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Oral lesions in pemphigus
ORAL
LESIONS
TN PEMPHIGUS
WAI,TER F. LEVER, M.I>., BOSTOS, MMS. RAL lesions play an important part in the diagnosis of pemphigus. Because of their different appearance in the various types of pemphigus, oral lesions aid in the allocation of a case to the correct type of pemphigus. Whenever lesions on the oral mucosa are the first manifestation of pemphigus and other lesions have not yet appeared, the correct diagnosis can be made only by identification of the oral lesions as lesions of pemphigus. In this communication the various types of pemphigus arc described with particular emphasis on the oral lesions encountered in each type. The descriptions are based chiefly on the clinical data from 114 patients with pemphigns admitted to the Massachusetts General Hospital between 1921 and 1911.
0
CIJASSIFICA’~‘ION
OF PEMPHTG~~S
There are three well-established types of pcmphigus, namely, pemphigus vulgaris, foliaceus, and vegetans; to these, two new types have been added in recent years, namely, pemphigus con junctivac or benign mucous membrane pemphigusl and pemphigus erythematodes or Senear-Usher tgpc of pemphigus.’ Furthermore, Brocq3 suggested a division of pemphigus vulgaris into t,wo types, an acute, malignant type (pemphigus subaigu malin) and a chronic, more benign type, The septic (acute, or butcher’s) pemphigus is no longer regarded as a type of true pemphigus but as a separate disease, since it has been estahlished that it represents a bullous eruption in the course of a sepsis.4 Clinical analysis of the 114 patients with pemphigus observed at the Massachusetts General Hospital between 1921 and 1941 has demonstrat,ed that, a separate consideration of these additional t,,vpes is justified, not only bccausc of differences in clinical appearance but also bccanse of the difference in prognosis. I. Penaphigus Vu7gnri.s Acutus (Brocq’s pemphigus subaigu malin) In this form the bullae on the skin are usually flaccid from the beginning. If they are tense originally, they become flaccid as they increase in size. The blisters break ca.sily. Occasionall>- no bullae form on the skin and t,he epithclium merely slides off, leaving an erosion. The erosions tend to enlarge as the epithelium becomes detached at the periphery. By peripheral est,ension and confluence of the erosions large areas of the body may become denuded. The large denuded arcas are the most- important clinical sign of this t,ypc (Fig. 1). They show little t,endency to heal. ,I\ large l)ercentapc of the patients is Jewish, 22 out of 33 patients ((i’i per ccnl ) belonged to the Jewish race. The average age of onset was 52. Tlic mortalil~ of Ihis form is very high, since 31 out of 33 pat,ients (94 l)c’r cent ) died of petnphig1ts. The average duration of the disease in those who died was seven months.
Waik-
P. Lever
Oral Lesions.-The mucous membranes of the mouth are involved in a large percentage of the cases. They were affected in 28 of the 33 patients (85 per cent). The disease frequently begins on the mucous membranes of the mouth. In 18 of the 33 patients (55 per cent) the mouth was the site of the first lesions. The oral involvement, if present, is usually severe. The type and appearance of the lesions are analogous to those on the skin. Intact bullae are rarely seen on the mucous membranes, because they break soon after formation and, just as on the skin, bullae often do not form at all, but the mucosal epithelium merely slides off. The erosions enlarge by peripheral extension, so that large areas in the mouth may become denuded. Of particular
Fig. L-Patient of their early rupture, milion border of the
with the lips.
pemphigus presence Patient
vulgaris of large died of
acutus. denuded pemphigus.
Note areas,
the absence of blisters and the involvement of
because the ver-
diagnostic significance is the extension of the lesions to the vermilion border of the lips and the adjoining skin which is usually not seen in the other forms of pemphigus. The erosions of the oral mucosa show an irregular border due to peripheral extension and confluence of the lesions and often have shreds of They may be covered with a whitish exudetached epithelium at the margin. date and they bleed easily. In the severest stage almost the whole oral mucosa may be transformed into one, large, eroded surface, The lips, gums, and
@-a~1Lesions in Pemphiyus
571
tongue usually show considerable swelling. There is increased salivation ; the sputum is frequently tinged with blood, and hemorrhagic crusts form on the lips. Because of the tenderness of the lesions mastication is difficult and swallowing painful so that a liquid diet, often becomes necessary. The lesions may extend into the pharynx and larynx, as observed in 12 of the 33 patients, and hoarseness results. The mucosal as well as the cutaneous lesions heal without scarring, but the tendency to heal usually is frustrated and progression is faster than healing. The acute form may start slowly with only a few lesions present on the skin or in the mouth for the first few months. These lesions, however, already show the characteristics of the acute form, namely, flaccid blisters and extending erosions. The diagnosis is, therefore, possible in most cases at this time. In the 18 cases in which the pemphigus start,ed in the mouth, the averegc interval between the appearance of mucous membrane and cutaneous lesions was 2.9 months; the longest interval observed was 11 months. When the cutaneous lesions appeared, t,he course was usually rapid, often leading to death within a few weeks. Presence or absenrc of oral lesions was of no prognostic significance; of the 2 patients with pemphigus vulgaris arutus who survived, one had mouth lesions and the other had none. II.
Penaphigus Veqetans
As discussed in another communication,” this form resembles pemphigus vulgaris acutus in its clinical picture in every respect except for t,he vegetations which form secondarily on the erosions (Fig. 2). It is rare that vegetations are found on all erosions. The erosions which show no vegetations are identical in appearance with those of pemphigus vulgaris acutus. The prognosis of pemphigus vegetans is grave, but apparently not quite as hopeless as in pemphigus vulgaris acutus. Friihwald,6 in reviewing the outcome of 147 cases as reported in the literature, found the mortality to be 73 per cent. He believed, however, that some addit,ional patients may have died subsequent to the period of observation. Two of the 3 patients with pemphigus vegetans seen at the Massachusetts General Hospital between 1921 and 1941 died; 1 is living. Many patient,s with pemphigns vcgctans are Jewish; 2 of the 3 patients in this series were Jewish. Oral Lesions.-Friihwald6 states that oral lesions are found in almost every case of pemphigus vegetans and t,hat the disease frequently starts on the oral mucosa. He found that the month was the site of the first lesions in 66 per cent of the cases published in t,he literature up to 1915. In all three cases of the presented series oral lesions were the first sympt,om. Vegetations on the oral mucosa arc rare. If they are absent, the oral lesions are identical with t,hose seen in pemphigus vulgaris acutus. If they are present, the vegetations appear as soft, dark red granulations. More common than in the mouth are vegetations along the vermilion border of the lips. In our three cases of pemphigus vegetans the vegetations were limited to the skin. III.
Penlphigus
Vdgaris
Chwonicu~s
In this form the bulla,c usually are tense. They may at,tain considerable size, becoming as large as ii em. in diameter. The bullae remain tense as they
572
Walter
ET. Lever
increase in size and do not break as easily as they do in pemphigus vulgaris acutus (Fig. 3). The erosions at the site of broken blisters do not extend at the periphery. The tendency to heal is well pronounced. This, form appears to be rare among Jews. All 35 patients in the series presented were Gentiles. This is the more remarkable if one considers that 67 per cent of the patients with pemphigus vulgaris acutus were Jewish. The average age of onset was 61. The mortality rate is much lower than in the acute form. Only 13 of the 35 patients, that is 37 per cent, died from pemphigus. The disease may heal after a few months’ duration, but may last. for years. Of the 22 patients with pemphigus vulgaris chronicus who did not die of pemphigus, 7 patients died from other diseases, 6 are free from lesions at the present time, and 9 are still developing lesions. All but 1 of the 9 patients have only a few lesions, not enough to interfere seriously with their routine of life.
Fig. erosions. are covered
Z.-Patient with Note involvement with crusts but
pemphigus of the do not
vegetans. Vegetations vermilion border of the show vegetations. Patient
have lips. died
formed on most The lesions on of pemphigus.
of the
the lips
Ornl Lesions.-The mucous membranes of the mouth arc affected in a smaller number of cases than in the acute form. Oral lesions were present in 17 of the 35 patients with pemphigus vulgaris chronicus, that is in 49 per
The disease rarely cent, as compared with 85 per cent in the acute form. starts in t,hc mouth ; the first lesions w(lrt: observed in the month in only 4 patients (11 per cent). The a1)pcaranc.c ol’ 1.11~oral lesions corresponds to see intact l)listcrs in the mouth, bethose on the skin. One can frequently ca.use they do not break as easily as in Ihc acute form of l~cmphigus vulgaris. The blisters usually arc small and the erosions at the sit,e of broken blisters do not tend to increase in size, so that the oral involvement is never as extensive as in pemphigus vulgaris acutus. The lesions do not extend to the vermilion border of the lips and the adjoining skin. The oral erosions, just as the
Fig.
X.--Patient that
with pemphigus the erosions are
vulgaris small
chronicus. and tend
to
Note that heal well.
many blisters are Patient is living.
tense
and
cutaneous, show a good tendency to heal. Salivation is slight or absent, and the saliva is not blood tinged. The mouth is only moderately tender, so that mastication and swallowing of solid food can usually be accomplished. Lesions may occur in the pharynx and larynx, as was observed in 3 of the patients. Involvement of the mouth appeared to be of no prognostic significance. Of the 17 patients with oral lesions, 5 died of pemphigus. Of the 18 patients without oral lesions, 8 died. Of the 15 patients still alive, 8 exhibited mouth lesions; 7 had no mouth lesions.
574
Walter IV.
Pemphigus
P. Lever Poliaceus
This form shows bullae on the skin only in the early stage and gradually assumes the appearance of a generalized exfoliative dermatitis from which it is, however, easily differentiated by the Nikolsky sign (the upper layers of the epidermis can be rubbed off by a stroke of the thumb). The mortality rate of pemphigus foliaceus was 56 per cent in the series presented, since 14 out of 25 patients died of pemphigus. Three patients died of other diseases, and 8 are living. The average age of onset was 48. Age appeared to be an important factor in the prognosis. Of 12 patients in whom the disease started before the age of 50, only 2 (1’7 per cent) died of pemphigus; whereas of 13 patients in whom the disease began at the age of 50 or later, 12 (92 per cent) died of pemphigus. Pemphigus foliaceus may be extremely chronic. In 4 of the surviving patients the disease has lasted for more than 10 years. Eight of the 25 patients (32 per cent) were Jewish. Oral Lesions.-Involvement of the oral mucosa seems to be uncommon in pemphigus foliaceus. In fact, it is believed that it may not occur at all. Fifteen of the 25 patients with pemphigus foliaceus in this series have been followed by the author, and no oral lesions were observed at any time. In the record of one of the other 10 patients a note was found stating that at one time oral lesions had been present. It has been impossible to verify this statement. Because many textbooks state that oral lesions occur in pemphigus foliaceus, the literature was consulted for exact information about the occurrence of oral lesions in pemphigus foliaceus. A thorough, though not complete, perusal of case reports in the literature revealed that mouth lesions were never described in any case of unquestionable pemphigus foliaceus. In all instances in which oral lesions were described the cases were not pemphigus foliaceus but pemphigus vulgaris acutus. Because pemphigus vulgaris acutus also shows exfoliation of the epidermis, some authors have applied the name of pemphigus foliaceus to these cases. It should be realized, however, that the type of exfoliation is different in the two diseases. In pemphigus foliaceus the exfoliation in tho early stage is superficial without’ development of denuded areas, and in the later stage occurs in form of a generalized superficial scaling, the scales being is small and flaky (Fig. 4). In pemphigus vulgaris acutus the exfoliation characterized by a separation of the whole epidermis at the periphery of the erosions, resulting in actual denudation. V. Pemph.igus Erythematodes (Senear-Usher Type of Pemphigus) The position of this form within the pemphigus group is still a matter of controversy. Gray* has suggested that pemphigus erythematodes represents a localized form of pemphigus foliaceus which may remain localized or may change into a generalized pemphigus foliaceus. This concept, however, cannot be applied to all cases, since several reports have appeared in which a pemphigus vulgaris developed subsequently. Six cases of pemphigus erythematodes were seen at the Massachusetts General Hospital. Four changed into pemphigus foliaceus ; in the other 2 patients the disease remained localized. The mortality
is zero in the localized cases, but in the cases in which the pemphigus erythematodes develops into pemphigus vulgaris or foliaceus the prognosis changes accordingly. Oral Lesions.-No oral lesions were observed in the 6 cases observed at the A review of all available reports in the literaMassachusetts General Hospital. ture of cases of pemphigus erythematodes, including the questionable cases, revealed the presence of oral lesions in 11 out of 71 cases. The exact appearance of the oral lesions was never described. One would expect that cases which represent a localized form of pemphigus foliaceus would show no oral lesions, while cases which represent an early stage of pemphigus vulgaris may show oral lesions from the beginning.
Fig. 4.-Patient erosions at the site epidermis exfoliate.
with pemphigus of broken blisters The lips are not
foliaceus. Note the absence of blisters are superficial, since only the upper involved. Patient died of pemphigus.
and that layers of
the the
VI. Pemphigus Gonjuncti~ae (Benign Mucous Membrane Pemphigus) The reasons for separate consideration of this form of pemphigus are the predilection of the lesions for the mucous membranes, particularly the conjunctivae, the tendency of the lesions to produrc scarring, and the benign, chronic course of the disease. Pemphigus conjunctivae always attacks the mucous membranes and in about half of the cases the skin. The conjunctivae are nearly always affected,
576
Walter
P. LCl’W
The lesions always and occasionally present the only area of involvement. produce scarring on the conjunctivae, frequently scarring on other mucous membranes, and occasionally scarring on the skin. Sixteen patients with this type of pemphigus were observed at the Massachusetts General Hospital bet,ween 1921 and 1941. The disease remained active for many years in all patients. None of them died of pemphigus. The average age of onset was 61. None of the patients was Jewish. All patients presented lesions on the conjunctivae. Fifteen of the 16 patients had also involvement of other areas. Lesions were present in the throat in 7 cases (44 per cent), with scarring in none ; in the esophagus in 4 cases (25 per cent) with scarring in all 4 cases; in the nose in 3 cases (19 per cent) with scarring in none; on the genital mucosa in 1 (6 per cent), with scarring in none. Seven patients (44 per cent) had cutaneous lesions which in 3 patients caused scarring of the skin. Oml Lesions.-Lesions in the mouth were observed in 13 out of 16 patients (Sl per cent). The disease started in the mouth in 4 patients and remained limited to the mouth for a period varying from 3 to 36 months, an average of 18.8 months. The oral lesions healed without scarring in 10 patients, while in 3 patients scars remained. Those lesions which heal without scarring appear as small and tense blisters scutt,ered over the oral mucosa. Intact blisters are frequently observed, since they often do no8 break for some time in spite of the friction to which they are exposed in the oral cavity. The ensuing erosions do not enlarge in size and tend to heal well. On the whole, the lesions resemble those observed in pemphigus vulgaris chronicus. The lesions are only moderately tender, and interference with eating is never a serious matter. In the patients in whom scarring ensues the erosions do not heal in certain areas. Instead, they slowly increase in size. After having attained a certain size, they remain present for a long period of time until finally healing with scarring occurs. The large erosions in this type differ from the large erosions seen in pemphigus vulgaris acutus in several points: The lesions show little or no progression at the periphery. The erosions appear cleaner than in pemphigus vulgaris acutus, since there are usually no shreds of epithelium at the border and no fibrinous exudate on them. They do not tend to bleed as easily. The involved oral mucosa does not appear swollen. Salivation is slight or absent, and the saliva is not blood tinged. The lesions cause less pain, so that they do not interfere with an adequate intake of food. Furthermore, the vermilion border of the lips which is a common site of lesions in pemphigus vulgaris acutus is not involved. Scarring is most frequently seen around the soft palate and the tonsillar pillars, but may be found elsewhere in the mouth, namely on the buccal mucous membrane, the tongue, or the mucous membranes of the lips. In 2 of the 3 patients in whom scarring on the oral mucosa occurred, the scarring was only moderate; in both patients the tonsillar pillars and the uvula had been destroyed. In the third patient, however, the scarring was severe ; the soft palate had become adherent to the posterior pharyngeal wall, leaving only a small opening between the. upper and the lower pharynx (Fig. 5).
DISCUSSION
Oral lesions are an important part of the clinical picture in four types of pemphigus : in pemphigus vulgaris acutus, pemphigus vegetans, pemphigus vulgaris chronicus, and pemphigus conjunct,ivae. The oral lesions in pemphigus vulgaris acutus, pemphigus vulgaris chronicus, and pemphigus conjunctivae differ from each ot,her in their appearance. The oral lesions of pemphigus
Fig. B.-Patient with benign mucous membrane pemphigus of two years’ duration. Two large erosions are shown, one on each side of the tongue. There were also large erosions elsewhere on the oral mucosa and lesions on the mucous membrane of the nose. The conjunctivae were not (or probably not yet) involved. Patient is living. (Patient of the Beth Israel Hospital, Boston, Mass.)
Fig. 0. -Patient with benign mucous membrane pemphigus Note that the soft palate has become View of the oral cavity. retropharyngeal wall. Lesions were also present on the conjunctivae.
of six completely Patient
years’ duration. attached to the is living.
OF PEMPHIGUS
Total
Pemph. vulg. acutus Pemphigus vegetans Pemph. vulg. chron. Pemphigus foliaceus Pemph. erythematodes Pemph. conjunctivae
TYPE
114
33 3 35 25 2 16
NUMBER OF PATIENTS
62
28 3 17
NUMBER
54
85 100 49
PER CENT
OF ORAL
FREQUENCY OF ORAL LESIONS
OCCURRENCE
IN
THE
29
18 3 4 0
25
55 100 11 0 0 25
FR.EQUENCY OF ONSET IN THE MOUTH PER NUMBER CENT
LESIONS
TABLE
I FORMS
18.8
2.9 2.5 4.5 -
INTERVAL BETWEEN ORAL AND OTHER LESIONSINTHOSP WHO HAD ORAL LESIONS FIRST MONTHS
VARIOUS
60
31 2 13 14 0 0
NUMBER
MORTALITY
OF PEMPHIGUS
52
94 66 37 56 0 0
PER CENT
I
OF PATIENTS
34
0
27 2 CT,
53
96 66 29 0
51
44 56 0 0
i 14 0 0 26
80
4
WITH ORAL I WITHOUT ORAL LESIONS LESIONS PER PER NUMBER CENT NUMBER CENT
MORTALITY
vegetans are identical with those of pemphigus rulgaris acutus except for the formation of vegetations in rare instances. Correct classification of the oral lesions in a patient who has no other lesions For example, a patient with exof pemphigus carries great responsibility. tensive erosions of the oral mucosa may have either pemphigus vulgaris acutus in which the mortality is almost. 100 per cent or pemphigus conjunctivae in which the mortality is zero. In the absence of other lesions the different appearance of the oral lesions is these two types is the only clinical sign to rely upon for a differential diagnosis. It should be remembered, however, that vounger age and Jewish race suggest more the diagnosis of pemphigus vulgaris acutus, while older age and non-Jewish race would favor a diagnosis of pemphigus conjunctivae. In addition, a thorough examination of the conjunctivae is advisable, since they may show beginning involvement, if the case under consideration is one of pemphigus conjunctivae. It has been frequently stated in the literature that the presence of mouth lesions in pemphigus suggests a grave prognosis. This statement should be qualified. It is true that the two types which show the severest oral involvement, namely pemphigus vulgaris acutus and pemphigus vegetans, have the highest mortality, but the mere presence of mouth lesions does not permit conclusions to be drawn concerning the prognosis. Pemphigus conjunctivae, for example, frequently shows oral involvement but, is a benign disease. Neither can it be said that the presence or absence of oral lesions in any particular type of pemphigus influences the prognosis. In pemphigus vulgaris acutus the mortality among patients with mouth lesions was 96 per cent, without mouth lesions 80 per cent. In pemphigus vulgaris chronicus the mortality was 29 per cent among patients with mouth lesions and 44 per cent among patients without mouth lesions. SUMMARY
1. The frequency and the appearance of the oral lesions in the various types of pemphigus have been discussed. 2. In a series of 114 cases of pemphigus 62 (54 per cent) showed involvement of the oral mucosa. Oral lesions were encountered in 85 per cent of the cases with pemphigus vulgaris acutus, in 100 per cent of the cases with pemphigus vegetans, in 49 per cent of the cases with pemphigus vulgaris chronicus, in 4 per cent of the cases with pemphigus foliaceus, in none of the cases with pemphigus erythematodes, and in 81 per cent of the cases with pemphigus conjunctivae. 3. The oral lesions in pemphigus vulgaris acutus, pemphigus vulgaris chronicus, and pemphigus conjunctirae differ enough to make their appearance an important part of the differential diagnosis. The oral lesions of pemphigus vegetans are idental with those of pemphigus vulgaris acutus except for the development of vegetations in rare instances. 4. The mortality rate differs widely between the various types of pemphigus. The presence or absence of oral lesions does not influence the prognosis in any of the types. 5. Oral lesions were the first symptom of pemphigus in 25 per cent of the cases. The initial lesions were observed in the mouth in 55 per cent of
the cases with pemphigus vulgaris acutus, in 10 per cent of the cases with pemphigus regetans, in 11 per cent of the cases with pemphigus vulgaris chronicus, in none of the casts with pemphigus foliaceus and pemphigus erythematodes, and in 25 per cent of the cases with pcmphigus conjunctivac. In the absence of other lesions the diagnosis of pemphigus must be made from the oral lesions alone. REFERENCES 1.
Ueber chronischen Pemphigus der SchleimhIute, Monatsschr. f. OhrenThost, A.: heilk., 30: 165, 1896. (b) Serefis. 8.: Ueber die prognostische Bedeutunp: der Schleimhautreriinderuneen beim Pemihigus, Dermat. S~chschr. 96: 145, 193.3: Senear. F. E., and Usher, B.: An Unusual Type of Pemphigus Combining Features of LUDUS Ervthematosus. Arch. Dermat. & Svph. 13: 761. 1926. Brocq, L:: S&me des &ptions bulleuses. Le” pemphigus iubaigu malin B bulles extensives, et faits eonnexes, Ann. de dermat. et de syph., 5th series 7: 449. 1919. Riecke. E.: Pemnhinus. In Handbuch der Haut;nd ‘Geschlechtskrankhkiten. , Berlin. I julius Sprin~er~1931. Vol. 7, part 2, pg. 370. Lever, W. F., and Talbott, J. H.: Pemphigus Vulgaris and Pemphigus Vegetans. A Suggestion for Distinction Iletween Two Types of Pemphigus Vulgaris, Namely an Acute and a Chronic Type, and a Comparison of Pemphigus Vegetans with the Acute Type. (To be published.) Friihwald, R.: Pemphigus Vegetans, Leipzig and Hamburg, 1915, L. Voss. Gray, A. M. H.: Pemphigus of the Senear-Usher Type, Proc. Royal So:. Med. 31: part 2, pg. 871, 1937/3S. (a)
\
2. 3. 4. 5.
6. 7.
I
270
COMMONWEAI,TII
AVENUE
LESIONS
TN PEMPHIGUS
WAI,TER F. LEVER, M.I>., BOSTOS, MMS. RAL lesions play an important part in the diagnosis of pemphigus. Because of their different appearance in the various types of pemphigus, oral lesions aid in the allocation of a case to the correct type of pemphigus. Whenever lesions on the oral mucosa are the first manifestation of pemphigus and other lesions have not yet appeared, the correct diagnosis can be made only by identification of the oral lesions as lesions of pemphigus. In this communication the various types of pemphigus arc described with particular emphasis on the oral lesions encountered in each type. The descriptions are based chiefly on the clinical data from 114 patients with pemphigns admitted to the Massachusetts General Hospital between 1921 and 1911.
0
CIJASSIFICA’~‘ION
OF PEMPHTG~~S
There are three well-established types of pcmphigus, namely, pemphigus vulgaris, foliaceus, and vegetans; to these, two new types have been added in recent years, namely, pemphigus con junctivac or benign mucous membrane pemphigusl and pemphigus erythematodes or Senear-Usher tgpc of pemphigus.’ Furthermore, Brocq3 suggested a division of pemphigus vulgaris into t,wo types, an acute, malignant type (pemphigus subaigu malin) and a chronic, more benign type, The septic (acute, or butcher’s) pemphigus is no longer regarded as a type of true pemphigus but as a separate disease, since it has been estahlished that it represents a bullous eruption in the course of a sepsis.4 Clinical analysis of the 114 patients with pemphigus observed at the Massachusetts General Hospital between 1921 and 1941 has demonstrat,ed that, a separate consideration of these additional t,,vpes is justified, not only bccausc of differences in clinical appearance but also bccanse of the difference in prognosis. I. Penaphigus Vu7gnri.s Acutus (Brocq’s pemphigus subaigu malin) In this form the bullae on the skin are usually flaccid from the beginning. If they are tense originally, they become flaccid as they increase in size. The blisters break ca.sily. Occasionall>- no bullae form on the skin and t,he epithclium merely slides off, leaving an erosion. The erosions tend to enlarge as the epithelium becomes detached at the periphery. By peripheral est,ension and confluence of the erosions large areas of the body may become denuded. The large denuded arcas are the most- important clinical sign of this t,ypc (Fig. 1). They show little t,endency to heal. ,I\ large l)ercentapc of the patients is Jewish, 22 out of 33 patients ((i’i per ccnl ) belonged to the Jewish race. The average age of onset was 52. Tlic mortalil~ of Ihis form is very high, since 31 out of 33 pat,ients (94 l)c’r cent ) died of petnphig1ts. The average duration of the disease in those who died was seven months.
Waik-
P. Lever
Oral Lesions.-The mucous membranes of the mouth are involved in a large percentage of the cases. They were affected in 28 of the 33 patients (85 per cent). The disease frequently begins on the mucous membranes of the mouth. In 18 of the 33 patients (55 per cent) the mouth was the site of the first lesions. The oral involvement, if present, is usually severe. The type and appearance of the lesions are analogous to those on the skin. Intact bullae are rarely seen on the mucous membranes, because they break soon after formation and, just as on the skin, bullae often do not form at all, but the mucosal epithelium merely slides off. The erosions enlarge by peripheral extension, so that large areas in the mouth may become denuded. Of particular
Fig. L-Patient of their early rupture, milion border of the
with the lips.
pemphigus presence Patient
vulgaris of large died of
acutus. denuded pemphigus.
Note areas,
the absence of blisters and the involvement of
because the ver-
diagnostic significance is the extension of the lesions to the vermilion border of the lips and the adjoining skin which is usually not seen in the other forms of pemphigus. The erosions of the oral mucosa show an irregular border due to peripheral extension and confluence of the lesions and often have shreds of They may be covered with a whitish exudetached epithelium at the margin. date and they bleed easily. In the severest stage almost the whole oral mucosa may be transformed into one, large, eroded surface, The lips, gums, and
@-a~1Lesions in Pemphiyus
571
tongue usually show considerable swelling. There is increased salivation ; the sputum is frequently tinged with blood, and hemorrhagic crusts form on the lips. Because of the tenderness of the lesions mastication is difficult and swallowing painful so that a liquid diet, often becomes necessary. The lesions may extend into the pharynx and larynx, as observed in 12 of the 33 patients, and hoarseness results. The mucosal as well as the cutaneous lesions heal without scarring, but the tendency to heal usually is frustrated and progression is faster than healing. The acute form may start slowly with only a few lesions present on the skin or in the mouth for the first few months. These lesions, however, already show the characteristics of the acute form, namely, flaccid blisters and extending erosions. The diagnosis is, therefore, possible in most cases at this time. In the 18 cases in which the pemphigus start,ed in the mouth, the averegc interval between the appearance of mucous membrane and cutaneous lesions was 2.9 months; the longest interval observed was 11 months. When the cutaneous lesions appeared, t,he course was usually rapid, often leading to death within a few weeks. Presence or absenrc of oral lesions was of no prognostic significance; of the 2 patients with pemphigus vulgaris arutus who survived, one had mouth lesions and the other had none. II.
Penaphigus Veqetans
As discussed in another communication,” this form resembles pemphigus vulgaris acutus in its clinical picture in every respect except for t,he vegetations which form secondarily on the erosions (Fig. 2). It is rare that vegetations are found on all erosions. The erosions which show no vegetations are identical in appearance with those of pemphigus vulgaris acutus. The prognosis of pemphigus vegetans is grave, but apparently not quite as hopeless as in pemphigus vulgaris acutus. Friihwald,6 in reviewing the outcome of 147 cases as reported in the literature, found the mortality to be 73 per cent. He believed, however, that some addit,ional patients may have died subsequent to the period of observation. Two of the 3 patients with pemphigus vegetans seen at the Massachusetts General Hospital between 1921 and 1941 died; 1 is living. Many patient,s with pemphigns vcgctans are Jewish; 2 of the 3 patients in this series were Jewish. Oral Lesions.-Friihwald6 states that oral lesions are found in almost every case of pemphigus vegetans and t,hat the disease frequently starts on the oral mucosa. He found that the month was the site of the first lesions in 66 per cent of the cases published in t,he literature up to 1915. In all three cases of the presented series oral lesions were the first sympt,om. Vegetations on the oral mucosa arc rare. If they are absent, the oral lesions are identical with t,hose seen in pemphigus vulgaris acutus. If they are present, the vegetations appear as soft, dark red granulations. More common than in the mouth are vegetations along the vermilion border of the lips. In our three cases of pemphigus vegetans the vegetations were limited to the skin. III.
Penlphigus
Vdgaris
Chwonicu~s
In this form the bulla,c usually are tense. They may at,tain considerable size, becoming as large as ii em. in diameter. The bullae remain tense as they
572
Walter
ET. Lever
increase in size and do not break as easily as they do in pemphigus vulgaris acutus (Fig. 3). The erosions at the site of broken blisters do not extend at the periphery. The tendency to heal is well pronounced. This, form appears to be rare among Jews. All 35 patients in the series presented were Gentiles. This is the more remarkable if one considers that 67 per cent of the patients with pemphigus vulgaris acutus were Jewish. The average age of onset was 61. The mortality rate is much lower than in the acute form. Only 13 of the 35 patients, that is 37 per cent, died from pemphigus. The disease may heal after a few months’ duration, but may last. for years. Of the 22 patients with pemphigus vulgaris chronicus who did not die of pemphigus, 7 patients died from other diseases, 6 are free from lesions at the present time, and 9 are still developing lesions. All but 1 of the 9 patients have only a few lesions, not enough to interfere seriously with their routine of life.
Fig. erosions. are covered
Z.-Patient with Note involvement with crusts but
pemphigus of the do not
vegetans. Vegetations vermilion border of the show vegetations. Patient
have lips. died
formed on most The lesions on of pemphigus.
of the
the lips
Ornl Lesions.-The mucous membranes of the mouth arc affected in a smaller number of cases than in the acute form. Oral lesions were present in 17 of the 35 patients with pemphigus vulgaris chronicus, that is in 49 per
The disease rarely cent, as compared with 85 per cent in the acute form. starts in t,hc mouth ; the first lesions w(lrt: observed in the month in only 4 patients (11 per cent). The a1)pcaranc.c ol’ 1.11~oral lesions corresponds to see intact l)listcrs in the mouth, bethose on the skin. One can frequently ca.use they do not break as easily as in Ihc acute form of l~cmphigus vulgaris. The blisters usually arc small and the erosions at the sit,e of broken blisters do not tend to increase in size, so that the oral involvement is never as extensive as in pemphigus vulgaris acutus. The lesions do not extend to the vermilion border of the lips and the adjoining skin. The oral erosions, just as the
Fig.
X.--Patient that
with pemphigus the erosions are
vulgaris small
chronicus. and tend
to
Note that heal well.
many blisters are Patient is living.
tense
and
cutaneous, show a good tendency to heal. Salivation is slight or absent, and the saliva is not blood tinged. The mouth is only moderately tender, so that mastication and swallowing of solid food can usually be accomplished. Lesions may occur in the pharynx and larynx, as was observed in 3 of the patients. Involvement of the mouth appeared to be of no prognostic significance. Of the 17 patients with oral lesions, 5 died of pemphigus. Of the 18 patients without oral lesions, 8 died. Of the 15 patients still alive, 8 exhibited mouth lesions; 7 had no mouth lesions.
574
Walter IV.
Pemphigus
P. Lever Poliaceus
This form shows bullae on the skin only in the early stage and gradually assumes the appearance of a generalized exfoliative dermatitis from which it is, however, easily differentiated by the Nikolsky sign (the upper layers of the epidermis can be rubbed off by a stroke of the thumb). The mortality rate of pemphigus foliaceus was 56 per cent in the series presented, since 14 out of 25 patients died of pemphigus. Three patients died of other diseases, and 8 are living. The average age of onset was 48. Age appeared to be an important factor in the prognosis. Of 12 patients in whom the disease started before the age of 50, only 2 (1’7 per cent) died of pemphigus; whereas of 13 patients in whom the disease began at the age of 50 or later, 12 (92 per cent) died of pemphigus. Pemphigus foliaceus may be extremely chronic. In 4 of the surviving patients the disease has lasted for more than 10 years. Eight of the 25 patients (32 per cent) were Jewish. Oral Lesions.-Involvement of the oral mucosa seems to be uncommon in pemphigus foliaceus. In fact, it is believed that it may not occur at all. Fifteen of the 25 patients with pemphigus foliaceus in this series have been followed by the author, and no oral lesions were observed at any time. In the record of one of the other 10 patients a note was found stating that at one time oral lesions had been present. It has been impossible to verify this statement. Because many textbooks state that oral lesions occur in pemphigus foliaceus, the literature was consulted for exact information about the occurrence of oral lesions in pemphigus foliaceus. A thorough, though not complete, perusal of case reports in the literature revealed that mouth lesions were never described in any case of unquestionable pemphigus foliaceus. In all instances in which oral lesions were described the cases were not pemphigus foliaceus but pemphigus vulgaris acutus. Because pemphigus vulgaris acutus also shows exfoliation of the epidermis, some authors have applied the name of pemphigus foliaceus to these cases. It should be realized, however, that the type of exfoliation is different in the two diseases. In pemphigus foliaceus the exfoliation in tho early stage is superficial without’ development of denuded areas, and in the later stage occurs in form of a generalized superficial scaling, the scales being is small and flaky (Fig. 4). In pemphigus vulgaris acutus the exfoliation characterized by a separation of the whole epidermis at the periphery of the erosions, resulting in actual denudation. V. Pemph.igus Erythematodes (Senear-Usher Type of Pemphigus) The position of this form within the pemphigus group is still a matter of controversy. Gray* has suggested that pemphigus erythematodes represents a localized form of pemphigus foliaceus which may remain localized or may change into a generalized pemphigus foliaceus. This concept, however, cannot be applied to all cases, since several reports have appeared in which a pemphigus vulgaris developed subsequently. Six cases of pemphigus erythematodes were seen at the Massachusetts General Hospital. Four changed into pemphigus foliaceus ; in the other 2 patients the disease remained localized. The mortality
is zero in the localized cases, but in the cases in which the pemphigus erythematodes develops into pemphigus vulgaris or foliaceus the prognosis changes accordingly. Oral Lesions.-No oral lesions were observed in the 6 cases observed at the A review of all available reports in the literaMassachusetts General Hospital. ture of cases of pemphigus erythematodes, including the questionable cases, revealed the presence of oral lesions in 11 out of 71 cases. The exact appearance of the oral lesions was never described. One would expect that cases which represent a localized form of pemphigus foliaceus would show no oral lesions, while cases which represent an early stage of pemphigus vulgaris may show oral lesions from the beginning.
Fig. 4.-Patient erosions at the site epidermis exfoliate.
with pemphigus of broken blisters The lips are not
foliaceus. Note the absence of blisters are superficial, since only the upper involved. Patient died of pemphigus.
and that layers of
the the
VI. Pemphigus Gonjuncti~ae (Benign Mucous Membrane Pemphigus) The reasons for separate consideration of this form of pemphigus are the predilection of the lesions for the mucous membranes, particularly the conjunctivae, the tendency of the lesions to produrc scarring, and the benign, chronic course of the disease. Pemphigus conjunctivae always attacks the mucous membranes and in about half of the cases the skin. The conjunctivae are nearly always affected,
576
Walter
P. LCl’W
The lesions always and occasionally present the only area of involvement. produce scarring on the conjunctivae, frequently scarring on other mucous membranes, and occasionally scarring on the skin. Sixteen patients with this type of pemphigus were observed at the Massachusetts General Hospital bet,ween 1921 and 1941. The disease remained active for many years in all patients. None of them died of pemphigus. The average age of onset was 61. None of the patients was Jewish. All patients presented lesions on the conjunctivae. Fifteen of the 16 patients had also involvement of other areas. Lesions were present in the throat in 7 cases (44 per cent), with scarring in none ; in the esophagus in 4 cases (25 per cent) with scarring in all 4 cases; in the nose in 3 cases (19 per cent) with scarring in none; on the genital mucosa in 1 (6 per cent), with scarring in none. Seven patients (44 per cent) had cutaneous lesions which in 3 patients caused scarring of the skin. Oml Lesions.-Lesions in the mouth were observed in 13 out of 16 patients (Sl per cent). The disease started in the mouth in 4 patients and remained limited to the mouth for a period varying from 3 to 36 months, an average of 18.8 months. The oral lesions healed without scarring in 10 patients, while in 3 patients scars remained. Those lesions which heal without scarring appear as small and tense blisters scutt,ered over the oral mucosa. Intact blisters are frequently observed, since they often do no8 break for some time in spite of the friction to which they are exposed in the oral cavity. The ensuing erosions do not enlarge in size and tend to heal well. On the whole, the lesions resemble those observed in pemphigus vulgaris chronicus. The lesions are only moderately tender, and interference with eating is never a serious matter. In the patients in whom scarring ensues the erosions do not heal in certain areas. Instead, they slowly increase in size. After having attained a certain size, they remain present for a long period of time until finally healing with scarring occurs. The large erosions in this type differ from the large erosions seen in pemphigus vulgaris acutus in several points: The lesions show little or no progression at the periphery. The erosions appear cleaner than in pemphigus vulgaris acutus, since there are usually no shreds of epithelium at the border and no fibrinous exudate on them. They do not tend to bleed as easily. The involved oral mucosa does not appear swollen. Salivation is slight or absent, and the saliva is not blood tinged. The lesions cause less pain, so that they do not interfere with an adequate intake of food. Furthermore, the vermilion border of the lips which is a common site of lesions in pemphigus vulgaris acutus is not involved. Scarring is most frequently seen around the soft palate and the tonsillar pillars, but may be found elsewhere in the mouth, namely on the buccal mucous membrane, the tongue, or the mucous membranes of the lips. In 2 of the 3 patients in whom scarring on the oral mucosa occurred, the scarring was only moderate; in both patients the tonsillar pillars and the uvula had been destroyed. In the third patient, however, the scarring was severe ; the soft palate had become adherent to the posterior pharyngeal wall, leaving only a small opening between the. upper and the lower pharynx (Fig. 5).
DISCUSSION
Oral lesions are an important part of the clinical picture in four types of pemphigus : in pemphigus vulgaris acutus, pemphigus vegetans, pemphigus vulgaris chronicus, and pemphigus conjunct,ivae. The oral lesions in pemphigus vulgaris acutus, pemphigus vulgaris chronicus, and pemphigus conjunctivae differ from each ot,her in their appearance. The oral lesions of pemphigus
Fig. B.-Patient with benign mucous membrane pemphigus of two years’ duration. Two large erosions are shown, one on each side of the tongue. There were also large erosions elsewhere on the oral mucosa and lesions on the mucous membrane of the nose. The conjunctivae were not (or probably not yet) involved. Patient is living. (Patient of the Beth Israel Hospital, Boston, Mass.)
Fig. 0. -Patient with benign mucous membrane pemphigus Note that the soft palate has become View of the oral cavity. retropharyngeal wall. Lesions were also present on the conjunctivae.
of six completely Patient
years’ duration. attached to the is living.
OF PEMPHIGUS
Total
Pemph. vulg. acutus Pemphigus vegetans Pemph. vulg. chron. Pemphigus foliaceus Pemph. erythematodes Pemph. conjunctivae
TYPE
114
33 3 35 25 2 16
NUMBER OF PATIENTS
62
28 3 17
NUMBER
54
85 100 49
PER CENT
OF ORAL
FREQUENCY OF ORAL LESIONS
OCCURRENCE
IN
THE
29
18 3 4 0
25
55 100 11 0 0 25
FR.EQUENCY OF ONSET IN THE MOUTH PER NUMBER CENT
LESIONS
TABLE
I FORMS
18.8
2.9 2.5 4.5 -
INTERVAL BETWEEN ORAL AND OTHER LESIONSINTHOSP WHO HAD ORAL LESIONS FIRST MONTHS
VARIOUS
60
31 2 13 14 0 0
NUMBER
MORTALITY
OF PEMPHIGUS
52
94 66 37 56 0 0
PER CENT
I
OF PATIENTS
34
0
27 2 CT,
53
96 66 29 0
51
44 56 0 0
i 14 0 0 26
80
4
WITH ORAL I WITHOUT ORAL LESIONS LESIONS PER PER NUMBER CENT NUMBER CENT
MORTALITY
vegetans are identical with those of pemphigus rulgaris acutus except for the formation of vegetations in rare instances. Correct classification of the oral lesions in a patient who has no other lesions For example, a patient with exof pemphigus carries great responsibility. tensive erosions of the oral mucosa may have either pemphigus vulgaris acutus in which the mortality is almost. 100 per cent or pemphigus conjunctivae in which the mortality is zero. In the absence of other lesions the different appearance of the oral lesions is these two types is the only clinical sign to rely upon for a differential diagnosis. It should be remembered, however, that vounger age and Jewish race suggest more the diagnosis of pemphigus vulgaris acutus, while older age and non-Jewish race would favor a diagnosis of pemphigus conjunctivae. In addition, a thorough examination of the conjunctivae is advisable, since they may show beginning involvement, if the case under consideration is one of pemphigus conjunctivae. It has been frequently stated in the literature that the presence of mouth lesions in pemphigus suggests a grave prognosis. This statement should be qualified. It is true that the two types which show the severest oral involvement, namely pemphigus vulgaris acutus and pemphigus vegetans, have the highest mortality, but the mere presence of mouth lesions does not permit conclusions to be drawn concerning the prognosis. Pemphigus conjunctivae, for example, frequently shows oral involvement but, is a benign disease. Neither can it be said that the presence or absence of oral lesions in any particular type of pemphigus influences the prognosis. In pemphigus vulgaris acutus the mortality among patients with mouth lesions was 96 per cent, without mouth lesions 80 per cent. In pemphigus vulgaris chronicus the mortality was 29 per cent among patients with mouth lesions and 44 per cent among patients without mouth lesions. SUMMARY
1. The frequency and the appearance of the oral lesions in the various types of pemphigus have been discussed. 2. In a series of 114 cases of pemphigus 62 (54 per cent) showed involvement of the oral mucosa. Oral lesions were encountered in 85 per cent of the cases with pemphigus vulgaris acutus, in 100 per cent of the cases with pemphigus vegetans, in 49 per cent of the cases with pemphigus vulgaris chronicus, in 4 per cent of the cases with pemphigus foliaceus, in none of the cases with pemphigus erythematodes, and in 81 per cent of the cases with pemphigus conjunctivae. 3. The oral lesions in pemphigus vulgaris acutus, pemphigus vulgaris chronicus, and pemphigus conjunctirae differ enough to make their appearance an important part of the differential diagnosis. The oral lesions of pemphigus vegetans are idental with those of pemphigus vulgaris acutus except for the development of vegetations in rare instances. 4. The mortality rate differs widely between the various types of pemphigus. The presence or absence of oral lesions does not influence the prognosis in any of the types. 5. Oral lesions were the first symptom of pemphigus in 25 per cent of the cases. The initial lesions were observed in the mouth in 55 per cent of
the cases with pemphigus vulgaris acutus, in 10 per cent of the cases with pemphigus regetans, in 11 per cent of the cases with pemphigus vulgaris chronicus, in none of the casts with pemphigus foliaceus and pemphigus erythematodes, and in 25 per cent of the cases with pcmphigus conjunctivac. In the absence of other lesions the diagnosis of pemphigus must be made from the oral lesions alone. REFERENCES 1.
Ueber chronischen Pemphigus der SchleimhIute, Monatsschr. f. OhrenThost, A.: heilk., 30: 165, 1896. (b) Serefis. 8.: Ueber die prognostische Bedeutunp: der Schleimhautreriinderuneen beim Pemihigus, Dermat. S~chschr. 96: 145, 193.3: Senear. F. E., and Usher, B.: An Unusual Type of Pemphigus Combining Features of LUDUS Ervthematosus. Arch. Dermat. & Svph. 13: 761. 1926. Brocq, L:: S&me des &ptions bulleuses. Le” pemphigus iubaigu malin B bulles extensives, et faits eonnexes, Ann. de dermat. et de syph., 5th series 7: 449. 1919. Riecke. E.: Pemnhinus. In Handbuch der Haut;nd ‘Geschlechtskrankhkiten. , Berlin. I julius Sprin~er~1931. Vol. 7, part 2, pg. 370. Lever, W. F., and Talbott, J. H.: Pemphigus Vulgaris and Pemphigus Vegetans. A Suggestion for Distinction Iletween Two Types of Pemphigus Vulgaris, Namely an Acute and a Chronic Type, and a Comparison of Pemphigus Vegetans with the Acute Type. (To be published.) Friihwald, R.: Pemphigus Vegetans, Leipzig and Hamburg, 1915, L. Voss. Gray, A. M. H.: Pemphigus of the Senear-Usher Type, Proc. Royal So:. Med. 31: part 2, pg. 871, 1937/3S. (a)
\
2. 3. 4. 5.
6. 7.
I
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COMMONWEAI,TII
AVENUE