normal or plump proliferative

endothelial cells. Slight and apparently insignificant foci of infiltration were present in the

dermis, arranged around dilated blood vessels. Very scarce bacilli could be observed in the

endothelial cells in few of the large vessels and in some nerve trunks of the deep dermis.

STAGE 2 . BACILLARY DISSEMINATION

Sixty-two biopsies comprised 32 males and 30 females (M:F ratio 1·1:1; the age range 15

years to 85 years, (median 39 years). The delay from the appearance of the first sign referable

to leprosy ranged from 1 month to 22 years (median 3 years, mean 3.4 years). The skin where

the specimens were taken were: diffuse infiltration 34, dysesthesia, anhidrosis and alopecia 5,

atrophic 5, hypochromic macule 7, erythematous macule 3, no information 8. The biopsy

sites were: inferior extremity 20, upper extremity 22, thorax 2, abdomen 1, ear lobe 13, no

information 4.


Histology

Dissemination of acid-fast-bacilli (AFB) extended progressively from the deep plexus to all

cutaneous blood vessels, first, into the blood vessels of the subcutis and reticular dermis; then

to vessels of the superficial plexus; and finally to capillaries of the papillary dermis. The

vessels showed acid-fast bacilli inside swollen endothelial cells, thrombosis, passive

congestion and ectasia. The lumen of the large vessels was reduced in size by intimal

proliferative thickening. Small infiltrates of mononuclear cells were arranged around blood

vessels of the dermis and subcutaneous fat tissue.

STAGE 3 . WELL-DEVELOPED

Fifty-five biopsies comprised 34 males and 21 females, M:F ratio 1·6:1; age range 12 years to

77 years, (median 28 years, mean 34·6. The delay from the appearance of the first sign

referable to leprosy ranged from 4 months to 20 years (median 2 years, mean 3.4 years). The

skin where the specimens were taken were: diffuse infiltration 29, dysesthesia, anhidrosis and

alopecia) 7, atrophic skin with dysesthesia, anhidrosis and alopecia 6, hypocromic macule 1,

erythematous macule 2, no information 10. Biopsy sites were: inferior extremity 26, upper

extremity 9, thorax 5, ear lobe 7, no information 8.

Histology

Well-developed lesions were characterised by vascular ectasia, focal passive congestion,

thrombi and an increase in capillaries. The blood vessels of the dermis and the subcutis

showed a swollen and prominent endothelium, thick wall and narrowed or obliterated lumen

(Figure 1A).

The infiltrate, which was composed of lymphocytes and macrophages, was slight, in the

dermis cuffing the blood vessels (Figure 1A), and in the subcutis invading the subcutaneous

fat. Variable numbers of Virchow cells were diffusely distributed around blood vessels in the

dermis and subcutaneous fat. Acid-fast staining showed bacilli in the perivascular

inflammatory infiltrate (Figure 1B) and, in the most cases within one or more of the

endothelial cells of the cutaneous blood vessels (Figures 1C–1E).

STAGE 4 . ISCHAEMIC NECROSIS DUE TO NON-INFLAMMATORY VASCULAR

OCCLUSION

Eight biopsies comprised 6 males and 2 females, M:F ratio 3:1; age range 29 years to 67

years, (median 38 years mean 3.1 years). The delay from the appearance of the first sign

referable to leprosy ranged from 6 days to 14 years (median 2 years, mean 3.1 years). All had

necrotic lesions of the skin, from which the specimens were taken. Biopsy sites were: inferior

extremity 2, upper extremity 3, and abdomen 1, no information 2.

Histology

The main feature in this fourth stage was a severe damage of blood vessels. The presence of

M. leprae in endothelial cells seemed responsible for this change. Histological appearance

was characterised by necrosis of epidermis and superficial dermis, angiogenesis, ectasia,

F. Vargas-Ocampo252

passive venous congestion and vascular occlusion caused by luminal thrombi and/or by

thickening of the vessel wall. Angiogenesis, ectasia, passive venous congestion, and luminal

thrombi were most evident in superficial dermis (Figures 2B, 2C, 3F) and in middle dermis

(Figure 2A).

Thickening of vessel wall with reduction of the lumen and sometimes with obliteration

was seen in vessels of the dermis (Figures 3B-3E) and of the subcutis (Figure 3A). The

inflammatory infiltrate and the presence of bacilli were similar to that of the previous third

stage.

STAGE 5 . ISCHAEMIC NECROSIS DUE TO INFLAMMATORY VASCULAR OCCLUSION

PLUS LEPROSY REACTION

Twenty-two biopsies comprised 9 males and 13 females, M:F ratio of 1:1·4; age range 12

years to 75 years, (median 39 years, mean 7.8 years). Delay from the appearance of the first

sign referable to leprosy ranged from 3 months to 28 years (median 3 years, mean 7.8 years).

All had necrotic lesions of the skin, from which the specimens were taken. The part of the

body where the biopsies specimens were taken was: inferior extremity 9, upper extremity 11,

no information 2.

Figure 1. Each section is from a different third stage case. 1A) shows a large and thick subcutaneous blood vessel,and in the dermis, thin perivascular inflammatory cuffs with a streak-like appearance. 1B) A band of inflammatoryinfiltrate is composed of mononuclear cells, without foam cells, containing numerous bacilli. Two capillaries intransverse section with bacilli (ca) can be seen. 1C–1E) shows high power views of blood vessels with numerousbacilli in endothelial cells and absence of infiltrated inflammatory, (1C) in superficial dermis, 1D) in mid dermis, and1E) in deep dermis (1A. H&E; £ 35, 1B. Fite-Faraco; X400, !C-1E. Fite-Faraco; £ 1000).


Histology

This fifth stage showed changes superimposed on the pre-existing occlusive vascular damage.

They included necrosis of epidermis (Figure 4B) and superficial dermis, hyalinisation and/or

deposits of fibrin in small blood vessel walls of the dermis and the subcutaneous fat tissue.

(Figures 4A–4E).

The cellular infiltrate around these vessels consisted of neutrophils, nuclear dust, a few

eosinophils, lymphocytes, and in rare cases red blood cells. Large vessels in the deeper

reticular dermis and in the subcutis showed pronounced thickening and intimal proliferation

causing reduction in vascular lumen and sometimes complete occlusion; their wall was

infiltrated by neutrophils and lymphocytes (Figure 4E). In addition, a dense predominantly

neutrophil infiltrate was seen involving the deeper dermis and the lobular portion of the

Figure 2. 2A) third stage lesion, showing a blood vessel distended by thrombus. 2B) this is a transition lesion betweenthird and fourth stages. The epidermis appears stretched and thinned with pyknotic malpighian cells. In thedermis, beneath of epidermis, thrombi (T) occlude the lumina of some superficial capillaries; there is noinflammatory infiltrate. 2C) from a lesion in fourth stage. This superficial lesion shows loss of epidermis, thrombosisand congestion of capillaries papillae Note the absence of inflammatory cells. This lesion heals “restitutio adintegrum”. 2D) from a case in fourth stage, exhibits loss of tissue that includes the epidermis and some superficialdermis, and a superficial vessel occluded by an amorphous homogeneous and acidophilic substance. (2A. H&E;£ 100, 2B–2D. H&E; £ 250).

F. Vargas-Ocampo254

subcutaneous fat tissue as a lobular panniculitis. In one case there was a granulomatous

reaction within and around a large blood vessel of the subcutis.

CHANGES FOUND IN OTHER STRUCTURES OF THE SKIN

AFB were found not only in blood vessels, but also in lymph vessels, nerves, hair follicles,

erector pili muscles, sebaceous glands, sweat glands, and in a few cases in the different layers

of the epidermis (Table 1).

Usually, bacilli were more abundant in sections of the biopsy specimens taken from the

ear lobe. Nerves and epidermal appendages showed different degrees of invasion,

degeneration and destruction by the inflammatory infiltrate, these changes being more

noticeable in the ischaemic tissue necrosis stages.

Discussion

Histopathologically, five stages of DLL were considered in this study, each of them having

different features. When the clinical data are correlated with the histological changes, the

three first stages, early, disseminated, and well-developed, correspond to the phase in which

patients have diffuse infiltration of entire skin The fourth and fifth stages of ischaemic

necrosis correspond to Lucio’s phenomenon or erythema necroticans. Endothelial cells seem

to be the main targets of the organism, and following invasion of M. leprae vascular damage

Figure 3. 3A) from a biopsy of a third stage lesion, showing a large vein in the subcutis with very thick wall, lumenalmost occluded and bacilli within endothelial cells. There is no inflammatory infiltrate. (3B–3D) three illustrationsfrom different third stage cases. They show vessels in the reticular dermis with prominent endothelial proliferationand numerous bacilli within a small (L in 3B) or obliterated vascular lumen. 3E) from fourth stage biopsy, shows ablood vessel occluded by extensive intimal proliferation and dermal necrosis. 3F) another example from a fourthstage lesion, exhibits superficial necrosis with loss of epidermis, obliterative changes of two superficial blood vesselswith homogenization and hyalinization of their walls. (3A. Fite-Faraco stain; £ 250, 3B–3D. Fite-Faraco stain; £1000, 3E. H&E; £ 250, 3F. H&E; £ 400).


Figure 4. All sections are from a fifth stage case. 4A) shows necrosis of the epidermis, leukocytoclastic vasculitis insmall blood vessels of the dermis and subcutis. In the lower left is an almost occluded blood vessel infiltrated byinflammatory cells. 4B) necrosis of the epidermis and leukocytoclastic vasculitis. 4C) leukocytclastic vasculitis in theupper dermis. 4D) This illustration shows two small vessels, in the lower dermis, stained acidophillicaly (v) andsurrounded by inflammatory infiltrate composed largely by neutrophils mixed with mononuclear cells. 4E)leukocytoclastic vasculitis in the subcutis. 4F) the subcutaneous blood vessel seen in 4A, shows endothelialproliferation and heavy infiltration by neutrophils, lymphocytes and histiocytes. (4A. H&E; £ 35, 4B. H&E; £ 160,4C. H&E; £ 400, 4D. H&E; £ 160, 4E. H&E; £ 400, 4F. H&E; £ 250).

F. Vargas-Ocampo256

occurs, suggesting that the colonisation of the endothelial cells by acid-fast bacilli could be

responsible for this damage. At the early stage, the changes consist of dilated vessels,

angiogenesis, and congestion. Endothelial bacillation varies considerably with the

progression of lesions. In the beginning, there are very few bacilli in the endothelial cells

of large blood vessels. As time goes by, organisms increase within the endothelial cells. Later,

bacilli spread progressively from the deep plexus to mid and small-sized vessels of the dermis

and subcutis to give rise to a well-developed histological lesion in which most of the sections

show all blood vessels having a bacillated endothelium, a finding already reported by

Martinez-Baez, who said: “: : :every time one sees the picture of a blood-vessel, one can

observe that the mentioned bacilli are present in one or more to the endothelial cells”.4

The presence and constitution of the infiltrate were variable and did not seem to be related

to the age of the lesion. Biopsies of some patients at a well-developed histological stage and

with a long clinical evolution up to 10 years showed only a slight perivascular mononuclear

infiltrate, while other cases with well-developed histological lesions but with a short clinical

history showed a dense mononuclear infiltrate. Relatively few Virchow-cells were seen

compared with the great number of bacilli.

The fourth stage of ischaemic necrosis due to non-inflammatory vascular occlusion is

characterised histologically by the presence of necrotic cutaneous lesions due to vascular

occlusion by endothelial proliferation or thrombosis, and clinically it coincides with the

appearance of discrete purple-coloured painful spots, which lead to ulceration of the skin

without systemic symptoms. It should be stressed that the fourth stage of ischaemic necrosis

due to non-inflammatory vascular occlusion seems to be caused by vascular injury induced by

invasion of the endothelial cells by Mycobacterium leprae15,16 and that tissue necrosis is due

to vascular occlusion by proliferative endothelium or thrombosis. At this stage systemic

symptoms do not develop and these are the cases that do not respond to thalidomide. This

pattern, the damage of which is seen with or without sparse inflammatory cells, seems to

correspond to the one that Rea used the term vasculosis.28

The fifth stage of ischaemic necrosis appears as an acute reactional state that may

supervene in such patients and aggravates the existing vascular damage. It is manifested

microscopically by necrosis of the superficial dermis and epidermis, leukocytoclastic

Table 1. Presence of Mycobacterium leprae in different structures of the skin in the 200 cases of this study

StructureCases with the structure

present in sections PercentageCases with M. leprae

in the structure Percentage

Epidermis: 200 100 3 1·5Basal cells 200 100 3 1·5Melanocytes 200 100 2 1Spinous cells 200 100 2 1Granulous cells 200 100 1 0·5Corneocytes 200 100 1 0·5

Hair follicles 102 51 47 46Sebaceous glands 81 40,5 6 7·4Pilli-erector muscles 101 50,5 51 50·5Sweat glands 155 77,5 12 7·7Nerves 43 21,5 40 93Lymp vessels 23 11·5 15 65·22Blood vessels 200 100 100 100


vasculitis in small blood vessel of the dermis and of the subcutis, and lobular panniculitis.

Mid-sized and large blood vessels show intimal proliferative thickening, a narrow vascular

lumen, and walls infiltrated by neutrophils and lymphocytes.

The fifth stage of ischaemic necrosis is considered here as a severe variant of ENL.29

When this happens the clinical disease is exacerbated; the number of spots increases suddenly

in several parts of the body, the pre-existing necrotic cutaneous lesions become aggravated

and systemic symptoms appear. It is suggested that ENL and Lucio’s phenomenon may result

from similar immunological mechanisms,10 both show immune-vasculitis resulting from

deposits of complement-fixing immune complexes in small blood vessel walls,17,29 and both

are may respond to thalidomide. In patients with either ENL or Lucio’s Phenomenon,

deposits of IgG and C3, as well as circulating immune complexes have been found in the wall

of small blood vessels.17 It is known that immune complexes activate the complement system

and become chemotatic for neutrophils, which ingest the immune complexes30 and are

subsequently destroyed in the form of nuclear fragmentation. Activation of the clotting

system results in the conversion of fibrinogen to fibrin. The histological picture shows

neutrophils, nuclear dust, and fibrin in the wall of small blood vessels, features that establish

the diagnosis of leukocytoclastic vasculitis (LCV).31 Clinically different manifestations are

described to LCV, including macules, papules, nodules, vesicles, bullae, and ulcers.32

Some immunological, histological and clinical aspects distinguish Lucio’s phenomenon

from ENL. Immunologically, Lucio’s phenomenon occurs in patients considered the most

anergic of the all-immunological spectrum of leprosy. Histologically, Lucio’s phenomenon

starts with heavy colonisation of the endothelial cells by acid-fast bacilli. It develops in a

tissue that already has severe vascular damage, and it is always associated with skin necrosis.

Clinically, Lucio’s phenomenon is an erythema necorcitans, characterised by red and painful

spots (manchas) that progress to necrosis and ulceration leaving atrophic stellar scars,

occurring in a skin with diffuse generalised infiltration and complete absence of nodules, and

appearing in untreated patients. In this study, one case of granulomatous vasculitis in the

subcutis was only observed in patients in this stage; a change that could contribute to

anoxia.12

Another noteworthy fact, in stages four and five, was the finding of vascular occlusion by

thrombi, with no signs of perivascular inflammation. The endothelium has on its surface a

number of anticoagulant and procoagulation properties which, when perturbed, may lead to

intravascular coagulation.33 Therefore the activation of the endothelial cell by organisms can

trigger a cascade of events leading to the conversion of fibrinogen to fibrin intravascular and

thrombosis that occlude arterioles and capillaries.34 – 36 Lucio and Alvarado remarked in their

work that in these patients the level of fibrin was always elevated, and the patients bleed less

during a surgical amputation.2

The nasal mucosa is involved early in the course of Lucio’s leprosy2 and at least 95% of

all patients with lepromatous leprosy have nasal involvement too.37 Leprosy bacilli may

spread though the bloodstream from the nose to another area of the body, among them the

skin.38 – 41

The results of this study support the hypothesis that in Lucio’s leprosy there are leprosy

bacilli in endothelial cells throughout the vasculature that promote the liberation of

substances by the endothelium that induce vascular reactivity as manifested by distended

vessels, morphological changes of the endothelial cells, areas of passive venous congestion

and foci of intravascular clotting, which proceed to disseminated intravascular coagulation

(DIC). DIC is one of the causes of death among these patients.14,21,22

F. Vargas-Ocampo258

It is suggested here that in all cases of lepromatous leprosy, be they nodular or diffuse, the

first lesion is the same: the colonisation of the endothelium by bacilli and that the course of

the disease be determined by the resistance of each patient to the micro-organism.

Suitable treatment can reverse the obliterative changes. Skin biopsies from treated

patients show vessels cleared of organisms. Some solid bacilli, however, can remain in the

media of great blood vessels, and persist in spite of treatment. In vessels of treated patients

thickness of the walls diminishes gradually and the lumen becomes wide and clean, the

disease does not progress and necrosis does not occur. Treatment with dapsone and

rifampicin3,6,15,16,42,43 is associated with the prompt cessation of new acute lesions.3,6,15,43

Consequently, the restoration of a normal endothelial cell state would be an important

objective in the treatment of a patient with diffuse leprosy of Lucio and Latapı. The two

important criteria for this diagnosis are: 1) diffuse non-nodular infiltration, and 2) heavy

vascular endothelial parasitisation by M. leprae.12

Conclusions

Histopathological findings suggest that diffuse leprosy of Lucio and Latapı is a vascular

disorder produced by the invasion of vascular endothelial cells by Mycobacterium leprae. It

would seem that once the bacilli have entered the endothelial cell, they induce endothelial cell

activation that leads to specific morphologic and functional changes, among which are

vascular ectasia, proliferation and swelling of the endothelium with thickness of the vessel

walls, angiogenesis, and activation of clotting which gives rise to thrombosis. These changes

characterise this variety of lepromatous leprosy.3 – 5,7 – 16,18,20 – 25,28,41,43 The necrotising

lesions of Lucio’s phenomenon are due first, to occlusive vasculopathy, without systemic

symptoms,16,17 and secondly, to a lepra reaction that aggravates vascular damage and causes

systemic signs and symptoms.

References

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