To the editor

HUMAN PATHOLOGY

Volume 25, No. 2 (February 1995)

m i c r o o r g a n i s m because the p a t i e n t h a d a history o f prostatitis a n d several AIDS patients with similar lesions have b e e n described lately, s'9 A n o t h e r possibility is that this p a t i e n t develo p e d a pathological i m m u n e activation s y n d r o m e involving C D 4 + T cells. T h e T h 2 - s u b g r o u p o f C D 4 + T cells p r o d u c e s i n t e r l e u k i n (IL)-4 a n d IL-5 lymphokines. Interleukin-4 ind u c e s proliferation o f B cells, w h e r e a s IL-5 is r e s p o n s i b l e for e o s i n o p h i l differentiation. 17 Unfortunately, n o f r o z e n tissue f r o m the biopsy s p e c i m e n is available to test this possibility.

Acknowledgment. We thank Dr Jacob Churg for assistance in preparation of the manuscript. REFERENCES 1. Savage COS: Pathogenesis of systemicvasculitis, in Churg A, Churg J (eds): SystemicVasculitides.New York-Tokyo, Igaku-Shoin, 1991, pp 7-30. 2. Jacobs MR, Mlen NB: Giant cell arteritis, in Churg A, Churg J (eds): SystemicVasculitides.New York-Tokyo, Igaku-Shoin, 1991, pp 143-157 3. Lanham JG, Churg J: Churg-Strauss Syndrome, in Churg A, Churg J (eds): SystemicVasculitides,New York-Tokyo, Igaku-Shoin, 1991, pp 101-120 4. Lie JT, Gordon LP, Titus JL: Juvenile temporal arteritis. Biopsy study of four cases.JAMA 234:496-499, 1975 5. BollingerA, Leu H-J,Brunner U:Juvenile arteritis of extra-cranialarteries with hyloereosinophilia.Klin Wochenschr 64:526-529, 1986

6. Lie JT, Michet CJ, Jr: Thromboangiitis obliterans with eosinophilia (Buerger's disease) of the temporal arteries. HUM PATHOL19:598-602, 1988 7. Ferguson GT, Starkebaum G: Thromboangiitis obliterans associated with idiopathic hypereosinophilia.Arch Intern Med 145:1726-1728, 1985 8. Enelow RS, Hussein M, Grant K, et al: V~sculitiswith eosinophilia and digital gangrene in a patient with acquired immunodefieiency syndrome. J Rheumatol 19:1813-1816, 1992 9. Schwartz ND, Yuen TS, Hollander H, Allen S, Fye KH: Eosinophilic vasculitis leading to amaurosis fugax in a patient with acquired immunodeficiency syndrome. Arch Intern Med 146:2059-2060, 1986 10. Canton CG, Bernis C, ParaisoV, Barril G, Garcia A, Osorio C, Rincon B, TraverJA: Renal failure in temporal arterids. AmJ Nephrol 12:380-383, 1992 11. Lie JT: Disseminatedvisceral giant cell arterifis. Histopathologic description and differentiation from other granulomatous vasculitides.AmJ Clin Path 69:299-305, 1978 12. Grishman E: Disseminatedgiant cell arteritis. Modern Path 6:633-636, 1993 13. Torres VE, DonadioJV,Jr: Clinicalaspects of the nephrotic syndrome in systemic diseases, in Cameron JS, Glassock RJ (eds): The Nephrofic Syndrome. New York, Marcel Decker, 1988, pp 555-651 14. Truong L, Kopelman RG, Williams GS, et al: Temporal arteritis and renal disease. Case report and reviewof the literature. Am J Med 78:171-175, 1985 15. StansfieldAG: Inflammatoryand reactive disorders, in StansfieldAG, d'Ardenne AJ (eds): Lymph Node BiopsyInterpretation, 2nd ed. Edinburgh, Scotland, Churchill Livingston, 1992, pp 55-115 16. FauciAS: The idiopathic hypereosinophilicsyndrome:Clinical,pathophysiologic and therapeutic considerations. Ann Int Med 79:78-92, 1982 17. Mosman TR: Helper T-cells and their lymphokines, in Feldman M, Lamb J, Owen MJ (eds): T-Cells.Wiley, New York, 1989, pp 177-210

CORRESPONDENCE l y m p h o i d malignancies. U n f o r t u n a t e l y , studies o f the epidemiology o f l y m p h o m a in this disease are u n c o m m o n . Second, given o u r c u r r e n t u n d e r s t a n d i n g o f the p a t h o g e n e s i s o f neoplasia, it is likely that a s e c o n d or possibly a series o f f u r t h e r genetic alterations w o u l d be necessary b e f o r e a malignancy d e v e l o p e d , c o n t r i b u t i n g to a later o n s e t o f l y m p h o i d tumors. I would w e l c o m e any c o m m e n t f r o m the authors.

G u i d e l i n e s for Letters Letters to the Editor will b e p u b l i s h e d at the disc r e t i o n o f the e d i t o r as space p e r m i t s a n d are subject to editing a n d a b r i d g e m e n t . They s h o u l d be typewritten, double-spaced, a n d s u b m i t t e d in triplicate. T h e y s h o u l d be limited to 500 words or less a n d to n o m o r e t h a n five p e r t i n e n t references.

MARTIN BULLOCK, MD Pathology R e s i d e n t University o f T o r o n t o T o r o n t o , Ontario, C a n a d a

On the Origin of Lymphoid Neoplasms in Rheumatoid Arthritis To the Editor:--With r e s p e c t to the article by Kamel et al 1 a n d the editorial by Dr Frizzera 2 discussing the origin o f l y m p h o i d n e o p l a s m s in r h e u m a t o i d arthritis, I would like to raise for discussion a n o t h e r m e c h a n i s m , n o t a d d r e s s e d by the authors, by which these n e o p l a s m s may arise. Specifically, could these patients have a g e n e t i c p r e d i s p o s i t i o n to b o t h r h e u m a t o i d arthritis a n d l y m p h o i d n e o p l a s m s with i n d e p e n d e n t m e c h a n i s m s for the d e v e l o p m e n t o f each? T h e c o m m o n origin may be a subtle i m m u n e deficiency o r abnormality o f i m m u n e regulation. An analogous situation may be the p r e d i s p o s i t i o n o f patients with c o m m o n variable i m m u n o d e ficiency to develop b o t h r h e u m a t o i d arthritis (as well as o t h e r a u t o i m m u n e disorders) a n d l y m p h o i d neoplasms. 3 S y m m o n s 4 alludes to this e x p l a n a t i o n in h e r article " N e o p l a s m s o f the I m m u n e System in R h e u m a t o i d Arthritis"; however, she dismisses it because (1) r h e u m a t o i d arthritis almost invariably p r e c e d e s the d e v e l o p m e n t o f a l y m p h o i d malignancy a n d (2) t h e r e is a linear increase in the cumulative relative risk o f l y m p h o i d neoplasia. However, r h e u m a t o i d arthritis generally has its o n s e t in early a d u l t h o o d a n d may p r e c e d e l y m p h o m a s in the majority o f cases simply b e c a u s e o f the differing pathobiology o f each illness. In o n e prospective study o f 220 patients with c o m m o n variable i m m u n o d e f i c i e n c y , t h r e e patients (the y o u n g e s t o f w h o m was 19 years old) ~ d e v e l o p e d

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1. KameI OW, van de Rijn M, LeBrun DP, et al: Lymphoid neoplasms in patients with rheumatoid arthritis and dermatomyositis:Frequency of EpsteinBarr virus and other features associatedwith immunosuppression.HUMPATHOL 25:638-643, 1994 2. Frizzera G: Immunosuppression, autoimmunity, and lymphoproliferative disorders. HUM PATHOL25:627-629, 1994 3. Sheller MC, Strober W, Eisenstein E, et al: New insights into common variable immunodeficiency.Ann Intern Med 118:720-730, 1993 4. SymmonsDP: Neoplasmsof the immune systemin rheumatoid arthritis. AmJ Med 78:22-28, 1985 (suppl 1A) 5. Kinlen LJ, Webster AB, Bird AG, et al: Prospective study of cancer in patients with hypogammaglobulinemia.Lancet 1:263-266, 1985

The above letter was referred to the authors of the article in question, who offer the following reply. To the Editor:--Dr Bullock raises an i m p o r t a n t p o i n t in his suggestion that a single genetic a b n o r m a l i t y c o u l d be responsible for the d e v e l o p m e n t o f r h e u m a t o i d arthritis a n d l y m p h o i d n e o p l a s m s in patients having b o t h o f these diseases. A l t h o u g h this is certainly a possible scenario, we are n o t aware o f evidence that may link these two diseases to a c o m m o n g e n e t i c defect. Dr Bullock p o i n t s o u t that patients with comm o n variable i m m u n o d e f i c i e n c y (CVI) can develop b o t h l y m p h o i d n e o p l a s m s a n d r h e u m a t o i d arthritis; however, in their review o f the subject Sneller et al 1 d o n o t provide data that link a u t o i m m u n e disorders a n d l y m p h o m a to a single g e n e t i c d e f e c t in patients with CVI. In animal m o d e l s that

CORRESPONDENCE

develop autoimmunity and malignancies, this p h e n o m e n o n "may be genetically restricted," but this has not been proven. 2 The situation in patients with rheumatoid arthritis is complex because these patients develop a spectrum of lymphoid neoplasms, at least some of which likely represent coincidental occurrence of rheumatoid arthritis and lymphoma in the same patient. With regard to the Epstein-Barr virus (EBV)associated lymphoid neoplasms in these patients, the finding that patients with rheumatoid arthritis have a T-cell defect that allows for uninhibited EBV-associated B-cell proliferation suggests that impaired cell-mediated immunity contributes, at least in part, to the uncontrolled proliferation of EBVdriven B-cell clones in these patients. 3 The possible compounding effect of immunosuppressive therapy on this background makes this a complex problem to study. Nonetheless, the finding that a subset of these lymphomas spontaneously regress after withdrawal of immunosuppressive therapy 4 suggests that iatrogenic i m m u n e system impairment plays a role in the development of these neoplasms. ONSI W. KAMEL,MD MATTHIJSVAN DE RIJN, MD, PHD ROGER A. WARNKE,MD RONALD F. DORFMAN,MD, FRCPATH Department of Pathology Stanford University Medical Center Stanford, CA GLAUCO FPdZZERA,MD Department of Pathology New York University Medical Center New York, NY 1. SnellerMC, StroberW, EisensteinE, et al: New insightsinto common variableimmunodeficiency.Ann Intern Med 118:720-730,1993 2. YonusJ,AhmedAll:Autoimmunityand malignancy.JAmAcadDermatol 23:720-723,1990 3. DepperJ, BluesteinH, ZvailerN: Impaired regulation of EBV virus induced lymphocyteproliferationin RA is due to a T-celldefect.J Immunol 127:1899-1902, 1981 4. Kamel OW, van de Rijn M, Weiss LM, et al: Reversiblelymphomas associated with Epstein-Barrvirus occurringduring methotrexate therapy for rheumatoid arthritisand dermatomyositis.N EnglJ Med 328:1317-1321,1993

Actin-Binding Protein Expression in Melanocytic Proliferations To the Editor:--Bouffard et al are to be congratulated for their exciting discovery that melanocytes in nevi and melanomas vary in their cytoplasmic content of actin-binding protein as a function of relation to the epidermis) Their reasoning that actin-binding protein, which cross links actin filaments to produce "gelation" of the cytoplasm, is essential for cell migration in the melanocytic series seems to be quite sound. We pathologists often infer (or confer) migratory activity based on interpretations of histological patterns, but now perhaps we can provide objective scientific evidence of migratory capability using our static images. Bouffard et al correctly point out that melanoma cell migration must play an important role in the processes of invasion and metastasis. I would like to add that migration also is necessary in normal melanocyte development because dermal melanocytes of neural crest derivation must cross the epidermal basement membrane before they can acquire keratinocytic partners in epidermal melanin units. 2 Several studies using sensitive ultrastructural methods have shown that dermal melanocytes may become apparent after ultraviolet irradiation of the epidermis, suggesting that melanocyte migration also may occur in normal epidermal tissue maintenance in the melanocytic series. 3 Bouffard et al's elegant demonstration that the pagetoid

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elements of superficial spreading malignant melanoma appear to be deficient in actin-binding protein is strong evidence against the classic teaching that the pagetoid pattern represents active infiltration of the epidermis by malignant melanomas.4 Rather, it represents an experimental confirmation of the alternative hypothesis that "distribution at all levels of the epidermis may reflect impairment of junctional interactions, permitting cells to be carried towards the epidermal surface by the flow of maturing keratinocytes."5 This in no way diminishes the importance of the pagetoid pattern as a diagnostic criterion for distinguishing melanomas from benign melanocytic proliferations.4 Bouffard et al also noted the apparent deficiency of actinbinding protein in the lentiginous components of compound and dysplastic nevi and superficial spreading melanomas. Following classic teachings about the histogenesis of nevi and melanomas that emphasize Abtropfung (the dropping down of melanocytes into the dermis), they suggest that benign and malignant melanocytes may gain actin-binding protein expression as they prepare to invade the dermis. As a propon e n t of the alternative hypothesis of Hochsteigerung (the rising up of melanocytes from dermis into epidermis, as in normal development3), I favor the interpretation that benign and malignant neoplastic melanocytes may lose actin-binding expression as they migrate from the dermis into the epidermis. More work is needed to distinguish between these two possibilities. I suggest that neoplastic melanocytes (like their normal counterparts) may express actin-binding protein as they traverse the dermis and cross the epidermal basement membrane but may no longer express actin-binding protein once they reach their "home" in the epidermis. 2'3'~ The authors do not list melanocytes alongside keratinocytes, fibroblasts, endothelial cells, etc as normally expressing actin-binding protein. If this means they have not observed actin-binding protein expression in normal melanocytes, this may constitute further evidence in favor of the hypothesis of a melanocyte differentiation pathway. STEW,~RTF. CRAMER, MD Rochester General Hospital Rochester, NY 1. BouffardD, DuncanLM, Howard CA, et al: Actin-bindingprotein expression in benign and malignantmelanocyticproliferations.HUM PATHOL 25:709-714, 1994 2. CramerSF:The melanocyticdifferentiationpathwayin congenitalmelanocyticnevi--Theoreticalconsiderations.PediatrPathol 8:253-265,1988 3. CramerSF:The originof epidermaImelanocytes--Implicationsfor the histogenesisof neviand melanomas.Arch Pathol Lab Med 115:115-119,1991 4. Mihm MC, Jr, Imber MJ: Malignantmelanoma, Sternberg SS (ed): DiagnosticSurgicalPathology,vol 1. NewYork, NY, Raven,1989,pp 114-118 5. Cramer SF: The neoplasticdevelopmentof malignantmelanoma--A biologicalrationale.AmJ Dermatopathol6:299-308,1984 (suppl 1) The above letter was referred to the authors of the article in question, who offer the following reply. To the Editor:--We agree with Dr Cramer that the lack of actin-binding protein (ABP) in pagetoid cells of malignant melanoma suggests that active cell locomotion is not required for these cells to spread throughout the epidermis. The findings support the hypothesis that pagetoid cells have lost their basement membrane interactions and are displaced by the flow of the maturing keratinocytes toward the outside surface. We interpreted the presence of ABP in benign and malignant melanocytes in intraepidermal and dermal nests as a necessary cytoskeletal protein used by the cells to infiltrate the dermis. We agree with Dr Cramer that it is difficult to assign "gain" or "loss" of ABP expression as a function of development of benign melanocytic proliferations or malignant tumor pro-