- Email: [email protected]
Herpetiform ulceration
Herpetiform ulceration Ralph I. Brook?, B.Ch.D., L.D.S., M.R.C.S., L.R.C.P., P.D.S.R.C.S.,” J. Philip Sapp, D.D.S., M.S.,“” Losdo)L, Onta,rio, Canada FACULTIES WESTERN
OF MEDICINE
AND
DENTISTRY,
THE
UNIVERSITY
and
OF
OSTARIO
The rationale for the clinical existence of a less commonly found form of recurrent oral ulceration, herpetiform ulceration (HFU), is presented, illustrated by six clinical cases. The clinical and laboratory features that separate it from recurrent herpetic ulceration (RHU) and recurrent minor aphthous ulceration (RAU) are discussed. Although a viral cause has been proposed for this condition, based on the finding of intranuclear bodies, electron microscopic and other laboratory investigations by the authors indicate that there is insufficient evidence at present to confirm this. Since HFU does have a significant number of histologic and immunologic features in common with recurrent aphthous ulceration, it is thought that it should be considered to be a variant of this condition until the true cause of it is revealed.
I
n 1960, Cooke1 described a form of oral ulceration characterized by recurrent crops of multiple small, shallow lesions, often twenty or more in number, that occurred on both keratinizing and nonkeratinizing tissues of the mouth and oropharynx. In describing the two cases used to illustrate the condition, Cooke pointed out the clinical similarities of the lesions to those caused by herpes simplex, without the corresponding histologic changes. In fact, the histologic features of the early lesions were nearly identical to those seen in aphthous ulceration. The additional fact that he could induce immediate temporary healing with a 2 per cent tetracycline mouthwash was considered by him to be an important feature of this condition, which he chose to call “herpetiform” ulceration. Since Cooke’s original paper, other authors*-” have found it useful to include such an entity in their clinical classification and treatment of oral ulcerations, although many still do not recognize its existence as a clinical condition, separate from a minor aphthous ulceration or recurrent herpes simplex infections. *Professor and Chairman, Department of Oral Medicine. **Department of Pathology, Division of Oral Pathology.
782
I7olume Sumber
Herpetifornz
42 2
ulceration
183
In this article, we will use clinical histories of what we think represent cases of herpetiform ulceration, in order to illustrate the spectrum of clinical findings in this condition and to show how it differs from both recurrent aphthous ulceration (RAU) and recurrent intraoral herpetic ulceration (RHU). The pertinent literature on the laboratory aspects of the subject will be reviewed and correlated with the results of some of our own investigations in an attempt to illustrate that, although herpetiform ulceration (IIFIJ) can be substantiated as a clinica: entity, its causation is still unknown. CASE REPORTS CASE 1
A 31.year-old woman developed numerous small, painful oral ulcers that began on the tongue but soon involved both lips and gingivae. The ulcers, which at first were of pinhead size, gradually enlarged and often coalesced. The patient had been given prednisolone and several local medicaments by her own physician, but without effect. Six months after the onset of the lesions, a rash developed over the extensor surfaces of the thighs and arms and on the face and breasts. These latter lesions were diagnosed as pityrinsis rosea, which soon responded to a cream prescribed by a dermatologist. The medical history was otherwise unremarkable. At thn time of examination in our clinic, there were multible small ulcers on the tongue and lips. The lesions responded to x 2 per cent tetracycline mouthwash, with immediate relief from the pain, followed by healing of the ulcers. The tetracycline WLS used for 4 days, and the patient remained free of ulcers for about 1 month. Recurrences followed, and the patient was made more comfortable with applications of Orabase. CASE 2
A 3%year-old woman had a 3-year history of multiple “canker sores.” The lesions first appeared after a prophylaxis. The patient stated that she “always had ulcers in the mouth, at least a couple of dozen at a time, which began as dots and got bigger.” Many medicaments had been tried without effect. No lesions were present elsewhere on the body, but on one occasion an intraoral vesicle was seen. Examination revealed numerous ulcers on the tongue, buccxl mucosa, and lips. The patient responded immediately to tetracycline therapy. CASE 3
A male patient, 38 years old, had had recurrent ulcers in occured mostly on the palate (Fig 1) and lips. The patient was which were associated with great discomfort. On one occasion, driver, became so distraught that he stopped his bus, which was a dentist’s office in order to seek advice on how to relieve the relief of his symptoms with a 2 per cent tetracycline mouthwash, 7 week.
the mouth for 2 years. They seldom free from ulcerations, the patient, who was a bus filled with passengers, outside pain. He received immediate and the lesions healed lvithin
CASE 4
When first were “pinhead always on the “rarely without rinse, but this topical steroids.
seen, a 23-year-old woman had a 2%-year history of recurrent oral ulcers. They in size but ran together. ” The lesions occurred in all parts of the mouth, but tongue. The patient had over sixty ulcers when originally seen, and she was an ulcer.” She received immediate relief at first with a 2 per cent tetracycline treatment became ineffective after a time. Some relief was again obtained mith
CASE 5
A SG-year-old man had a 3-year history of multiple small ulcers throughout the mouth. There mere “forty or fifty ulcers at a time.” The tongue and lips were most severely affected (Fig. 2). Response to a tetracycline mouthwash produced remissions for as long as a month,
Brookc attd Xapp
184
B$.
1. Case 3. Palatal
lesions in a S&year-old
Fig. 8. Case 5. Lip and tongue condition.
man. The patient
lesions in a S&year-old
man with
also had lip lesions.
a a-year history
of the
CASE 6
A 35year-old man had suffered from recurrent ulcerations for 5 years. On occasion, fifty ulcers or more would occur; t.hese involved mostly the tongue (Fig. 3). Until he was seen in our clinic, remissions were rare, lasting less than 1 week. The condition readily responded to n tetracycline mouthwash.
METHODS
Biopsy specimens of the lesions were examined with the light microscope in all cases, and with the electron microscope in Cases 1 and 3. Prior to biopsy, smears were taken for cytologic examination. Viral cultures were performed in Cases 1, 2, and 4. In Cases 1 and 2, immunofluorescent techniques were used in an attempt to find autoantibodies to human and mouse skin within the marginal epithelium surrounding the lesions and the patient’s serum.
Volume Number
42 2
Fig. 3. Case 6. Tongue lesions in a X-year-old man with a S-year history of ~‘ecu~‘~‘~mccs. On occasion, fifty or more ulcers would lx present, involving mostly the tongue.
RESULTS light
microscopy
The most, constant finding by light microscopy was that of a shallow ulcer with a fibrinopurulent, exudate fillin g the crater, level with the surface (Fig. 4). At the margins, the ulcer frequently extended into the surrounding stratum spinosum, producing a slight cleft. The cells of the stratum spinosum in the immediate area of the cleft contained both intercellular and intracellular edema. In some of the adjacent areas, further removed from the clefts, the cells of the stratum spinosum containetl both clear ~11s with prominent, (lark, centrally placed nuclei, and eosinophilic cells with intensely staining cytoplasms. Infrequent findings were small intraepithclial vesicles of eosinophilic fluid and inflammatory cells within the stratum spinosum (Fig. 5). The epithelium surrounding these vesicles appeared to be undergoing severe tlcgenerativc changes and was very atrophic. This condition was interprctctl to rcprcsent a stage of necrosis prior to ulceration. The underlying conncctivc tissue rontaincd a predominantly lymphocytic infiltrate which was mild in the superficial areas beneath the cpithelium, but which extcntlcd deeply into the arcas bcncath the ulcerations. The routine microscopic diagnosis of the tissue submitted was usually reported to bc a nonspc4fir ulceration. Electron
microscopy
In the cases examined ultrastructurally, it was apparent that the intermediate cells of the stratum spinosum in the margins of the ulcer were generally larger in size. The nuclei of these cells were large and smooth, with little peripheral heterochromatin, and frequently contained more than one large nucleolus. Nultiplc sections through the epithelial cells from the periphery of the ulcers ciid not rcvcal viral bodies typical of herpes simplex.” Intranuclear inclusion
186
Brooke
Oral Surg. August, 1976
and Sapp
Fig. 4. Typical histology of the shallow ulcers with the fibrinopurulent exudate filling the crater and the “clefting” of the peripheral epithelidm. (Magnification, x40.) Fig. 5. Photomicrograph of an infrequently found intraepithelial vesicle exhibiting degeneration of the surrounding epithelium and a lymphocytic infiltrate within the underlying connective tissue. (Magnification, x100.)
bodies were commonly elsewhere. Viral
found
in these cells and will
be reported
on in detail
cultures
Viral
cultures were negative for all cases in which they were performed.
lmmunofluorescent
studies
The lesions were negative for autoantibodies in both Cases 1 and 2. In Case 2, the serum was negative for antibodies at all dilutions with the use of human skin, but was weakly positive for pemphigus antibodies with the use of mouse skin at 1:4 dilutions. It was negative for dilutions of 1:16 and 1:64. In Case 1, serum was negative at all dilutions with the use of both human and mouse skin. DISCUSSION
The cases presented all had the following clinical features in common: (1) There were numerous small, shallow lesions that could be found on any intraoral
Volume Number
42 2
Herpe~~form ulceration
187
mueosal surface. (2) The lesions began as small pinhead-sized erosions that gradually enlarged and eventually coalesced. (3) The lesions were more painful to the patient than would be suspected by their size. (4) The lesions were present almost continuously for 1 to 3 years, with relatively short remissions. (5) The patient received immediate but temporary relief from the symptoms when treated with a 2 per cent tetracycline mouthwash. (This latter statement is based on the subjective reports of paGents and not on a controlled clinical trial.) Since most of these clinical features are reminiscent of a recurrent herpetic infection, many clinicians, who do not further investigate such cases, may mistakenly diagnose them as recurrent herpes infections and treat them accordingly. If laboratory tests are empIoyed in such cases, it is soon found that. : (I ) t.he herpes simplex virus cannot be isolated by culture or found by electron microscopy; (2) repeated cytologic smears fail to reveal the typical multinucleated epithelial giant cells found in the herpetic lesions; (3) the findings by light microscopy are nearly identical with those described for recurrent aphthous ulcers; and (4) immunofluorescent and serologic techniques are negative for antibodies to herpes virus. These results may lead to a diagnosis of recurrent aphthous ulceration. Because of these conflicting features, many British investigators have, for some time, thought that such cases deserve a special clinical category and have advocated the term herpetiform alceratio)z. They believe that proved recurrent. intraoral herpetic stomatitis is rare and that most cases thus diagnosed actually represent various forms of recurrent aphthous ulcers or herpetiform ulceration. Lehner,4 in analyzing the clinical, pabhologic, and immunologic features of 210 cases of recurrent oral ulceration, has classified them into three main groups: (1) major aphthous ulcerations, (2) minor aphthous ulcerations, and (3) herpetiform ulceration. Also included in his classification were the recurrent oral ulcerations associated with Behcet’s syndrome. Evidence was presented to show that the category of major aphthous ulcerations (periadenitis mucosa necrotica rccurrens) is not a distinct entity but merely a larger-sized variant of recurrent minor aphthous ulceration (RAU) . In his study, the rarity of herpetiform ulceration was pointed out, in that he could define it in only 9 per cent of the 210 cases. Sixty-three per cent of the patients suffered from minor aphtbous ulcerations, and 12 per cent had major aphthac. The remainder had recurrent oral ulcerations associated with Behcet’s syndrome. ldehner and Sagebicl,’ in a attempt to differentiate minor aphthous ulcerations from herpetiform ulceration by means of light and electron microscopy, had findings similar to those obtained by us in this investigation. As mentioned above, the significance of these will be discussed in another article. The possibility that major, minor, and herpctiform variants of aphthous ulceration may represent an immune condition has also been investigated.33 + IN* In a review of some of these studies by Francis,ls it was pointed out that the early aphthous lesions were clinically, microscopically, and immunologically very similar to the oral lesions of Behcet’s syndrome. Lehner* has presented immunologic evidence to support his contention that minor aphthous ulcers and major aphthous ulcers are two closely related varieties of the same condition, and that the lesions associated with Behcet’s syndrome cannot be differentiated by means
Oral Surg. August, IQ76
of immunologic techniques from either type of aphthous ulceration or from herpetiform ulceration. As long ago as 1941, Touraino’” suggested that aphthous ulceration may, in fact, he at one end of a spectrum of disease which in its mildest form presents as the occasional minor aphthous ulcer and in its severest and most, widespread form involves other mucosal tissues, sucl~ as eyes and genitals, i.e., Behcct’s syntlromr. If this concept of “aphthosis ’ is eventually proved to be correct, it may well be tha.t herpct.iform ulceration will fit into the over-all picture. l’ntil such a unifying pathogcncsis is evolved, we think that thr concept of ITFII as it separa.tc clinical entity, as originally suggested h?- Cooke, is justified. Some of t,hc cases illustrated were seen in the clinics of’ the Leeds Dental School and Hospital, and we wish to thank Professor F. E. Hopper and Mr. John \Viggles~vorth for thei] help and adviw during the management of those craws. REFERENCES
the Oral Mucosx Br. Dent. 1. (:ooko. H. E. I).: The Diagnosis of Bullous Lesions Afrectinlr J. 109’:%-96, 1960. = Findings in Recurrent Oral Ulceration, 2. Lehner, T., and Sagebiel, R. TV.: Fine Structural Br. Dent. j. 121: 4514-456; 1966. and Manawment of Recurrent Oral Ulecration. Br. Dent. J. 3. Lehner. T.: Autoimmunitv ., 122: l&20, 1967. in Oral Diseases, With Special Reference to Recurrent Oral 4. Lehner, T.: rlutoimmunity Ulceration, Proc. R. Soe. Med. 61: 515-521, 1968. 5. ('dWSOl1, R. A.: Essentials of Dental Surgery and Pathology, etl. 2, London, 1968, J. 6r A. Churchill, Ltd., p. 199. 6. Carson, R. A.: Oral Ulceration-Clinical Aspects, O~ar, SVRG. 33: 912-921, 1972. 7. Kay, L. W.. and Haskell. R.: Color Atlas of Oro-Facial Diseases, Chicago, ., 1971, Year Booi Mrdic& Publishers, i. 240. 8. Dolby, A. E.: Management of Recurrent Oral Ulceration, Practitioner 210: 403-408, 1973. 9. Pindborg, J. .T.: Atlas of Diseases of the Oral Murosa, rd. 2, Copenhagen, 19i3, Ejnar Munksgtcard, 1,. 140. In Dalton, A. J., and Haguenau, E’.: Ultra10. Roizman, B., and Spear, P. G.: Herpesviruses. structure of Animal Viruses and Bacteriophages, Nrw York, 1973, academic Press, vol. 5, pp. 83-I 07. Effects of Scra and Peripheral Blood Aphthous Ulcerations. 11. Dolby, A. E. : Recurrent Lymphocytes Upon Oral Epithelial Tissue Culture Cells, Immunology 17: 709-774, 1969. 12. Dolby, A. E.: Mikulicz’s Recurrent Oral Aphthae. Histopathological Comparison With 2 Xxperimentnlly Induced Immunological Reactions, Br. J. Dermatol. 83: 674-679, 1970. 13. Addy, A., and Dolby, A. E.: Aphthous Ulcerat.ion: The Anti Nuclear Factor, J. Dent. Res. 51: 1594-1595, 1972. Aphthous E. A., Barile, M. F., Lee, W. B., and Stanely, H. R.: Recurwnt 14. Grnykowski, Rtomntitis, J.A.M.A. 196: 637-644, 1966. 13. Francis, T. C.: Recurrent Aphthous St,omatitis and Behcet’s Disease, ORAI, SURG. 30: 47648i, 1970. 16. Touraine, 112. D.: L’Aphthose, Buli. Sot. Franc. Derm. Syph. 48: 61-103, 1941. Reprint requests to: Dr. R. I. Brookc Department of Oral Medicine Faculty of Dentistry The University of Western Ontario London, Ontario, Canada
OF MEDICINE
AND
DENTISTRY,
THE
UNIVERSITY
and
OF
OSTARIO
The rationale for the clinical existence of a less commonly found form of recurrent oral ulceration, herpetiform ulceration (HFU), is presented, illustrated by six clinical cases. The clinical and laboratory features that separate it from recurrent herpetic ulceration (RHU) and recurrent minor aphthous ulceration (RAU) are discussed. Although a viral cause has been proposed for this condition, based on the finding of intranuclear bodies, electron microscopic and other laboratory investigations by the authors indicate that there is insufficient evidence at present to confirm this. Since HFU does have a significant number of histologic and immunologic features in common with recurrent aphthous ulceration, it is thought that it should be considered to be a variant of this condition until the true cause of it is revealed.
I
n 1960, Cooke1 described a form of oral ulceration characterized by recurrent crops of multiple small, shallow lesions, often twenty or more in number, that occurred on both keratinizing and nonkeratinizing tissues of the mouth and oropharynx. In describing the two cases used to illustrate the condition, Cooke pointed out the clinical similarities of the lesions to those caused by herpes simplex, without the corresponding histologic changes. In fact, the histologic features of the early lesions were nearly identical to those seen in aphthous ulceration. The additional fact that he could induce immediate temporary healing with a 2 per cent tetracycline mouthwash was considered by him to be an important feature of this condition, which he chose to call “herpetiform” ulceration. Since Cooke’s original paper, other authors*-” have found it useful to include such an entity in their clinical classification and treatment of oral ulcerations, although many still do not recognize its existence as a clinical condition, separate from a minor aphthous ulceration or recurrent herpes simplex infections. *Professor and Chairman, Department of Oral Medicine. **Department of Pathology, Division of Oral Pathology.
782
I7olume Sumber
Herpetifornz
42 2
ulceration
183
In this article, we will use clinical histories of what we think represent cases of herpetiform ulceration, in order to illustrate the spectrum of clinical findings in this condition and to show how it differs from both recurrent aphthous ulceration (RAU) and recurrent intraoral herpetic ulceration (RHU). The pertinent literature on the laboratory aspects of the subject will be reviewed and correlated with the results of some of our own investigations in an attempt to illustrate that, although herpetiform ulceration (IIFIJ) can be substantiated as a clinica: entity, its causation is still unknown. CASE REPORTS CASE 1
A 31.year-old woman developed numerous small, painful oral ulcers that began on the tongue but soon involved both lips and gingivae. The ulcers, which at first were of pinhead size, gradually enlarged and often coalesced. The patient had been given prednisolone and several local medicaments by her own physician, but without effect. Six months after the onset of the lesions, a rash developed over the extensor surfaces of the thighs and arms and on the face and breasts. These latter lesions were diagnosed as pityrinsis rosea, which soon responded to a cream prescribed by a dermatologist. The medical history was otherwise unremarkable. At thn time of examination in our clinic, there were multible small ulcers on the tongue and lips. The lesions responded to x 2 per cent tetracycline mouthwash, with immediate relief from the pain, followed by healing of the ulcers. The tetracycline WLS used for 4 days, and the patient remained free of ulcers for about 1 month. Recurrences followed, and the patient was made more comfortable with applications of Orabase. CASE 2
A 3%year-old woman had a 3-year history of multiple “canker sores.” The lesions first appeared after a prophylaxis. The patient stated that she “always had ulcers in the mouth, at least a couple of dozen at a time, which began as dots and got bigger.” Many medicaments had been tried without effect. No lesions were present elsewhere on the body, but on one occasion an intraoral vesicle was seen. Examination revealed numerous ulcers on the tongue, buccxl mucosa, and lips. The patient responded immediately to tetracycline therapy. CASE 3
A male patient, 38 years old, had had recurrent ulcers in occured mostly on the palate (Fig 1) and lips. The patient was which were associated with great discomfort. On one occasion, driver, became so distraught that he stopped his bus, which was a dentist’s office in order to seek advice on how to relieve the relief of his symptoms with a 2 per cent tetracycline mouthwash, 7 week.
the mouth for 2 years. They seldom free from ulcerations, the patient, who was a bus filled with passengers, outside pain. He received immediate and the lesions healed lvithin
CASE 4
When first were “pinhead always on the “rarely without rinse, but this topical steroids.
seen, a 23-year-old woman had a 2%-year history of recurrent oral ulcers. They in size but ran together. ” The lesions occurred in all parts of the mouth, but tongue. The patient had over sixty ulcers when originally seen, and she was an ulcer.” She received immediate relief at first with a 2 per cent tetracycline treatment became ineffective after a time. Some relief was again obtained mith
CASE 5
A SG-year-old man had a 3-year history of multiple small ulcers throughout the mouth. There mere “forty or fifty ulcers at a time.” The tongue and lips were most severely affected (Fig. 2). Response to a tetracycline mouthwash produced remissions for as long as a month,
Brookc attd Xapp
184
B$.
1. Case 3. Palatal
lesions in a S&year-old
Fig. 8. Case 5. Lip and tongue condition.
man. The patient
lesions in a S&year-old
man with
also had lip lesions.
a a-year history
of the
CASE 6
A 35year-old man had suffered from recurrent ulcerations for 5 years. On occasion, fifty ulcers or more would occur; t.hese involved mostly the tongue (Fig. 3). Until he was seen in our clinic, remissions were rare, lasting less than 1 week. The condition readily responded to n tetracycline mouthwash.
METHODS
Biopsy specimens of the lesions were examined with the light microscope in all cases, and with the electron microscope in Cases 1 and 3. Prior to biopsy, smears were taken for cytologic examination. Viral cultures were performed in Cases 1, 2, and 4. In Cases 1 and 2, immunofluorescent techniques were used in an attempt to find autoantibodies to human and mouse skin within the marginal epithelium surrounding the lesions and the patient’s serum.
Volume Number
42 2
Fig. 3. Case 6. Tongue lesions in a X-year-old man with a S-year history of ~‘ecu~‘~‘~mccs. On occasion, fifty or more ulcers would lx present, involving mostly the tongue.
RESULTS light
microscopy
The most, constant finding by light microscopy was that of a shallow ulcer with a fibrinopurulent, exudate fillin g the crater, level with the surface (Fig. 4). At the margins, the ulcer frequently extended into the surrounding stratum spinosum, producing a slight cleft. The cells of the stratum spinosum in the immediate area of the cleft contained both intercellular and intracellular edema. In some of the adjacent areas, further removed from the clefts, the cells of the stratum spinosum containetl both clear ~11s with prominent, (lark, centrally placed nuclei, and eosinophilic cells with intensely staining cytoplasms. Infrequent findings were small intraepithclial vesicles of eosinophilic fluid and inflammatory cells within the stratum spinosum (Fig. 5). The epithelium surrounding these vesicles appeared to be undergoing severe tlcgenerativc changes and was very atrophic. This condition was interprctctl to rcprcsent a stage of necrosis prior to ulceration. The underlying conncctivc tissue rontaincd a predominantly lymphocytic infiltrate which was mild in the superficial areas beneath the cpithelium, but which extcntlcd deeply into the arcas bcncath the ulcerations. The routine microscopic diagnosis of the tissue submitted was usually reported to bc a nonspc4fir ulceration. Electron
microscopy
In the cases examined ultrastructurally, it was apparent that the intermediate cells of the stratum spinosum in the margins of the ulcer were generally larger in size. The nuclei of these cells were large and smooth, with little peripheral heterochromatin, and frequently contained more than one large nucleolus. Nultiplc sections through the epithelial cells from the periphery of the ulcers ciid not rcvcal viral bodies typical of herpes simplex.” Intranuclear inclusion
186
Brooke
Oral Surg. August, 1976
and Sapp
Fig. 4. Typical histology of the shallow ulcers with the fibrinopurulent exudate filling the crater and the “clefting” of the peripheral epithelidm. (Magnification, x40.) Fig. 5. Photomicrograph of an infrequently found intraepithelial vesicle exhibiting degeneration of the surrounding epithelium and a lymphocytic infiltrate within the underlying connective tissue. (Magnification, x100.)
bodies were commonly elsewhere. Viral
found
in these cells and will
be reported
on in detail
cultures
Viral
cultures were negative for all cases in which they were performed.
lmmunofluorescent
studies
The lesions were negative for autoantibodies in both Cases 1 and 2. In Case 2, the serum was negative for antibodies at all dilutions with the use of human skin, but was weakly positive for pemphigus antibodies with the use of mouse skin at 1:4 dilutions. It was negative for dilutions of 1:16 and 1:64. In Case 1, serum was negative at all dilutions with the use of both human and mouse skin. DISCUSSION
The cases presented all had the following clinical features in common: (1) There were numerous small, shallow lesions that could be found on any intraoral
Volume Number
42 2
Herpe~~form ulceration
187
mueosal surface. (2) The lesions began as small pinhead-sized erosions that gradually enlarged and eventually coalesced. (3) The lesions were more painful to the patient than would be suspected by their size. (4) The lesions were present almost continuously for 1 to 3 years, with relatively short remissions. (5) The patient received immediate but temporary relief from the symptoms when treated with a 2 per cent tetracycline mouthwash. (This latter statement is based on the subjective reports of paGents and not on a controlled clinical trial.) Since most of these clinical features are reminiscent of a recurrent herpetic infection, many clinicians, who do not further investigate such cases, may mistakenly diagnose them as recurrent herpes infections and treat them accordingly. If laboratory tests are empIoyed in such cases, it is soon found that. : (I ) t.he herpes simplex virus cannot be isolated by culture or found by electron microscopy; (2) repeated cytologic smears fail to reveal the typical multinucleated epithelial giant cells found in the herpetic lesions; (3) the findings by light microscopy are nearly identical with those described for recurrent aphthous ulcers; and (4) immunofluorescent and serologic techniques are negative for antibodies to herpes virus. These results may lead to a diagnosis of recurrent aphthous ulceration. Because of these conflicting features, many British investigators have, for some time, thought that such cases deserve a special clinical category and have advocated the term herpetiform alceratio)z. They believe that proved recurrent. intraoral herpetic stomatitis is rare and that most cases thus diagnosed actually represent various forms of recurrent aphthous ulcers or herpetiform ulceration. Lehner,4 in analyzing the clinical, pabhologic, and immunologic features of 210 cases of recurrent oral ulceration, has classified them into three main groups: (1) major aphthous ulcerations, (2) minor aphthous ulcerations, and (3) herpetiform ulceration. Also included in his classification were the recurrent oral ulcerations associated with Behcet’s syndrome. Evidence was presented to show that the category of major aphthous ulcerations (periadenitis mucosa necrotica rccurrens) is not a distinct entity but merely a larger-sized variant of recurrent minor aphthous ulceration (RAU) . In his study, the rarity of herpetiform ulceration was pointed out, in that he could define it in only 9 per cent of the 210 cases. Sixty-three per cent of the patients suffered from minor aphtbous ulcerations, and 12 per cent had major aphthac. The remainder had recurrent oral ulcerations associated with Behcet’s syndrome. ldehner and Sagebicl,’ in a attempt to differentiate minor aphthous ulcerations from herpetiform ulceration by means of light and electron microscopy, had findings similar to those obtained by us in this investigation. As mentioned above, the significance of these will be discussed in another article. The possibility that major, minor, and herpctiform variants of aphthous ulceration may represent an immune condition has also been investigated.33 + IN* In a review of some of these studies by Francis,ls it was pointed out that the early aphthous lesions were clinically, microscopically, and immunologically very similar to the oral lesions of Behcet’s syndrome. Lehner* has presented immunologic evidence to support his contention that minor aphthous ulcers and major aphthous ulcers are two closely related varieties of the same condition, and that the lesions associated with Behcet’s syndrome cannot be differentiated by means
Oral Surg. August, IQ76
of immunologic techniques from either type of aphthous ulceration or from herpetiform ulceration. As long ago as 1941, Touraino’” suggested that aphthous ulceration may, in fact, he at one end of a spectrum of disease which in its mildest form presents as the occasional minor aphthous ulcer and in its severest and most, widespread form involves other mucosal tissues, sucl~ as eyes and genitals, i.e., Behcct’s syntlromr. If this concept of “aphthosis ’ is eventually proved to be correct, it may well be tha.t herpct.iform ulceration will fit into the over-all picture. l’ntil such a unifying pathogcncsis is evolved, we think that thr concept of ITFII as it separa.tc clinical entity, as originally suggested h?- Cooke, is justified. Some of t,hc cases illustrated were seen in the clinics of’ the Leeds Dental School and Hospital, and we wish to thank Professor F. E. Hopper and Mr. John \Viggles~vorth for thei] help and adviw during the management of those craws. REFERENCES
the Oral Mucosx Br. Dent. 1. (:ooko. H. E. I).: The Diagnosis of Bullous Lesions Afrectinlr J. 109’:%-96, 1960. = Findings in Recurrent Oral Ulceration, 2. Lehner, T., and Sagebiel, R. TV.: Fine Structural Br. Dent. j. 121: 4514-456; 1966. and Manawment of Recurrent Oral Ulecration. Br. Dent. J. 3. Lehner. T.: Autoimmunitv ., 122: l&20, 1967. in Oral Diseases, With Special Reference to Recurrent Oral 4. Lehner, T.: rlutoimmunity Ulceration, Proc. R. Soe. Med. 61: 515-521, 1968. 5. ('dWSOl1, R. A.: Essentials of Dental Surgery and Pathology, etl. 2, London, 1968, J. 6r A. Churchill, Ltd., p. 199. 6. Carson, R. A.: Oral Ulceration-Clinical Aspects, O~ar, SVRG. 33: 912-921, 1972. 7. Kay, L. W.. and Haskell. R.: Color Atlas of Oro-Facial Diseases, Chicago, ., 1971, Year Booi Mrdic& Publishers, i. 240. 8. Dolby, A. E.: Management of Recurrent Oral Ulceration, Practitioner 210: 403-408, 1973. 9. Pindborg, J. .T.: Atlas of Diseases of the Oral Murosa, rd. 2, Copenhagen, 19i3, Ejnar Munksgtcard, 1,. 140. In Dalton, A. J., and Haguenau, E’.: Ultra10. Roizman, B., and Spear, P. G.: Herpesviruses. structure of Animal Viruses and Bacteriophages, Nrw York, 1973, academic Press, vol. 5, pp. 83-I 07. Effects of Scra and Peripheral Blood Aphthous Ulcerations. 11. Dolby, A. E. : Recurrent Lymphocytes Upon Oral Epithelial Tissue Culture Cells, Immunology 17: 709-774, 1969. 12. Dolby, A. E.: Mikulicz’s Recurrent Oral Aphthae. Histopathological Comparison With 2 Xxperimentnlly Induced Immunological Reactions, Br. J. Dermatol. 83: 674-679, 1970. 13. Addy, A., and Dolby, A. E.: Aphthous Ulcerat.ion: The Anti Nuclear Factor, J. Dent. Res. 51: 1594-1595, 1972. Aphthous E. A., Barile, M. F., Lee, W. B., and Stanely, H. R.: Recurwnt 14. Grnykowski, Rtomntitis, J.A.M.A. 196: 637-644, 1966. 13. Francis, T. C.: Recurrent Aphthous St,omatitis and Behcet’s Disease, ORAI, SURG. 30: 47648i, 1970. 16. Touraine, 112. D.: L’Aphthose, Buli. Sot. Franc. Derm. Syph. 48: 61-103, 1941. Reprint requests to: Dr. R. I. Brookc Department of Oral Medicine Faculty of Dentistry The University of Western Ontario London, Ontario, Canada