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Brit. J. vener. Dis. (1957), 33, 5.

COMPARATIVE STUDIES ON THE HISTO-PATHOLOGYOF SYPHILIS, YAWS, AND PINTA*t

BY

C. M. HASSELMANN+From the Universitdts-Hautklinik, Erlangen

The mass campaigns against treponemal diseasesin various countries undertaken by the UnitedNations World Health Organization (WHO) .andthe United Nations International Children's Emer-gency Fund (UNICEF) together with the respectivenational governments have again focused intereston the epidemiology, mode of transmission andinfection, clinical manifestations, and control andtreatment, of these treponematoses, viz. syphilis,framboesia tropica (yaws), and pinta. The magnitudeof the various yaws control programmes in theworld is illustrated by the fact that more than 60million people have been examined and over 10million treated. In Indonesia alone, where the largestprogramme is under way, the figures show that,during the first survey, between June 1950, and June1956, over 20 million people were examined out ofan estimated total population of 27 million in thecampaign areas, and a little more than 2-9 millioncases of yaws were treated. During the secondsurvey nearly 23 million people were examined, anda little more than one million treated. Although inSouth-East Asia and the Pacific Islands the inci-dence of yaws varies greatly fronA one country toanother, the average seems still to be about 10 percent. for the first survey, with my own data collectedin Indonesia in 1950 to 1951 indicating an overallincidence of 17 7 per cent. in the different targetareas then under survey. When assessing the yawscampaign in the Philippines in 1952, I found anincidence of less than 10 per cent. in the targetareas, with cumulative data indicating nearly 200,000cases treated out of about 3 5 million examined(i.e. about 5 - 7 per cent.).

Apart from their respective causative treponemes(Treponema pallidumn of syphilis, Treponemna pertenueof yaws, and Treponemna pinta Herrejoni of pinta)

and different modes of transmission, the variousclinical lesions typical of each of these three tre-ponemal diseases are conditioned by their distinctivebehaviour in the host's tissues.

This precise "histio-biotropism" governs, in itsturn, both the morphology and the histo-p4thologyof the various clinical manifestations, as establishedby human and animal experimental evidence(Goodpasture, 1923; Sellards, Lacy, and Sch6bl,1926; Schobl, Sellards, and Lacy, 1926; Schobl andSellards, 1926; Schobl, 1928; Schobl and Hassel-mann, 1932; Hasselmann, 1930, 1931, 1932, 1933,1938a,b, 1949, 1951, 1952, 1953a,b,c, 1955;Turner, 1937; Turner, Hollander, and Schaeffer,1953; McLeod and Turner, 1946; Hollanderand Turner, 1955).

SyphilisWhereas the primary indurated papular lesion in

syphilis may soon progress into the well-knownsharply punched-out ulcer, or "hard chancre", theinitial framboetic papular lesion soon grows into apapilloma, without any tendency to necrosis at thisearly stage of the yaws infection.

In syphilis, the usual necrosis of the primaryindurated papular lesion leading to the typical hardchancre is obviously due to the direct toxic actionof T. pallidum. The epidermis proper may show onlymoderate acanthosis and spongiosis. In the cutis,rather sharply outlined infiltrations consist of roundcells, fibroblasts, and histiocytes, some of which maybe already of the epithelioid type, plasma cells, someeosinophils, and even occasional giant cells. Incontrast to the plasma cells often dominating thecellular infiltrates in yaws, the plasma cells in syphilisoccasionally show marked evidence of hyalinedegeneration. The most conspicuous features insyphilis, both in the primary papular stage andchancre as well as in the secondary syphilides, arethe frequent pronounced inflammatory changes inthe intima and media of the capillaries, with cellular

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* Received for publication December 1956.t Paper given at the 7th International Congress of Comparative

Pathology, Lausanne, Switzerland, 1955.$ Formerly W.H.O. Chief Medical Adviser to the Treponematosis

Control Programme, Indonesia, and Special Consultant to the Philip-pine Treponematosis Control Programme.

on January 16, 2020 by guest. Protected by copyright.

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BRITISH JOURNAL OF VENEREAL DISEASES

proliferation, and evenna (Figs 1-4).

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Fig. !.-Perigenital syphilitic papule (Condyloma latum). Prolifera-lion of intima and media with partial obliteration, cellular infiltrate.

(All sections stained by haematoxylin and eosin.)

Fig. 2.-Syphilitic papule with extensive perivascular infiltratest and

vascular pathology with partial obliteration of lumen.

Fig. 3.-Syphilitic papule: extensive vascular pathology with partial

obliteration of the lumen.

Fig. 4.-Late tubero-serpiginous syphilide. Massive vascular pathology.

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HISTO-PATHOLOGY OF SYPHILIS, YAWS, AND PINTA

YawsIn contrast, the initial framboetic papule soon

grows into a papilloma (Figs 5, 6, and 7), nearlyalways with an exuberant inflammatory responsein the epidermis and cutis. The characteristichisto-pathological architecture both of the initialyaws papule, or papilloma, and of the metastaticgeneralized polypapillomata is the usually enormousacanthosis of the epidermis proper, and the severeinflammatory changes in corium and cutis with thecommon appearance of a "plasmocytoma". Hyper-keratosis and parakeratosis soon cannot be seenbecause of the early loss of the stratum corneum andthe stratum granulosum, respectively. The stratumspinosum shows very marked broadening of itsentire width, usually an enormous downgrowth ofthe rete pegs into the cutis and even into the sub-cutis. Intra- and inter-cellular oedema is marked,with occasional vacuolization and degeneration,including disappearance of pigment. Often, dia-pedesis of neutrophils may lead to the formation ofmiliary intra-epidermal micro-abscesses, so typicalof yaws. However. so-called "epidermiolysis" maybe present, but without the otherwise typical"dropped-off" or hazy, "moth-eaten" phenomenonencountered, e.g. in lichen ruber planus. Theinflammatory response of the tissues may be somarked that clinically the epidermal surface is lost,serum oozes out, and a non-adherent, yellowishcrust results, consisting of dried serum and epi-dermal scales covering the soft, non-induratedpapilloma.

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Fig. 6.-Polypapillomata framboesica: these lesions around the facialorifices might easily lead to rhinopharyngitis mutilans ("gangosa")

through obvious allergic exacerbation.

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Fig. 5.-Initial so-called "primary" mother-yaws papilloma with"lymphogenic" local "daughter-yaws".

This usually enormous inflammatory pathologyin the corium and cutis attests to the acute responseof these mesodermal parts. Both stratum papillareand stratum reticulare show an extremely loosecellular infiltration, markedly oedematous, withpredominating plasma cells, fibroblasts, and histio-cytes, some of which are already of the epithelioidtype, with round cells, and a few eosinophils; giant Fig. 7.-Polypapillomata of the metastatic generalized stage of yaws.

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8 BRITISH JOURNAL OF VENEREAL DISEASES

cells are rarely encountered. In this typical "plasmo- ricytoma" the blood vessels are not affected, either el ' #4in the initial yaws papule or papilloma, or in the e

metastatic polypapillomatous efflorescences. Intimaand media remain quite intact, there being neithercellular infiltration nor endothelial proliferation $ i8(Figs 8, 9, 10, 11, 12, 13). No coagulative necrosisN:.f

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Fig. 8.-Yaws papilloma. Enormous acanthosis and loose cellular Fig. 9.-High magnification of Fig. 8. Extremely loose celinfiltrate in conium and cutis, mainly of plasma cells ("Plasmocytoma"). infiltrate of corium and cutis with many plasma cells. No psthc

of intima or media.A.'~~~~~~~~~~~~~~~~~~~N'

Fig. 10.-Yaws papilloma: medium magnification. Migration of Fig. 11.-High magnification of Fig. 10 showing penineutrophils through epidermis, formation of intra-epidermal micro- vascular infiltrations, but with normal intima and

abscesses. No vascular pathology of intima or media. media,

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HISTO-PATHOLOGY OF SYPHILIS, YA WS, AND PINTA

occurs and consequently no ulcer formation results.Experimental evidence appears to suggest that onlyin the very late stage of framboesia tropica doessudden necrosis with ulceration set in, if and when

Fig. 12.-High magnificationof Fig. 11. Perivascular infil-trate with plasma cells, fibro-blasts and histiocytes, somebeing of the epithelioid type.

No vascular pathology.

sensitization has developed to such an extent thatany sudden increase of antigen may enhance anapparent allergic exacerbation of pre-existing skinlesions.

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Fig. 13.-High magnificationof Fig. 11. Slight perivascularinfiltrates in upper corium;

normal walls of vessels.

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In the field and dispensaries, patients with ulcera-tions may be numerous, and it always remainsdifficult to ascertain the exact pathogenesis in theselate yaws cases. Experimentally, Schobl and others(1928) succeeded in reproducing in the PhilippineMacaccus cynomolgus all clinical stages of yawsincluding ulcerative rhinopharyngitis mutilans("gangosa") (Fig. 14).

Fig. 14.-Rhinopharyngitis mutilans ("gangosa") of the late ulcera-tive stage of yaws.

Schobl stated:"Initial or metastatic yaws on mucous membranes

are not known to exist; but direct spreading of primaryor metastatic yaws from the skin across the directmuco-cutaneous border on to the mucous membranesis by no means an uncommon occurrence. This speaksin favour of my contention that the starting point ofgangosa is the skin yaw or late ulcerating yaws lesion,extending directly on to the mucous membrane, . . .

that the histo-pathological process affects a veryextensive area of the mucous membrane, far greaterthan the area which actually undergoes the realulceration in any stage of the development of thecondition, . . . by direct extension of skin lesions,either early (by super-infection) or late, on to themucous membranes of the nose shows that this modeof pathology is the commonest if not the only one."

Since then no further experimental work has beenconducted to increase our knowledge of ulcerationscaused by framboesia alone, including those givingrise to the bone lesions which are not frequently seenin the field but are yet so important (Hackett, 1946).Experimentally, we have never seen bone lesionsdevelop except from pre-existing skin lesions, whichare encountered during the stage of metastaticgeneralization as well as during the later stages.Since treponemata have never been demonstratedin these bone lesions, or in the similar syphiliticlesions, it may be safe to assume that the bonechanges are toxic, perhaps allergic. This view issupported by Chiari (1938), who described identicalbone changes in children with long-standing pyo-dermia.

This "toxic" or "allergic" pathogenesis applies tothe hyperkeratotic, often fissured, keratodermia ofthe soles of the feet and/or the palms of the hands inlate yaws which is seen in over 50 per cent. of yawspatients in the field (Fig. 15). No treponemes arefound in these lesions, which must be strictly differ-entiated from the common clavus thickening. Theymay be compared with the obviously "allergic"palmar and plantar hyperkeratoses occasionallyobserved in chronic gonorrhoea.

Fig. 15.-Keratodermia plantaris framboesica, with extensive hyper-keratosis and deep painful fissures.

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HISTO-PATHOLOGY OF SYPHILIS, YAWS, AND PINTA

Histo-pathological changes in rhinopharyngitismutilans (gangosa) occur, frequently because of theclose ontogenic relationship of the mucous mem-branes of the facial orifices to the adjacent outerskin. In embryo-genesis, upgrowth of the mandi-bular arch and nasal and maxillary processes aroundthe stomodeum forms the final facial contours. Fora time, the ectodermal lining comes into directcontact with entoderm of the fore-gut, pressingaside the intervening mesoderm. Incidentally,gangosa pathology affects the mucosa only up tothe area which coincides both with the pocket ofSessel and with the sensory border of the maxillarytrigeminus ramus. As to intimal or medial path-ology so typical of syphilitic ulcerations, Hallen-berger (1916) stated that in gangosa, too, the bloodvessels show no changes.

It is imperative to realize that the clinical mor-phology and the relevant histo-pathology of theinitial "primary" yaws lesion are identical withthose of the metastatic polypapillomata, whereasin syphilis both the morphology and the histo-pathological architecture are quite distinct in theprimary syphilitic chancre and the various secondarysyphilides.Pinta

In this disease, the histo-pathological architectureis similar to that found in yaws, except that allergicexacerbation of existing skin pintides with ulcerformation never occurs. Hence, clinically, pintaefflorescences are not known to break down. Incomparison with the histo-pathological changes inyaws, the inflammatory changes in pinta are of onlyvery moderate degree. Acanthosis is only slight,and leucocytic diapedesis is minimal without theformation of intra-epidermal abscesses.

In pinta, there is the same singular freedom fromvascular pathology at all stages of the disease, andin all clinical manifestations. At most, in pintides oflong standing, a slight swelling of some endothelialnuclei of the intima may be noticeable (Figs 16. 17, 18).

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Fig. 17.-Scaly circinate pintide. Marked hyperkeratosis, atrophy ofrete malpighi from pressure underneath of oedematous corium, withpathological perivascular infiltrate. Intact intima and media.

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Fig. 16.-Pintide. Sl.ght parakeratosis, acanthosis, and spongiosis;moderate perivascular infiltrates in cutis. No pathology of intima or

media.(I am indebted for this biopsy material to Dr. FraoAisco 1. Marquez,

Mexico, D.F.).

Fig. 18.-Pintide, high magnification showing only slight swelling ofendothelial nuclei, without proliferation of intima, and no narrowing

of capillary vessels.

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ConclusionDuring both the early stages of yaws with the

initial papular, or papillomatous lesion, and theso-called "secondary" framboesial period withmetastatic polypapillomata, the characteristic ten-dency of T. pertenue to affect the upper layers of theskin only, without affecting the cardiovascular andcentral nervous systems, may be described as the"epidermiotropism" of yaws treponemes.

In this connexion it may not be amiss to pointto the painstaking research of Williams (1935) andof Cole, Harkin, Kraus, and Moritz (1955) whofound numerous examples of bone lesions on theAmerican continents dating from pre-Columbiantimes, but none whatsoever in Europe, Africa, orAsia before 1494. As mentioned above, experi-mental evidence established that it is only in thelater periods of the framboesial disease, when adefinite allergic stage already exists, that any suddenincrease in antigen production may result in anexacerbation of yaws lesions with subsequentulcerations and the typical allergic histo-pathology.

In contrast, the well-known syphilitic pathologyaffecting both intima and media with proliferationof the intima, and with the narrowing and evenobliteration of the vascular lumina (Heubner'sendarteritis), is definite evidence of the preference ofT. pallidum for the mesodermal layers, i.e. "meso-dermotropism". Alternatively, inasmuch as T. palli-dum invades and affects all layers, the term "pan-blastotropism" might be used for the treponema ofsyphilis.

Finally, since Weichbrodt and Jahnel (1919)pointed out that the treponemes are "frigitropic"and "thermophobic" (Bessemans, 1937), it has beenestablished that:

experimental results suggest that the optimum tem-perature for the in vivo multiplication of treponemesis in the neighbourhood of 350 to 37°C. and that thedevelopment of treponemal lesions in a given tissueis related, in part at least, to the approximation of thelocal temperature to this level (Hollander and Turner,1955).

Hence, apart from the distinct preference for thevarious skin layers of the treponemes causingsyphilis, yaws, and pinta, the existing local tempera-ture appears to condition, at least to some extent,both the appearance and clinical morphology oftreponemal pathology.

In spite of the decline in the incidence of syphilisapparently due to the spectacular and still unfailingtherapeutic efficacy of the penicillins, and to bettersocial and follow-up conditions, many practical

as well as scientific problems still remain regardingsyphilis, as long as T. pallidum survives, and foci ofinfection persist. Not the least will be the increaseof syphilis among people in the tropics where yaws,which had guaranteed a relative cross-immunityagainst naturally-acquired syphilis, has now been somuch reduced as a result of successful mass treatmentcampaigns (Manson-Bahr, 1954).

Summary(1) The comparative histo-pathology of syphilis,

yaws, and pinta is discussed.(2) The distinct tendency of both the T. pertenue

of yaws, and of the T. pinta (carate) of pinta toaffect the upper layers of the skin only, withoutaffecting the cardiovascular and central nervoussystems, and the non-existence of congenital yawsor pinta may be described as "epidermiotropism".By contrast, the well-known syphilitic changes ofthe inner organs and the cardiovascular and centralnervous systems are indicative of what may betermed the "mesodermotropism" or "panblasto-tropism" of T. pallidum.

(3) This different biological behaviour in thetissues of the host largely explains the differences inthe clinical and pathological symptoms and lesionsin these diseases.

REFERENCES

Bessemans, J. F. A. (1930). Urol. cutan. Rev., 34, 71.Chiari, 0. von (1938). Arch. Kinderheilk., 115, 149.Cole, H. N., Harkin, J. C., Kraus, B. S., and Moritz, A. R. (1955).

A.M.A. Arch. Derm. 71, 231.Goodpasture, E. W. (1923). Philipp. J. Sci., 22, 263.Hackett, C. J. (1946). Trans. roy. Soc. trop. Med. Hyg., 40, 206.Hallenberger, -. (1916). Arch. Schiffs-u. Tropenhyg., 20, Beiheft 3.Hasselmann, C. M. (1930). Zbl. Haut-u. GeschlKr., 33, 273.

(1931). China med. J., 45, 1131.(1932). Caduceus, 11, 105.(1933). China med. J., 47, 584.

-(1938a). Ber. phys. med. Ges. Wurzburg (1937), n.s. 61, 51.(1938b). Arch. Derm. Syph. (Chicago), 38, 837.(1949). Arch. Derm. Syph. (Berl.), 189, 340.(1951). O.S.R. News (Indonesia), 3, 156.(1952). A.M.A. Arch. Derm. Syph., 66, 107.(1953a). J. sci. Res. (Djakarta), 2, 39.

-(1953b). Amer. J. Syph., 37, 151.(1953c). Z. Haut-u. GeschlKr., 15, 347.(1955). Zbl. Bakt. 1 Abt. Orig., 164, 289.

Hollander, D. H., and Turner, T. B. (1954.). Amer. J. Syph., 38, 489.McLeod, C., and Turner, T. B. (1946). Ibid., 30, 442.Manson-Bahr, P. E. C. (1954). Trans. roy. Soc. trop. Med. Hyg., 48,

242.Schobl, 0. (1928). Philipp. J. Sci., 35, 209.

and Hasselmann, C. M. (1932). Arch. Schiffs-u. Tropenhyg., 36,Beiheft 2.

and Sellards, A. W. (1926). Philipp. J. Sci., 31, 1.-, and Lacy, G. R. (1926). Ibid., 30, 475.

Sellards, A. W., Lacy, G. R., and Schobl, 0. (1926). Ibid., 30, 463.Turner, T. B. (1937). Amer. J. Hyg., 25, 477.

Hollander, D. H., and Schaeffer, K. (1953). Bull. Wld Hlth Org.,8, 7.

Weichbrodt, R., and Jahnel, F. (1919). Dtsch. med. Wschr., 45, 483.Williams, H. U. (1935). Arch. Path. (Chicago), 20 .596.

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