INTERNATIONAL JOURNAL OF LEPROSY Volume 40, Number I Printed in the U.S.A. The Identification of Leprosy Among Epithelioid

j Cell Granulomas of the Skin 1,2

J. P. Wiersema and C. H. Binford3

The World Health Organization in 1966 staining the leprosy bacilli, the diagnosis estimated (2) that the world prevalence of should not be a difficult problem. Should leprosy was 10,786,000 and in 1970 stated the lesion, however, present histopathologi­ that, since the previous report, 500,000 new cally an epithelioid cell granulomatous cases had been registered, In the mainland reaction, a specific diagnosis will be diffi­ of the United States, Hawaii, Puerto Rico cult to make. The problem would be that of and the Virgin Islands there are approx­ differentiating tuberculoid leprosy from tu­ imately 2,600 known cases. berculosis or other mycobacterial diseases In the past two decades many citizens of of the skin, sarcoidosis, mycosis, syphilis, the U.S.A. traveling or serving in areas berylliosis, erythema annulare, etc. where leprosy is endemic, have had pos­ In the course of attempting, by histopath­ sible exposure to leprosy. During the ologic methods, to specifically diagnose same periods many residents of endemic epithelioid cell granulomatous lesions of areas have come to the U.S.A. for education the skin, particularly when leprosy was or other purposes. considered a possible diagnosis, we have During recent years civilian pathologists used special procedures and made certain have submitted for consultation to the observations which may be useful to pathol­ Armed Forces Institute of Pathology an ogists confronted with similar problems, increasing number of cases in which the Importance of histopathologic examina­ diagnosis of leprosy had been made or tion of the skin in the diagnosis of lep­ considered a possibility, The cases present­ rosy. The pathologist may wonder if there ing the most difficulty, both to contribut­ are not simpler means to diagnose or ex­ ing pathologists and to the staff of the clude leprosy than the histopathplogic ex­ AFIP, have been those which histopatholog­ amination of a skin biopsy specimen in­ ically demonstrated an epithelioid cell cluding a meticulous search for acid-fast granulomatous reaction. Most pathologists bacilli. in the U.S.A. have had no opportunity to Leprosy cannot be excluded by a nega­ gain practical experience in the histopath­ tive history of exposure to leprosy in the ologic diagnosis of leprosy. Emphasis on family or community. Badger (1) reported leprosy is probably lacking in many pathol­ that of 294 patients admitted from the ogy training programs. The pathologist con­ State of Louisiana to the National Lepro­ fronted by a biopsy from a patient in which sarium at Carville, only 63.6% had known leprosy is considered a possibility, usually exposure to leprosy. In addition, the has to consult a textbook for assistance. If tremendous increase of international traffic the lesion is one of lepromatous leprosy and in recent years and military operations his laboratory succeeds in successfully presently, and during the past decades, in areas with a high incidence of leprosy have 1 Received for publication 29 July 1971. considerably increased the number of peo­ 2 This work was supported by Grants AI-07266 and AI-220 from the Nati onal Institute of Allergy ple living in non-endemic areas who may and Infectious Diseases, National Institutes of have had possible contact with leprosy pa­ Health, Bethesda, Maryland. tients. 3 J. P. Wiersema, M.D., Leonard Wood Memori­ al-National Institues of Health Fellow in Pathol­ The human leprosy bacillus has not yet ogy, Leonard Wood Memorial: Armed Forces In­ been acceptably cultivated in vitro. Inoc­ stitute of Pathology, Washington. D.C. Present Ad­ dress: Department of Pathology, Good Samaritan ulation of Mycobacterium leprae in animals Hospital. Dayton, Ohio; and C. H. Binford. M.D .• 'has produced in ears and foot pads of Chief, Special Mycobacterial Diseases Branch, Armed rodents mild but characteristic infections Forces Institute of Pathology, and Medical Director, Leonard Wood Memorial. Washington, D.C. with primary invasion of dermal nerves 10 40, 1 Wiersema & Binford: Histopathologic Identification of Tuberculoid Leprosy 11

( 3). Shepard (9) has been successful in the epithelioid granulomatous lesion of lep­ using the foot pads of mice to demonstrate rosy in proper perspective, it should be multiplication of the leprosy bacilli, but to stated that the first sign of leprosy is usually obtain measurable growth 3,000 organisms a macular lesion of the skin that may be must be inoculated. This method therefore hypesthetic or anesthetic. Microscopically, cannot be used in diagnosing tuberculoid or such lesions reveal a nonspecific dermatitis other paucibacillary types of leprosy be­ with involvement of small dermal nerves. cause a homogenate of the biopsy specimen This stage of the disease is called INDE­ usually would not yield enough bacilli for TERMINATE LEPROSY. Progression of successful inoculation of a mouse. Even if the infection in most instances produces there were enough bacilli for animal inocu­ either one of two distinctly different types lation, six months or more would be re­ of disease: LEPROMATOUS LEPROSY or quired before the results were known. TUBERCULOID LEPROSY; or a form At present there is no practical laborato­ with features of both called BORDERLINE ry method for establishing or confirming a (DIMORPHOUS or INTERMEDIATE) clinical diagnosis of leprosy other than the LEPROSY. histopathologic examination of a biopsy or In lepromatous leprosy numerous lesions the demonstration of acid-fast bacilli in a develop in the skin, the superficial nerve smear made from a lesion in a patient with trunks, and the mucous membranes of the lesions clinically typical of leprosy. The upper respiratory tract. The eyes, lymph latter examination is usually of no help in a nodes, and testes are often affected and, in case of an epithelioid granulomatous addition, microscopic lesions occur in the inflammatory response because of sparsity of liver, spleen, and bone marrow. The lesions acid-fast bacilli. For such cases histopath­ are composed almost entirely of histiocytes ologic examination of a biopsy is the only which contain numerous acid-fast bacilli. It valid laboratory method for confirming or is generally believed that in lepromatous excluding a clinical diagnosis of leprosy. leprosy there is lack of effective cellular Because of the grave psychologic and immunity against the bacilli. social effects . on the patient and his family In tuberculoid leprosy, lesions occur that may follow a diagnosis of leprosy a principally in the skin and superficial nerve physician often hesitates to make this diag­ trunks. Although the number'of skin lesions nosis on the findings of clinical examination is usually small, they may attain very large alone. The pathologist therefore should sizes. The natural course of tuberculoid lep­ give as much support as possible to confirm rosy is characterized by exacerbations and or reject a diagnosis of leprosy. remissions occurring at irregular intervals. The pathologist should always keep in Long periods of complete arrest of the mind the possibility of leprosy any time in disease are observed in many patients. his routine practice that he encounters an Active lesions usually reveal distinct enigmatic inflammatory lesion of the skin, epithelioid cell granulomas, but in re­ even if leprosy is not suspected by the gressive centers of skin lesions, the orig­ clinician. In the files of the Armed Forces inal epithelioid cell granulomas often dis­ Institute of Pathology there is a significant appear and the inflammatory reaction be­ number of cases in which pathologists have comes nonspecific and finally subsides accurately diagnosed leprosy when that di­ completely. The bacilli are usually very agnosis had not been considered by the difficult to find in tuberculoid leprosy. It is clinician. The correct identification of the generally believed that the growth of M. disease by pathologists resulted in the ad­ leprae in tuberculoid leprosy patients is ministration of effective treatment before limited because of cellular resistance. Con­ irreversible deformities occurred. Three il­ sidering the small number of bacilli demon­ lustrative cases have been reported (4). strable in tuberculoid lesions, the epithe­ Epithelioid cell granulomas in leprosy. lioid cell granulomatous response is very In this paper there will be no attempt to severe. In contrast to lepromatous leprosy, discuss comprehensively the features of the in which nerves, although heavily infected, several types of leprosy. However, to place are well-preserved for a long time, the 12 International Journal of Leprosy 1972

dermal nerves in tuberculoid lesions are stained red in properly stained sections. soon destroyed after being invaded by very Decolorization should be sufficient to ade­ few bacilli. The severe inflammatory re­ quately decolorize the small nerves and the sponse in lesions of tuberculoid leprosy is stroma. The histopathologic technician considered to be a manifestation of delayed should have unstained sections of known type hypersensitivity. leprosy tissue to demonstrate the adequacy In the borderline (dimorphous, interme­ of staining. diate) lesions in which the epithelioid cell In his daily practice that includes speci­ granulomatous reaction is predondnant, mens of skin, the pathologist commonly bacilli, as in the tuberculoid lesions, may be pays little attention to the dermal nerves, difficult to demonstrate. because they usually reveal no changes con­ Disti~ct characteristics of leprotic epi­ tributory to the diagnosis of most dermato­ thelioid cell granulomas of the skin. Lep­ logic conditions. Since the dermal nerves rosy bacilli have the unique propensity to are often severely damaged and there­ invade and multiply in perineural and in­ fore are difficult to recognize in tuberculoid traneural cells and spread within nerves. leprosy, the pathologist may easily overlook This so-called PRIMARY INVASION of the distinct characteristics of leprotic nerve nerves demonstrates a poorly understood involvement in an epithelioid cell inflam­ host parasite relationship. M. leprae is the matory lesion of the skin. This, and the only acid-fast bacillus known to occur in hu­ paucity of acid-fast bacilli, make it neces­ man disease that primarily invades nerves. sary that the pathologist follows a systemat­ Evidence of primary invasion of nerves by ic pattern of examination to make or reject acid-fast bacilli therefore warrants a defin­ a diagnosis of leprosy in an epithelioid cell ite diagnosis of leprosy. inflammatory lesiop of the skin. In contrast with advanced lepromatous The hematoxylin and eosin stained sec­ leprosy the number of skin lesions occur­ tions are examined first. As will be dis­ ring in patients with tuberculoid leprosy is cussed later, it will be helpful for the pathol­ small. The epithelioid cell granulomatous ogist to draw an outline of the section on inflammatory infiltrates are often dis­ a piece of paper and to sketch inflammato­ tributed around and within nerves. Nerves ry infiltrates and nerves in this outline. The apparently are the loci minores resistentiae number of nerves, or rather, the number of in this resistant form of leprosy. cuts across nerves, is counted. In this way Technic of examination. The biopsy spec­ the relationship between nerves and imen should be taken from the periphery of inflammatory infiltrates is determined. the most active appearing lesion of the In our practice the search for M. leprae skin, as determined by the degree of eleva­ in epithelioid cell granulomas of the skin is tion and erythema. It should include a usually restricted to nerves, remnants of narrow margin of nomlal appearing skin nerves, foci of necrosis, and subepidermal peripheral to the lesion. To provide oppor­ free zones. In case the dermal nerves are tunity to identify and examine nerves in destroyed beyond recognition, the centers of depth, it should include the entire thick­ large inflammatory infiltrates are searched. ness of the dermis and a thin portion of These centers are mos't likely the sites subcutaneous adipose tissue. The specimen where nerves were situated previous to must be cut on the microtome in a plane their destruction. perpendicular to the margin of the lesion so On observing an acid-fast bacillus in a that the histologic sections will include a skin lesion, the pathologist obviously must narrow margin of apparently normal skin. determine under an oil immersion lens that Two hematoxylin and eosin, and ten ac­ it is located in tissue and is not a "floater." id-fast stained sections usually provide If the sections were stained along with sufficient material for examination. The other sections containing acid-fast bacilli, a Fite-Faraco acid-fast method (II) is far bacillus situated on the surface of the sec­ superior to the standard Ziehl-Neelsen tion could be a contaminant. Also, a bacil­ method for the demonstration of M. leprae lus located upon or under rather than with­ in tissue sections. The keratin of hairs is in a nerve may be a displaced bacillus. 40, 1 Wiersema & Binford: Histopathologic Identification of Tuberculoid Leprosy 13

The limitation of the search for M. Zeprae is located in a damaged nerve. The other to the above mentioned areas in tubercu­ two bacilli are located in the midst of in­ loid leprosy makes the examination of ten flammatory infiltrates probably at the sites acid-fast stained sections feasible for the of totally destroyed nerves. practicing pathologist who desires to Severe damage of the dermal nerves, document or reasonably exclude a diagno­ perineural focalization of the inflammatory sis of tuberculoid leprosy. infiltrate, and the occurrence of bacilli in a In order to chart the amount and dis­ nerve an<;l at the possible sites of destroyed tribution of the infiltrates in epithelioid cell nerves are outstanding features of the in­ granulomas of the skin and show the rela­ volvement of nerves in tuberculoid leprosy. tion of tht' infiltrate to nerves and bacilli, In this paucibacillary epithelioid cell gran­ we prepared illustrative profiles of the sec­ ulomatous inflammatory lesion of the skin, tions. the observation of a single acid-fast bacillus Preparation of profiles. In each case a in a nerve is acceptable proof of leprosy. low power photomicrograph of the entire Case 2. Figure 2 demonstrates a sarcoid section stained with hematoxylin and eosin lesion on the skin of the right forearm of a was mounted on a piece of glass. The parts 54 year old man. of the dermis and subcutaneous tissue The infiltrates of the lower dermis are which were not infiltrated were cut out circular and distinct rather than elongated with a razor blade and removed from the or plexiform. Perineural distribution of the plate. The resulting silhouette of the inflammatory infiltrate is not evident. There inflammatory infiltrates, epidermis and are 11 well-preserved nerves in one section. nerves was photographed. Acid-fast bacilli are not observed. On the photograph of the profile the In such an epithelioid cell inflammatory NERVES were marked with black or white lesion of the skin with infiltrates in all levels dots and indicated by horizontal arrows. In of the dermis, the absence of involvement cases with few bacilli, arrows were mounted of dermal nerves is evidence against lepro­ vertically to point out the areas where acid­ sy. The patient had several classical signs fast bacilli were observed in one or more sec­ of sarcoidosis. tions stained by the acid-fast method. Areas It is of interest to note that in Figure 1 selected for high power photomicrographs and in Figure 2 respectively. the evidence were indicated by a capital letter and a of involvement of dermal nerves and the symbol 1. lack of evidence of involvement of dermal nerves appear only in the lower part of the DERMAL EPITHELIOID CELL dermis. If the biopsies had been taken GRANULOMA superficially so that the level of the neural Tuberculoid leprosy compared with sar· plexus of the lower dermis had not been coidosis; importance of bacillary nerve in· included, distinction of the two lesions volvement in leprosy. would likely have been impossible. Case 1. Figure 1 demonstrates the margin Focally necrotizing epithelioid cell gran. of a single lesion on the dorsum of the left ulomas in tuberculoid leprosy with con. forearm of a 13 year old Surinam girl of spicuous involvement of dermal nerves. East Indian descent. Case 3. Figure 3 demonstrates a lesion on The elongated large infiltrates in the the left forearm of a 50 year old diabetic lower part of the figure are located at the woman in Guam. She had a history of site of the neural plexus of the lower der­ recurrent, erythematous, annular and arcu­ mis. The small infiltrates in the mid-demiis ate infiltrations on the trunk, face and ex­ and in the superficial dermis follow the tremities. pattern of distribution of the comparatively The elongated infiltrates follow the pat­ small motor nerves that come from the tern of distribution of the dermal nerves. plexus. There are only three nerves. Two The centers of two infiltrates are necrotic. nerves are severely damaged. The necrosis is indistinguishable from Three acid-fast bacilli are observed in caseation as occurring in tuberculosis. one specially stained section. One bacillus There is only one nerve that can be iden- 14 I nternationa l Journal of Leprosy 1972

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FIG. 2. Sarcoidosis: no involvement of dermal nerves. Lesion on forearm of 54-year­ old man. AFIP Acc. 314241. (A) Profile of epidermis and infi ltrate. The dots represent eleven well-preserved nerves which are indicated by horizontal arrows. Hematoxylin and eosin x 5 \4 AFIP neg. 67-4659. (B) Well cir­ cumscribed distinct epitheli oid cell granulomatous infiltrates at B' in A. The horizontal arrows indicate three well-preserved nerves in the margins of the infiltrates. Hematoxylin a nd eosin. x 42. AFIP neg. 67-1738. (C) Infiltrate at C' in A, x 265. The h orizontal arrow points to an undam­ aged nerve. Hematoxylin and eosin. AFIP neg. 67-1739.

tilled. It is severly damaged and contains Case 4. More of a diagnostic problem one beaded, acid-fast bacillus. was the biopsy of a plaque-like lesion on Perineural focalization of the epithelioid the cheek of a 20 year old Surinam man of inflammatory infiltrate, the severe nerve East Indian descent demonstrated in Fig­ damage and the demonstration of an acid­ ure 4. The man had, in addition, erythema­ fast bacillus in a nerve are characteristic for tous plaques on his trunk and extremities. tuberculoid leprosy. Although the clinical The predominately epithelioid cellular picture with multiple lesions on trunk, face inflammatory infiltrate is massive and re­ and extremities might suggest dimorphous places the entire dermis. Some epithelioid leprosy, the histopathologic features in this fo ci of the mid-dermis show central necro­ biopsy are those of tuberculoid leprosy. sis. Nerves are not observed in multiple

Facing page FIG. 1. Tubercul oi d leprosy with conspicuous involvement of dermal nerves. Margin of sin gle lesion on forearm of 13-year-old Surinam girl. AFIP Ace. 1122490. (A) Hematoxylin and eosin. x 7 If.,. AFIP neg. 65-1637. (B) Profile of epidermis a nd infiltrate demonstrated in A. Horizontal arrows point toward three dots that represent all nerves observed in this section. Vertical arrows point toward the sites of three bacilli observed in one acid-fast stained section . The extent and distribution o f the inflammatory infiltrates correspond with the pattern of dermal nerves. Hematoxylin and eosin. x 61f.,. AFIP neg. 65-1637. (C) A higher power of the perineural infiltrate at C' in B. There are a few remaining nerve fibers which' are Indicated by the horzontal arrow. The inset shows one bacillus In same nerve in a n acid-fast stained section. Hematoxylin a nd eosin, x 130. AFIP neg. 65-164l. Inset: Fite-Faraco acid-fast stain, (x 1.350) AFIP neg. 65-1640. (D) Infiltrate at D' in B. x 150. The remaining fi bers of a severely damaged nerve are indicated by the horizontal arrow. Hematoxylin and eosin . AFIP neg. 67-2205. (E) The Infiltrate at E' in B demonstrates a typical tuberculoid epithelioid cell granulomatous reaction including a rim of lymphocytes. One Langhans' g iant cell is seen amidst the epithelioid cells. t H ematoxylin a nd eosin, x 115. AFIP neg. 64-2427. 16 International Journal of Leprosy 1972

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FIG. 3. Tuberculoid leprosy with conspicuous involvement of dermal nerves and with focal necrosis. Lesion on forearm of 50-year-old woman in Guam. AFIP Ace. 116067. (A) Profile of epidermis and Infiltrate. The only nerve seen Is Indicated by the dot at the point of the horizontal arrow. The vertical arrows Indicate the sites of two bacilli which were seen In one acid-fast stained section. One In the nerve and the other In a necrotic center of a granuloma. Hematoxylin and eosin, x 9. AFIP neg. 65-3920. (B) Epithelioid cell infiltrate at B' In A, x 115. Dark shaded center of Infiltrate represents necrosis. Hematoxylin and eosin. AFIP neg. 65-3918. (C) Infiltrate at C' in A, x 115. Horizontal arrow indicates the remaining fibers of a damaged nerve. Hematoxylin and eosin. AFIP neg. 65-3917. (D) Nerve at D' in A, x 995. Verti­ cal arrow indicates a beaded acid-fast bacillus within the damaged nerve. Flte-Faraco acid-fast stain. AFIP neg. 3919.

Facing page FIG. 4. Tuberculoid leprosy with conspicuous involvement of dermal nerves and with extensive necrosis. Lesion on cheek of 20-year-old Surinam man. AFIP Ace. 1122520. (A) The entire dermis Is replaced by Inflammatory Infiltrate. The cleft is an artifact. Dermal nerves are not preserved. Vertical arrow Indicates the site of two bacilli In an acid-fast stained section. Hematoxylin and eosin, x 7. AFIP neg. 65-1642. (B) Part of Infltrate at B' in A, x 130. Necrotic area surrounded by epithelioid cells and occasional Langhans' giant cells. Hematoxylin and eosin. AFIP neg. 65-1644. (C) Area at C, in A, x 1,000. Vertical arrow Indicates two bacilli In Immediate vicinity of hair follicle. Fite acid-fast stain. AFIP neg. 67-6181. 40, 1 W iersel1w & Binford: 11 istopathologic Identification of T ulJerculoid Leprosy 17 18 International Journal of Leprosy 1972 sections. Examination of several acid-fast the thigh of a Filipino woman who came stained sections revealed occasional bacilli to the U.S.A. two years before the biopsy in necrotic areas and ' in subepithelial free was taken. The lesion was described as an zones. erythematous, annular plaque that was The total destruction of dermal nerves jn anes thetic to pinprick. There was also this massive inflammatory inBltrate is sug­ anesthesia of the fi ngers. Both the consultant gestive but not diagnostic for leprosy. The dermatologist and the pathologist felt that occurrence of acid-fast bacilli in the subepi­ the woman had leprosy. dermal free zone is strong addition al sup­ In the superfi cial dermis there is a cord­ port fo r a diagnosis of leprosy. Epitheli oid like, inflammatory infiltrate composed of cell inflammatory inBltrate, fewness of acid­ epithelial cells and Langhans' giant cells en­ fas t bacilli, and damage of nerves are con­ veloped by lymphocytes. Several inBltrates sistent with tuberculoid leprosy. are also noted in the mid- and lower der­ If the biopsy had included the margin of mis. the lesion with a small part of normal skin, Twelve nerves are identified. Two nerves perineural focalization of inflammatory are not related to inflammatory infiltrate. infiltrate and damaged nerves with acid­ The other ten nerves are located in the fast bacilli would most likely have been peripheral parts or in the margins of present between the normal skin and the inflammatory infiltrates. No nerve is sur­ massive inBltrate and have given the pathol­ rounded by epithelioid cells. All nerves ogist more confidence to make a diagnosis appear well-preserved. of leprosy. One acid-fast stained section reveals 11 Focal necrosis of epithelioid cell inflam­ bacilli in six different locations. Seven matory inBltrates of the skin is not incon­ bacilli are noted in the subepidermal zone. sistent with leprosy. The necrosis is usually Four bacilli are observed in two nerves. confined to the centers of few inBltrates of The presence of acid-fast bacilli in nerves the mid-dermis. The necrosis apparently is convincing evidence of leprosy. The occurs at the sites of dermal nerves. In appearance of the epithelioid cell inflam­ tuberculoid leprosy we have never ob­ matory infiltrate and paucity of bacilli are served massive superfi cial necrosis and en­ features of tuberculoid leprosy. suing ulceration in lesions of the skin. Mas­ Case 6. Figure 6 demonstrates a biopsy sive necrosis of epithelioid cell granulomas specimen, from the margin of a macule on of peripheral nerve trunks with the forma­ the left buttock of a 35 year old female tion of a so-called nerve abscess is not Bush Negro in Surinam. She also had a uncommon in tuberculoid leprosy. lesion on the skin of one of her fe et. The Inconspicuous nerve involvement in tu­ macule of the buttock was hypopigmented berculoid leprosy. in the center and it had somewhat inBltrat­ Case 5. Figure 5 demonstrates a lesion on ed margins. There was no loss of sensitivity

Facing page FIG. 5. Tubercul oid leprosy; inconspicuous involvement of dermal nerves. Lesion on thigh of Filipino woman. AFIP Acc. 1225637. (A) Profil e of epidermis a nd infiltra te. The horizontal arrows indicate 12 well-preserved nerves m a rked by dots. T en nerves a re s itua ted in the m a rgins of inflammator y infiltra tes. Two nerves a re not connected with inflamma tory infiltra tes. Six vertical a rrrows indicate sites of 11 bacilll observed in one acid-fast sta ined section . Seven bacilli occur in the subepidermal zone. Hem atoxy­ lin and eosin. x 5. AFIP neg. 67-4182. (B) Area B' in A. x 250. The inflamma tory infiltra te Is composed of epithelioid cells. lym phocytes a nd a L angha ns' g ia nt cell. A sma ll nerve, indicated by horizonta l a rrow. is not inVO lved . Hem atoxylin a nd eosin. AFIP neg. 67-4190. (C) Area at C' in A. x 65. This inflammatory infiltrate is connected with bra nching nerve . indicated by th ree horizon tal a rrows. Hem a toxylin a nd eosin. AFIP neg. 67-2209. (D ) Subepidermal zone a t D' in A. x 1.000. Vertical a rrow indicates seemingly dividing bacillus. Fite-F a raco acid-fast stain . AFIP neg. 67-4 201. (E) Subepiderma l zone a t E ' in A. x 1.000. Vertical a rrow indicates acid-fast bacil­ lus. F ite-Fa raco acid-fast sta in. AFIP neg. 67-4196. (F) Subepidermal zone a t F' in A. x 1.000. Vertical a rrow Indicates acid-fast bacillus. Fite-Fa raco a cid-fast stain. AFIP neg. 67-4195. (G) Subepiderma l zone at G' In A. x 1,000. Vertical a rrow indicates three acid-fast bacilli. F lte­ Faraco acid-fast sta in. AFIP neg. 67-4107. (H) Small nerve at H' in A. x 1,000. Vertical a rrow indicat es beaded acid-fast bacillus with in a nerve. Fite-F a raco acid-fast sta in. AFIP neg. 67-4200. (I) Sma ll nerve a t I' in A. x 1.000. Vertical a r row indicates two opposed acid-fast bacill within a nerve. Fite-Faraco acid-fast sta in. AFIP neg. 67-4198. (J) Sma ll nerve at J ' In A. x 1,000. Ver­ t ica l a rrow indicateS acid-fast bacillus. The nerves illustra ted in Area 1 a nd Area J a re the sam e. but photographed in different focus. Fite-Faraco acid-fast sta in. AFIP neg. 67-4199. 40, 1 Wiersema & Binfo-rd: Histopathologic Identification of Tuberculoid Leprosy 19

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demonstrable in the affected areas of the Twenty-eight nerves are present. Ten skin and bacteriologic examination of the nerves are noted in the left part of the margin of the lesion on the buttock was profile and 18 nerves are noted in the right negative for acid-fast bacilli. part. On the left of the profile seven nerves A cord-like inflammatory infiltrate occu­ are related to or situated within inflamma­ pies the superficial dermis. On the left side tory infiltrates, and three nerves are sur­ it touches the epidermis at several places rounded by unaltered dermal connective but on the right side a subepidermal free tissue. In the right part of the profile five zone is preserved. Several inflammatory nerves are related to or situated within infiltrates are present in the mid-dermis inflammatory infiltrates and thirteen nerves and a few infiltrates occur in the lower are surrounded by unaltered connective dermis. tissue. The nerves appear well-preserved. Fourteen nerves are noted in one sec­ The examination of two acid-fast stained tion. Nine nerves are connected with, or sections reveals three bacilli in nerves. The situated within, inflammatory infiltrates. demonstration of bacilli in these nerves Most nerves appear well-preserved. justilles the diagnosis of leprosy in this Search of five acid-fast stained sections epithelioid cell granuloma. reveals five bacilli. One bacillus is iden­ Absence of nerve involvement in sar­ tilled in an apparently undamaged nerve. coidosis and non-leprotic mycobacterial Three bacilli occur in the subepidermal granulomas. zone. One bacillus is located in an inflam­ Case 8. Figure 8 demonstrates an epi­ matory infiltrate. thelioid cell granuloma of the skin in a 27 Although involvement of dermal nerves year old man with sarcoidosis. is not conspicuous the observation of an The distribution of the inflammatory unmistakable acid-fast bacillus in a nerve infiltrate is not unlike that in Figure 7. The is considered diagnostic for leprosy. The large infiltrate is composed of well-defined epithelioid inflammatory infiltrate and pau­ circular clusters of epithelioid cells with city of acid-fast bacilli are features of tu­ very few lymphocytes. Such a distinct nod­ berculoid leprosy. ular pattern of epithelioid cell granulomas Case 7. Figure 7 demonstrates a hypo­ with only few lymphocytes would not be pigmented macular lesion on the forearm of expected in leprosy. a 21 year old Bush Negro of Surinam. At There are 16 nerves. Nerves are not the time of biopsy the patient had similar present in the large inflammatory infiltrate. macules on the left cheek, the right upper Five nerves are connected with small arm, and the volar side of the right infiltrates. All nerves are well-preserved. forearm. The margins of the macules were Bacilli are not observed in several acid-fast elevated. stained sections. The patient had several A massive epithelioid cell inflammatory other signs of sarcoidosis. infiltrate replaces part of the superficial and Case 9. This illustrates how diagnostic mid-dermis. The infiltrate extends to the difficulties may be encountered in epitheli­ basal layer of the epidermis which, above oid cell granulomas of the skin caused by the infiltrate, is somewhat stretched. Small mycobacteria other than M. leprae. Figure inflammatory infiltrates occur in other parts 9 demonstrates a lesion on the right leg of of the dermis. an 85 year old woman, born in Norway

Facing page FIG. 6. Tuberculoid ,leprosy with inconspicuous involvement of dermal nerves. Lesion on buttock of 35-year-old Surinam woman. AFIP Acc. 1122499. (A) Profile of epidermis and Infiltrate. Horizontal a r rows Indicate 14 nerves marked with dots. Vertical arrows Indicate sites of five bacilli observed In five acid-fast stained sections. Hematoxy­ lin and eosin. x 6¥". AFIP neg. 65-1638. (B) Subepidermal zone at B' in A. x 1.000. Vertical ar­ row indicates acid-fast baclllus. Fite-Faraco stain. AFIP neg. 67-1922. (C) Area at C' in A. x 65. Epidermis. subepidermal zone and superficial inflammatory intlltrate are lllustra ted. Hematoxylin and eosin. AFIP neg. 67-2209. (D) Area at D' In A. x 75. Hematoxylin and eosjn. x 75. AFIP neg. 67-2213. (E) Subepidermal zone at E' in A. x 1,000. Vertical arrow indicates acid-fast bacil­ lus. Fite-Faraco acid-fast stain. AFIP neg. 67-1924 . (F) Nerve a nd inflammatory infiltrate at F' In A. x 1.000. Horizontal arrow indicates nerve and vertical arrow Indicates acid-fast bacillus within the nerve. Fite-Faraco acid-fast stain. AFIP neg. 67-1926. (G) Epithelioid cell Inflamma­ tory Intlltrate at G' In A, x 260. Horizontal arrow indicates damaged nerve. Hematoxylin and • eosin. AFIP neg. 67-2215. 22 I nternationa 1 Journal of Leprosy 1972

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FIG. 8. Sarcoidosis. Lesion on forearm of 27-year-old man. AFIP Ace. 516640. (A) Profile ot epidermis and infiltrate. Fifteen horizontal arrows indicate 16 nerves marked by dots. Hematoxylin and eosin, x 4'h. AFIP neg. 67-1683. (B) Area at B' in A, x 42. Nodular, epithelioid cell inflammatory inflltrate. Nerves not present. Hematoxylin and eosin. AFIP neg. 67-1741. (C) Inflammatory inflltrate at C' in A, x 100. Horizontal arrow indicates well-preserved nerve. Hematoxylin and eosin. AFIP neg. 67-1740.

and, since her 20th year, living in the the greater part of the dermis. Small U.S.A. ; presently in Minnesota. Her physi­ infiltrates occur in the remaining part of the cian thought that she might have had con­ dermis. The inflammatory infiltrates are tact with leprosy patients in her youth or composed of lymphocytes and plasma cells during visits to her native country. with clusters of epithelioid cells. Subcutaneous nodules, varying from pin­ Nine nerves are present. Six nerves are point to 3 cm in diameter, were present on located within inflammatory infiltrates and the posterior aspect of the right calf. The three nerves are surrounded by unaltered largest nodule was bluish-red, slightly dermal connective tissue. Nerves are not warm, and moderately tender. The skin observed within foci of epithelioid cells. surface was intact. Similar lesions were Acid-fast stained sections reveal numer­ present at the skin of the right patella and ous bacilli. Most bacilli are situated within on the left wrist. inflammatory cells. Bacilli are not observed On histopathologic section a large, mas­ in nerves. sive, inflammatory in£ltrate has replaced If this were a case of leprosy many

Facing page Fig. 7. Tuberculoid leprosy; inconspicuous involvement of nerves. Lesion on fore­ arm of 21-year-old Surinam man. AFIP Ace. 1122510. (A) Profile ot epidermis and Inflltrate. Horizontal arrows indicate 28 nerves marked with dots. Two vertical arrows Indicate sites ot three bacilli observed In two acid-fast stained sections. Hematoxylin and eosin. x 4. AFIP neg. 67-2218. (B) Epithelioid cell Inflammatory inflltrate at B' in A, x 225 . Small nerve Indicated with h orizontal arrow. Hematoxylin and eosin. AFIP neg. 67-2223. (C) Nerve at C, In A. x 1080. Vertical arrow Indicates acid-tast bacillus. Flte-Faraco acld­ fast stain. AFIP neg. 67-2225. (D) Inflammatory Infiltrate at D' In A. x 225. Horizontal arrows Indicate two small nerves. Hematoxylin and eosin. AFIP neg. 67-2222. (E) Nerve at E' In A. x 1080. Vertical arrows Indicate two beaded acld-tast bacillI. Fite-Faraco acld-tast stain. AFIP neg. • 67-2226 . 24 International Journal of Leprosy 1972

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B FIG. 9. Unclassified mycobacterial infection of skin. Nodular lesion on leg of 85- year-aId woman. AFIP Ace. 1159132. (A) Protlle of epidermis and Infiltrate. Nine horizontal arrows indicate nerves, marked with dots. Sites of numerous acid-fast bacilli not indicated. Hematoxylin and eosin, x 5. AFIP neg. 67-4927. (B) Area at B' in A, x 1190. Numerous, mostly intracellular aCid-fast bacilli indicated with vertical arrows. Fite-Faraco acid-fast stain. AFIP neg. 65-1481. (C) Area at C' in A, x 250. Horizontal arrow indicates damaged nerve. Epithelioid cell Infiltrate in lower part of picture. Bacllli were not observed in nerves. Hematoxylin and eosin. AFIP neg. 67-4924 . 40, 1 Wiersema & Binford: Histopathologic Identification of Tuberculoid Leprosy 25

bacilli should be present in nerves. In the Acid-fast bacilli are abundant. Most absence of nerve involvement we excluded bacilli occur in nerves where they are often leprosy as a possible diagnosis. Further aggregated in clusters. Several bacilli are laboratory studies failed to identify the also noted in inflammatory cells. mycobacteria causing this lesion and fur­ The extensive, loosely arranged, epitheli­ ther clinical studies did not confirm a diag­ oid cell inflammatory infiltrate of the der­ nosis of leprosy. mis which does not encroach on the basal Epithelioid cell granuloma of the skin in layer of the epidermis, and the slight dam­ reactional tuberculoid leprosy. age of dermal nerves notwithstanding the Case 10. Figure 10 demonstrates a rep­ presence of numerous bacilli are features resentative example of a lesion of the skin that lead to a diagnosis of borderline lep­ in a patient with tuberculoid leprosy in rosy. reaction. The biopsy was taken from the margin of a large maculoanesthetic lesion DISTINCT HISTOPATHOLOGIC on the right arm of a 25 year old Cantonese CHARACTERISTICS OF THE VARIOUS Chinese woman who lived in Malaysia, LEPROTIC EPITHELIOID CELL GRANULOMAS OF THE SKIN North Borneo. The right ulnar nerve was OBSERVED IN BIOPSY SPECIMENS thickened. Scrapings from the lesion of the skin were negative for acid-fast bacilli. The Review of the biopsy material. The cases clinical diagnosis was dimorphous lelprosy. presented illustrate a variety of leprotic The distribution of the inHammatory epithelioid cell granulomas of the skin en­ infiltrate follows the pattern of distribution countered in biopsy specimens that were of dermal nerves. The infiltrates are com­ forwarded to the Armed Forces Institute of posed of foci of epithelioid cells surrounded Pathology during the years 1963-1966. The by lymphocytes intermixed with few plas­ biopsies were taken specifically for diagnos­ ma cells. Lymphocytes are very numerous tic purposes, not for research. It can be in the infiltrates of the lower dermis. Nerves assumed that most patients consulted the are not observed. Acid-fast bacilli are nu­ physicians at the time they became con­ merous. cerned about their skin diseases and that, If this were not a case of leprosy, several in several instances, the local pathologists nerves should have been noted in the large consulted the Armed Forces Institute of areas of uninvolved dermal tissue between Pathology because of the diagnostic diffi­ the inflammatory infiltrates. The total ab- culties. The presented cases, therefore, illus­ . sence of dermal nerves in this focalized, trate the histopathology of epithelioid cell mycobacterial inflammatory lesion supports granulomas of the skin that occur in active a diagnosis of tuberculoid leprosy in this lesions of untreated patients with tubercu­ mycobacterial granuloma. The large num­ loid or borderline leprosy, and they include ber of acid-fast bacilli and lymphocytes several uncommon variants. Caseous necro­ indicate a reactional phase of the infection. sis in epithelioid cell granulomas of the skin Epithelioid cell granuloma of the skin in is rarely seen in biopsies taken for observ­ dimorphous leprosy. ing progress in tuberculoid leprosy. It Case 11. Figure 11 demonstrates a typical is not infrequently encountered in biopsy example of a borderline lesion of the skin. specimens taken for the initial diagnosis. The biopsy was taken from a nodule on the The clinical changes in the lesions with right forearm of a four year old Surinam boy. necrosis may have disturbed the patient so The distribution of the inflammatory much that medical attention was sought. In infiltrate is perineural. The infiltrates are fact, one of the first descriptions of epitheli­ composed of ill-defined epithelioid cell foci oid cell granulomas in skin lesions of lepro­ and lymphocytes. The infiltrate approaches sy patients mentions the occurrence of co­ but does not encroach on the basal layer of agulation necrosis (J adassohn) (6) . Fur­ the epidermis. thermore, epithelioid cell granulomas of the There are 11 nerves. All nerves are sur­ skin with inconspicuous iIivolvement of rounded by infiltrates. The nerves are only nerves, although uncommon in patients slightly damaged by infiltrate. with tuberculoid leprosy, are not infre- 26 International Journal of Leprosy 1972

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A 40, 1 Wiersema & Binford: Histopathologic Identifi cation of Tuberculoid Leprosy 27

quently encountered in diagnostic biopsy under treatment already for considerable specimens because such lesions, in particu­ time (7). lar if they are small, often do not present From the foregoing, it is evident that for anesthesia, the clinical hallmark for the proper evaluation of a biopsy specimen the diagnosis of leprosy. Therefore, the clini­ pathologist should be informed about the cian is more apt to seek the assistance of a nature of the disease of the patient, the pathologist. With the exception of the spec­ type and activity of the biopsied lesion, imen illustrated in Figure 4 all specimens and the site from which the specimen was chosen for illustration were taken from the taken. This information is of particular im­ margins of active lesions and, in addition, portance in case leprosy is suspected clini­ included the entire thickness of the dermis. cally, but not supported by the findings in a Superficial biopsy specimens or biopsy spec­ biopsy specimen. Such negative findings im ens taken from in active lesions or inac­ can be interpreted as evidence against lep­ tive parts of lesions are often insufficient rosy only if the biopsy specimen was for making a histopathologic diagnosis of taken from the margin of an actively leprosy. In such instances, the pathologist growing skin lesion. in his report should mention the inadequa­ Leprotic nerve involv~ment versus sec­ cy of the specimen. ondary nerve involvement. Epithelioid cell The outlined selection of the illustrated inflammatory dermal lesions usually cause varieties of leprotic epithelioid cell inflam­ severe and often permanent damage to the matory lesions of the skin implies certain skin regardless of their etiology. This dam­ restrictions for their use as a reference in age, resulting in atrophy or scarring, in­ the practice of laboratory pathology. Tu­ volves the epidermis altering its pigmenta­ berculoid leprosy is a disease with an un­ tion, the blood vessels, the appendages, predictable course. Long periods of arrest and connective tissue. The dermal nerves, often alternate with relatively short periods protected as they are by sheaths of epineu­ of activity. During disease arrest, anesthet­ rium and perineurium, are more resistant to ic, hypopigmented macules may be damage than the other elements of the present. Such macules do not increase in skin. But massive inflammatory infiltrates size, their margins are not infiltrated, and may overwhelm the dermal nerves. In such microscopically there is, at the most, only inflammatory lesions, it is not unusual to minor chronic nonspecific inflammatory find the number of nerves decreased, to . infiltrate. Acid-fast bacilli usually cannot be observe nerves amidst inflammatory cells, demonstrated. Such atypical inflammatory and to note actual inflammatory infiltration lesions are often observed in biopsy speci­ and damage of occasional nerves. mens that were taken from lesions of the In severe, nonleprotic, mycobacterial in­ skin in persons who were examined be­ fection of the skin, phagocytic cells carry­ cause they had been in close contact with ing bacilli may have migrated into a nerve leprosy patients, or in which macules were through a damaged perineurium. noted during an examination for another When comparing nerve involvement in illness. A different picture of the histopa­ animals experimentally infected with the thology of lesions of the skin in tuberculoid human leprosy bacillus with those infected leprosy will also be obtained when biopsy experimentally with the murine leprosy specimens are taken from a group of pa­ bacillus ( Mycobacterium lepraemurium ), tients with an established diagnosis of tu­ we found that, while the human leprosy berculoid leprosy, and perhaps have been bacillus regularly selectively invades intact

Faci ng page FIG. 10. Tuberculoid leprosy in reaction. Lesion on arm of 25-year-old Cantonese Chinese women in Malaysia, North Borneo. AFIP Ace. 1132582. (A) Profile ot epidermis and Infiltrate. Nerves not present. Numerous acid-fast bacilli not Indicated. Hematoxylin and eosin. x 11 'h. AFIP neg. 65-2393. (B) Area at B' In A x 225 EpitheliOid cell inflammatory Infiltrate surrounded by broad rim ot lymphocytes. He~atoxYll~ a nd eosin. AFIP neg. 65-1656. (C) Area at Co in A. x lOBO. including part of epitheli oid cell infiltra te shown in Figure B. Clusters of acid-fast bacilli indicated by vertical arrows. Fite-Faraco acid-fast stain. AFIP neg. 65-1657 . • 28 International Journal of Leprosy 1972

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FIG. 11. Dimorphus leprosy. Nodule on arm of 4-year-old Surinam boy. AFIP Ace. 1080913. (A) Profile of epidermis and infiltrate. Horizontal arrows Indicate 11 nerves ma rked with dots. Numerous acid-fast bacmi not Indicated. Hematoxylin and eosin. x 11. AFIP neg. 66-9321. (B) Area at B' in A, x 265. Horizontal arrow Indicates nerve. Hematoxylin and eosin. AFIP neg. 67-1674. (C) Area at C' In A, x 875, with same nerve as In Figure B. Vertical arrows indicate bacm!. Flte-Faraco acid-fast stain. AFIP neg. 67-1672. (D) Nerve at D' In A, x 875. Vertical arrows indicate clusters of bacm!. Fite-Faraco aCid-fast stain. AFIP neg. 67-1673. 40, 1 Wiersema & Binford: Histopathologic Identification of Tuberculoid Leprosy 29

nerves, the murine bacillus only involved sebaceous glands. A narrow rim of unin­ nerves when there had been a massive volved dermal tissue is usually noted at infection of all tissues including nerves. In several places between the inflammatory searching for nerve involvement in skin in:6.Itrate and the overlying epidermis. Ac­ lesions caused by mycobacteria, the pathol­ id-fast bacilli, often solidly stained, are usu­ ogist therefore must distinguish primary ally easily found in these subepidermal from secondary nerve involvement. zones. Some nerves, adjacent to or sur­ In massive, typical epithelioid cell rounded. by inflammatory infiltrates but inflammatory lesions of tuberculoid leprosy usually appearing well-preserved, contain most, and sometimes all, dermal nerves are occasional acid-fast bacilli. destroyed beyond recognition. If remnants In cases of tuberculoid leprosy with of incompletely destroyed nerves are prominent involvement of dermal nerves, present, acid-fast bacilli usually are not inflammatory in:6.Itrate is usually noted in difficult to find. The number of bacilli all levels of the dermis. In contrast to observed in nerves is usually in inverse lepromatous leprosy, superficial inflamma­ relation to the extent of damage of nerves. tory infiltrates do not spare the subepider­ In massive, atypical epithelioid cell mal zone but typically encroach on the inflammatory lesions of the skin in border­ basal cells of the epidermis. A subepider­ line leprosy, many dermal nerves are par­ mal clear zone is usually observed focally in tially preserved and contain acid-fast bacilli. borderline leprosy. In most instances the Outside of nerves in this form of leprosy largest inflammatory in:6.Itrates are located acid-fast bacilli are often noted in macro­ in the lower dermis around the nerves. phages. Klingmiiller (7) reported the occurrence In massive mycobacterial epithelioid cell of acid-fast bacilli in the immediate subepi­ inflammatory lesions of the skin that are not dermal zone of the skin of patients with caused by M. leprae, some well-preserved tuberculoid leprosy. He also suggested that nerves are usually found easily in the lower in leprosy the bacilli from active lesions are dermis but they do not contain bacilli. seeded by the bloodstream and lodge in Only, as was observed in our experimental small vessels of the skin particularly those studies of murine leprosy, nerves over­ around small nerves and appendages. whelmed by massive granulomatous Binford (3) demonstrated that inocula­ infiltrate may contain acid-fast bacilli but tion of the dermis of ears of golden ham­ they are more numerous in the in:6.Itrate sters with M. leprae frequently produced outside the nerve than within the nerve. In histologic evidence of leprotic involvement fact, even in such severe cases, the observa­ of dermal nerves but generally not before tion of acid-fast bacilli within the nerves is one year after inoculation, although inflam­ very rare . matory in:6.Itrate and evidence of multipli­ • Conspicuous leprotic nerve involvement cation of M. leprae was noted much earlier versus inconspicuous leprotic nerve involve­ in several experiments. The invasion of ment. Although nerves apparently are the nerves by M. leprae is a slow process. loci minores resistentiae for M. leprae in To us it is resonable to assume that tuberculoid leprosy, histologic nerve in­ inconspicuous involvement of nerves in volvement is not conspicuous in all biopsy lesions of the skin of patients with tubercu­ specimens of otherwise typical tuberculoid loid leprosy may occur if M. leprae are leprosy skin lesions. The lesions of tubercu­ seeded in the superficial, papillary dermis. loid leprosy in which dermal nerves gener­ Local proliferation of M. leprae will soon ally appear well-preserved and the inflam­ provoke a rather severe inflammatory re­ matory in:6.Itrate is not obviously localized sponse in the superficial dermis of persons around nerves are probably relatively who are allergic to the bacilli. In the young (Figs. 5, 6, 7). meantime, M. leprae may have invaded In cases of inconspicuous involvement of tiny nerve twigs of the superficial dermis dermal nerves, the greater part of the but the twigs cannot be recognized in inflammatory infiltrate is observed in the routine tissue sections. At the time the • superfIcial dermis, above the level of the superficial inflammatory infiltrate has be- 30 International Journal of Leprosy 1972

come clinically visible, most nerves of the ders; lymphocytes and plasma cells are not mid- and lower dermis are still not invad­ numerous. ed. In a biopsy specimen of such a lesion, The pathologist, however, should realize leprotic involvement of nerves will not be that his interpretation of a small portion of conspicuous. a lesion may not be in full agreement with On the other hand, lesions with evident the opinion of the clinician, who must make histologic involvement of nerves at the time his classification on the sum total of all data of biopsy may have originated from hema­ available on the case. togenous seeding of M. Zeprae in the lower levels of the dermis, close to well recogniz­ LEGAL, SOCIAL, AND MEDICAL able dermal nerves, for example in the IMPLICATIONS OF A DIAGNOSIS OF LEPROSY vicinities of the lower portions of hair folli­ cles. Or, M. Teprae may even have reached The pathologist who makes a definite the skin by spreading along nerve twigs diagnosis of leprosy on the examination of a from a focus in a subcutaneous nerve trunk. biopsy specimen should be aware that In case of progression of a local infection of several countries still enforce laws that lim­ . the skin the distinction between the two it the opportunities for work and for move­ types may be obscure, as for example in ments of leprosy patients and compel their Case 4. The observation of acid-fast bacilli treatment in leprosaria. A diagnosis of lep­ in the subepithelial zone suggests however, rosy may therefore incur severe financial that the infection orginated in the superfi­ loss to the patient even if he is not disa­ cial dermis. bled. It is a general practice that a diagno­ Tuberculoid leprosy versus borderline sis of leprosy may require immediate dis­ leprosy. Once the pathologist has recog­ charge from a military service. nized leprotic involvement of nerves in a In spite of the greatly improved progno­ biopsy specimen of the skin, the distinction sis for the leprosy patient that has resulted between tuberculoid leprosy and border­ from the use of effective sulfone drugs and line leprosy is usually not difficult in ep­ the efforts of enlightened health officials to ithelioid cell inBammatory lesions. integrate leprosy with other controllable In tuberculoid leprosy, nerves invaded infectious diseases, the social status of a by M. Zeprae are severely damaged and known leprosy patient, or a patient sus­ soon destroyed beyond recognition; epithe­ pected of having leprosy, is not enviable in lioid cells with occasional Langhans' giant many communities. cells form the centers of most inBammatory Once a definite diagnosis of leprosy has infiltrates. There are varying numbers of been made, treatment with drugs is indi­ lymphocytes in the peripheral portions of cated and lifetime use of the drug is often the inBammatory infiltrates; bacilli are recommended in order to prevent relapse difficult to find, except during phases of of the disease. severe reaction characterized by conspicu­ A pathologist should never make or ous plasmacellular and lymphocytic confirm a suspected diagnosis of leprosy infiltrate around epithelioid cell foci. Typi­ upon evidence other than that obtained cally in tuberculoid leprosy which is not from his own examination. In case of reactive, the inflammatory infiltrates are doubt, proposal of the examination of an­ usually well-circumscribed with clear-cut other biopsy specimen or consultation of boundaries. another pathologist is often far better for In borderline leprosy, the dermal nerves, the sake of the patient than to report a although invaded by M. Teprae, are usually diagnosis as "consistent with leprosy." Sus­ not destroyed beyond recognition; picion of leprosy can be reported verbally infiI.trates of nonspecifi c histiocytes are of­ to the clinician. Both the pathologist and ten noted next to the epithelioid cell the clinician should not be reluctant to infiltrates; bacilli are easily found in nerves consult their colleagues with experience in and often also in inBammatory cells; occa­ leprosy if they are inexperienced in the sional globi may occur; the inflammatory disease, even if there is little or no doubt infiltrate is often. massive with vague bor- about the diagnosis. 40, 1 Wiersema & Binford: Histopathologic Identification of Tuberculoid Leprosy 31

Pathologists, of course, should be aware cionales requieren que la lepra sea considerada of the possible legal implications that may como una posibilidad diagnostica en lesiones arise from 1) missing an obvious diagnosis de la piel 0 de los nervios, ha dado como of leprosy, and 2) making an erroneous resultado el que un numero significativo de casos posibles de lepra sean enviados en con­ diagnosis of leprosy. sulta al Armed Forces Institute of Pathology. SUMMARY Cuando se considera que la lepra es una de las posibilidades cHnicas, una biopsia de lepra Increasing awareness among pathologists lepromatosa act iva no debiera significar un that international travel requires that lepro­ gran proDlema para el patologo. Sin embargo, sy be considered as a diagnostic possibility las lesiones que muestran una reaccion granulo­ in lesions of the skin or nerves, results in a matosa de celulas epitelioides requiren un es­ significant number of cases of possible lep­ tudio histopatologico muy cuidadoso para po­ rosy being sent in consultation to the der diferenciar entre lepra y otras enfermeda­ Armed Forces Institute of Pathology. des de la piel caracterizadas por una reaccion granulomatosa con celulas epiteliodes. When leprosy is considered as a clinical Con el proposito de describir minuciosamen­ possibility a specimen of active leproma­ te las caracteristicas histopatologicas de la lepra tous leprosy should present no great prob­ tuberculoide, comparandola con la sarcoidosis ' lem to the pathologist. Lesions demonstrat­ y granulomas no leproticos de la piel produci­ ing an epithelioid cell granulomatous reac­ dos por micobacterias, se prepararon esquemas tion, however, require very careful histo­ de lesiones histopatologicas a partir de micro­ pathologic study in order to differentiate fotografias con pequeno aumento de casos ilus­ leprosy from other skin conditions charac­ trativos, para demostrar el tipo de infiltracion terized by an epithelioid cell granulomatous y la relacion del infiltrado y de los bacilos con los nervi os. reaction. De nuestro estudio se obtuvo evidencia de In an effort to pinpoint the histopatho­ que existian dos modelos de distribucion de las logic characteristics of tuberculoid leprosy alteraciones histopatologicas producidas por la and compare it with sarcoidosis and non­ lepra tuberculoide. En uno de elios la distribu­ leprotic mycobacterial granulomas of the cion del infiltrado seguia los nervios dermicos skin, histopathologic lesion profiles from mayores y menores, que por 10 general estaban low power photomicrographs were destruidos en forma total 0 subtotal, los ba­ prepared from illustrative cases to depict cilos, si se encontraban present~s , por 10 gen­ the pattern of infiltration and the relation­ eral se ubi caban en los sitios donde habian ship of the infiltrate and bacilli to nerves. estado los nervios destruidos, 0 en los rest os de nervios que aun persistian. En el segundo In our study two patterns of distribution modelo, en el cual el infiltrado era prominente of the histopathologic changes in tuber­ en la dermis superficial, se observaban por 10 culoid leprosy emerged. In one the dis­ general bacilos en la zona subepidermica y en tribution of the infiltrate followed the large los nervios que aun no estaban atacados por el and small dermal nerves which were usual­ infiltrado; la distribucion perineural del inffitra­ ly totally or subtotally destroyed and bacil­ do no era demasiado evidente. Este estudio li, if found, were usually at sites of de­ pone de relieve la especial predileccion del stroyed nerves or in remnants of persisting M ycobacterium Zeprae por los nervios. i nerves. In the second in which the infiltrate RESUM:£ was prominent in the superficial dermis bacilli were usually seen in the subepider­ Les pathologistes sont de plus en plus con­ mal zone and in nerves that were not yet scients du fait qu'a la suite des voyages inter­ nationaux, la lepre doit etre consideree comme involved by infiltrate; perineural distribu­ un diagnostic possible en cas de lesions ner­ tion of the infiltrate was not conspicuous. . veuses ou cutanees. En consequence, un nom­ The study emphasizes the peculiar pre­ bre notable de cas suspects de lepre sont en­ dilection of Mycobacterium leprae for voyes en consultation a l'Institut de Pathologie nerves. e des Forces Armees. (Armed Forces Institute of Pathology). RESUMEN Lorsque la lepre est consideree com me un EI hecho de que los patologos esten cada diagnostic c\.inique possible, l'examen d'une dia mas conscientes de que los viajes interna- preparation de lepre lepromateuse active ne • 32 International Journal of Leprosy 1972 devrait pas soulever de grave problemes pour Cette etude souligne la predilection particu­ Ie pathologiste. Toutefois, la presence de le­ liere de M ycobacterium leprae pour les nerfs. sions indiquant une reaction granulomateuse a cellules epithelioides, exige une etude histo­ REFERENCES pathologique tres soigneuse, afin de distinguer la lepre des autres conditions cutanees carac­ 1. BADGER, L. F. Epidemiology, Chapter VI. terisees par une reaction de ce type. In: Leprosy in Theory and Practice. R. G. Une etude a ete menee, afin de mettre en Cochrane and T. F. Davey, Eds. Bristo'l, evidence les caracteristiques histopathologiques John Wright & Sons, Ltd.; Baltimore, Wil­ de la lepre .tuberculoide, et de les comparer liams and Wilkins Co., 2nd ed., 1964, p. 69- avec celles relevees dans la sarcoidose et dans 97. des granulomes cutanes d'origine mycobacte­ 2. BECHELLI, L. M. and MARTINEZ DOMIN­ rienne non lepreuse. Les caracteristiques histo­ GUEZ, V. The leprosy problem in the world. pathologiques des lesions, telles quelles appa­ Bull. WId Hlth Org. 34 (1966) 811-826. raissent sur des photomicrographies a faible 3. BlNFORD, C. H. Transmission of Mycobac­ agrandissement, a partir de cas demonstratifs, terium Zeprae to animals. Nerve involve­ ont ete passees en revue, afin de montrer Ie ment in ears of hamsters. Internat. J. Lep­ schema d'infiltration, de meme que la relation rosy 33 (1965) 865-874. entre l'infiltrat des bacilles d'une part et les 4. BINFORD, C. H. Pathology-the doorway to nerfs d'autre part. the understanding of leprosy. American J. Au cours de cette etude, deux schemas sont Clin. Path. 51 (1969) 681-698. apparus en ce qui concerne la distribution des 5. FITE, G. L. , CAMBRE, P. J. and TURNER, modifications histopathologiques dans la lepre M. H. Procedure for demonstrating lepra tuberculoide. Dans l'un de ces schemas, la dis­ bacilli in paraffin sections. Arch Path. 43 tribution des infiltrats suivait les nerfs dermi­ (1947) 624-625. ques, gros et petits, qui etaient generalement totalement, ou presque totalement, detruits. Les 6. JADASSOHN, J. Ve!"handlungen der deutschen bacilles, quand ils etaient presents, se trouvaient dermatologischen. Gesellschaft 6 (1899) 508: generalement a l'endroit des nerfs detruits, ou quoted in Fite, G. L. Leprosy from the dans les vestiges des nerfs encore presents. histologic point of view. Arch. Path. 35 Dans Ie second schema, caracterise par Ie fait (1943) 611-644. que l'infiltrat predominait dans Ie derme super­ 7. KLINGMULLER, V. Die Lepra. Berlin, Julius ficiel, les bacilles etaient generalement observes Springer, 1930. dans la zone sousepidermique et dans les nerfs 8. RAMASOOTA, T., JOHNSON, W . C. and qui n'etaient pas encore atteints par l'infiltrat. GRAHAM, J. H. Cutaneous sarcoidosis and La distribution perineurale de l'infiltrat n'etait tuberculoid leprosy. Arch. Dermatol. 96 pas bien marquee. (1967) 259-268.