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Borrelia burgdorferi-associated cutaneous B cell lymphoma: Clinical and immunohistologic characterization of four cases Claus Garbe, M D , a Harald Stein, MD, b Dieter Dienemann, M D , b and Constantin E. Orfanos, M D ~ Berlin, Federal Republic of Germany Four patients with low-grade malignant B cell lymphoma of the skin in association with chronic Borrelia burgdorferi infection are presented. Plaque-shaped or nodular erythematous lesions with ill-defined borders were seen. Clinical progression was slow; the skin tumors occurred for up to 7 to 15 years. Extracutaneous involvement was found in only one case. Immunohistologic investigations showed an expression of B cell markers with restriction to only one light chain type and absence of T cell antigens. The growth fraction was 5% to 30%, as shown with the monoclonal antibody Ki-67. The immunoarchitecture of the tumors in three patients was unusual compared with established criteria for cutaneous B cell lymphoma and revealed similarities to mueosa-associated B cell lymphoma. Some immunohistologic heterogeneity may indicate the development of monoelonal proliferation that originated from different phases of B lymphocytic differentiation. In three cases no clinical signs ofB. burgdorferi infection were found; in one patient acrodermatitis chronica atrophicans was present. The occurrence of aerodermatitis chronica atrophicans and malignant lymphomas was frequently reported in the European literature before B. burgdorferi was recognized. These findings suggest a relation between B. burgdorferi infection and cutaneous B cell lymphoma. In geographic regions where infected ticks are present, borreliosis should be considered in patients with cutaneous B cell lymphoma. (J AM ACAD DEe.MATOL1991;24:584-90.)
Infection with Borrelia burgdorferi has been proven to be the cause of erythema chronicum migrans (ECM), acrodermatitis chronica atrophicans (ACA), and lymphocytoma. For the last entity the designation lymphadenosis benigna cutis (B~fverstedt) is preferred in Europe. T h e common etiology and the transmission of these diseases by tick bites had already been suggested in the 1960s because of the similarity in the geographic distribution of these three skin diseases, that is, in areas where the tick Ixodes ricinus is present.l All attempts to find the causative organism failed, however, until 1982, when Burgdorfer et al. 2 in the United States isolated the spirochete Borrelia burgdorferi from the tick From the Departments of Dermatology~ and Pathology, b University Medical Center Steglitz, The Free UnEversity of Berlin, Presented in part at the International Symposium on Cutaneous Lymphoma, Copenhagen, Oct. 28-30, 1988. Accepted for publication Oct. 23, 1989. Reprint requests: C. Garbe, MD, Department of Dermatology, University Medical Center Steglitz, The Free University of Berlin, Hindenburgdamm 30, D-1000 Berlin 45, FRG.
584
Ixodes dammini, suggested to be the vector of L y m e disease) Recently, B. burgdorferi was isolated from the peripheral blood of patients with Lyme disease 4 and from lesional skin of patients with E C M , 5 ACA, 6 and !ymphocytoma. 7 Up to now, no other skin diseases have been reported to be caused by B. burgdorferi, but, before the spirochetal cause of these diseases was known, European authors occasionally described patients with A C A and cutaneous malignant lymphomas. 8-1~ In borreliosis one may distinguish between (1) localized infections (1 to 10 weeks), including the clinical entities E C M and lymphocytoma; (2) early generalized infections (10 weeks to 1 year), with arthralgia, headaches, meningopolyneuritis (Bannwarth's syndrome), arthritis, and myocarditis; and (3) chronic infections (>1 year) leading to A C A , polyarthritis, and encephalomyelitis. 11"13 We recently reported two patients with low-grade malignant cutaneous B cell lymphoma (CBCL) and chronic B. burgdorferi infection.14 In this article we describe four patients in whom thorough immunohistologic investigations were performed.
Volume 24 Number 4 April 1991
Borrelia burgdorferi-associated B cell lymphoma
CASE R E P O R T S Case 1 A 72-year-old woman had the characteristic clinical appearance of A C A on the thighs and on the dorsum of the hands (Fig. 1). Multiple plaques and nodules were present on the legs and thighs (Fig. 2). No lymph nodes were palpable, and liver and spleen were of normal size. Histologic examination of a biopsy specimen taken from a nodule on the right foot revealed in the mid and deep dermis a nodular infiltrate arranged mainly around vessels, with the exception of a narrow subepidermal zone. A predominance of small and medium-sized lymphoid cells with monomorphic cleaved nuclei was present (Fig. 3). Within the infiltrates were also some blastlike cells with the features of centroblasts. Immunohistologic findings are shown in Table I (Figs. 4-6). Non-Hodgkin's lymphoma (B cell type) of small to medium-sized cells with cleaved nuclei, partly with blasfic transformation, was diagnosed. A bone marrow specimen showed a nodular infiltrate of monomorphous mature lymphocytes and lymphoplasmocytoid cells. Hematopoeitic cells were diminished, but maturation was normal. The findings were consistent with a diagnosis of low-grade malignant non-Hodgkin's lymphoma (B cell type). Further investigations (e.g., blood cell counts, immunoelectrophoresis, chest x-ray film, abdominal ultrasound) revealed no visceral manifestations. Serologic tests revealed a positive B. burgdorferi fiter (Table II). Treatment with penicillin intramuscularly, 1 million IU/day, was administered for 3 weeks. While the inflammatory lesions of A C A clearly regressed, the plaques and nodules of the lymphoma persisted. A few nodular lesions were excised, but no further treatment was given.
Case 2 A 67-year-old woman had a nodule on the back that was excised 8 years previously. The diagnosis was benign lymphocytoma. Six years later two new nodules developed on the back. At this time serologic investigation was positive for B. burgdorferi (Table II). The patient was treated with penicillin (3 million IU for 10 days). One year later the patient had erythematous nodules on the back and face (Fig. 7, A). No enlarged lymph nodes were found, and the liver and spleen were not enlarged. Histologic examination of a skin biopsy specimen revealed nodular and confluent infiltrates in the mid and deep dermis that were arranged partially around vessels and the adnexa. In the center of the nodules follicular structures, consisting mainly ofcentroblasts, were present, but in some areas centrocytes predominated. Especially in the areas rich in centroblasts, the follicular structures were irregularly shaped. Immunohistologic findings are shown in Table I (Fig. 8). Non-Hodgkin's lymphoma of
585
Table I. Immunohistologic findings of B. burgdorferi-associated C B C L
Antigenexpression
B cell markers CD19 CD21 CD22 IgM IgD r chain )t chain T cell markers1" CD3 CD5 Activation markers CD10 (CALLA) CD30 (Ki-1)~; Proliferation marker Ki-67:[:
+ + + + + + .
+ + + + .
.
.
. .
. .
. .
. .
+ + + + + +
+ + + +
-
+ -
-
+
5%
15%
10%
30%
*Antibodies from Dakopatts, Glestrup, Denmark. Alkaline phosphatase-antialkaline phosphatase(APAAP) techniquewas used. #Negativestainingof tumorcellsbut positivestaining of numerousreactiveT cells surroundingtumor infiltrates. :]:Antibodiesfromthe Department&Pathology,SteglitzMedicalCenter, The Free Universityof Berlin (West). APAAP technique.
centroblastic-centrocytictype with transformation to centroblastic type (CBCL) was diagnosed. Further investigations (e.g., blood cell counts, immunoelectrophoresis, bone marrow puncture, chest x-ray film, abdominal ultrasound) revealed no visceral involvement. Serologic investigations revealed a B. burgdorferi titer of 1:128 (immunofluorescence technique). Radiation of the lesions was proposed to the patient, but she preferred excision, which was carried out; no further systemic treatment was performed.
Case 3 A 63-year-old woman had several plaques up to 6 cm in diameter on the dorsum of both thighs. In addition, flat, follicularly accentuated infiltrations were detected on the legs (Fig. 7, B). No lymphadenopathy was present, and the liver and spleen were not enlarged. Histologic examination of skin lesions revealed diffuse cell infiltrates in the entire dermis with a narrow, noninvolved subepidermal zone consisting of small monomorphous lymphoid cells with cleaved nuclei. The immunohistologic findings are shown in Table I. Non-Hodgkin's lymphoma (B cell type) with small cells and cleaved nuclei was diagnosed. Further investigations (e.g, blood counts, immunoelectrophoresis, bone marrow puncture, chest x-ray film, and computed tomography of the abdomen and pelvis) re-
586
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Garbe et al.
Fig. 1. Case 1. A C A of left hand. Fig. 2. Case 1. Nodular and follicular accentuated lesions on legs.
Table II. Clinical features of four cases of malignant C B C L associated with B. burgdorferi infection Case No.
Sex/Age (yr)
Duration (yr)
Localization of CBCL
1 2 3 4
F/72 F/67 F/63 M/82
Unknown 8 7 15
Both legs Back, face Both legs Left arm
I [
Systemic involvement Bone marrow None None None
B. burgdorferi tilers* 1:16000 (IFT) 1:400 (IFf) >1000 U (ELISA) > 1000 U (ELISA)
ELISA. Enzyme-linkedimmunosorbentassay;IF?',immunotluoresceneetechnique. *P~itive levels:>1:64 (IFT) or >64 U (ELISA),
vealed no visceral involvement. Serologic investigations showed a positive B. burgdorferi titer (Table II). The patient was treated with 1 million IU penicillin intramuscularly for 14 days, and the B. burgdorferi titer decreased. Some lesions were excised; 36 months later the lesions were still present but were flatter, No new lesions developed.
Case 4 An 82-year-old man had had an erythematous nodule on the left arm excised 15 years ago. The histologic diagnosis was benign lymphoplasia. Five years ago a nodule developed in the same site. The tumor was excised and the surrounding area radiated, The histologic diagnosis was pseudolymphoma. Physical examination revealed on the left arm two ill-defined erythematous nodules, 2.5 era in diameter, that had developed during the last 2 years. No
enlarged lymph nodes were found, and the liver and spleen were not palpable. Histologic examination revealed nodular infiltrates in the mid and deep dermis; a narrow subepidermal zone remained uninvolved. The nodules consisted of a mixture of lymphoid cells. Mostly medium-sized cells with cleaved nuclei and some intermingled blasflike cells were found. The immunohistologic findings are shown in Table I. Non-Hedgkin's lymphoma (B cell type) of medium-sized cells with cleaved nuclei was diagnosed. Further investigations (blood cell counts, bone marrow puncture, immunoelectrophoresis, chest x-ray film, and abdominal ultrasound) were negative. Serologic investigation revealed a positive Treponema palfidum hemagglutination titer (1:320), a positive fluorescent titer antibody absorption test result and a negative VDRL. The B. burgdorferi titer was elevated (Table II). The patient was
Volume 24 Number 4 April 1991
Borrelia burgdorferi-associated B cell lymphoma
587
Fig. 3. Case 1. Infiltrate composed of small to medium-sized lymphoid cells with cleaved nuclei in mid dermis. (Giemsa stain; • Fig. 4. Case 1. Tumor cells positive for the B cell marker 4KB5. (Alkaline phosphatase-antialkaline phosphatase [APAAP] technique; • Fig. 5. Case 1. Tumor cells positive for light Kchain and negative for ~. (APAAP technique; • Fig. 6. Case 1. Diffuse arrangement of dendritic reticulum cells stained with CD21. (APAAP technique; •
treated with 1 million IU penic~ha intramuscularly for 14 days. The skin lesions persisted after administration of oral tetracyclines; the patient also received additional local x-ray treatment (30 Gy). After several weeks all lesions regressed. DISCUSSION
Our cases indicate that CBCL m a y occur in association with B. burgdorferi infection. The cutane-
ous lesions are ill-defined plaques or erythematous nodules that slowly progress. The histologic picture was characterized by nodular and/or confluent infiltrates located in the mid and deep dermis with an uninvolved narrow subepidermal zone. The infiltrates were monomorphous and contained mainly one or two types of lymphoid cells. The criteria for distinguishing C B C L f r o m benign lymphocytoma were fulfilled; that is, (1) the
588 Garbe et al.
Journal of the American Academy of Dermatology
Fig. 7. A, Case 2. Nodular tumors on back. B, Case 3. Plaque-shaped lesions with follicular infiltrates on thigh.
Fig. 8. Case 2. Germinal center-like arrangement of dendritic reticulum cells stained with CD21. (APAAP technique; X 100.) absence of follicular structures in cases 1, 3, and 4, and (2) the presence of blastlike cells in the follicular structures in case 2, corresponding with the diagnosis of follicular germinal center cell lymphoma (B cell lymphoma of the centroblastic/cen-
trocytic type), but not with pseudolymphoma) 4-17 The immunohistologic findings confirmed the neoplastic nature of the infiltrates in all tumors examined. Polyclonal lymphoid infiltrates are usually benign, whereas monoclonal infiltrates are mostly malignant.18 Monoclonal immunoglobulin-produchag B cells showed the expression of only one light immunoglobulin chain. All cases revealed restriction of light chains with expression of Kchains in the absence of), chains. In contrast, benign lymphocytoma cell infiltrates are characterized by a "mosaic" pattern with K-positive and X-positive cells. On the basis of these histologic and immunohistochemical criteria, the tumors in these patients must be CBCL192~; however, with the exception of case 2, their inclusion into one of the entities of the Kiel classification system was difficult. Morphologically, the tumors in patients 1, 3, and 4 were most suggestive of centrocytic lymphoma, but their immunophenotype was not clearly consistent with this diagnosis because CD5 antigen was not expressed, as generally found2Z; on the other hand, the absence of CD10 (CALLA) did not support the diagnosis of centroblastic/centrocytic lymphoma. Absence of the CD5 and CALLA antigens has been reported for the centrocyte-like type of mucosa-associated B cell lymphoma. 23 Possibly a specific differentiation of B lymphocytes may occur
Volume24 Number 4 April 199l
Borrelia burgdorferi-associated B cell lymphoma 589
Table III. Features of 22 cases of malignant lymphomas occurring simultaneously with A C A described before titers of B. burgdorferi infections were determined*
I Yes No Unknown
Multiple
Lymphoma
I
Located
lesions
on ACA
at extremities
Systemic involvement
15 7 --
12 9 1
14 5 3
4 9 9
]
Monoclonal gammopathy
2 10 10
*Datafromreference14.
under some circumstances in human mucosa and also in human skin. As a common denominator, both organs provide direct interactions with environmental antigens. In patient 2 the typical immunophenotype of germinal center cell lymphomas (centroblastic/centrocytic type, CALLA +) was detected. In patient 4 the Ki-1 antigen (CD30) was regularly expressed on the tumor cells, representing a particular state of cell activation. These findings underline some heterogeneity of the CBCL seen in our cases. The monoclonal proliferation and malignant transformation of lymphoid cells in B. burgdorferi infection may therefore originate from different phases of B cell differentiation. The growth fraction of B lymphocytes as determined by nuclear staining with the Ki-67 monoclonal antibody was rather small in patients 1 to 3 (5% to 15%) and was typical of low-grade lymphocytic malignancies. In patient 4 the portion of proliferating cells was 30%, a value indicating highgrade malignancy. However, the course of the disease was followed up for 15 years in this patient without clear evidence of progression. The lymphomas remained limited to one skin area and did not involve organs other than the skin. Because the monoclonal antibody Ki-67 labels tumor cells in all phases of their proliferation, from the Gt to the mitosis phase, the slow progression may possibly be due to an arrest of the cell cycle during the premitotic phases. As a major common denominator, the patients with CBCL described here showed a high titer of antibodies against B. burgdorferi, typical of the chronic stage of the infection. In addition, ACA was also present in patient 1, an additional indicator of chronic infection with B. burgdorferi. In the European literature we found 22 cases in which the simultaneous presence of ACA and malignant lymphoma has been reported. 14 In most cases the mul-
ticentric appearance of CBCL was mentioned, frequently arising in the inflamed skin of ACA. Systemic involvement was rarely seen, but in two patients monoclonal gammopathy was described (Table III). These reports contain obvious similarities to our patients. In some patients transformation of benign lyrnphocytoma to malignant lymphoma may occur. 24-27 Benign lymphocytomas may first appear as mixed lymphocytic infiltrations in early and in later stages of B. burgdorferi infection. Also, in two of our patients benign lymphocytoma was first diagnosed with later transition to malignant lymphoma. Pathogenetically clonal proliferation and transition to malignancy may occur consecutively in chronic inflammation caused by infective organisms. 19 The evidence for malignancy in our cases is based on ( 1) the histologic findings, (2) the immunohistologic findings, (3) the long course of the disease with recurrences after excision and radiation in two cases and systemic involvement in one case, and (4) the lack of response to antibiotic treatment. Despite the long course, the tumors remained limited to the skin in three patients and bone marrow involvement was detected only in patient 1. These findings underline the low grade of CBCL malignancy. The occurrence of B. burgdorferi-associated, low-grade malignant CBCL may be more frequent than believed. For 3 years we have directed our attention on this particular association and have discovered four cases, although in the metropolitan Berlin area B. burgdorferi is rare compared with other regions in Germany and elsewhere in Europe. In the West Germany about 20% of all ticks are vectors of Borrelia infection. Because B. burgdorferi infection may be asymptomatic in many cases, Borrelia-associated CBCL of low-grade malignancy may occur more often than is presently recognized.
590
Garbe et al.
REFERENCES
1. Hauser W. Wahrscheinliche Infektionskrankheiten der Haut. In: Marchionini A, Gftz H, eds. Handbuch der Haut- und Gesehlechtskrankheiten, Erg/inzungswerke; Vol 4. New York: Springer, 1965:556-629. 2. Burgdorfer W, Barbour AG, I-[ayes SF, et al. Lyme disease: a tick-borne spirochetosis? Science 1982;216:1317-9. 3. Steere AC, Malawista SE, Hardin 2A, et al. Erythema chronicum rnigrans and Lyme arthritis: the enlarging clinical spectrum. Ann Intern Med 1977;86:685-98. 4. Benaeh JL, Bosler EM, Hanrahan JP, et al. Spirochetes isolated from the blood of two patients with Lyme disease. N Engl J Med 1983;308:740-2. 5. Asbrink E, Hederstedt B, Hovmark A. The spiroehetaletiology of erythema chronicum migrans AfzeUus. Acta Derm Venereol (Stockh) 1984;64:291-5. 6. Asbrink E, Flovrnark A, Hederstedt B. The spirochetal etiology of acrodermatitis chornica atrophicans Herx_heimer. Acta Derm Venereol (Stockh) 1984;64:506-12. 7. Hovmark A, Asbrink E, Olsson I. The spkochetal etiology of lymphadenosis benigna curls solitaria. Acta Derm Venereol (Stoekh) 1986;66:479-84. 8. Orfanos CE, Steigleder GK. Die tumorbildende kutane Form des Morbus WaldenstrSm. Dtseh Med Wochenschr 1967;33:1449-54, 1475-77. 9. Braun-Falco O, Guggenberger K, Burg G, et al. Immunozytom unter dem Bild einer Acrodermatitis chronica atrophicans. Hautarzt 1978;29:644-7. 10. Geiger H-G, Hagedorn M, Petres J. Retikulumzellsarkom bei Acrodermatitis chroniea atrophicans Herxheimer. Z Hautkr 1974;49:359-65. 11. Asbrink E. Erytbema chronieum migrans Afzelius and acrodermatitis ehronica atrophieans: early and late manifestations of ixodes ricinus-borne Borrelia spirochetes. Acta Derm Venereol (Stockh) 1985;118(suppl):l-63. 12. Ackermann R. Erythema-migrans-Bqrreliose und Friihsommer-Meningoenzephalitis. Dtseh Arzteblatt 1986;83; 1765-74. 13. Weber K, Schierz G, Wilkse B, et al. Das Lymphozytom-eine Borreliose? Z Hautkr 1985;60:1585-98. 14. Garbe C, Stein H, GoUnick H, et al. Kutanes B-Zell-Lymphom bei chronischer Borrelia-Burgdorferi-Infektion: Bericht fiber 2 F~ille und Literaturiibersicht. Hautarzt 1988;39:717-26.
Journal of the American Academy of Dermatology
15. Burg G, Braun Falco O. Cutaneous lymphomas, pseudolymphomas, and related disorders. New York: Springer, 1983;415-41. 16. Lange Wantzin G, Hou-Jensen K, Nielsen M, et al. Cutaneous lymphocytomas: clinical and histological aspects. Acta Derm Venereol (Stockh) 1982;62:119-24. 17. MacDonald DM. Histopathological differentiation of benign and malignant cutaneous lymphocytic infiltrates. Br J Dermatol 1982;107:715-8. 18. Willemze R, de Graaff-Reitsma CB, van Vloten WA, et al. The cell population of cutaneous B-cell lymphomas. Br J Dermatol 1983;108:395-409. 19. Kerl H, Ackerman AB. Cutaneous pseudolymphomas. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al, eds. Dermatology in general medicine. New York: McGraw-Hill, 1987:1118-30. 20. Ralfkiaer E, Lange Wantzin G, Mason DY, et al. Characterization of benign cutaneous lymphocytic infiltrates by monoclonal antibodies. Br J Dermatol 1984;111:635-45. 21. Willemze R, Meijer CJLM, Sebeffer E, et al. Diffuse large cell lymphomas of follicular center cell origin presenting in the skin. Am J Pathol 1987;126:325-33. 22. Stein H, Mason DY. Immunological analysis of tissue sections in diagnosis of lymphoma. In: Hoffbrand AV, ed. Recent advances in haematology; vol. 4. Edinburgh: Churchill Livingstone, 1985. 23. Isaacson PG, Spencer J. Malignant lymphoma of mucosaassociated lymphoid tissue. Histopathology 1987;11:44562. 24. Shelley WB, Wood MG. Observations on occult malignant lymphomas in the skin. Cancer 1976;38:1757-70. 25. Shelley WB, Gray Wood M, Wilson JF, et al. Premaligrtant lymphoid hyperplasia: preceding and coexisting with malignant lymphoma in the skin. Arch Dermatol 1981; 117:500-3. 26. Bork K, Hoede N, Korting GW. UngewShnliche Friihver~inderungen bei Malignem Lymphom vom B-Zell-Typ mit niedrigen Malignit~tsgrad. Z Hautkr 1980;55:1061-3. 27. Halevy A' Sandbank M" Transf~176 ~ lymph~176 cutis into a malignant lymphoma in association with the sign of Leser-Tr61at. Acta Derm Venereol (Stockh) 1987; 76:172-5.
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Borrelia burgdorferi-associated cutaneous B cell lymphoma: Clinical and immunohistologic characterization of four cases Claus Garbe, M D , a Harald Stein, MD, b Dieter Dienemann, M D , b and Constantin E. Orfanos, M D ~ Berlin, Federal Republic of Germany Four patients with low-grade malignant B cell lymphoma of the skin in association with chronic Borrelia burgdorferi infection are presented. Plaque-shaped or nodular erythematous lesions with ill-defined borders were seen. Clinical progression was slow; the skin tumors occurred for up to 7 to 15 years. Extracutaneous involvement was found in only one case. Immunohistologic investigations showed an expression of B cell markers with restriction to only one light chain type and absence of T cell antigens. The growth fraction was 5% to 30%, as shown with the monoclonal antibody Ki-67. The immunoarchitecture of the tumors in three patients was unusual compared with established criteria for cutaneous B cell lymphoma and revealed similarities to mueosa-associated B cell lymphoma. Some immunohistologic heterogeneity may indicate the development of monoelonal proliferation that originated from different phases of B lymphocytic differentiation. In three cases no clinical signs ofB. burgdorferi infection were found; in one patient acrodermatitis chronica atrophicans was present. The occurrence of aerodermatitis chronica atrophicans and malignant lymphomas was frequently reported in the European literature before B. burgdorferi was recognized. These findings suggest a relation between B. burgdorferi infection and cutaneous B cell lymphoma. In geographic regions where infected ticks are present, borreliosis should be considered in patients with cutaneous B cell lymphoma. (J AM ACAD DEe.MATOL1991;24:584-90.)
Infection with Borrelia burgdorferi has been proven to be the cause of erythema chronicum migrans (ECM), acrodermatitis chronica atrophicans (ACA), and lymphocytoma. For the last entity the designation lymphadenosis benigna cutis (B~fverstedt) is preferred in Europe. T h e common etiology and the transmission of these diseases by tick bites had already been suggested in the 1960s because of the similarity in the geographic distribution of these three skin diseases, that is, in areas where the tick Ixodes ricinus is present.l All attempts to find the causative organism failed, however, until 1982, when Burgdorfer et al. 2 in the United States isolated the spirochete Borrelia burgdorferi from the tick From the Departments of Dermatology~ and Pathology, b University Medical Center Steglitz, The Free UnEversity of Berlin, Presented in part at the International Symposium on Cutaneous Lymphoma, Copenhagen, Oct. 28-30, 1988. Accepted for publication Oct. 23, 1989. Reprint requests: C. Garbe, MD, Department of Dermatology, University Medical Center Steglitz, The Free University of Berlin, Hindenburgdamm 30, D-1000 Berlin 45, FRG.
584
Ixodes dammini, suggested to be the vector of L y m e disease) Recently, B. burgdorferi was isolated from the peripheral blood of patients with Lyme disease 4 and from lesional skin of patients with E C M , 5 ACA, 6 and !ymphocytoma. 7 Up to now, no other skin diseases have been reported to be caused by B. burgdorferi, but, before the spirochetal cause of these diseases was known, European authors occasionally described patients with A C A and cutaneous malignant lymphomas. 8-1~ In borreliosis one may distinguish between (1) localized infections (1 to 10 weeks), including the clinical entities E C M and lymphocytoma; (2) early generalized infections (10 weeks to 1 year), with arthralgia, headaches, meningopolyneuritis (Bannwarth's syndrome), arthritis, and myocarditis; and (3) chronic infections (>1 year) leading to A C A , polyarthritis, and encephalomyelitis. 11"13 We recently reported two patients with low-grade malignant cutaneous B cell lymphoma (CBCL) and chronic B. burgdorferi infection.14 In this article we describe four patients in whom thorough immunohistologic investigations were performed.
Volume 24 Number 4 April 1991
Borrelia burgdorferi-associated B cell lymphoma
CASE R E P O R T S Case 1 A 72-year-old woman had the characteristic clinical appearance of A C A on the thighs and on the dorsum of the hands (Fig. 1). Multiple plaques and nodules were present on the legs and thighs (Fig. 2). No lymph nodes were palpable, and liver and spleen were of normal size. Histologic examination of a biopsy specimen taken from a nodule on the right foot revealed in the mid and deep dermis a nodular infiltrate arranged mainly around vessels, with the exception of a narrow subepidermal zone. A predominance of small and medium-sized lymphoid cells with monomorphic cleaved nuclei was present (Fig. 3). Within the infiltrates were also some blastlike cells with the features of centroblasts. Immunohistologic findings are shown in Table I (Figs. 4-6). Non-Hodgkin's lymphoma (B cell type) of small to medium-sized cells with cleaved nuclei, partly with blasfic transformation, was diagnosed. A bone marrow specimen showed a nodular infiltrate of monomorphous mature lymphocytes and lymphoplasmocytoid cells. Hematopoeitic cells were diminished, but maturation was normal. The findings were consistent with a diagnosis of low-grade malignant non-Hodgkin's lymphoma (B cell type). Further investigations (e.g., blood cell counts, immunoelectrophoresis, chest x-ray film, abdominal ultrasound) revealed no visceral manifestations. Serologic tests revealed a positive B. burgdorferi fiter (Table II). Treatment with penicillin intramuscularly, 1 million IU/day, was administered for 3 weeks. While the inflammatory lesions of A C A clearly regressed, the plaques and nodules of the lymphoma persisted. A few nodular lesions were excised, but no further treatment was given.
Case 2 A 67-year-old woman had a nodule on the back that was excised 8 years previously. The diagnosis was benign lymphocytoma. Six years later two new nodules developed on the back. At this time serologic investigation was positive for B. burgdorferi (Table II). The patient was treated with penicillin (3 million IU for 10 days). One year later the patient had erythematous nodules on the back and face (Fig. 7, A). No enlarged lymph nodes were found, and the liver and spleen were not enlarged. Histologic examination of a skin biopsy specimen revealed nodular and confluent infiltrates in the mid and deep dermis that were arranged partially around vessels and the adnexa. In the center of the nodules follicular structures, consisting mainly ofcentroblasts, were present, but in some areas centrocytes predominated. Especially in the areas rich in centroblasts, the follicular structures were irregularly shaped. Immunohistologic findings are shown in Table I (Fig. 8). Non-Hodgkin's lymphoma of
585
Table I. Immunohistologic findings of B. burgdorferi-associated C B C L
Antigenexpression
B cell markers CD19 CD21 CD22 IgM IgD r chain )t chain T cell markers1" CD3 CD5 Activation markers CD10 (CALLA) CD30 (Ki-1)~; Proliferation marker Ki-67:[:
+ + + + + + .
+ + + + .
.
.
. .
. .
. .
. .
+ + + + + +
+ + + +
-
+ -
-
+
5%
15%
10%
30%
*Antibodies from Dakopatts, Glestrup, Denmark. Alkaline phosphatase-antialkaline phosphatase(APAAP) techniquewas used. #Negativestainingof tumorcellsbut positivestaining of numerousreactiveT cells surroundingtumor infiltrates. :]:Antibodiesfromthe Department&Pathology,SteglitzMedicalCenter, The Free Universityof Berlin (West). APAAP technique.
centroblastic-centrocytictype with transformation to centroblastic type (CBCL) was diagnosed. Further investigations (e.g., blood cell counts, immunoelectrophoresis, bone marrow puncture, chest x-ray film, abdominal ultrasound) revealed no visceral involvement. Serologic investigations revealed a B. burgdorferi titer of 1:128 (immunofluorescence technique). Radiation of the lesions was proposed to the patient, but she preferred excision, which was carried out; no further systemic treatment was performed.
Case 3 A 63-year-old woman had several plaques up to 6 cm in diameter on the dorsum of both thighs. In addition, flat, follicularly accentuated infiltrations were detected on the legs (Fig. 7, B). No lymphadenopathy was present, and the liver and spleen were not enlarged. Histologic examination of skin lesions revealed diffuse cell infiltrates in the entire dermis with a narrow, noninvolved subepidermal zone consisting of small monomorphous lymphoid cells with cleaved nuclei. The immunohistologic findings are shown in Table I. Non-Hodgkin's lymphoma (B cell type) with small cells and cleaved nuclei was diagnosed. Further investigations (e.g, blood counts, immunoelectrophoresis, bone marrow puncture, chest x-ray film, and computed tomography of the abdomen and pelvis) re-
586
Journal of the American Academy of Dermatology
Garbe et al.
Fig. 1. Case 1. A C A of left hand. Fig. 2. Case 1. Nodular and follicular accentuated lesions on legs.
Table II. Clinical features of four cases of malignant C B C L associated with B. burgdorferi infection Case No.
Sex/Age (yr)
Duration (yr)
Localization of CBCL
1 2 3 4
F/72 F/67 F/63 M/82
Unknown 8 7 15
Both legs Back, face Both legs Left arm
I [
Systemic involvement Bone marrow None None None
B. burgdorferi tilers* 1:16000 (IFT) 1:400 (IFf) >1000 U (ELISA) > 1000 U (ELISA)
ELISA. Enzyme-linkedimmunosorbentassay;IF?',immunotluoresceneetechnique. *P~itive levels:>1:64 (IFT) or >64 U (ELISA),
vealed no visceral involvement. Serologic investigations showed a positive B. burgdorferi titer (Table II). The patient was treated with 1 million IU penicillin intramuscularly for 14 days, and the B. burgdorferi titer decreased. Some lesions were excised; 36 months later the lesions were still present but were flatter, No new lesions developed.
Case 4 An 82-year-old man had had an erythematous nodule on the left arm excised 15 years ago. The histologic diagnosis was benign lymphoplasia. Five years ago a nodule developed in the same site. The tumor was excised and the surrounding area radiated, The histologic diagnosis was pseudolymphoma. Physical examination revealed on the left arm two ill-defined erythematous nodules, 2.5 era in diameter, that had developed during the last 2 years. No
enlarged lymph nodes were found, and the liver and spleen were not palpable. Histologic examination revealed nodular infiltrates in the mid and deep dermis; a narrow subepidermal zone remained uninvolved. The nodules consisted of a mixture of lymphoid cells. Mostly medium-sized cells with cleaved nuclei and some intermingled blasflike cells were found. The immunohistologic findings are shown in Table I. Non-Hedgkin's lymphoma (B cell type) of medium-sized cells with cleaved nuclei was diagnosed. Further investigations (blood cell counts, bone marrow puncture, immunoelectrophoresis, chest x-ray film, and abdominal ultrasound) were negative. Serologic investigation revealed a positive Treponema palfidum hemagglutination titer (1:320), a positive fluorescent titer antibody absorption test result and a negative VDRL. The B. burgdorferi titer was elevated (Table II). The patient was
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Borrelia burgdorferi-associated B cell lymphoma
587
Fig. 3. Case 1. Infiltrate composed of small to medium-sized lymphoid cells with cleaved nuclei in mid dermis. (Giemsa stain; • Fig. 4. Case 1. Tumor cells positive for the B cell marker 4KB5. (Alkaline phosphatase-antialkaline phosphatase [APAAP] technique; • Fig. 5. Case 1. Tumor cells positive for light Kchain and negative for ~. (APAAP technique; • Fig. 6. Case 1. Diffuse arrangement of dendritic reticulum cells stained with CD21. (APAAP technique; •
treated with 1 million IU penic~ha intramuscularly for 14 days. The skin lesions persisted after administration of oral tetracyclines; the patient also received additional local x-ray treatment (30 Gy). After several weeks all lesions regressed. DISCUSSION
Our cases indicate that CBCL m a y occur in association with B. burgdorferi infection. The cutane-
ous lesions are ill-defined plaques or erythematous nodules that slowly progress. The histologic picture was characterized by nodular and/or confluent infiltrates located in the mid and deep dermis with an uninvolved narrow subepidermal zone. The infiltrates were monomorphous and contained mainly one or two types of lymphoid cells. The criteria for distinguishing C B C L f r o m benign lymphocytoma were fulfilled; that is, (1) the
588 Garbe et al.
Journal of the American Academy of Dermatology
Fig. 7. A, Case 2. Nodular tumors on back. B, Case 3. Plaque-shaped lesions with follicular infiltrates on thigh.
Fig. 8. Case 2. Germinal center-like arrangement of dendritic reticulum cells stained with CD21. (APAAP technique; X 100.) absence of follicular structures in cases 1, 3, and 4, and (2) the presence of blastlike cells in the follicular structures in case 2, corresponding with the diagnosis of follicular germinal center cell lymphoma (B cell lymphoma of the centroblastic/cen-
trocytic type), but not with pseudolymphoma) 4-17 The immunohistologic findings confirmed the neoplastic nature of the infiltrates in all tumors examined. Polyclonal lymphoid infiltrates are usually benign, whereas monoclonal infiltrates are mostly malignant.18 Monoclonal immunoglobulin-produchag B cells showed the expression of only one light immunoglobulin chain. All cases revealed restriction of light chains with expression of Kchains in the absence of), chains. In contrast, benign lymphocytoma cell infiltrates are characterized by a "mosaic" pattern with K-positive and X-positive cells. On the basis of these histologic and immunohistochemical criteria, the tumors in these patients must be CBCL192~; however, with the exception of case 2, their inclusion into one of the entities of the Kiel classification system was difficult. Morphologically, the tumors in patients 1, 3, and 4 were most suggestive of centrocytic lymphoma, but their immunophenotype was not clearly consistent with this diagnosis because CD5 antigen was not expressed, as generally found2Z; on the other hand, the absence of CD10 (CALLA) did not support the diagnosis of centroblastic/centrocytic lymphoma. Absence of the CD5 and CALLA antigens has been reported for the centrocyte-like type of mucosa-associated B cell lymphoma. 23 Possibly a specific differentiation of B lymphocytes may occur
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Borrelia burgdorferi-associated B cell lymphoma 589
Table III. Features of 22 cases of malignant lymphomas occurring simultaneously with A C A described before titers of B. burgdorferi infections were determined*
I Yes No Unknown
Multiple
Lymphoma
I
Located
lesions
on ACA
at extremities
Systemic involvement
15 7 --
12 9 1
14 5 3
4 9 9
]
Monoclonal gammopathy
2 10 10
*Datafromreference14.
under some circumstances in human mucosa and also in human skin. As a common denominator, both organs provide direct interactions with environmental antigens. In patient 2 the typical immunophenotype of germinal center cell lymphomas (centroblastic/centrocytic type, CALLA +) was detected. In patient 4 the Ki-1 antigen (CD30) was regularly expressed on the tumor cells, representing a particular state of cell activation. These findings underline some heterogeneity of the CBCL seen in our cases. The monoclonal proliferation and malignant transformation of lymphoid cells in B. burgdorferi infection may therefore originate from different phases of B cell differentiation. The growth fraction of B lymphocytes as determined by nuclear staining with the Ki-67 monoclonal antibody was rather small in patients 1 to 3 (5% to 15%) and was typical of low-grade lymphocytic malignancies. In patient 4 the portion of proliferating cells was 30%, a value indicating highgrade malignancy. However, the course of the disease was followed up for 15 years in this patient without clear evidence of progression. The lymphomas remained limited to one skin area and did not involve organs other than the skin. Because the monoclonal antibody Ki-67 labels tumor cells in all phases of their proliferation, from the Gt to the mitosis phase, the slow progression may possibly be due to an arrest of the cell cycle during the premitotic phases. As a major common denominator, the patients with CBCL described here showed a high titer of antibodies against B. burgdorferi, typical of the chronic stage of the infection. In addition, ACA was also present in patient 1, an additional indicator of chronic infection with B. burgdorferi. In the European literature we found 22 cases in which the simultaneous presence of ACA and malignant lymphoma has been reported. 14 In most cases the mul-
ticentric appearance of CBCL was mentioned, frequently arising in the inflamed skin of ACA. Systemic involvement was rarely seen, but in two patients monoclonal gammopathy was described (Table III). These reports contain obvious similarities to our patients. In some patients transformation of benign lyrnphocytoma to malignant lymphoma may occur. 24-27 Benign lymphocytomas may first appear as mixed lymphocytic infiltrations in early and in later stages of B. burgdorferi infection. Also, in two of our patients benign lymphocytoma was first diagnosed with later transition to malignant lymphoma. Pathogenetically clonal proliferation and transition to malignancy may occur consecutively in chronic inflammation caused by infective organisms. 19 The evidence for malignancy in our cases is based on ( 1) the histologic findings, (2) the immunohistologic findings, (3) the long course of the disease with recurrences after excision and radiation in two cases and systemic involvement in one case, and (4) the lack of response to antibiotic treatment. Despite the long course, the tumors remained limited to the skin in three patients and bone marrow involvement was detected only in patient 1. These findings underline the low grade of CBCL malignancy. The occurrence of B. burgdorferi-associated, low-grade malignant CBCL may be more frequent than believed. For 3 years we have directed our attention on this particular association and have discovered four cases, although in the metropolitan Berlin area B. burgdorferi is rare compared with other regions in Germany and elsewhere in Europe. In the West Germany about 20% of all ticks are vectors of Borrelia infection. Because B. burgdorferi infection may be asymptomatic in many cases, Borrelia-associated CBCL of low-grade malignancy may occur more often than is presently recognized.
590
Garbe et al.
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