Originalia F. Strle, D. P l e t e r s k i - R i g l e r , G. S t a n e k , A. P e j o v n i k - P u s t i n e k , E. R u z i c , J. C i m p e r m a n
Solitary Borrelial Lymphocytoma: Report of 36 Cases Introduction Summary: Thirty-six cases of borrelial lymphocytoma were detected during the period 1986 to 1990 in Slovenia. Borrelial lymphocytoma was located on the ear lobe in 17 persons, ten female and seven male, with a median age of 12 years (range 2-56). Fourteen of these 17 were children under 14 years of age. A tick bite was remembered by 15 patients a median of 30 days before borrelial lymphocytoma developed. The most frequent month of onset was September. Erythema migrans preceded or accompanied borrelial lymphocytoma in eight cases. In 15 cases, eight female and seven male, borrelial lymphocytoma was localized on the mamilla. Median age of these patients was 42 years (range 15-72). Twelve had a tick bite about 45 days (median value) before the onset of borrelial lymphocytoma, which occurred most frequently in August. Erythema migrans was reported in 13 patients and preceded borrelial lymphocytoma in ten cases. In another four patients borrelial lymphocytoma was localized on the nose, scrotum, upper arm and shoulder. Antibiotic treatment with phenox3anethylpenicillin (n=16), ceftriaxone (n=8), doxycycline (n = 9), azithromycin (n = 2) and penicillin G (1) led to complete recovery within an average of three weeks in all cases. Zusammenfassung: Solitiires Borrelien-Lymphozytom. Bericht iiber 36 Fiille. Zwischen 1986 und 1990 wurden in Slowenien 36 Patienten mit einem BorrelienLymphozytom erfaf3t. Bei 17 Patienten, 10 weiblichen und sieben m~innlichen, mit einem medianen Alter yon 12 Jahren war das Borrelien-Lymphozytom am Ohrl~ippchen lokalisiert, t4 dieser Patienten waren Kinder unter 14 Jahren. t5 der Patienten hatten einen Zeckenstich 45 Tage (Median) vor Manifestation des Borrelien-Lymphozytoms, das am h/iufigsten im September auftrat. Ein Erythema migrans bestand gleichzeitig oder ging dem Borrelien- Lymphozytom in 8 F/illen voraus. Bei 15 Patienten, acht weiblichen und sieben m/innlichen, war das Borrelien-Lymphozytom an der Mammille lokalisiert. Das mediane Alter dieser Patienten war 42 Jahre (15-72). Zw61f hatten einen Zeckenstich circa 45 Tage bevor sich ein BorrelienLymphozytom entwickelte, das am h~iufigsten im August auftrat. Bei weiteren vier Patienten war das Borrelien-Lymphozytom auf der Nase, dem Scrotum, Oberarm und Schulter lokalisiert. Eine antibiotische Behandlung mit Phenoxymethylpenicillin (n=16), Ceftriaxon (n=8), Doxycyclin (n=9), Azithromycin (n=2) oder Penicillin (n = 1) fiihrte durchschnittlich innerhalb yon drei Wochen zur vollst~indigen Heilung.
At the turn of the century, Spiegler [1] and Fendt [2] described dermatological abnormalities which were similar to sarcoma but of benign character. More than 25 years later, the term lymphocytoma cutis was used for these lesions [3,4]. Biifverstedt [4] coined the term lymphadenosis benigna cutis (LBC) in 1943. LBC presents various clinical and histological features, occurring as LBC solitaria and dispersa. Solitary manifestations are found in children and adults, disperse lesions only in adults [5]. The etiology of the disperse LBC is not yet clarified [6]. Recently, the solitary skin disorder has been named more specifically borrelial lymphocytoma; however, it remains questionable whether all solitary lymphocytomas are due to an infection by Borrelia burgdorferi [6,7]. Cases with substantial evidence for this etiology may be designated as borrelial lymphocytoma. Up to now, solitary borrelial lymphocytoma has been proven to result from a Borrelia burgdorferi infection by cultivation of the organism in a single case [8] and has been suggested by elevated antibody titers [7-9] and by demonstration of spirochetal organisms in silver-stained sections of biopsies [10[. The borrelial etiology is further supported by the presence of other manifestations of Lyme borreliosis such as erythema migrans [5,6,9] and acrodermatitis chronica atrophicans [5], and by transition into erythema migrans of intradermal injection of tissue homogenate of an ear lobe lymphocytoma [11]. Solitary borrelial lymphocytoma is characterized histologically by a dense polyclonal lymphocytic infiltrate, sometimes having germinative centers, in the dermis and/or subcutis and presents clinically as a red to dark bluish-red nodule or swelling of a few centimeters in diameter. The ear lobe and the mamilla are the sites most frequently affected. The lesion may be painful to touch. Untreated borrelial lymphocytoma may persist for many months [6,9,12]. This report comprises data on 36 consecutive patients with borrelial lymphocytoma who were registered in Slovenia during the period 1986 to 1990.
Patients and Methods Diagnosis of borrelial lymphocytomain 36 cases was made at the Department of Infectious Diseases at the University Medical Received: 4 February 1992/Revisionaccepted: 1 June 1992 Dr. reed. F. Strle, Dr. reed. D. Pleterski-Rigler, Dr. reed. J. Cimperman, Departmentof InfectiousDiseases,UniversityMedicalCentre Ljubljana, Japljeva 2, 61000 Ljubljana, Slovenia; Dr. reed. A. Pejovnik- Pustinek, Department of Dermatology,MedicalCentre Celje,Kersnikova1, 63000 Celje, Slovenia;Dr. reed. E. Ruzie, Institute of Microbiology,University of Ljubljana,Zaloska4, 61000 Ljubljana,Slovenia;Dr. reed. G. Stanek, Hygiene-Institut der Universit/it, Kinderspitalgasse 15, A-1095 Wien, Austria.
Infection20 (1992) No. 4 © MMV MedizinVerlagGmbH Mfinchen,M~nchen 1992
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F. Strle et al.: Borrelial Lymphocytoma Centre Ljubljana, Slovenia, during the years 1986 to 1990, and at the Department of Dermatology at the Medical Centre Celje, Slovenia, from 1986 to 1988. At least one of the authors was involved in the diagnosis, treatment, and follow-up of each patient. Routine examination of blood cytology and immunology was performed in all patients. Diagnosis of lymphocytoma was established clinically. PathohistologicaI examination of the lesions was done in cases in which the manifestation was clinically unclear, especially when erythema migrans or serum antibodies to BorreIia burgdorferi were not present. Lymphocytoma was interpreted to be of borrelial origin in patients with typical erythema migrans or a reliable history of it, and/or with serum antibodies to Borrelia
No
8 7
7
~ ....... 6
I:! ;I
JAN.
burgdorferi. Blood samples for serological investigations were taken at the first visit when lymphocytoma was diagnosed, and again four to six weeks later in all cases; in selected cases additional samples were obtained even months later. In case of seronegativity of the first samples, further serological examination was clone another six to eight weeks later. Antibodies against Borretia burgdorferi were determined by ELISA at the Hygiene Institute of the University of Vienna and by an indirect immunofiuorescence assay (IFA) at the Institute of Microbiology, University of Ljubljana. Results considered positive were those above a threshold of 4.0 ELISA units (equivalent to an optical density of 0.450 at a wavelength of 492 nm for a serum specimen diluted 1:1000) or those with IFA titers --> 1:256, without serum preabsorption with Tteponema phagedenis. All patients received antibiotic treatment with substances reported to be effective in local and/or disseminated manifestations of Lyme borreliosis [t3,14]. Statistical evaluation of quantitative and qualitative data was done by Wilcoxon sum rank test and by chi-square test, respectively.
FE~.
MAN.
APR.
MAY
JUN.
JUL,
AUG,
SEP,
OOT.
NOV,
OEC
Figure 1: Seasonal onset of borrelial lymphocytoma.
seven in 1989 and 11 in 1990. In the majority of patients the onset of borrelial lymphocytoma was in the second half of the year (Figure 1 ). The median age of all cases was 23 years, ranging from 2 to 72 years. Sixteen (44%) of the patients were children under 15 years of age.
Borrefial Lymphocytoma of the Ear Lobe Borrelial lymphocytoma was localized on the ear lobe in 17 patients, ten females and seven males ( / a b l e 1). Median age of these patients was 8 years (range 2 to 56 years). All except two female patients recalled a tick bite. Borrelial lymphocytoma developed within six to 180 days (median 30 days) after the tick bite, and a median of five weeks (ten days to six months) passed from the onset of the skin lesion until diagnosis. It presented as a red-purple to bluish-purple swelling or a nodule of 0.5 to 2.5 cm in diameter on the ear lobe. In some patients the swelling expanded along the rim of the ear lobe. Erythema migrans developed concomitant with borrelial lymphocytoma in eight cases and spread out from the area
Results From 1986 to 1990, 36 consecutive patients with a solitary borrelial lymphocytoma were detected in Slovenia. Two cases each were diagnosed in 1986 and 1987, 14 in 1988,
Table 1 : Basic epidemiological and clinical data, IFA antibody titers, treatment and outcome of patients with lymphocytoma on the ear lobe.
1 2 3 4 5 6 7 8 9 10 1t 12 13 14 15 t6 17
5 10 9 13 6 8 10 8 23 7 56 28 10 ? 3 2 5
M F F F M M M F F M F F F F F M M
+ + + + + + +~ + + + + + + + ~ +
75 ?" 90 25 6 ?" 7 l0 3(I 30 60 30 180 30 20 21
June Sept Nov Aug Juiy Aug Oct Sept Aug Sept Oct Dee Sept Jan June Oct Sept
90 35 30 45 i0 14 21 28 60 60 45 105 14 181) 150 10 13
-+ + . . . . . + + + t+ , + + + '+ . . . . .
+ +
+ + + + + + + . .
.
.
.
128 256 neg neg 256 neg neg neg 256 128 neg 256 neg neg 128 256 256
256 256 128 neg neg neg neg neg 256 256 neg 256 neg 512 512 128 neg
128 I28 neg neg 128 neg neg neg 128 256 neg 128 neg neg neg 128 128
256 P M P 256 P M P 256 P G neg b P M P neg P M P neg P M P neg P M P neg P M P 256 D O X 256 P M P negbDOX 512 P M P neg P M P 512 P M P 512 C E F 128 P M P I28 PMP CEF
1M 2M 8 M 2 M 2 M 2M 2 M 2 M 200 mg 2M 200 mg 4M 2 M 2M 1g 1.5 M 3M 1g
21 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 21 14
l0 2 3 3.5 1 1.5 1.5 1.5 4 2 3.5 4 2 8 4 I 7
Several tick bites, no exact date. Seroconversion found at later examinations. Tick bite at a distance from erythema migrans and lymphocytorna, Insect bite. BL = borrelial lymphocytoma; PMP = phenoxymethylpenicillin; PG = penicillin G; D O X = doxycycline: CEF = ceftriaxone.
26 / 202
I n f e c t i o n 20 (1992) N o . 4
© M M V M e d i z i n V e r l a g G m b H M f i n c h e n , M¢inchen 1992
F. Strle et al.: Borreliat Lymphocytoma of the affected ear in seven cases. In one case erythema migrans was located on the thigh. Mild itching was the only local symptom in eight patients. One patient, a girl aged 9 years (patient no. 3, Table 1), had a tick bite behind her left ear in August 1987. In October she was admitted to the hospital because of left-sided facial palsy. Spinal tap revealed cerebrospinal fluid (CSF) with lymphocytic pleocytosis. Five weeks later borrelial lymphocytoma developed on her left ear lobe. Borderline serum values of specific IgG antibodies were detected (IFA titer 1:128; ELISA 4.0 units); two months later the tests were clearly positive (IFA IgM negative, IgG 1:256; ELISA IgG 4.6 units). Mild constitutional symptoms such as moderate headache, general malaise and fatigue were reported by three patients. Regional enlarged lymph nodes of the neck were seen in eight of the 17 patients. Hematological and immunological parameters were within the normal range in all patients. In all patients the changes on the ear were so typical that the clinical picture alone was enough to establish the diagnosis of solitary lymphocytoma. Histological examination was performed only in two patients and showed a dense lymphocytic infiltrate in the dermis and subcutis. Specific antibodies to Borrelia burgdorferi were demonstrable in blood specimens of 11 patients drawn at their first visit (Table 1). Subsequent serological tests of three other patients (nos. 4, 8 and 11; Table 1) were positive 2.5, 3 and 3.5 months after the first examination, i.e. 3.5, 4.5 and 5 months after the onset of borrelial lymphocytoma. Three patients remained seronegative. A complete resolution of the lymphocytoma lesions was achieved a median of three weeks (range one to ten weeks) after the onset of treatment (Table 1). In one child, a 5-year-old boy (patient no. 17, Table 1 ), borrelial lymphocytoma developed three weeks after a tick bite on
his left ear. At the beginning of treatment with oral penicillin, he experienced another tick bite on his right ear. Despite antimicrobial treatment he developed an additional lymphocytoma on the right auricle 11 days later. A regimen of intravenous ceftriaxone lg per day for 14 days was then administered and resulted in complete resolution.
Borrelial Lymphocytoma of the Breast Borrelial lymphocytoma was localized on the areola mammae in 15 patients, eight women and seven men, with a median age of 44 years (range 15 to 72 years) (Table 2). Twelve patients had a history of tick bite. In ten of them the tick bite was located within 15 cm around the nipple. Borrelial lymphocytoma developed within a median of 45 days (range five days to five months) after the tick bite, and a median of 70 days (range four weeks to 12 months) passed from the onset of the skin lesion until the diagnosis. Due to the considerable time lapse, the disease could not be accurately reviewed in all patients. Thirteen of the 15 patients presented with erythema migrans on the breast. Ten reported an erythema migrans that preceded borrelial lymphocytoma by 14 days to 1.5 months. In two patients erythema migrans coincided with borrelial lymphocytoma. In a 58-year-old female patient erythema migrans developed one month after the onset of borrelial lymphocytoma. All patients except one reported localized discomfort in the region of the areola mammae; they were bothered by their clothing, and the area was painful to touch. Mild itching, breast tension, burning and pain of the thoracic wall on the affected side were complaints of nine, eight, six, and four patients, respectively. Upon inspection, nipples were found to be asymmetric but, with one exception, showed no discoloration. Nipples
Table 2: Basic epidemiological and clinical data, IFA antibody titers, treatment and outcome of patients with lymphocytoma on the nipple.
1 2 3
72 53 34
F F M
+" -~ +
45 45 20
Aug Sept Nov
60 70 45
+ + +
+ + +
+ + +
--
128 256 256
256 256 256
neg 256 128
256 D O X 256 D O X 128 A Z I
4 5 6 7 8 9 10 11 12
49 68 15 24 18 35 44 35 58
M M M F F M M M F
+
70
+ + + 4 + + +
2A 90 21 25 75 5m 5
Aug Aug July Nov July June Jan Dec Oct
360 120 28 270 50 60 120 60 35
-~ + + + + + + +
+ + t + + +
+ + + + + + +
+ + + + -
neg 128 neg 256 512 neg 128 256 neg
512 512 neg 256 i28 neg 256 512 neg
neg neg neg 256 256 neg 128 128 neg
256 512 neg 256 256 neg 256 512 neg
i3 14 15
23 54 47
F F F
+ +
60 30
Nov Oct Aug
210 90 240
+ + +
+ + +
+ + +
4
512 neg 128
512 neg 512
512 neg neg
512 D O X 128¢ P M P 512 C E F
CEF CEF DOX CEF PMP DOX CEF CEF AZI
200 nag 200 mg 500 mg 250 mg 2 g i.v. 2 g i.v. 200 mg 2 g Lv. 6 M 200 mg 2 g i.v. 2 g i.v. 1000mg 500 mg 200 mg 3 M 2 g i.v,
14 14 2 8 14 14 14 14 14 14 14 14 1 4 14 14 14
4 3 2 ? 5 1.5 75 2 2 3 10 1,5 5 5 ?
Tick bite at a distance from erythema migrans and lymphocytoma, Insect bite. Seroeonversion found at later examinations. BL = borrelial lymphocytoma; D O X = doxycycline; PMP = phenoxymethylpenicillin; AZI = azithromyein; CEF = ceftriaxone; ? = lymphocytoma surgically removed,
I n f e c t i o n 20 (1992) N o . 4
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203 / 27
F. Strle et al.: Borrelial Lymphocytoma
[~Rrrm [ RADICULONEURfrls
....
~%x,~,--~
--I AUG
SEPT
OCT
NOV
DEC
JAN
Figure 2: Clinical course of long-lasting borrelial lymphocytoma (patient no. 5, Table 2). Th = antibiotic therapy.
tARTH~ALGI~ ~ACACHE TICK 81TE
ICYM ~
AUG'l SEpT I OC3, "~ NOV ~ ~ , ~ 1987
~
~
~]
SEPT
OCT
T~'A
~ FIE~ z ' il~
t ,pR I MA¥
JU~4 1988
JUL
AUG
Figure 3: Clinical course of long-lasting borrelial lymphocytoma (patient no. 7, Table 2). Th = antibiotic therapy; EM = erythema migrans.
of the affected area were edematous, painful to touch and, in eight patients completely, in four patients partly hardened. Infiltration was regularly found in the areola mammae in a diameter of up to 3 cm. Eight patients had enlarged lymph nodes on the affected side. At the first visit, 11 patients had elevated antibodies to Borrelia burgdorferi (Table 2). In the remaining four patients the presence of erythema migrans attested to Lyme borreliosis. In one of these four patients, significant elevation of antibody titers was found at later examinations. Complete resolution of borrelial lymphocytoma was observed within 1.5 to 10 weeks (median three weeks) after the start of antibiotic treatment. A 49-year-old patient (patient no. 4, Table 2) had a tick bite in June 1987. Erythema migrans developed three weeks later, persisting for two months and affecting the entire left thorax. Approximately one week before erythema migrans resolved, the left nipple became swollen and sensitive to touch. The patient also experienced itching and transitory burning in the nipple. He complained of local discomfort, fatigue and muscle pain in
the limbs. In mid September he began suffering from headache and episodic attacks of vertigo; he reported cardiac arrhythmias as well. In early October he experienced radicular pains on the left side of the thorax. He became nervous, impatient and irritable. For about two months he suffered from insomnia due to severe pain. Later, the pains ceased, but fatigue and occasional severe headaches, increasing impairment of concentration as well as the changes on the breast persisted. In spring 1988 he began experiencing pains in the elbow. Despite several consultations with physicians the case was not clarified. In August 1988 he was referred to the Department of Infectious Diseases. At this time, his left nipple was swollen and its upper half in particular was hardened and sensitive to touch. A nodule of 2.5 cm in diameter was palpable, Histological examination of a biopsy of the nodule indicated lymphocytoma, but we were not able to demonstrate spirochetes in it by a silver stain. CSF was taken and revealed 9 x 106 lymphocytes/1. CSF protein and glucose were within the normal range. Ceftriaxone, 2 g intravenously for 14 days, was administered. One month after the treatment the patient was free of all symptoms. In December 1988 transitory pains recurred. The course of disease in two other patients with long-lasting borrelial lymphocytoma and other manifestations is shown in Figures 2 and 3. Borrelial Lymphocytoma on Sites Other than the Ear and Mamilla In the remaining four patients borrelial lymphocytoma was localized on the nose, shoulder, upper arm and scrotum (Table 3). Diagnosis of lymphoc3:toma was made by" pathohistological investigation of biopsies from the affected skin. Dense lymphocytic infiltration was found in all cases, and in two of them germinative centers were seen. Borrelial etiology was suggested by seropositivity and by" the presence or a history of erythema migrans. Discussion
Borrelial lymphocytoma, a rare manifestation of Lyme borreliosis, is known throughout Europe, but there are no reports from the USA. Only one study on a larger number of patients suffering from borrelial lymphocytoma has been published since laboratory diagnosis of Borrelia burgdorferi infection became possible [9]. In Austria and in
Table 3: Basic epidemiological and clinical data, IFA antibody titers, treatment and outcome of patients with lymphocytoma on various locations (other than the ear and mamilla).
I
I 2 3 4
8 7 52 35
M M M M
-: + +
BL = borrelial lymphocytoma; PMP
28 / 204
30 7
Oct June May Sept
nose scrotum arm shoulder
360 30 45 210
= phenoxymethylpenicitlin; DOX
+ 4-
+ + +
+ + + +
-
neg 128 256 neg
256 neg 256 256
neg 128 128 neg
256 128 256 256
PMP PMP DOX DOX
2 MEGA 1 MEGA 200 mg 200 mg
t4 14 t4 14
8 2.5 4 ?
= doxycycline; ? = l y m p h o c y t o m a s u r g i c a l l y r e m o v e d .
Infection 20 (1992) No. 4 © MMV Medizin Verlag GmbH Mtinchen, Mfinchen 1992
F. Strle et al.: Borretial Lymphocytoma Sweden the frequency is reported to be less than 3% and about 1.6%, respectively [15,16]. In Slovenia, only 18 of 1,582 registered patients with a proven Borrelia burgdorferi infection in the years 1986 to 1988 [17,18] (1.1%) had lymphocytoma. The most common site of borrelial lymphocytoma in our patients was on the ear lobe in children and on the nipple in adults. This coincides with observations of other researchers [6,9]. The reasons for such distinctive localizations are not completely understood. Asbrink et al. [12] hypothesized that borreliae prosper at a temperature below 37°C. This would explain why the ear lobe and the nipple, i.e. the cooler parts of the body, are most frequently affected. However, there are some additional explanations. Lymphocytoma on the ear lobe is easy to notice and can be easily recognized due to its characteristic appearance (if, of course, the physician is familiar with the disorder). Changes in the nipples and nodules in the breast often scare the patient into seeking medical help, while the physician has to use various diagnostic measures to achieve the chance of correct diagnosis. Nodules found in other areas of the skin, whether in the dermis or subcutis, are usually no cause to consult a physician. Even if the patient seeks medical attention in such cases, it is difficult to establish a clinical diagnosis without other manifestations of a borrelial infection. It is even more difficult to interpret the differences in the localization of borrelial lymphocytoma in children and adults. Possibly, one reason may be the different sites of tick bites. It is known that ticks are usually found on vegetation a few centimeters up to one meter above ground. This explains why erythema migrans is localized much more frequently on the face of children than adults, e.g., in 23% and 4%, respectively [19]. It would also explain why ear lobe borrelial lymphocytoma is found predominantly in children. Yet, the localization of the tick bite does not explain why borrelial lymphocytoma on the breast is an exception in children. It seems possible, if not likely, that there are local tissue factors which support development of borrelial lymphocytoma on the breast in adults. The 36 patients with borrelial lymphocytoma presented here comprise 18 females and 18 males. Twenty-nine reported a tick bite. In 24 of them (83%) the tick bite was in closest vicinity to the location of the subsequent borrelial lymphocytoma. Thus, in a great majority of patients the spirochetes may spread from the site of the bite to the site where the disorder appears. This is well known from erythema migrans, which spreads out from the site of inoculation. In our cases borrelial lymphocytoma was located in the area of erythema migrans in 24 of 25 patients with concomitant erythema migrans. However, in comparison with erythema migrans, borrelial lymphocytoma develops later and lasts longer. There is a time interval of 30 days from the tick bite to the occurrence of borrelial lymphocytoma. In 616 patients
with erythema migrans, the skin lesion developed at the site of the tick bite within a median time of only 12 days [19]. Erythema migrans, the typical early manifestation of Lyme borreliosis, preceded borrelial lymphocytoma in 19 of our 25 cases. An interesting observation was made in one child, who first exhibited facial palsy and later on borrelial lymphocytoma on the ear lobe. This is in agreement with the observation that central nervous system infection may be not infrequently the first manifestation of Lyme borreliosis in children [20]. Differences were observed between patients with borrelial lymphocytoma on the ear lobe and those affected on the breast. Ear lobe borrelial lymphocytoma is most predominantly seen in children, breast borrelial lymphocytoma in adults (age difference p < 0.05). Similar results have been reported previously [9]. Fourteen of 17 patients with ear lobe lymphocytoma had no other systemic symptoms, whilst 12 of 15 patients with breast borrelial lymphocytoma recalled constitutional symptoms (p < 0.01). Borrelial lymphocytoma may be the only manifestation of Lyme borreliosis, and ear lobe borrelial lymphocytoma may be relatively easy to recognize. Its borrelial etiology, however, is not fully confirmed in persons seropositive to Borrelia burgdorferi. The borrelial etiology is more conclusive if an erythema migrans or a reliable history of it is present. In breast borrelial lymphocytoma, the clinical diagnosis is more difficult to establish and the differential diagnosis is wider. Seropositivity and other signs and symptoms of Lyme borreliosis are helpful clues for making the correct diagnosis. It is most difficult to diagnose borrelial lymphocytoma on locations other than the ear and breast, especially in cases in which borrelial lymphocytoma is the only manifestation and/or the patient is seronegative. In these cases a tissue biopsy is mandatory. However, even skin biopsy specimens showing dermal lymphocytic infiltrates with germinal centers are only suggestive and not specific. Attempts to cultivate spirochetal organisms from borrelial lymphocytoma lesions were only successful in a single case [91. The traditional treatment of borrelial lymphocytoma is based on the empiric observation of the efficacy of penicillin. Most of our patients were treated for 14 days, children predominantly with phenoxymethylpenicillin, and adults with doxycycline, 2 x 100 mg per day orally. In case of concomitant neurologic or joint symptoms, intravenous ceftriaxone, 2 g daily, was administered. For this study it is not possibe to evaluate the efficacy of treatment with individual antibiotics due to the smaller number of patients. It seems, however, that the time of full recovery depends on the duration of borrelial lymphocytoma prior to the beginning of treatment. The development of a borrelial lymphocytoma during treatment with phenoxymethylpenicillin and a significant elevation of Borrelia burgdorferi antibody titers in four of 15 patients indicate the need for prospective studies comparing
Infection 20 (1992) No. 4 © MMV Medizin Verlag GmbH Mfinchen, Mtinchen 1992
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F. Strle et al.: Borrelial Lymphocytoma
traditional treatment of this manifestation with the efficacy of other antibiotics. Additional studies are also needed to confirm some new or partly new findings of the present report (e.g. time and local relation of borrelial
lymphocytoma to tick bite and erythema migrans, and the reasons for ear lobe and nipple manifestations) as well as to explain the distinctive localization of borrelial lymphocytoma in children and adults.
References 1. Spiegler, E.: l]ber die sogenannte Sarcomatosis cutis. Arch. Dermatol. Syph. 27 (1984) 163-174. 2. Fendt, H.: Beitr/ige zur Kenntnis der sogenannten sarcoiden Geschwiilste der Haut. Arch. Dermatol. Syph. 53 (1900) 213-242. 3. Kaufmann-Wnlf, M.: Llber gutartige lymphocytfire Neubildungen der Scrotalhaut des Kindes. Arch. Dermatol. Syph. 130 (1921) 425-439. 4. B/ifi,Terstedt, B.: 13ber die Lymphadenosis benigna cutis. Eine klinische und pathologisch-anatomische Studie. Acta Derm. Venereol. 23 (Suppl. 11) (1943) 1-202. 5. B/ifverstedt, B.: Lymphadenosis benigna cutis (LACB); its nature, course and prognosis. Acta Derm. Venereol. 40 (1960) 10-18. 6. Asbrink, E., Hovmark, A.: Early and late cutaneous manifestations in Ixodes-borne borreliosis (erythema migrans borretiosis, Lyme borreliosis). Ann. NY Acad. Sci. 539 (1988) 4-15. 7. Weber, K., Sehierz, G., Wilske, B., Preac-Mursic, V.: Das Lymphozytom - eine Borreliose? Z. Hautkr. 60 (1985) 1585-1598. 8. Hovmark, A., Asbrink, E., Olsson, L: The spirochetal etiology of lymphadenosis benigna cutis solitaria. Acta. Derm. Venereol. 66 (1986) 479- 484. 9. Asbrink, E., Hovmark, A., Olsson, L: Lymphadenosis benigna eutis solitaria - borrelia lymphocytoma in Sweden. Zentralbl. Bakteriol. (Suppl. 18) (1989) 156-163. 10. Frithz, A., Lagerhoim, B.: Acrodermatitis chronica atrophicans, erythema chronicum migrans and lymphadenosis benigna eutis spirochetal diseases? Acta Derm. Venereol. 63 (1983) 432-436. 11. Paschoud, J. M.: Die Lymphadenosis benigna cutis als fibertragbare lnfektionskrankheit. Hautarzt 9 (1958) 311-315.
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12. Asbrink, E., Hovmark, A.: Cutaneous manifestations in lxodes-borne borrelia spirochetosis. Int. J. Dermatol. 26 (1987) 215-223. 13. Weber, K., Preac-Mursic, V., Neubert, U., Thurmayer, R., Herzer, P., Wilske, B., Schierz, G., Marget, W.: Antibiotic therapy of early European Lyme borreliosis and acrodermatitis chronica atrophicans. Ann. NY Acad. Sci. 539 (1988) 324-345.
14. Dattwyler, IL J., Halperin, J. J., Volkman, D. J., Luft, B. J.: Treatment of late Lyme borreliosis - randomised comparison of ceftriaxone and penicillin. Lancet i (1988) 1191-1t94.
15. Stanek, G., Pletschette, M., Flamm, H., Hirschi, A. M., Aberer, E., Kristoferitseh, W., Schmutzhard, E.: European Lyme borreliosis. Ann. NY Acad. Sci. 539 (1988) 274-282.
16. Lanner, M., Hederstedt, B., Asbrink, E., Hovmark, A., Stiernstedt, G.: Serodiagnosis of borrelia infections during 1986 in Sweden. Zentralbl. Bakteriol. (Suppl. 18) (1989) 69-74.
17. Strle, F., Pejovnik-Pustinek, A., Stanek, G., Pleterski, D., Rakar, R.: Lyme borreliosis in Slovenia in 1986. Zentralbl. Bakteriol. (Suppl. 18) (1989) 50-54.
18. Strle, F., Cimperman, J., Pejovnik-Pustinek, A., Stanek, G., Pleterski-Rigler, D., Jereb, M., Ruzic, E.: Lyme borreliosis: Epidemioloski podaci za Sloveniju. In: Ropa¢, D. (ed.): Lyme borelioza u Jugoslaviji. Medicinska akademija Hrvatske, Zagreb 1989, pp. 35M3.
19. Strle, F., Cimperman, J., PleterskilRigler, D., Stanek, G., PejovnikPustinek, A., Jereb, M., Ruzic, E.: Lyme borelioza u Sloveniji. In: Ropac, D. (ed.): Lyme borelioza u Jugoslaviji. Medieinska akademija Hrvatske, Zagreb 1989, pp. 93-100.
Infection 20 (1992) No. 4 © MMV Medizin Verlag GmbH Mfinchen, Mfinchen 1992
Solitary Borrelial Lymphocytoma: Report of 36 Cases Introduction Summary: Thirty-six cases of borrelial lymphocytoma were detected during the period 1986 to 1990 in Slovenia. Borrelial lymphocytoma was located on the ear lobe in 17 persons, ten female and seven male, with a median age of 12 years (range 2-56). Fourteen of these 17 were children under 14 years of age. A tick bite was remembered by 15 patients a median of 30 days before borrelial lymphocytoma developed. The most frequent month of onset was September. Erythema migrans preceded or accompanied borrelial lymphocytoma in eight cases. In 15 cases, eight female and seven male, borrelial lymphocytoma was localized on the mamilla. Median age of these patients was 42 years (range 15-72). Twelve had a tick bite about 45 days (median value) before the onset of borrelial lymphocytoma, which occurred most frequently in August. Erythema migrans was reported in 13 patients and preceded borrelial lymphocytoma in ten cases. In another four patients borrelial lymphocytoma was localized on the nose, scrotum, upper arm and shoulder. Antibiotic treatment with phenox3anethylpenicillin (n=16), ceftriaxone (n=8), doxycycline (n = 9), azithromycin (n = 2) and penicillin G (1) led to complete recovery within an average of three weeks in all cases. Zusammenfassung: Solitiires Borrelien-Lymphozytom. Bericht iiber 36 Fiille. Zwischen 1986 und 1990 wurden in Slowenien 36 Patienten mit einem BorrelienLymphozytom erfaf3t. Bei 17 Patienten, 10 weiblichen und sieben m~innlichen, mit einem medianen Alter yon 12 Jahren war das Borrelien-Lymphozytom am Ohrl~ippchen lokalisiert, t4 dieser Patienten waren Kinder unter 14 Jahren. t5 der Patienten hatten einen Zeckenstich 45 Tage (Median) vor Manifestation des Borrelien-Lymphozytoms, das am h/iufigsten im September auftrat. Ein Erythema migrans bestand gleichzeitig oder ging dem Borrelien- Lymphozytom in 8 F/illen voraus. Bei 15 Patienten, acht weiblichen und sieben m/innlichen, war das Borrelien-Lymphozytom an der Mammille lokalisiert. Das mediane Alter dieser Patienten war 42 Jahre (15-72). Zw61f hatten einen Zeckenstich circa 45 Tage bevor sich ein BorrelienLymphozytom entwickelte, das am h~iufigsten im August auftrat. Bei weiteren vier Patienten war das Borrelien-Lymphozytom auf der Nase, dem Scrotum, Oberarm und Schulter lokalisiert. Eine antibiotische Behandlung mit Phenoxymethylpenicillin (n=16), Ceftriaxon (n=8), Doxycyclin (n=9), Azithromycin (n=2) oder Penicillin (n = 1) fiihrte durchschnittlich innerhalb yon drei Wochen zur vollst~indigen Heilung.
At the turn of the century, Spiegler [1] and Fendt [2] described dermatological abnormalities which were similar to sarcoma but of benign character. More than 25 years later, the term lymphocytoma cutis was used for these lesions [3,4]. Biifverstedt [4] coined the term lymphadenosis benigna cutis (LBC) in 1943. LBC presents various clinical and histological features, occurring as LBC solitaria and dispersa. Solitary manifestations are found in children and adults, disperse lesions only in adults [5]. The etiology of the disperse LBC is not yet clarified [6]. Recently, the solitary skin disorder has been named more specifically borrelial lymphocytoma; however, it remains questionable whether all solitary lymphocytomas are due to an infection by Borrelia burgdorferi [6,7]. Cases with substantial evidence for this etiology may be designated as borrelial lymphocytoma. Up to now, solitary borrelial lymphocytoma has been proven to result from a Borrelia burgdorferi infection by cultivation of the organism in a single case [8] and has been suggested by elevated antibody titers [7-9] and by demonstration of spirochetal organisms in silver-stained sections of biopsies [10[. The borrelial etiology is further supported by the presence of other manifestations of Lyme borreliosis such as erythema migrans [5,6,9] and acrodermatitis chronica atrophicans [5], and by transition into erythema migrans of intradermal injection of tissue homogenate of an ear lobe lymphocytoma [11]. Solitary borrelial lymphocytoma is characterized histologically by a dense polyclonal lymphocytic infiltrate, sometimes having germinative centers, in the dermis and/or subcutis and presents clinically as a red to dark bluish-red nodule or swelling of a few centimeters in diameter. The ear lobe and the mamilla are the sites most frequently affected. The lesion may be painful to touch. Untreated borrelial lymphocytoma may persist for many months [6,9,12]. This report comprises data on 36 consecutive patients with borrelial lymphocytoma who were registered in Slovenia during the period 1986 to 1990.
Patients and Methods Diagnosis of borrelial lymphocytomain 36 cases was made at the Department of Infectious Diseases at the University Medical Received: 4 February 1992/Revisionaccepted: 1 June 1992 Dr. reed. F. Strle, Dr. reed. D. Pleterski-Rigler, Dr. reed. J. Cimperman, Departmentof InfectiousDiseases,UniversityMedicalCentre Ljubljana, Japljeva 2, 61000 Ljubljana, Slovenia; Dr. reed. A. Pejovnik- Pustinek, Department of Dermatology,MedicalCentre Celje,Kersnikova1, 63000 Celje, Slovenia;Dr. reed. E. Ruzie, Institute of Microbiology,University of Ljubljana,Zaloska4, 61000 Ljubljana,Slovenia;Dr. reed. G. Stanek, Hygiene-Institut der Universit/it, Kinderspitalgasse 15, A-1095 Wien, Austria.
Infection20 (1992) No. 4 © MMV MedizinVerlagGmbH Mfinchen,M~nchen 1992
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F. Strle et al.: Borrelial Lymphocytoma Centre Ljubljana, Slovenia, during the years 1986 to 1990, and at the Department of Dermatology at the Medical Centre Celje, Slovenia, from 1986 to 1988. At least one of the authors was involved in the diagnosis, treatment, and follow-up of each patient. Routine examination of blood cytology and immunology was performed in all patients. Diagnosis of lymphocytoma was established clinically. PathohistologicaI examination of the lesions was done in cases in which the manifestation was clinically unclear, especially when erythema migrans or serum antibodies to BorreIia burgdorferi were not present. Lymphocytoma was interpreted to be of borrelial origin in patients with typical erythema migrans or a reliable history of it, and/or with serum antibodies to Borrelia
No
8 7
7
~ ....... 6
I:! ;I
JAN.
burgdorferi. Blood samples for serological investigations were taken at the first visit when lymphocytoma was diagnosed, and again four to six weeks later in all cases; in selected cases additional samples were obtained even months later. In case of seronegativity of the first samples, further serological examination was clone another six to eight weeks later. Antibodies against Borretia burgdorferi were determined by ELISA at the Hygiene Institute of the University of Vienna and by an indirect immunofiuorescence assay (IFA) at the Institute of Microbiology, University of Ljubljana. Results considered positive were those above a threshold of 4.0 ELISA units (equivalent to an optical density of 0.450 at a wavelength of 492 nm for a serum specimen diluted 1:1000) or those with IFA titers --> 1:256, without serum preabsorption with Tteponema phagedenis. All patients received antibiotic treatment with substances reported to be effective in local and/or disseminated manifestations of Lyme borreliosis [t3,14]. Statistical evaluation of quantitative and qualitative data was done by Wilcoxon sum rank test and by chi-square test, respectively.
FE~.
MAN.
APR.
MAY
JUN.
JUL,
AUG,
SEP,
OOT.
NOV,
OEC
Figure 1: Seasonal onset of borrelial lymphocytoma.
seven in 1989 and 11 in 1990. In the majority of patients the onset of borrelial lymphocytoma was in the second half of the year (Figure 1 ). The median age of all cases was 23 years, ranging from 2 to 72 years. Sixteen (44%) of the patients were children under 15 years of age.
Borrefial Lymphocytoma of the Ear Lobe Borrelial lymphocytoma was localized on the ear lobe in 17 patients, ten females and seven males ( / a b l e 1). Median age of these patients was 8 years (range 2 to 56 years). All except two female patients recalled a tick bite. Borrelial lymphocytoma developed within six to 180 days (median 30 days) after the tick bite, and a median of five weeks (ten days to six months) passed from the onset of the skin lesion until diagnosis. It presented as a red-purple to bluish-purple swelling or a nodule of 0.5 to 2.5 cm in diameter on the ear lobe. In some patients the swelling expanded along the rim of the ear lobe. Erythema migrans developed concomitant with borrelial lymphocytoma in eight cases and spread out from the area
Results From 1986 to 1990, 36 consecutive patients with a solitary borrelial lymphocytoma were detected in Slovenia. Two cases each were diagnosed in 1986 and 1987, 14 in 1988,
Table 1 : Basic epidemiological and clinical data, IFA antibody titers, treatment and outcome of patients with lymphocytoma on the ear lobe.
1 2 3 4 5 6 7 8 9 10 1t 12 13 14 15 t6 17
5 10 9 13 6 8 10 8 23 7 56 28 10 ? 3 2 5
M F F F M M M F F M F F F F F M M
+ + + + + + +~ + + + + + + + ~ +
75 ?" 90 25 6 ?" 7 l0 3(I 30 60 30 180 30 20 21
June Sept Nov Aug Juiy Aug Oct Sept Aug Sept Oct Dee Sept Jan June Oct Sept
90 35 30 45 i0 14 21 28 60 60 45 105 14 181) 150 10 13
-+ + . . . . . + + + t+ , + + + '+ . . . . .
+ +
+ + + + + + + . .
.
.
.
128 256 neg neg 256 neg neg neg 256 128 neg 256 neg neg 128 256 256
256 256 128 neg neg neg neg neg 256 256 neg 256 neg 512 512 128 neg
128 I28 neg neg 128 neg neg neg 128 256 neg 128 neg neg neg 128 128
256 P M P 256 P M P 256 P G neg b P M P neg P M P neg P M P neg P M P neg P M P 256 D O X 256 P M P negbDOX 512 P M P neg P M P 512 P M P 512 C E F 128 P M P I28 PMP CEF
1M 2M 8 M 2 M 2 M 2M 2 M 2 M 200 mg 2M 200 mg 4M 2 M 2M 1g 1.5 M 3M 1g
21 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14 21 14
l0 2 3 3.5 1 1.5 1.5 1.5 4 2 3.5 4 2 8 4 I 7
Several tick bites, no exact date. Seroconversion found at later examinations. Tick bite at a distance from erythema migrans and lymphocytorna, Insect bite. BL = borrelial lymphocytoma; PMP = phenoxymethylpenicillin; PG = penicillin G; D O X = doxycycline: CEF = ceftriaxone.
26 / 202
I n f e c t i o n 20 (1992) N o . 4
© M M V M e d i z i n V e r l a g G m b H M f i n c h e n , M¢inchen 1992
F. Strle et al.: Borreliat Lymphocytoma of the affected ear in seven cases. In one case erythema migrans was located on the thigh. Mild itching was the only local symptom in eight patients. One patient, a girl aged 9 years (patient no. 3, Table 1), had a tick bite behind her left ear in August 1987. In October she was admitted to the hospital because of left-sided facial palsy. Spinal tap revealed cerebrospinal fluid (CSF) with lymphocytic pleocytosis. Five weeks later borrelial lymphocytoma developed on her left ear lobe. Borderline serum values of specific IgG antibodies were detected (IFA titer 1:128; ELISA 4.0 units); two months later the tests were clearly positive (IFA IgM negative, IgG 1:256; ELISA IgG 4.6 units). Mild constitutional symptoms such as moderate headache, general malaise and fatigue were reported by three patients. Regional enlarged lymph nodes of the neck were seen in eight of the 17 patients. Hematological and immunological parameters were within the normal range in all patients. In all patients the changes on the ear were so typical that the clinical picture alone was enough to establish the diagnosis of solitary lymphocytoma. Histological examination was performed only in two patients and showed a dense lymphocytic infiltrate in the dermis and subcutis. Specific antibodies to Borrelia burgdorferi were demonstrable in blood specimens of 11 patients drawn at their first visit (Table 1). Subsequent serological tests of three other patients (nos. 4, 8 and 11; Table 1) were positive 2.5, 3 and 3.5 months after the first examination, i.e. 3.5, 4.5 and 5 months after the onset of borrelial lymphocytoma. Three patients remained seronegative. A complete resolution of the lymphocytoma lesions was achieved a median of three weeks (range one to ten weeks) after the onset of treatment (Table 1). In one child, a 5-year-old boy (patient no. 17, Table 1 ), borrelial lymphocytoma developed three weeks after a tick bite on
his left ear. At the beginning of treatment with oral penicillin, he experienced another tick bite on his right ear. Despite antimicrobial treatment he developed an additional lymphocytoma on the right auricle 11 days later. A regimen of intravenous ceftriaxone lg per day for 14 days was then administered and resulted in complete resolution.
Borrelial Lymphocytoma of the Breast Borrelial lymphocytoma was localized on the areola mammae in 15 patients, eight women and seven men, with a median age of 44 years (range 15 to 72 years) (Table 2). Twelve patients had a history of tick bite. In ten of them the tick bite was located within 15 cm around the nipple. Borrelial lymphocytoma developed within a median of 45 days (range five days to five months) after the tick bite, and a median of 70 days (range four weeks to 12 months) passed from the onset of the skin lesion until the diagnosis. Due to the considerable time lapse, the disease could not be accurately reviewed in all patients. Thirteen of the 15 patients presented with erythema migrans on the breast. Ten reported an erythema migrans that preceded borrelial lymphocytoma by 14 days to 1.5 months. In two patients erythema migrans coincided with borrelial lymphocytoma. In a 58-year-old female patient erythema migrans developed one month after the onset of borrelial lymphocytoma. All patients except one reported localized discomfort in the region of the areola mammae; they were bothered by their clothing, and the area was painful to touch. Mild itching, breast tension, burning and pain of the thoracic wall on the affected side were complaints of nine, eight, six, and four patients, respectively. Upon inspection, nipples were found to be asymmetric but, with one exception, showed no discoloration. Nipples
Table 2: Basic epidemiological and clinical data, IFA antibody titers, treatment and outcome of patients with lymphocytoma on the nipple.
1 2 3
72 53 34
F F M
+" -~ +
45 45 20
Aug Sept Nov
60 70 45
+ + +
+ + +
+ + +
--
128 256 256
256 256 256
neg 256 128
256 D O X 256 D O X 128 A Z I
4 5 6 7 8 9 10 11 12
49 68 15 24 18 35 44 35 58
M M M F F M M M F
+
70
+ + + 4 + + +
2A 90 21 25 75 5m 5
Aug Aug July Nov July June Jan Dec Oct
360 120 28 270 50 60 120 60 35
-~ + + + + + + +
+ + t + + +
+ + + + + + +
+ + + + -
neg 128 neg 256 512 neg 128 256 neg
512 512 neg 256 i28 neg 256 512 neg
neg neg neg 256 256 neg 128 128 neg
256 512 neg 256 256 neg 256 512 neg
i3 14 15
23 54 47
F F F
+ +
60 30
Nov Oct Aug
210 90 240
+ + +
+ + +
+ + +
4
512 neg 128
512 neg 512
512 neg neg
512 D O X 128¢ P M P 512 C E F
CEF CEF DOX CEF PMP DOX CEF CEF AZI
200 nag 200 mg 500 mg 250 mg 2 g i.v. 2 g i.v. 200 mg 2 g Lv. 6 M 200 mg 2 g i.v. 2 g i.v. 1000mg 500 mg 200 mg 3 M 2 g i.v,
14 14 2 8 14 14 14 14 14 14 14 14 1 4 14 14 14
4 3 2 ? 5 1.5 75 2 2 3 10 1,5 5 5 ?
Tick bite at a distance from erythema migrans and lymphocytoma, Insect bite. Seroeonversion found at later examinations. BL = borrelial lymphocytoma; D O X = doxycycline; PMP = phenoxymethylpenicillin; AZI = azithromyein; CEF = ceftriaxone; ? = lymphocytoma surgically removed,
I n f e c t i o n 20 (1992) N o . 4
© M M V M e d i z i n V e r l a g G m b H M i i n c h e n , M 6 n c h e n 1992
203 / 27
F. Strle et al.: Borrelial Lymphocytoma
[~Rrrm [ RADICULONEURfrls
....
~%x,~,--~
--I AUG
SEPT
OCT
NOV
DEC
JAN
Figure 2: Clinical course of long-lasting borrelial lymphocytoma (patient no. 5, Table 2). Th = antibiotic therapy.
tARTH~ALGI~ ~ACACHE TICK 81TE
ICYM ~
AUG'l SEpT I OC3, "~ NOV ~ ~ , ~ 1987
~
~
~]
SEPT
OCT
T~'A
~ FIE~ z ' il~
t ,pR I MA¥
JU~4 1988
JUL
AUG
Figure 3: Clinical course of long-lasting borrelial lymphocytoma (patient no. 7, Table 2). Th = antibiotic therapy; EM = erythema migrans.
of the affected area were edematous, painful to touch and, in eight patients completely, in four patients partly hardened. Infiltration was regularly found in the areola mammae in a diameter of up to 3 cm. Eight patients had enlarged lymph nodes on the affected side. At the first visit, 11 patients had elevated antibodies to Borrelia burgdorferi (Table 2). In the remaining four patients the presence of erythema migrans attested to Lyme borreliosis. In one of these four patients, significant elevation of antibody titers was found at later examinations. Complete resolution of borrelial lymphocytoma was observed within 1.5 to 10 weeks (median three weeks) after the start of antibiotic treatment. A 49-year-old patient (patient no. 4, Table 2) had a tick bite in June 1987. Erythema migrans developed three weeks later, persisting for two months and affecting the entire left thorax. Approximately one week before erythema migrans resolved, the left nipple became swollen and sensitive to touch. The patient also experienced itching and transitory burning in the nipple. He complained of local discomfort, fatigue and muscle pain in
the limbs. In mid September he began suffering from headache and episodic attacks of vertigo; he reported cardiac arrhythmias as well. In early October he experienced radicular pains on the left side of the thorax. He became nervous, impatient and irritable. For about two months he suffered from insomnia due to severe pain. Later, the pains ceased, but fatigue and occasional severe headaches, increasing impairment of concentration as well as the changes on the breast persisted. In spring 1988 he began experiencing pains in the elbow. Despite several consultations with physicians the case was not clarified. In August 1988 he was referred to the Department of Infectious Diseases. At this time, his left nipple was swollen and its upper half in particular was hardened and sensitive to touch. A nodule of 2.5 cm in diameter was palpable, Histological examination of a biopsy of the nodule indicated lymphocytoma, but we were not able to demonstrate spirochetes in it by a silver stain. CSF was taken and revealed 9 x 106 lymphocytes/1. CSF protein and glucose were within the normal range. Ceftriaxone, 2 g intravenously for 14 days, was administered. One month after the treatment the patient was free of all symptoms. In December 1988 transitory pains recurred. The course of disease in two other patients with long-lasting borrelial lymphocytoma and other manifestations is shown in Figures 2 and 3. Borrelial Lymphocytoma on Sites Other than the Ear and Mamilla In the remaining four patients borrelial lymphocytoma was localized on the nose, shoulder, upper arm and scrotum (Table 3). Diagnosis of lymphoc3:toma was made by" pathohistological investigation of biopsies from the affected skin. Dense lymphocytic infiltration was found in all cases, and in two of them germinative centers were seen. Borrelial etiology was suggested by seropositivity and by" the presence or a history of erythema migrans. Discussion
Borrelial lymphocytoma, a rare manifestation of Lyme borreliosis, is known throughout Europe, but there are no reports from the USA. Only one study on a larger number of patients suffering from borrelial lymphocytoma has been published since laboratory diagnosis of Borrelia burgdorferi infection became possible [9]. In Austria and in
Table 3: Basic epidemiological and clinical data, IFA antibody titers, treatment and outcome of patients with lymphocytoma on various locations (other than the ear and mamilla).
I
I 2 3 4
8 7 52 35
M M M M
-: + +
BL = borrelial lymphocytoma; PMP
28 / 204
30 7
Oct June May Sept
nose scrotum arm shoulder
360 30 45 210
= phenoxymethylpenicitlin; DOX
+ 4-
+ + +
+ + + +
-
neg 128 256 neg
256 neg 256 256
neg 128 128 neg
256 128 256 256
PMP PMP DOX DOX
2 MEGA 1 MEGA 200 mg 200 mg
t4 14 t4 14
8 2.5 4 ?
= doxycycline; ? = l y m p h o c y t o m a s u r g i c a l l y r e m o v e d .
Infection 20 (1992) No. 4 © MMV Medizin Verlag GmbH Mtinchen, Mfinchen 1992
F. Strle et al.: Borretial Lymphocytoma Sweden the frequency is reported to be less than 3% and about 1.6%, respectively [15,16]. In Slovenia, only 18 of 1,582 registered patients with a proven Borrelia burgdorferi infection in the years 1986 to 1988 [17,18] (1.1%) had lymphocytoma. The most common site of borrelial lymphocytoma in our patients was on the ear lobe in children and on the nipple in adults. This coincides with observations of other researchers [6,9]. The reasons for such distinctive localizations are not completely understood. Asbrink et al. [12] hypothesized that borreliae prosper at a temperature below 37°C. This would explain why the ear lobe and the nipple, i.e. the cooler parts of the body, are most frequently affected. However, there are some additional explanations. Lymphocytoma on the ear lobe is easy to notice and can be easily recognized due to its characteristic appearance (if, of course, the physician is familiar with the disorder). Changes in the nipples and nodules in the breast often scare the patient into seeking medical help, while the physician has to use various diagnostic measures to achieve the chance of correct diagnosis. Nodules found in other areas of the skin, whether in the dermis or subcutis, are usually no cause to consult a physician. Even if the patient seeks medical attention in such cases, it is difficult to establish a clinical diagnosis without other manifestations of a borrelial infection. It is even more difficult to interpret the differences in the localization of borrelial lymphocytoma in children and adults. Possibly, one reason may be the different sites of tick bites. It is known that ticks are usually found on vegetation a few centimeters up to one meter above ground. This explains why erythema migrans is localized much more frequently on the face of children than adults, e.g., in 23% and 4%, respectively [19]. It would also explain why ear lobe borrelial lymphocytoma is found predominantly in children. Yet, the localization of the tick bite does not explain why borrelial lymphocytoma on the breast is an exception in children. It seems possible, if not likely, that there are local tissue factors which support development of borrelial lymphocytoma on the breast in adults. The 36 patients with borrelial lymphocytoma presented here comprise 18 females and 18 males. Twenty-nine reported a tick bite. In 24 of them (83%) the tick bite was in closest vicinity to the location of the subsequent borrelial lymphocytoma. Thus, in a great majority of patients the spirochetes may spread from the site of the bite to the site where the disorder appears. This is well known from erythema migrans, which spreads out from the site of inoculation. In our cases borrelial lymphocytoma was located in the area of erythema migrans in 24 of 25 patients with concomitant erythema migrans. However, in comparison with erythema migrans, borrelial lymphocytoma develops later and lasts longer. There is a time interval of 30 days from the tick bite to the occurrence of borrelial lymphocytoma. In 616 patients
with erythema migrans, the skin lesion developed at the site of the tick bite within a median time of only 12 days [19]. Erythema migrans, the typical early manifestation of Lyme borreliosis, preceded borrelial lymphocytoma in 19 of our 25 cases. An interesting observation was made in one child, who first exhibited facial palsy and later on borrelial lymphocytoma on the ear lobe. This is in agreement with the observation that central nervous system infection may be not infrequently the first manifestation of Lyme borreliosis in children [20]. Differences were observed between patients with borrelial lymphocytoma on the ear lobe and those affected on the breast. Ear lobe borrelial lymphocytoma is most predominantly seen in children, breast borrelial lymphocytoma in adults (age difference p < 0.05). Similar results have been reported previously [9]. Fourteen of 17 patients with ear lobe lymphocytoma had no other systemic symptoms, whilst 12 of 15 patients with breast borrelial lymphocytoma recalled constitutional symptoms (p < 0.01). Borrelial lymphocytoma may be the only manifestation of Lyme borreliosis, and ear lobe borrelial lymphocytoma may be relatively easy to recognize. Its borrelial etiology, however, is not fully confirmed in persons seropositive to Borrelia burgdorferi. The borrelial etiology is more conclusive if an erythema migrans or a reliable history of it is present. In breast borrelial lymphocytoma, the clinical diagnosis is more difficult to establish and the differential diagnosis is wider. Seropositivity and other signs and symptoms of Lyme borreliosis are helpful clues for making the correct diagnosis. It is most difficult to diagnose borrelial lymphocytoma on locations other than the ear and breast, especially in cases in which borrelial lymphocytoma is the only manifestation and/or the patient is seronegative. In these cases a tissue biopsy is mandatory. However, even skin biopsy specimens showing dermal lymphocytic infiltrates with germinal centers are only suggestive and not specific. Attempts to cultivate spirochetal organisms from borrelial lymphocytoma lesions were only successful in a single case [91. The traditional treatment of borrelial lymphocytoma is based on the empiric observation of the efficacy of penicillin. Most of our patients were treated for 14 days, children predominantly with phenoxymethylpenicillin, and adults with doxycycline, 2 x 100 mg per day orally. In case of concomitant neurologic or joint symptoms, intravenous ceftriaxone, 2 g daily, was administered. For this study it is not possibe to evaluate the efficacy of treatment with individual antibiotics due to the smaller number of patients. It seems, however, that the time of full recovery depends on the duration of borrelial lymphocytoma prior to the beginning of treatment. The development of a borrelial lymphocytoma during treatment with phenoxymethylpenicillin and a significant elevation of Borrelia burgdorferi antibody titers in four of 15 patients indicate the need for prospective studies comparing
Infection 20 (1992) No. 4 © MMV Medizin Verlag GmbH Mfinchen, Mtinchen 1992
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F. Strle et al.: Borrelial Lymphocytoma
traditional treatment of this manifestation with the efficacy of other antibiotics. Additional studies are also needed to confirm some new or partly new findings of the present report (e.g. time and local relation of borrelial
lymphocytoma to tick bite and erythema migrans, and the reasons for ear lobe and nipple manifestations) as well as to explain the distinctive localization of borrelial lymphocytoma in children and adults.
References 1. Spiegler, E.: l]ber die sogenannte Sarcomatosis cutis. Arch. Dermatol. Syph. 27 (1984) 163-174. 2. Fendt, H.: Beitr/ige zur Kenntnis der sogenannten sarcoiden Geschwiilste der Haut. Arch. Dermatol. Syph. 53 (1900) 213-242. 3. Kaufmann-Wnlf, M.: Llber gutartige lymphocytfire Neubildungen der Scrotalhaut des Kindes. Arch. Dermatol. Syph. 130 (1921) 425-439. 4. B/ifi,Terstedt, B.: 13ber die Lymphadenosis benigna cutis. Eine klinische und pathologisch-anatomische Studie. Acta Derm. Venereol. 23 (Suppl. 11) (1943) 1-202. 5. B/ifverstedt, B.: Lymphadenosis benigna cutis (LACB); its nature, course and prognosis. Acta Derm. Venereol. 40 (1960) 10-18. 6. Asbrink, E., Hovmark, A.: Early and late cutaneous manifestations in Ixodes-borne borreliosis (erythema migrans borretiosis, Lyme borreliosis). Ann. NY Acad. Sci. 539 (1988) 4-15. 7. Weber, K., Sehierz, G., Wilske, B., Preac-Mursic, V.: Das Lymphozytom - eine Borreliose? Z. Hautkr. 60 (1985) 1585-1598. 8. Hovmark, A., Asbrink, E., Olsson, L: The spirochetal etiology of lymphadenosis benigna cutis solitaria. Acta. Derm. Venereol. 66 (1986) 479- 484. 9. Asbrink, E., Hovmark, A., Olsson, L: Lymphadenosis benigna eutis solitaria - borrelia lymphocytoma in Sweden. Zentralbl. Bakteriol. (Suppl. 18) (1989) 156-163. 10. Frithz, A., Lagerhoim, B.: Acrodermatitis chronica atrophicans, erythema chronicum migrans and lymphadenosis benigna eutis spirochetal diseases? Acta Derm. Venereol. 63 (1983) 432-436. 11. Paschoud, J. M.: Die Lymphadenosis benigna cutis als fibertragbare lnfektionskrankheit. Hautarzt 9 (1958) 311-315.
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Infection 20 (1992) No. 4 © MMV Medizin Verlag GmbH Mfinchen, Mfinchen 1992
