I
II
Cutaneous manifestations of angioimmunoblastic lymphadenopathy Joel E. Bernstein, M.D., Keyoumars Soltani, M.D., and Allan L. Lorincz, M.D.
Chicago, IL Angioimmunoblastic lymphadenopathy (AIL) is an uncommon immunoproliferative disorder with a presentation similar to malignant lymphoma but with a benign histopathologic picture. We report a case of a 49-year-old woman with AIL who manifested a pruritic maculopapular eruption as her presenting complaint and whose disease pursued an aggressive clinical course. Forty-four percent of patients with AIL experience a nonspecific dermatitis that in general is maculopapular and precedes other clinical symptoms by at least several weeks. AIL should be included in the differential diagnosis of any maculopapular eruption of unknown etiology accompanied by lymphadenopathy. (J AM ACAODEgMA'rOL1:227-232, 1979.)
Angioimmunoblastic lymphadenopathy (AIL) is an uncommon disease first described by Lukes and Tindle' and Frizzera et al. z It has attracted a great deal of attention for its relatively benign histopathologic picture coupled with an aggressive clinical course. The disease has an acute onset and a presentation suggestive of malignant lymphoma with generalized lymphadenopathy, hepatosplenomegaly, maculopapular rash, fever, weight loss, polyclonal hypergammaglobulinemia, and Coombs'-positive hemolytic anemia. 1-5 Although patients from 26 to 92 years of age are reported to have had AIL, it is generally a disease of the elderly (mean age at onset, 60.6 years) with no sexual or racial predilection. Histologically, the involved lymph nodes resemble Hodgkin's disease and feature a diagnostic triad of immunoblastic proliferation, small vessel arborization, and interstitial deposition of an amorphous acidophilic material. 6,r Current thinking is consistent with a From the Section of Dermatology, Department of Medicine, The University of Chicago Hospitals and Clinics and The Pritzker School of Medicine. Reprint requests to: Dr. Joel E. Bernstein, 950 East 59th St., Box 409, Chicago, IL 60637. 0190-9622/79/030227 +06500.60/0 9 1979 Am Acad Dermatol
benign immunoproliferative disorder in which a deficiency of T cell regulatory functions allows for an abnormal proliferation and autoaggressive reaction of B cells, probably precipitated by acute and chronic antigenic stimulation. 2'8'9 While most early reports did not regard AIL as a truly malignant process, an increasing number of cases have been reported to progress to a frank neoplastic condition, l~ Nathwani et a112 recently observed not only malignant transformation of AIL, but also the coexistence of AIL and immunoblastic lymphoma in the same lymph node or at different sites in the same patient. The authors concluded that such patients illustrate the difficulties often encountered in attempting to draw a sharp line between benign and malignant disorders, and they emphasized the need to consider the preponderance of clinical and laboratory data in establishing the malignant nature of equivocal cases. Although skin involvement has been reported in up to 50% of patients with AIL, the characteristic pruritic maculopapular rash has often passed unnoticed early in the course of the disease, or scant attention has been paid to its significance. Unlike our case report, none of the three previously re227
228
Journal of the American Academy of Dermatology
B e r n s t e i n et al
and a pruritic cutaneous eruption and was hospitalized for l0 days at another hospital in Chicago. A diagnosis of infectious mononucleosis was made on clinical appearance, although heterophil agglutination was negative. Resolution was apparently uneventful with the disappearance of the skin rash and lymphadenopathy. There was a history of long-term occupational exposure to hair dyes and bleaches, but there was no history of recent exposure to chemicals or systemic medications. Physical examination showed a well-nourished woman in some distress due to intense pruritus. An erYthematous, nonblanching eruption, consisting of macules 2-5 mm in diameter and barely palpable papules, was noted over much of her body; the eruption was most extensive on the lower extremities (Fig. 1). Lymphadenopathy was generalized with symmetric, somewhat tender, mobile, cervical, axillary, epitrochlear, and inguinal lymph nodes varying up to 3 cm in size. There was no hepatosplenomegaly.
Laboratory data
Fig. 1. Erythematous, nonblanching maculopapular eruption on the right thigh. ported cases in the d e r m a t o l o g i c literature have exhibited the characteristic m a c u l o p a p u l a r eruption, and, further, in n o n e o f these cases was the pruritic eruption the p r e s e n t i n g complaint, t2, ~4, t5 Most cases of AIL h a v e been diagnosed retrospectively, which has p r e v e n t e d adequate description of cutaneous manifestations. T h e cun'ent case has afforded the opportunity for m o r e extensive p r o s p e c t i v e evaluation and also has provided the impetus for a r e v i e w of the skin manifestations o f the disease in the 147 o t h e r published cases.~, 2, 4, 6-26
CASE REPORT A 49-year-old beautician was admitted to the University of Chicago in October, 1977, following an 8-week history of a pruritic maculopapular eruption, originally on the face and neck, which progressed rapidly to involve the rest of her body. She denied fever, night sweats, malaise, weakness, or other constitutional symptoms. The patient had Graves' disease diagnosed and treated with I ~ in 197 2 and had been on thyroid extract, 3 gr per day, since then. Approximately 5 months prior to admission, she noted fever, malaise, pharyngitis, lymphadenopathy,
Initial laboratory values were as follows: hemoglobin, 11.7%; hematocrit, 36.1; white blood cell count, 3,800 per cubic millimeter, with 66% neutrophils, 17% lymphocytes, 8,9% eosinophils, 6% monocytes, 2% stimulated lymphocytes, and 1% band forms; platelets, 251,000 per cubic millimeter; and reticulocyte count, 0.8%. The peripheral blood smear showed mild anisocytosis. Erythrocyte sedimentation rate was 20 mm per hour. Chest and upper and lower gastrointestinal x-ray examinations, urinalysis, thyroid functions, abdominal ultrasound, and liver-spleen scan were all within normal limits. Gallium scan demonstrated bilateral hilar and mediastinal uptake. Serum protein eieetrophoresis was essentially within normal limits except for a reversed A/G ratio (albumin, 3.08 gm; globulin, 3.9 gin; total protein, 7.00 gm). Liver and renal function tests were nomaal except for an elevated LDH of 148 IU with an LD3 fraction of 38.7% (normal LDH, 12-55 IU; normal LDa, 15% to 25%). The VDRL and FTA-ABS test findings were nonreactive. Determinations for rheumatoid factor, alpha fetoprotein, cold agglutinins, cryoglobulins, cryofibrinogen, as well as antinuclear, anti-deoxyribonucleic acid, antimitochondrial, antismooth muscle, antiparietal cell, antithyroglobulin, and antitoxoplasmosis antibodies were all negative. Comprehensive viral and fungal studies were unremarkable except for elevated antibody titers to cytomegalic inclusion virus, 16 (normal complement fixation titers, 0-1.9) and influenza A virus, 32 (nolrnal complement fixation titers, 0-1.9). Direct immunefluorescence examination of the frozen skin biopsy speci-
Volume 1 Number 3 September, 1979
Fig. 2. Lymph node displaying proliferation of finely arborized vessels and diffuse infiltration with lymphocytes, plasma cells, and immunoblasts. (Hematoxylineosin stain; x 400.)
Angioimmunoblastic lymphadenopathy
229
Fig. 3. Amorphous intracellular deposits of hyalin material in lymph node. (Hematoxylin-eosin stain; x 400.)
men using monospecific human immunoglobulin failed to reveal IgG, IgA, IgM, IgE, or Ca in the tissue.
Histopathoiogic data Lymph nodes. The biopsy specimen was a firm, well-demarcated right cervical lymph node measuring 3 . 0 • 2 1 5 0.8 cm. Capsular, pericapsular, and trabecular tissue showed diffuse infiltration with lymphocytes, plasma cells, and immunoblasts associated with a marked proliferation of finely arborized vessels (Fig. 2). Mitoses as well as reticulin were focally prominent, and amorphous intercellular deposits of periodic acid-Schiff-positive hyalin material were observable (Fig. 3). Bone marrow. The bone core biopsy showed a slight increase in cellularity. About 60% of the marrow was replaced by a diffuse and patchy, dense cellular infiltrate composed of mature lymphocytes, histiocytes, and eosinophils. The hematopoietic elements showed a normal maturation pattern, and no quantitative abnormalities were seen in the megakaryocytic series. Skin. Three biopsy specimens of skin were reviewed. The epidermis was unremarkable in one of the specimens, while mild hyperkeratosis and acanthosis were observed in the other two. The entire dermis was edematous, and focal perivascular infiltrates consisting of lymphocytes, histiocytes, and a few large mononuclear cells were seen in all specimens (Fig. 4).
Immunologic and cytogenetie data Intradermal tests for mumps, Candida albicans, tuberculin, and streptokinase-streptodornase were all
Fig. 4. Focal lymphohistiocytic dermal perivasculitis. (Hematoxylin-eosin stain; • 400.) negative. The sheep erythrocyte rosette assay for T lymphocytes was performed by conventional methods.27 Of the isolated lymphocytes, 73% produced E rosettes, whereas 7% made EAC rosettes. No autolymphocytotoxic antibodies were detected. An unusual finding was co-rosetting of human red cells in the EAC-rosetting assay. The significance of this finding is unknown. A portion of lymph node was prepared for chromosomal studies, Although only thirteen metaphases were observed, all were normal diploid metaphases. Course After the initial work-up, the patient was discharged without treatment, but with the caution to avoid further exposure to hair dyes or bleaches in order to exclude the possible source of chronic antigenic stimulation. Skin
Journal of the American Academy of Dermatology
230 Bernstein et al
Table I. Skin manifestations of AILD Onset N -- 148
Before other symptoms
Total rashes, 65 (44%) Maculopapular, 59 (40% of all patients and 91% of all rashes) Other (purpura, pruritus, nodules), 6 (4% of all patients and 9% of all rashes) Table II. Skin involvement and prognosis of AILD i
Mean survival without skin involvement (N = 14)
19.8 months (3 alive)
Mean survival with I skin involvement (N = 19) [
22.3 months (6 alive)
testing to occupational contactants was considered but was delayed until improvement in the patient's clinical status. Her condition remained well controlled without treatment over the first 9 months, her only major complication being the development of two large benign gastric ulcers for which she received cimetidine. Two additional lymph node biopsies were obtained and were consistent with AIL with no evidence for malignant transformation. In July, 1978, she presented with an acute abdomen. Laparotomy was performed, and masses of large mesenteric lymph nodes were observed; several were removed for histologic examination. These lymph nodes again showed changes consistent with AIL. The patient was started on oral prednisone 40 mg per day in August, 1978, and in October, 1978, dosage was reduced to 30 mg per day. In November, 1978, the patient developed generalized herpes zoster and expired in January, I979, despite vigorous therapy with systemic adenine arabinoside. COMMENT Most data of AIL have been collected retrospectively so that the spectrum of clinical and laboratory variables has not been completely described. The current case represents one of the few prospectively reported cases and is also significant in its initial presentation being a pruritic maculopapular eruption. Skin "rash" has been noted to be a common
15 15
]
At same time
1
After
I
Unspecified
10 5
0 0
40 39
5
0
1
feature of the clinical presentation of angioimmunoblastic lymphadenopathy. However, the nature, prevalence, and significance of this eruption have yet to be defined. In order to ascertain the role of the cutaneous eruption more clearly, 147 previously reported cases have been reviewed. Skin involvement in AlL is not a universal phenomenon (Table I). Sixty-five of the 148 patients included in this review had a nonspecific dermatitis (44% of the 148). Of these, 91% had skin eruptions that were characterized as maculopapular, and 9% had purpuric eruptions or severe, generalized pruritus without obvious skin involvement. In 75% of such cases in which a maculopapular eruption was reported, skin involvement preceded other clinical symptoms by from several weeks to 1 year. In 25% of such cases, the maculopapular eruption appeared concomitantly with other constitutional signs and symptoms. In all such cases, signs or symptoms referable to the skin accompanied other symptoms. The prognosis of AlL is generally poor. 1, 2, lz It is interesting to examine the relationship between skin involvement and prognosis (Table II). Such data are hard to collect since few studies present survival figures for those with and without rashes. For the nineteen patients with skin involvement for which survival from time of initial diagnosis of AlL could be calculated, the mean survival was 22.3 months. Comparable mean survival for fourteen patients without skin involvement was 19.8 months. This difference is not statistically significant (p > 0.10) and is probably due to earlier diagnosis of the disease in subjects with such eruptions. Previous reports have claimed that as many as
Volume 1 Number 3 September, 1979
80% of patients with AIL and skin involvement have a history of prior drug u s e . 1~ However, our review indicates that only 3I% (twenty of sixtyfour patients) of patients with skin involvement have a history of prior drug use. Perhaps of greater interest is the nature of the possible offending agents. While these have spanned a wide gamut of chemotherapeutic agents, penicillin (six patients) and phenytoin (four patients) have been reported most frequently. While our patient had no history of recent systemic medication, she had chronic occupational exposure to hair dyes and bleaches. Although there have been no previous reports indicating an association between topical medication and AIL, chronic antigenic stimulation from percutaneous 'absorption cannot be excluded in this patient. The association with phenytoin is especially interesting, as Lukes and Tindle I have commented on the morphologic similarity of AIL and anticonvulsant-induced pseudolymphoma. Both conditions involve an immunologic hyporesponsiveness during a period of lymphoproliferation. 28-s~When such proliferative lymphadenopathy is present in conjunction with an altered immunosurveillance system, malignant changes may be more likely. Thus, AIL, much like phenytoin-induced pseudolymphoma syndrome, seems to bridge a gap between benign and malignant histopathologic disorders. Although our patient had a normal immunoglobulin profile, 67% of reported cases of AIL manifest a hyperglobulinemia, with polyclonal hyperglobulinemia the commonest abnormality. On the basis of such immunoglobulin alterations, as well as the benign histologic appearance and common association with previous drug therapy, it had been proposed that AIL is a nonneoplastic disease resulting from a proliferation of B lymphocytes and possibly triggered by a hypersensitivity reaction to an antigenic stimulus? However, defects in delayed hypersensitivity to ubiquitous antigens, as demonstrated by the anergic response of our patient to common skin test antigens, suggested a defect in the T lymphocyte system as well. Recent reports have shown such defects in number or function of the T lymphocyte system8'
Angioimmunoblastic lymphadenopathy
231
z0,2~ as well as an abnormal proliferation of B cells, z~ Thus, the defect in the T lymphocyte system may result in decreased suppressor T cell influence on B cells, allowing abnormal proliferation and hyperactivity of the B cell system. Alternately, the hyperglobulinemia and B cell hyperproliferation may result from a neoplastic process, leading to evolution of a malignant lymphoma. The increasing number of cases of AIL reported to terminate in immunoblastie lymphoma, lz immunoblastic sarcoma, 1~ and Hodgkin's disease 1~ support such a possibility. While our patient had a normal chromosomal pattern, cytogenetic studies of three previously reported patients with AlL have demonstrated some abnormalities, primarily aneuploidy, ta'zl Since clones of cells carrying acquired chromosomal anomalies frequently suggest a neoplastic process, such chromosome abnormalities constitute further support for the malignant nature of AIL. More knowledge about the pathogenesis of this condition may lead to significant advances in our understanding of malignant transformation. Proper therapy for this condition is still controversial. There have been proponents of steroid therapy, systemic chemotherapy, and conservative management without therapy. Levamisole as a stimulant of the thymus-dependent lymphoid system has been tried with encouraging results, ~8 but our patient's course did not warrant such treatment. The recent report of Nathwani et a112 would indicate that no treatment would appear to be slightly better than prednisone or chemotherapy. This is not surprising since most patients with AIL succumb to infection, and thus the immune response that patients are able to mount against foreign invaders may be the most significant factor in their survival. Angioimmunoblastic lynaphadenopathy is being reported with increasing frequency due to the recognition of this disorder as a distinctive clinical entity. Our patient with AIL manifested a pruritic maculopapular eruption as her presenting complaint. It is important for dermatologists to include AIL in the differential diagnoses of any maculopapular eruption of unknown etiology when it is accompanied by lymphadenopathy.
232
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B e r n s t e i n et al
REFERENCES
1. Lukes RJ, Tindle BH: Immunoblastic lymphadenopathy. A hyperimmune entity resembling Hodgkin's disease. N Eng[ J Med 292: 1-8, 1975. 2. Frizzera G, Moran EM, Rappaport H: Angio-immunoblastie lymphadenopathy with dysproteinaemia. Lancet 1: 1070- 1073, 1974. 3. Frizzera G, Moran EM, Rappaport H: Angio-immunoblastic lymphadenopathy. Diagnosis and clinical course. Am J Med 59:803-818, 1975. 4. Moore SB, Harrison EG Jr, Weiland LH: Angioimmunoblastic lymphadenopathy. Mayo Clin Proc 51:273280, 1976. 5. Hussey HH: Immunoblastic lymphadenopathy, lAMA 236:2098, 1976. (Editorial.) 6. Matz LR, Papadimitriou JM, Carroll JR, et al: Angioimmunoblastic lymphadenopathy with dysproteinemia. Cancer 40:2152-2160, 1977. 7. Valdes AJ, Blair OM: Angioimmunoblastic lymphadenopathy with dysproteinemia. Immunohistologic and ultrastructural studies. Am J Clin PathoI 66:551-559, 1976. 8. Palutka M, Khilanani P, Weise R: Immunologic and electronmicroscopic characteristics of a case of immunoblastic lymphadenopathy. Am J Clin Pathol 65:929940, 1976. 9. Cooperberg AA, de Champlain MB, Siminovitch J, et al: Immunoblastic lymphadenopathy: Case report and literature review. Can Med Assoc J 117:53-57, 1977. I0. Yataganas X, Papadimitriou C, Pangolis G, et al: Angio-immunoblastic lymphadenopathy terminating as Hodgkin' s disease. Cancer 39:2183-2189, 1977. I 1. Goh KO, Bakemeier RF: Is angioimmunoblastic lymphadenopathy with dysproteinemia a malignant disease? J Am Med Wom Assoc 33:38-40, 1978, 12. Nathwani BN, Rappaport H, Moran EM, et al: Malignant lymphoma arising in angioimmunoblastic lymphadenopathy. Cancer 41:578-606, 1978. 13. Wechsler HL, Stavrides A: Immunoblastie lymphadenopathy with purpura and cryoglobulinemia. Arch Dermatol 113:636-641, 1977. 14. Krain LS, Levin JM, Schultz B: Decreased serum complement in the Gardner-Diamond syndrome. Immunofluorescent findings and association with angioimmunoblastic lymphadenopathy Cuffs 21:80-84, 1978. 15. Matloff RB, Neiman RS: Angioimmunoblastic lymphadenopathy. A generalized lymphoproliferative disorder with cutaneous manifestations. Arch Dermatol 114:9294, I978. 16. Pruzanski W, Sutton DM, Pantalony D: Angioimmuno-
17. 18. 19. 20. 21. 22.
23. 24. 25.
26. 27.
28.
29. 30. 31.
blastic lymphadenopathy: An immunochemical study. Clin Immunol Immunopathol 6:62-76, t976. Lapes MJ, Vivacqua RJ, Antoniades K: Immunoblastic lymphadenopathy associated with phenytoin (diphenylhydantoin). Lancet 1: 198, 1976. (Letter.) Bensa J-C, Faure J, Martin H, et al: Levamisole in angio-immunoblastic lymphadenopathy. Lancet 1:1081, 1976. Kalus MJ: Immunoblastic lymphadenopathy. A report of two cases. Arch Pathol Lab Med 100:465-468, 1976. Kreisler JM, Morino E, Moneo I, et al: Immunological findings in immunoblastic lymphadenopathy. A detailed case study. Clin Exp Immunol 27:497-501, 1977. Sadovsky R, Zazakos C: Angioimmunoblastic lymphadenopathy: Common symptoms, uncommon diagnosis. Postgrad Med 62:213-216, 1977. Averback P, Salama SS, Moinuddin M: Hashimoto's thyroiditis with immunoblastic lymphadenopathy and unusual "macaroni cells." Can Med Assoc J 117:41-43, 1977. Rudders RA, DeLellis R: Immunoblastic lymphadenopathy. A mixed proliferation ofT and B lymphocytes. Am J Clin Pathol 68:518-521, 1977. Myers TI, Cole SR, Pastuszak WT: Angioimmunoblastic lymphadenopathy: PleuraI-pulmonary disease. Cancer 41:266-271, 1978. Neiman RS, Dervan P, Haudenschild C, et al: Angioimmunoblastic lymphadenopathy: An ultrastructural and immunologic study with review of the literature. Cancer 41:507-518, 1978. Kosmidis PA, Axelrod AR, Palacas C, Shahl M: Angioimmunoblastic lymphadenopathy. A T-cell deficiency. Cancer 42:447-452, 1978. Jondal M, Holm G, Wigzell H: Surface markers on human T and B lymphocytes. I. A large population of lymphocytes forming nonimmune rosettes with sheep red blood cells. J Exp Med 136:207-215, 1972. Lapes M, Antonaides K, Gartner W Jr, et al: Conversion of a benign lymphoepithelial salivary gland lesion to lymphocytic lymphoma during dilantin therapy. Correlation with dilantin-induced lymphocyte transformation in vitro. Cancer 38: 1318-1322, 1976. Halevy S, Feuerman El: Pseudolymphoma syndrome. Dermatologica 155:321-327, 1977. Charlesworth EN: Phenytoin-induced pseudolymphoma syndrome: An immunologic study. Arch Dermatol 113:477-480, 1977. Hossfeld DK, H6ffken K, Schmidt CJ, et al: Chromosome abnormalities in angioimmunoblastic lymphadenopathy. Lancet 1:198, 1976. (Letter.)
II
Cutaneous manifestations of angioimmunoblastic lymphadenopathy Joel E. Bernstein, M.D., Keyoumars Soltani, M.D., and Allan L. Lorincz, M.D.
Chicago, IL Angioimmunoblastic lymphadenopathy (AIL) is an uncommon immunoproliferative disorder with a presentation similar to malignant lymphoma but with a benign histopathologic picture. We report a case of a 49-year-old woman with AIL who manifested a pruritic maculopapular eruption as her presenting complaint and whose disease pursued an aggressive clinical course. Forty-four percent of patients with AIL experience a nonspecific dermatitis that in general is maculopapular and precedes other clinical symptoms by at least several weeks. AIL should be included in the differential diagnosis of any maculopapular eruption of unknown etiology accompanied by lymphadenopathy. (J AM ACAODEgMA'rOL1:227-232, 1979.)
Angioimmunoblastic lymphadenopathy (AIL) is an uncommon disease first described by Lukes and Tindle' and Frizzera et al. z It has attracted a great deal of attention for its relatively benign histopathologic picture coupled with an aggressive clinical course. The disease has an acute onset and a presentation suggestive of malignant lymphoma with generalized lymphadenopathy, hepatosplenomegaly, maculopapular rash, fever, weight loss, polyclonal hypergammaglobulinemia, and Coombs'-positive hemolytic anemia. 1-5 Although patients from 26 to 92 years of age are reported to have had AIL, it is generally a disease of the elderly (mean age at onset, 60.6 years) with no sexual or racial predilection. Histologically, the involved lymph nodes resemble Hodgkin's disease and feature a diagnostic triad of immunoblastic proliferation, small vessel arborization, and interstitial deposition of an amorphous acidophilic material. 6,r Current thinking is consistent with a From the Section of Dermatology, Department of Medicine, The University of Chicago Hospitals and Clinics and The Pritzker School of Medicine. Reprint requests to: Dr. Joel E. Bernstein, 950 East 59th St., Box 409, Chicago, IL 60637. 0190-9622/79/030227 +06500.60/0 9 1979 Am Acad Dermatol
benign immunoproliferative disorder in which a deficiency of T cell regulatory functions allows for an abnormal proliferation and autoaggressive reaction of B cells, probably precipitated by acute and chronic antigenic stimulation. 2'8'9 While most early reports did not regard AIL as a truly malignant process, an increasing number of cases have been reported to progress to a frank neoplastic condition, l~ Nathwani et a112 recently observed not only malignant transformation of AIL, but also the coexistence of AIL and immunoblastic lymphoma in the same lymph node or at different sites in the same patient. The authors concluded that such patients illustrate the difficulties often encountered in attempting to draw a sharp line between benign and malignant disorders, and they emphasized the need to consider the preponderance of clinical and laboratory data in establishing the malignant nature of equivocal cases. Although skin involvement has been reported in up to 50% of patients with AIL, the characteristic pruritic maculopapular rash has often passed unnoticed early in the course of the disease, or scant attention has been paid to its significance. Unlike our case report, none of the three previously re227
228
Journal of the American Academy of Dermatology
B e r n s t e i n et al
and a pruritic cutaneous eruption and was hospitalized for l0 days at another hospital in Chicago. A diagnosis of infectious mononucleosis was made on clinical appearance, although heterophil agglutination was negative. Resolution was apparently uneventful with the disappearance of the skin rash and lymphadenopathy. There was a history of long-term occupational exposure to hair dyes and bleaches, but there was no history of recent exposure to chemicals or systemic medications. Physical examination showed a well-nourished woman in some distress due to intense pruritus. An erYthematous, nonblanching eruption, consisting of macules 2-5 mm in diameter and barely palpable papules, was noted over much of her body; the eruption was most extensive on the lower extremities (Fig. 1). Lymphadenopathy was generalized with symmetric, somewhat tender, mobile, cervical, axillary, epitrochlear, and inguinal lymph nodes varying up to 3 cm in size. There was no hepatosplenomegaly.
Laboratory data
Fig. 1. Erythematous, nonblanching maculopapular eruption on the right thigh. ported cases in the d e r m a t o l o g i c literature have exhibited the characteristic m a c u l o p a p u l a r eruption, and, further, in n o n e o f these cases was the pruritic eruption the p r e s e n t i n g complaint, t2, ~4, t5 Most cases of AIL h a v e been diagnosed retrospectively, which has p r e v e n t e d adequate description of cutaneous manifestations. T h e cun'ent case has afforded the opportunity for m o r e extensive p r o s p e c t i v e evaluation and also has provided the impetus for a r e v i e w of the skin manifestations o f the disease in the 147 o t h e r published cases.~, 2, 4, 6-26
CASE REPORT A 49-year-old beautician was admitted to the University of Chicago in October, 1977, following an 8-week history of a pruritic maculopapular eruption, originally on the face and neck, which progressed rapidly to involve the rest of her body. She denied fever, night sweats, malaise, weakness, or other constitutional symptoms. The patient had Graves' disease diagnosed and treated with I ~ in 197 2 and had been on thyroid extract, 3 gr per day, since then. Approximately 5 months prior to admission, she noted fever, malaise, pharyngitis, lymphadenopathy,
Initial laboratory values were as follows: hemoglobin, 11.7%; hematocrit, 36.1; white blood cell count, 3,800 per cubic millimeter, with 66% neutrophils, 17% lymphocytes, 8,9% eosinophils, 6% monocytes, 2% stimulated lymphocytes, and 1% band forms; platelets, 251,000 per cubic millimeter; and reticulocyte count, 0.8%. The peripheral blood smear showed mild anisocytosis. Erythrocyte sedimentation rate was 20 mm per hour. Chest and upper and lower gastrointestinal x-ray examinations, urinalysis, thyroid functions, abdominal ultrasound, and liver-spleen scan were all within normal limits. Gallium scan demonstrated bilateral hilar and mediastinal uptake. Serum protein eieetrophoresis was essentially within normal limits except for a reversed A/G ratio (albumin, 3.08 gm; globulin, 3.9 gin; total protein, 7.00 gm). Liver and renal function tests were nomaal except for an elevated LDH of 148 IU with an LD3 fraction of 38.7% (normal LDH, 12-55 IU; normal LDa, 15% to 25%). The VDRL and FTA-ABS test findings were nonreactive. Determinations for rheumatoid factor, alpha fetoprotein, cold agglutinins, cryoglobulins, cryofibrinogen, as well as antinuclear, anti-deoxyribonucleic acid, antimitochondrial, antismooth muscle, antiparietal cell, antithyroglobulin, and antitoxoplasmosis antibodies were all negative. Comprehensive viral and fungal studies were unremarkable except for elevated antibody titers to cytomegalic inclusion virus, 16 (normal complement fixation titers, 0-1.9) and influenza A virus, 32 (nolrnal complement fixation titers, 0-1.9). Direct immunefluorescence examination of the frozen skin biopsy speci-
Volume 1 Number 3 September, 1979
Fig. 2. Lymph node displaying proliferation of finely arborized vessels and diffuse infiltration with lymphocytes, plasma cells, and immunoblasts. (Hematoxylineosin stain; x 400.)
Angioimmunoblastic lymphadenopathy
229
Fig. 3. Amorphous intracellular deposits of hyalin material in lymph node. (Hematoxylin-eosin stain; x 400.)
men using monospecific human immunoglobulin failed to reveal IgG, IgA, IgM, IgE, or Ca in the tissue.
Histopathoiogic data Lymph nodes. The biopsy specimen was a firm, well-demarcated right cervical lymph node measuring 3 . 0 • 2 1 5 0.8 cm. Capsular, pericapsular, and trabecular tissue showed diffuse infiltration with lymphocytes, plasma cells, and immunoblasts associated with a marked proliferation of finely arborized vessels (Fig. 2). Mitoses as well as reticulin were focally prominent, and amorphous intercellular deposits of periodic acid-Schiff-positive hyalin material were observable (Fig. 3). Bone marrow. The bone core biopsy showed a slight increase in cellularity. About 60% of the marrow was replaced by a diffuse and patchy, dense cellular infiltrate composed of mature lymphocytes, histiocytes, and eosinophils. The hematopoietic elements showed a normal maturation pattern, and no quantitative abnormalities were seen in the megakaryocytic series. Skin. Three biopsy specimens of skin were reviewed. The epidermis was unremarkable in one of the specimens, while mild hyperkeratosis and acanthosis were observed in the other two. The entire dermis was edematous, and focal perivascular infiltrates consisting of lymphocytes, histiocytes, and a few large mononuclear cells were seen in all specimens (Fig. 4).
Immunologic and cytogenetie data Intradermal tests for mumps, Candida albicans, tuberculin, and streptokinase-streptodornase were all
Fig. 4. Focal lymphohistiocytic dermal perivasculitis. (Hematoxylin-eosin stain; • 400.) negative. The sheep erythrocyte rosette assay for T lymphocytes was performed by conventional methods.27 Of the isolated lymphocytes, 73% produced E rosettes, whereas 7% made EAC rosettes. No autolymphocytotoxic antibodies were detected. An unusual finding was co-rosetting of human red cells in the EAC-rosetting assay. The significance of this finding is unknown. A portion of lymph node was prepared for chromosomal studies, Although only thirteen metaphases were observed, all were normal diploid metaphases. Course After the initial work-up, the patient was discharged without treatment, but with the caution to avoid further exposure to hair dyes or bleaches in order to exclude the possible source of chronic antigenic stimulation. Skin
Journal of the American Academy of Dermatology
230 Bernstein et al
Table I. Skin manifestations of AILD Onset N -- 148
Before other symptoms
Total rashes, 65 (44%) Maculopapular, 59 (40% of all patients and 91% of all rashes) Other (purpura, pruritus, nodules), 6 (4% of all patients and 9% of all rashes) Table II. Skin involvement and prognosis of AILD i
Mean survival without skin involvement (N = 14)
19.8 months (3 alive)
Mean survival with I skin involvement (N = 19) [
22.3 months (6 alive)
testing to occupational contactants was considered but was delayed until improvement in the patient's clinical status. Her condition remained well controlled without treatment over the first 9 months, her only major complication being the development of two large benign gastric ulcers for which she received cimetidine. Two additional lymph node biopsies were obtained and were consistent with AIL with no evidence for malignant transformation. In July, 1978, she presented with an acute abdomen. Laparotomy was performed, and masses of large mesenteric lymph nodes were observed; several were removed for histologic examination. These lymph nodes again showed changes consistent with AIL. The patient was started on oral prednisone 40 mg per day in August, 1978, and in October, 1978, dosage was reduced to 30 mg per day. In November, 1978, the patient developed generalized herpes zoster and expired in January, I979, despite vigorous therapy with systemic adenine arabinoside. COMMENT Most data of AIL have been collected retrospectively so that the spectrum of clinical and laboratory variables has not been completely described. The current case represents one of the few prospectively reported cases and is also significant in its initial presentation being a pruritic maculopapular eruption. Skin "rash" has been noted to be a common
15 15
]
At same time
1
After
I
Unspecified
10 5
0 0
40 39
5
0
1
feature of the clinical presentation of angioimmunoblastic lymphadenopathy. However, the nature, prevalence, and significance of this eruption have yet to be defined. In order to ascertain the role of the cutaneous eruption more clearly, 147 previously reported cases have been reviewed. Skin involvement in AlL is not a universal phenomenon (Table I). Sixty-five of the 148 patients included in this review had a nonspecific dermatitis (44% of the 148). Of these, 91% had skin eruptions that were characterized as maculopapular, and 9% had purpuric eruptions or severe, generalized pruritus without obvious skin involvement. In 75% of such cases in which a maculopapular eruption was reported, skin involvement preceded other clinical symptoms by from several weeks to 1 year. In 25% of such cases, the maculopapular eruption appeared concomitantly with other constitutional signs and symptoms. In all such cases, signs or symptoms referable to the skin accompanied other symptoms. The prognosis of AlL is generally poor. 1, 2, lz It is interesting to examine the relationship between skin involvement and prognosis (Table II). Such data are hard to collect since few studies present survival figures for those with and without rashes. For the nineteen patients with skin involvement for which survival from time of initial diagnosis of AlL could be calculated, the mean survival was 22.3 months. Comparable mean survival for fourteen patients without skin involvement was 19.8 months. This difference is not statistically significant (p > 0.10) and is probably due to earlier diagnosis of the disease in subjects with such eruptions. Previous reports have claimed that as many as
Volume 1 Number 3 September, 1979
80% of patients with AIL and skin involvement have a history of prior drug u s e . 1~ However, our review indicates that only 3I% (twenty of sixtyfour patients) of patients with skin involvement have a history of prior drug use. Perhaps of greater interest is the nature of the possible offending agents. While these have spanned a wide gamut of chemotherapeutic agents, penicillin (six patients) and phenytoin (four patients) have been reported most frequently. While our patient had no history of recent systemic medication, she had chronic occupational exposure to hair dyes and bleaches. Although there have been no previous reports indicating an association between topical medication and AIL, chronic antigenic stimulation from percutaneous 'absorption cannot be excluded in this patient. The association with phenytoin is especially interesting, as Lukes and Tindle I have commented on the morphologic similarity of AIL and anticonvulsant-induced pseudolymphoma. Both conditions involve an immunologic hyporesponsiveness during a period of lymphoproliferation. 28-s~When such proliferative lymphadenopathy is present in conjunction with an altered immunosurveillance system, malignant changes may be more likely. Thus, AIL, much like phenytoin-induced pseudolymphoma syndrome, seems to bridge a gap between benign and malignant histopathologic disorders. Although our patient had a normal immunoglobulin profile, 67% of reported cases of AIL manifest a hyperglobulinemia, with polyclonal hyperglobulinemia the commonest abnormality. On the basis of such immunoglobulin alterations, as well as the benign histologic appearance and common association with previous drug therapy, it had been proposed that AIL is a nonneoplastic disease resulting from a proliferation of B lymphocytes and possibly triggered by a hypersensitivity reaction to an antigenic stimulus? However, defects in delayed hypersensitivity to ubiquitous antigens, as demonstrated by the anergic response of our patient to common skin test antigens, suggested a defect in the T lymphocyte system as well. Recent reports have shown such defects in number or function of the T lymphocyte system8'
Angioimmunoblastic lymphadenopathy
231
z0,2~ as well as an abnormal proliferation of B cells, z~ Thus, the defect in the T lymphocyte system may result in decreased suppressor T cell influence on B cells, allowing abnormal proliferation and hyperactivity of the B cell system. Alternately, the hyperglobulinemia and B cell hyperproliferation may result from a neoplastic process, leading to evolution of a malignant lymphoma. The increasing number of cases of AIL reported to terminate in immunoblastie lymphoma, lz immunoblastic sarcoma, 1~ and Hodgkin's disease 1~ support such a possibility. While our patient had a normal chromosomal pattern, cytogenetic studies of three previously reported patients with AlL have demonstrated some abnormalities, primarily aneuploidy, ta'zl Since clones of cells carrying acquired chromosomal anomalies frequently suggest a neoplastic process, such chromosome abnormalities constitute further support for the malignant nature of AIL. More knowledge about the pathogenesis of this condition may lead to significant advances in our understanding of malignant transformation. Proper therapy for this condition is still controversial. There have been proponents of steroid therapy, systemic chemotherapy, and conservative management without therapy. Levamisole as a stimulant of the thymus-dependent lymphoid system has been tried with encouraging results, ~8 but our patient's course did not warrant such treatment. The recent report of Nathwani et a112 would indicate that no treatment would appear to be slightly better than prednisone or chemotherapy. This is not surprising since most patients with AIL succumb to infection, and thus the immune response that patients are able to mount against foreign invaders may be the most significant factor in their survival. Angioimmunoblastic lynaphadenopathy is being reported with increasing frequency due to the recognition of this disorder as a distinctive clinical entity. Our patient with AIL manifested a pruritic maculopapular eruption as her presenting complaint. It is important for dermatologists to include AIL in the differential diagnoses of any maculopapular eruption of unknown etiology when it is accompanied by lymphadenopathy.
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B e r n s t e i n et al
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