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A case of cutaneous T-cell lymphoma expressing γδ T-cell receptors
Journal of the American Academy of Dermatology Volume 28, Number 2, Part 2
Pulmonary colonization with M. chelonae should be considered a source of disseminated infection in immunocompromised patients and may become more prevalent with advances in organ transplantation. In addition, the presence of subcutaneous nodules on the extremities of an immunocompromised host warrants a search for atypical mycobacteria. In our case, an AFB smear of skin biopsy tissue was instrumental in the diagnosis of disseminated M. chelonae and prompt initiation of treatment. REFERENCES 1. MurdochME, Leigh 1M.Sporotrichoid spreadof cutaneous Mycobacterium chelonae infection. Clin Exp Dermatol 1989;14:309-12. 2. Woods GL, Washington lA. Mycobacteria other than Mycobacterium tuberculosis: review of microbiologic and clinical aspects. Rev Infect Dis 1987;9:275-94.
M. chelonae with preexisting pulmonary colonization 3. HigginsEM, Lawrence CM. Sporotrichoid spreadof Mycobacterium chelonae. Clin Exp Dermatol1988;13:234-6. 4. Hamrick HJ, MadduxDW, LowryEK, et al. Mycobacterium chelonae facialabscess: casepresentationand review of cutaneous infection dueto RunyonGroup IV organisms. Pediatr Infect Dis J 1984;3:335-40. 5. WallaceRJ. Clinical presentation, diagnosis, and therapy of cutaneous and pulmonary infections due to the rapidly growing mycobacteria, M. fortuitum and M. chelonae. Clin Chest Moo 1989;10:419-29. 6. RighterJ, Hart GD, HowesM, et al. Mycobacteriumchelonae: report of a caseof septicemia and review of the literature. Diagn Microbiolinfect Dis 1983;1:323-9. 7. Cooper JF, Lichtenstein MJ, Graham BS. Mycobacterium chelonae: a cause of nodular skin lesions with a proclivity for renaltransplantrecipients. Am J Moo 1989;86:173-7. 8. Collins CH, Uttley AH. In-vitroactivity of seventeen antimicrobial compounds against seven species of mycobacteria. J Antimicrob Chemother 1988;22:857-61.
A case of cutaneous T-cell lymphoma expressing 'YO T-cell receptors Mayumi Fujita, MD, Yoshiki Miyachi, MD, Fukurni Furukawa, MD, Eiko Toichi, MD, Ikuko Furukawa, MD, Naoko Nakajima, MD, and Sadao Imamura, MD Kyoto, Japan Cutaneous T-cell lymphoma expressing 'YO T-cell receptors (TCRs) is rare; only a few cases have been reported. We report another case of the disease that had a fatal outcome and differs from two previously reported cases in its clinical, histologic, and immunohistochemical aspects. The patient had multiple skin tumors with central crusts; she showed no response to chemotherapy and died within 1 year. Histologic findings included perivascular infiltrates in the dermis and subcutaneous tissue with no epidermotropism; the large lymphoid cells had a phenotype of CDl-, CD3+, CD4-,CDS-, CD25-/+, CD30-, CD3S-/+, HLA-DR+, and 'YO TCR ({JFl-, TCRol +, OTCSI-, Ti'YA+, BBr). The differences in the phenotype of 'YO T-cell malignancies may reflect the uniqueness of its clinical and histologic features. A study of 'YO T-cell malignancies may disclose important biologic features of 'YO TCR+ cells. (J AM ACAD DERMATOL 1993;2S:355-60.)
Human T cells recognize antigens with their T-cell receptors (TCR) that are associated with the CD3 polypeptide complex. Most CD3+ peripheral T cells express ex. and {3 chains of TCR, whereas only From the Department of Dermatology, Faculty of Medicine, Kyoto University. Reprint requests: Mayumi Fujita, MD, Department of Dermatology, Faculty of Medicine, Kyoto University, Kyoto, Japan. Copyright © 1993 by the American Academy of Dermatology. 0190-9622/93 $1.00+.10 16/4/39627
approximately 5% express "( and 0 chains.' Because 'Yo TCR+ cells are poorly understood, investigation of a disease associated with 'Yo TCR+ cells may disclose important characteristics of these cells. To date, several "(0 T-cell malignancies have been reported.r" Picker et al.2 reported that among 62 T-cell lineage lymphomas only two TCR-"(o+ neoplasms were identified, both of which were from thymic (Tdymphoblastic) lymphomas. Gaulard et a1. 6 identified 6 TCR "(0+ lymphomas among 57 355
356 Fujita et al.
Fig. 1. Skin with a central crusted nodule on right side of neck.
Journal of the American Academy of Dermatology February 1993
gastrointestinal endoscopy, and bone marrow biopsy specimen showed no abnormalities. A diagnosis of non-Hodgkin's lymphoma (T-cell lineage lymphoma) was made. The patient was treated with prednisone, 40 mg/day, and cyclophosphamide, 100 rng/day, with no effect. Two months later the patient reported dysgraphia, a gait disturbance, vertigo, and tremor of the upper extremities. Computed tomographic scans of the head demonstrated enlarging lesions in the left caudatum and lenticula. One month later, ulcers of the rectum and esophagus were noted. The patient's general condition and skin eruptions worsened and did not respond to chemotherapy. The patient became oliguric and died 6 months later. Permission for an autopsy was refused.
Tissue Studies
cases of peripheral T-cell lymphomas; none of the 6 cases had skin involvement. To the best of our knowledge, only two cases of 'YO T-cell lymphomas of the skin have been reported; one was a Tvlymphoblastic lymphoma that involved mediastinum and skin' and the other showed disseminated pagetoid reticulosis both clinically and histologically.' We report a case of cutaneous 'YO T-cell lymphoma that differs from the two previously reported cases clinically, histologically, and imrnunohistochemically. CASE REPORT A 60-year-old woman had several asymptomatic, erythematous plaques and nodules. Four years previously she had noted an erythematous nodule in her left popliteal region that healed spontaneously with scarring. Other lesions developed on the forearms, neck, and left leg, some of which cleared spontaneously. The patient had a body weight loss of 25 kg during the past year. Physical examination revealed a plum-colored, ulcerated tumor that was 3 em in diameter, had a central crust, and was located on the right side of the neck (Fig. 1). In addition, several nodules and indurated plaques were observed in the axillae and on the extremities. Lymphadenopathy was absent. Results of routine laboratory studies showed an increase in band cells and eosinophils and elevation of C-reactive protein (0.9 rng/dl), lactate dehydrogenase (698 IUjL), creatine phosphokinase (202 IU/L), and -v-globulin (25%). The human T-Iymphotropic virus type I status of the patient was negative. Computed tomographic scans showed moderate splenomegaly, inflammation of the lower lung, and infiltrated masses in the left scapular muscles, pectoral muscles, and breasts. A 67Ga-scintigram showed accumulations in the left thigh, head, and neck. Results of a bone scintigram,
Biopsy specimens obtained from three cutaneous lesions were processed for light microscopic examination, immunohistochemical studies, and DNA analysis. For immunohistochemical studies the specimens were fixed in periodate-lysine-paraformaldehyde solution and stained with avidin-biotin-peroxidase complex, as described previously/ The monoclonal antibodies used in this study are listed in Table 1. For gene analysis, DNA was extracted from the specimens and digested with EcoRI or BamHI, electrophorized, and transferred to a nylon membrane. Southern blot hybridization was performed with EcoRI-HindIII fragments of the C{n region of the T-cell receptor gene." Because T'Y probes were not available when we first observed the patient, DNA was not analyzed for TCR-')' or TCR-o gene rearrangement.
Results Histopathologic examination of the cutaneous tumors showed a perivascular infiltrate of lymphoid cells, histiocytes, eosinophils, and plasma cells in the dermis and subcutaneous tissue (Fig. 2). The walls ofthe vesselswere hypertrophic. Medium- to large-sized atypical lymphoid cells with large hyperchromatic nuclei were scattered throughout the infiltrate. Some nuclei were convoluted or multilobated, and mitotic figures were often observed. No epidermotropism was shown, and a grenz zone was present. Immunohistochemical staining showed that the largesized lymphoid cells had an aberrant T-cell phenotype (CDl-, CD3+, CD4-, CDS-) (Fig. 3, A and B) and variable degrees of activation antigens (HLA-DR+, CD25-/+, CD38-/+), with no expression of B-cell antigen (CD20-) or Ki-I antigen (CD30-). They expressed "/0 TCR (TCRBI +, BTCSI-, BBr, Ti')'A+), but not 0i{3 TCR ({3Fl-) (Fig. 3, C and D). Reactive small-sized lymphoid cells had a helper T-cell phenotype (CD3+,
Journal of the American Academy of Dermatology Volume 28, Number 2, Part 2
Cutaneous T-cell lymphoma expressing 'YO TCRs 357
Fig. 2. Histopathology of the skin lesions. A, Perivascular infiltrates in the dermis and subcutaneous tissue. There is no epidermotropism, and a grenz zone is present. B, Higher magnification of the infiltrates. Medium- to large-sized lymphoid cells with large hyperchromatic nuclei are evident. Some of the nuclei are convoluted or multilobated. (Hematoxylin-eosin stain. A, xSO; B, X400.)
DISCUSSION CD4+) or a suppressor T-cell phenotype (CD3+, CDS+) and expressed a{'JTCR ({'JFI +, TCROl-, oTCSI-, BBr, Ti')'A-). Hybridization with a C{'JI probe disclosed no clonal rearrangement of the TCR-{'J gene. DNA analysis was not performed for TCR-')' or TCR-o gene rearrangement.
Malignant lymphomas of the skin, excluding mycosis fungoides and Sezary syndrome, are heterogeneous clinically, histologically, and immunohistochemically. The most common histologic subtype is diffuse large-cell lymphoma, I 0 and the tumor cells
Journal of the American Academy of Dermatology February 1993
358 Fujita et al.
Fig. 3. Immunohistochemistry of the skin lesions. Large-sized lymphoid cells reactive with anti-CD3 antibody (A) and TCRBI antibody (C) but not with anti-CD4 antibody (B) or I3Fl antibody (D). (Methyl green stain; X400.)
Table I. Monoclonal antibodies used in this study Cluster designation
CDI CD3 CD4 CDS CD20 CD25 CD30
CD38
Antibody
Source
Antigen distribution
OKT6 Leu-4 Leu-3a Leu-2a Bl Anti-Tac Ki-l OKTIO Anti-HLA-DR I3Fl TCRBI BTCSl BB3 TiyA
Ortho* Becton-Dickinsont Becton-Dickinsont Becton-Dickinson] Coulter:j:
Thymocytes, Langerhans cells Pan-T cells (TCR complex) T helper/inducer, monocytes, Langerhans cells T suppressor/cytotoxic, natural killer cells subset Pan-B cells Activated T cells (IL-2 receptor) Activated T and B cells, Reed-Sternberg cells Activated T and B cells Class II MHC antigen Pan-aI3TCR+ cells Pan-'YOTCR+ cells VBl+ cells VB2+ cells V'Y9+ cells
§ Dakopatts] Ortho*
Becton-Dickinson t T-Cell Sciencesf T-Cell Sciencesj] T-Cell Sciences'[' # **
MHC, Major histocompatibility complex. *Ortho Diagnostic Systems, Inc., Raritan, N.J. tBecton Dickinson Immunocytometry Systems, San Jose, Calif. iCoulter Electronics, Hialeah, Fla. §A gift from Dr. T. Uchiyama (Kyoto, Japan). [Dakopatts A/S, Copenhagen, Denmark. ,T·Cell Sciences, Inc., Cambridge, Mass. #A gift from Dr. L. Moretta (Geneva, Italy). **Agift from Dr. T. Hercend (Cedex, France).
express either B or T phenotype. II, 12 However, reports of T-cell lymphoma of the skin expressing 'YO TCR are rare. 5, 7 The case reported by Falini et al.5 was aT-lymphoblastic lymphoma that involved skin and mediastinum and expressed a phenotype of CDl +, CD2+, CD3+, CD4+, CD8+, CD2S+, CD30+, HLA-DR-with 'YO TCRCfJFl-, TCRM +, oTCSl +, BBr). Berti et aI,7 described a patient
with disseminated pagetoid reticulosis in whom the epidermotrophic T-cell infiltrate showed a phenotype of CD 1-, CDr, CD3+, CD4-, CDS-, CD2S-, CD30-, HLA-DR- with yo TCR CI3Fl-, TCRM +, oTCSl-, Ti'YA-, BBr). In this report we have presented a case of cutaneous 'YO T-cell lymphoma that differs from the two previously reported cases in its clinical, histologic,
Journal of the American Academy of Dermatology Volume 28, Number 2, Part 2
and immunohistochemical features. The patient did not have a mediastinal mass, and the neoplastic cells showed no epidermotropism and a phenotype of
CDl-, CD3+, CD4-, CD8-, CD2S- I+, CD30-, CD38-/+, HLA-DR+ and 'YO TCR (,BFl-, TCROl+, oTCSI-, Ti'YA+, BBr).Although molecular studies of TCR'Y and TCRo gene rearrangement were not performed, our phenotypic da ta of the large lymphoid cells and the results of Southern blot analysis showing no rearrangement of TCR-,B gene favor clonality of 'YO TCR+ cells. It is unknown whether the skin was the primary site of the disease, because computed tomographic scans at admission to the hospital showed splenomegaly and masses in muscles. However, the cutaneous nodules developed 4 years before our first examination, which suggests that the skin lesions may be primary. Although the biologic role of 'YO TCR+ cells has not been demonstrated definitively, the limited diversity of the gene l 3, 14 and the unique anatomic distribution 15, 16 suggest that the 'YO TCR+ cells may participate in host defense against the invasion of various pathogens. 17 This is supported by recent reports that 'YO TCR+ cells participate in the immune response to mycobacterial antigens. 1S- 24 However, other studies indicate that 'YO TCR+ cells increase not only in mycobacterial infections, but also in the synovial fluid of patients who have rheumatoid arthritis" and in the gut epithelium of patients who have coeliac disease. 25, 26 The phenotypes of these 'YO TCR+ cells are V02+, V'Y9+ in mycobacterial infection/" and rheumatoid arthritis,21 which is similar to that of most peripheral blood 'YO TCR+ cells, but they are vsr-, vor, V'Y9- in coeliac disease.i" which is consistent with that in the small intestine. The 'Yo TCR+ cells in normal human skin also express VO 1-, V 02+, V'Y9+. 27 In our case, however, the V region gene was V 01-, V V1'9+, which is not consistent with these phenotypes. Possible explanations include the existence of another new phenotype of 'Yo TCR+ cells and a phenotypic change in 'Yo TCR+ cells when they are transformed. In addition, the phenotype in our case was not the same as the two previously reported cases of 'YO T-cell malignancy of the skin" 7
or,
We thank Dr. L. E. Golitz, Denver General Hospital, for his helpful comments about the histologic findings of the patient. We also thank Dr. Koh Nakata for providing monoclonal antibodies, Ms. Fumiko Owatari for technical assistance, and Mr. Arimitsu Hasegawa for photographic works.
Cutaneous T-cell lymphoma expressing 'YO TCRs 359 REFERENCES
1. Raulet DH. The structure, function, and molecular genetics ofthe-y/ 0T cell receptor. Ann Rev Immunol1989;7:175207. 2. Picker LJ, Brenner MB, MichieS, et al. Expression ofT cell receptor delta chains in benign and malignant T lineage lymphoproliferations. Am J Patho11988;132:401-S. 3. Champagne E, Takihara Y, Sagman U, et al, The isolation of the human 'Y chain gene and its expression in normal T cells and T cell leukemias. Leukemia 1988;2:717-2L 4. Griesinger F, Greenberg IN, Kersey 1H. T cell receptor 'Y and {j rearrangements in hematologic malignancies: relationship to lymphoid differentiation. J Clin Invest 1989; 84:506-16. 5. Falini B, Flenghi L, Fagioli M, et aL T-lyrnphoblastic lymphomas expressing the non-disulfide-linked form of the T-cell receptor 'Ylo: characterization with monoclonal antibodies and genotypic analysis. Blood 1989;74:2501-7. 6. Gaulard P, Bourquelot P, Kanavaros P, et al. Expression of the a/f3 and 'Ylf3 T-cell receptors in 57 cases of peripheral T-celllyrnphomas: identification of a subset of "f15 T-cell lymphomas. Am J Pathol /990;137:617-28. 7. Berti E, Cerri A, Cavicchini S, et al. Primary cutaneous 1'/5 T-cell lymphoma presenting as disseminated pagetoid reticulosis. J Invest DermatoI1991;96:718-23. 8. Fujita M, Furukawa F, Horiguchi Y, et aL Regional development of Langerhans cells and formation of Birbeck granules in human embryonic and fetal skin. J Invest DermatoI1991;97:65-72. 9. Southern EM. Detection of specificsequences among DNA fragments separated by gel electrophoresis. J Mol BioI 1975;18:503-17. 10. BurkeJS, Hoppe RT, Cibull M, et al. Cutaneous malignant lymphoma: a pathologic study of 50 cases with clinical analysis of 37. Cancer 1981;47:300-10. 11. Knowles DM II, Halper 1P, Jakobiec FA. The immunologic characterization of 40 extranodallyrnphoid infiltrates: usefulness in distinguishing between benign pseudolymphoma and malignant lymphoma. Cancer 1982;49:232135. 12. Wood GS, Burke JS, Horning S, et al. The immunologic and clinicopathologic heterogeneity of cutaneous lymphomas other than mycosis fungoides. Blood 1983;62:464-72. 13. Saito H, Kranz DM, Takagaki Y, et aL Complete primary structure of a heterodimeric T-cell receptor deduced from cDNA sequences. Nature 1984;309:757-62. 14. Heilig JS, Tonegawa S. Diversity of murine gamma genes and expression in fetal and adult T lymphocytes. Nature 1986;322:836-40. 15. Stingl G, Konig F, Yamada H, et al. Thy1+ dendritic epidermal cells express T3 antigen and the T-cell receptor 0 chain. Proc Nat! Acad Sci USA 1987;84:4586-90. 16. Goodman T, Lefrancois L. Expression of the 'YO T cell receptor on intestinal CD8+ intraepithelial lymphocytes. Nature 1988;336:479-81. 17. Janeway CA, Jones Jr. B, Hayday A.Specificityand function of T cells bearing 'YO receptors. Immunol Today 1988;9:73-6. 18. Janis EM, Kaufmann SHE, Schwartz RH, et aLActivation of T cells in the primary immune response to Mycobacterium tuberculosis. Science 1989;224:713-6. 19. Kabelitz D, Bender A, Schondelmaier S, et al. A large fraction of human peripheral blood 'Y/ 0+ T cells is activated by Mycobacterium tuberculosis but not by its 65-kD heat shock protein. J Exp Med 1990;171:667-79. 20. Happ MP, Kubo RT, Palmer E, et al. Limited receptor
Fujita et al. repertoire in a mycobacteria-reactive subset of "(D T lymphocytes. Nature 1989;342:696-8. 21. Holoshitz H, Konig F, Coligan lE, et al. Isolation ofCD4-, CDS- mycobacteria reactive T lymphocyte clones from rheumatoid arthritis synovial fluid. Nature 1989;339: 226-9.
22. Modlin RL, Pirmetz C, Hofman FM, et al. Lymphocyte bearing antigen-specific 'YO T-cell receptors accumulate in human infectious disease lesions. Nature 1989;339: 544-8. 23. Inoue T, Yoshikai Y, Matsuzaki G, et al. Early appearing 'Y/o..bearing T cells during infection with Calmette Guerin Baccilus. J Immunol1991;146:2754-62. 24. Kabelitz D, Bender A, Prospero T. The primary response of human 'Y/o+ T cells to Mycobacterium tuberculosis is
Journal of the American Academy of Dermatology February 1993
restricted to V'Y 9-bearing cells. J Exp Moo 1991; 173:1331-8. 25. Spencer J, Isaacson PG, Diss TC, et a!. Expression of disulfide-linked and non-disulfide-linked forms of the T cell receptor 'Y/o heterodimer in human intestinal intraepitheliallymphocytes. Eur J Immuno11989;19:1335-8. 26. Trejdosiewicz LK, CalabreseA, Smart CJ, et al. 'YO T cell receptor-positive cells of the human gastrointestinal mucosa: occurrence and V region gene expression in Heliobacter pylori-associated gastritis, coeliac disease and inflammatory bowel disease. Clio Exp Immunol 1991; 84:440-4. 27. Dupuy P, Heslan M, Fraitag S, et a1. T-cell receptor-v/f bearing lymphocytes in normal and inflammatory human skin. J Invest Dermatol 1990;94:764-8.
Necrosis of the hand after extravasation of intravenously administered phenytoin Anne G. Hayes, MD, and Thomas McC. Chesney, MD
Memphis, Tennessee
Extravascular escape of intravenously administered phenytoin can result in serious local soft tissue complications. Injury can range from simple phlebitis to chemical cellulitis or, in extreme cases, frank tissue necrosis that necessitates amputation. The histopathologic findings include extensive necrosis and sloughing of epidermis, widespread necrosis of dermis, subcutaneous tissue, muscles and nerves, and extensive thrombotic occlusion of vessel lumens. Results ofelastic tissue stains reveal thatthe thrombosed vessels are exclusivelyveins and venules. Vascular fibrinoid necrosis, leukocytoclasis, and true inflammatory vasculitis are not features. This is the first detailed report of the histopathologic alterations associated with this therapeutic misadventure. (J AM ACAD DERMATOL 1993;28:360-3.) Although seemingly a simple method of drug delivery, intravenous therapy requires specialized equipment, experienced personnel, and careful observation, 1,2 One risk is the chance misdirection of intravenous infusions. Brown et aP estimated that extravasation occurs in 11% of intravenous infusions in children. Riyami" reported that as many as 22.8% From theDepartments of Pathology and Medicine-Dermatology, University of Tennessee at Memphis and Baptist Memorial Hospital. Partially presented as a poster at theAnnual Meeting oftheAmerican Society of Dermatopathology, Dallas, Tex. Dec. 4-6, 1991. Reprint requests: Thomas McC. Chesney, MD, Baptist Memorial Hospital, Department of Pathology, 899 Madison Ave., Memphis, TN 38146. Copyright @ 1993 by the American Academy of Dermatology. 0190-9622/93 $1.00 +.10 16/4/39626
360
of intravenous infusions in adults result in extravascular escape. Fortunately, most of these incidents are recognized immediately and have little or no ill effect. However, serious local soft-tissue complications can ensue. In extreme cases, extensive tissue necrosis may occur. 1-8 At this time phenytoin is perhaps the most widely used intravenous anticonvulsant agent. Severe extravasation injury from this agent has been reported9- 12 and is mentioned in the Physician's Desk References? Although previous case reports have thoroughly described the clinical findings associated with phenytoin extravasation, the histopathologic features have not been elaborated. A patient at our institution recently developed severe tissue necrosis of the hand as a consequence of
Pulmonary colonization with M. chelonae should be considered a source of disseminated infection in immunocompromised patients and may become more prevalent with advances in organ transplantation. In addition, the presence of subcutaneous nodules on the extremities of an immunocompromised host warrants a search for atypical mycobacteria. In our case, an AFB smear of skin biopsy tissue was instrumental in the diagnosis of disseminated M. chelonae and prompt initiation of treatment. REFERENCES 1. MurdochME, Leigh 1M.Sporotrichoid spreadof cutaneous Mycobacterium chelonae infection. Clin Exp Dermatol 1989;14:309-12. 2. Woods GL, Washington lA. Mycobacteria other than Mycobacterium tuberculosis: review of microbiologic and clinical aspects. Rev Infect Dis 1987;9:275-94.
M. chelonae with preexisting pulmonary colonization 3. HigginsEM, Lawrence CM. Sporotrichoid spreadof Mycobacterium chelonae. Clin Exp Dermatol1988;13:234-6. 4. Hamrick HJ, MadduxDW, LowryEK, et al. Mycobacterium chelonae facialabscess: casepresentationand review of cutaneous infection dueto RunyonGroup IV organisms. Pediatr Infect Dis J 1984;3:335-40. 5. WallaceRJ. Clinical presentation, diagnosis, and therapy of cutaneous and pulmonary infections due to the rapidly growing mycobacteria, M. fortuitum and M. chelonae. Clin Chest Moo 1989;10:419-29. 6. RighterJ, Hart GD, HowesM, et al. Mycobacteriumchelonae: report of a caseof septicemia and review of the literature. Diagn Microbiolinfect Dis 1983;1:323-9. 7. Cooper JF, Lichtenstein MJ, Graham BS. Mycobacterium chelonae: a cause of nodular skin lesions with a proclivity for renaltransplantrecipients. Am J Moo 1989;86:173-7. 8. Collins CH, Uttley AH. In-vitroactivity of seventeen antimicrobial compounds against seven species of mycobacteria. J Antimicrob Chemother 1988;22:857-61.
A case of cutaneous T-cell lymphoma expressing 'YO T-cell receptors Mayumi Fujita, MD, Yoshiki Miyachi, MD, Fukurni Furukawa, MD, Eiko Toichi, MD, Ikuko Furukawa, MD, Naoko Nakajima, MD, and Sadao Imamura, MD Kyoto, Japan Cutaneous T-cell lymphoma expressing 'YO T-cell receptors (TCRs) is rare; only a few cases have been reported. We report another case of the disease that had a fatal outcome and differs from two previously reported cases in its clinical, histologic, and immunohistochemical aspects. The patient had multiple skin tumors with central crusts; she showed no response to chemotherapy and died within 1 year. Histologic findings included perivascular infiltrates in the dermis and subcutaneous tissue with no epidermotropism; the large lymphoid cells had a phenotype of CDl-, CD3+, CD4-,CDS-, CD25-/+, CD30-, CD3S-/+, HLA-DR+, and 'YO TCR ({JFl-, TCRol +, OTCSI-, Ti'YA+, BBr). The differences in the phenotype of 'YO T-cell malignancies may reflect the uniqueness of its clinical and histologic features. A study of 'YO T-cell malignancies may disclose important biologic features of 'YO TCR+ cells. (J AM ACAD DERMATOL 1993;2S:355-60.)
Human T cells recognize antigens with their T-cell receptors (TCR) that are associated with the CD3 polypeptide complex. Most CD3+ peripheral T cells express ex. and {3 chains of TCR, whereas only From the Department of Dermatology, Faculty of Medicine, Kyoto University. Reprint requests: Mayumi Fujita, MD, Department of Dermatology, Faculty of Medicine, Kyoto University, Kyoto, Japan. Copyright © 1993 by the American Academy of Dermatology. 0190-9622/93 $1.00+.10 16/4/39627
approximately 5% express "( and 0 chains.' Because 'Yo TCR+ cells are poorly understood, investigation of a disease associated with 'Yo TCR+ cells may disclose important characteristics of these cells. To date, several "(0 T-cell malignancies have been reported.r" Picker et al.2 reported that among 62 T-cell lineage lymphomas only two TCR-"(o+ neoplasms were identified, both of which were from thymic (Tdymphoblastic) lymphomas. Gaulard et a1. 6 identified 6 TCR "(0+ lymphomas among 57 355
356 Fujita et al.
Fig. 1. Skin with a central crusted nodule on right side of neck.
Journal of the American Academy of Dermatology February 1993
gastrointestinal endoscopy, and bone marrow biopsy specimen showed no abnormalities. A diagnosis of non-Hodgkin's lymphoma (T-cell lineage lymphoma) was made. The patient was treated with prednisone, 40 mg/day, and cyclophosphamide, 100 rng/day, with no effect. Two months later the patient reported dysgraphia, a gait disturbance, vertigo, and tremor of the upper extremities. Computed tomographic scans of the head demonstrated enlarging lesions in the left caudatum and lenticula. One month later, ulcers of the rectum and esophagus were noted. The patient's general condition and skin eruptions worsened and did not respond to chemotherapy. The patient became oliguric and died 6 months later. Permission for an autopsy was refused.
Tissue Studies
cases of peripheral T-cell lymphomas; none of the 6 cases had skin involvement. To the best of our knowledge, only two cases of 'YO T-cell lymphomas of the skin have been reported; one was a Tvlymphoblastic lymphoma that involved mediastinum and skin' and the other showed disseminated pagetoid reticulosis both clinically and histologically.' We report a case of cutaneous 'YO T-cell lymphoma that differs from the two previously reported cases clinically, histologically, and imrnunohistochemically. CASE REPORT A 60-year-old woman had several asymptomatic, erythematous plaques and nodules. Four years previously she had noted an erythematous nodule in her left popliteal region that healed spontaneously with scarring. Other lesions developed on the forearms, neck, and left leg, some of which cleared spontaneously. The patient had a body weight loss of 25 kg during the past year. Physical examination revealed a plum-colored, ulcerated tumor that was 3 em in diameter, had a central crust, and was located on the right side of the neck (Fig. 1). In addition, several nodules and indurated plaques were observed in the axillae and on the extremities. Lymphadenopathy was absent. Results of routine laboratory studies showed an increase in band cells and eosinophils and elevation of C-reactive protein (0.9 rng/dl), lactate dehydrogenase (698 IUjL), creatine phosphokinase (202 IU/L), and -v-globulin (25%). The human T-Iymphotropic virus type I status of the patient was negative. Computed tomographic scans showed moderate splenomegaly, inflammation of the lower lung, and infiltrated masses in the left scapular muscles, pectoral muscles, and breasts. A 67Ga-scintigram showed accumulations in the left thigh, head, and neck. Results of a bone scintigram,
Biopsy specimens obtained from three cutaneous lesions were processed for light microscopic examination, immunohistochemical studies, and DNA analysis. For immunohistochemical studies the specimens were fixed in periodate-lysine-paraformaldehyde solution and stained with avidin-biotin-peroxidase complex, as described previously/ The monoclonal antibodies used in this study are listed in Table 1. For gene analysis, DNA was extracted from the specimens and digested with EcoRI or BamHI, electrophorized, and transferred to a nylon membrane. Southern blot hybridization was performed with EcoRI-HindIII fragments of the C{n region of the T-cell receptor gene." Because T'Y probes were not available when we first observed the patient, DNA was not analyzed for TCR-')' or TCR-o gene rearrangement.
Results Histopathologic examination of the cutaneous tumors showed a perivascular infiltrate of lymphoid cells, histiocytes, eosinophils, and plasma cells in the dermis and subcutaneous tissue (Fig. 2). The walls ofthe vesselswere hypertrophic. Medium- to large-sized atypical lymphoid cells with large hyperchromatic nuclei were scattered throughout the infiltrate. Some nuclei were convoluted or multilobated, and mitotic figures were often observed. No epidermotropism was shown, and a grenz zone was present. Immunohistochemical staining showed that the largesized lymphoid cells had an aberrant T-cell phenotype (CDl-, CD3+, CD4-, CDS-) (Fig. 3, A and B) and variable degrees of activation antigens (HLA-DR+, CD25-/+, CD38-/+), with no expression of B-cell antigen (CD20-) or Ki-I antigen (CD30-). They expressed "/0 TCR (TCRBI +, BTCSI-, BBr, Ti')'A+), but not 0i{3 TCR ({3Fl-) (Fig. 3, C and D). Reactive small-sized lymphoid cells had a helper T-cell phenotype (CD3+,
Journal of the American Academy of Dermatology Volume 28, Number 2, Part 2
Cutaneous T-cell lymphoma expressing 'YO TCRs 357
Fig. 2. Histopathology of the skin lesions. A, Perivascular infiltrates in the dermis and subcutaneous tissue. There is no epidermotropism, and a grenz zone is present. B, Higher magnification of the infiltrates. Medium- to large-sized lymphoid cells with large hyperchromatic nuclei are evident. Some of the nuclei are convoluted or multilobated. (Hematoxylin-eosin stain. A, xSO; B, X400.)
DISCUSSION CD4+) or a suppressor T-cell phenotype (CD3+, CDS+) and expressed a{'JTCR ({'JFI +, TCROl-, oTCSI-, BBr, Ti')'A-). Hybridization with a C{'JI probe disclosed no clonal rearrangement of the TCR-{'J gene. DNA analysis was not performed for TCR-')' or TCR-o gene rearrangement.
Malignant lymphomas of the skin, excluding mycosis fungoides and Sezary syndrome, are heterogeneous clinically, histologically, and immunohistochemically. The most common histologic subtype is diffuse large-cell lymphoma, I 0 and the tumor cells
Journal of the American Academy of Dermatology February 1993
358 Fujita et al.
Fig. 3. Immunohistochemistry of the skin lesions. Large-sized lymphoid cells reactive with anti-CD3 antibody (A) and TCRBI antibody (C) but not with anti-CD4 antibody (B) or I3Fl antibody (D). (Methyl green stain; X400.)
Table I. Monoclonal antibodies used in this study Cluster designation
CDI CD3 CD4 CDS CD20 CD25 CD30
CD38
Antibody
Source
Antigen distribution
OKT6 Leu-4 Leu-3a Leu-2a Bl Anti-Tac Ki-l OKTIO Anti-HLA-DR I3Fl TCRBI BTCSl BB3 TiyA
Ortho* Becton-Dickinsont Becton-Dickinsont Becton-Dickinson] Coulter:j:
Thymocytes, Langerhans cells Pan-T cells (TCR complex) T helper/inducer, monocytes, Langerhans cells T suppressor/cytotoxic, natural killer cells subset Pan-B cells Activated T cells (IL-2 receptor) Activated T and B cells, Reed-Sternberg cells Activated T and B cells Class II MHC antigen Pan-aI3TCR+ cells Pan-'YOTCR+ cells VBl+ cells VB2+ cells V'Y9+ cells
§ Dakopatts] Ortho*
Becton-Dickinson t T-Cell Sciencesf T-Cell Sciencesj] T-Cell Sciences'[' # **
MHC, Major histocompatibility complex. *Ortho Diagnostic Systems, Inc., Raritan, N.J. tBecton Dickinson Immunocytometry Systems, San Jose, Calif. iCoulter Electronics, Hialeah, Fla. §A gift from Dr. T. Uchiyama (Kyoto, Japan). [Dakopatts A/S, Copenhagen, Denmark. ,T·Cell Sciences, Inc., Cambridge, Mass. #A gift from Dr. L. Moretta (Geneva, Italy). **Agift from Dr. T. Hercend (Cedex, France).
express either B or T phenotype. II, 12 However, reports of T-cell lymphoma of the skin expressing 'YO TCR are rare. 5, 7 The case reported by Falini et al.5 was aT-lymphoblastic lymphoma that involved skin and mediastinum and expressed a phenotype of CDl +, CD2+, CD3+, CD4+, CD8+, CD2S+, CD30+, HLA-DR-with 'YO TCRCfJFl-, TCRM +, oTCSl +, BBr). Berti et aI,7 described a patient
with disseminated pagetoid reticulosis in whom the epidermotrophic T-cell infiltrate showed a phenotype of CD 1-, CDr, CD3+, CD4-, CDS-, CD2S-, CD30-, HLA-DR- with yo TCR CI3Fl-, TCRM +, oTCSl-, Ti'YA-, BBr). In this report we have presented a case of cutaneous 'YO T-cell lymphoma that differs from the two previously reported cases in its clinical, histologic,
Journal of the American Academy of Dermatology Volume 28, Number 2, Part 2
and immunohistochemical features. The patient did not have a mediastinal mass, and the neoplastic cells showed no epidermotropism and a phenotype of
CDl-, CD3+, CD4-, CD8-, CD2S- I+, CD30-, CD38-/+, HLA-DR+ and 'YO TCR (,BFl-, TCROl+, oTCSI-, Ti'YA+, BBr).Although molecular studies of TCR'Y and TCRo gene rearrangement were not performed, our phenotypic da ta of the large lymphoid cells and the results of Southern blot analysis showing no rearrangement of TCR-,B gene favor clonality of 'YO TCR+ cells. It is unknown whether the skin was the primary site of the disease, because computed tomographic scans at admission to the hospital showed splenomegaly and masses in muscles. However, the cutaneous nodules developed 4 years before our first examination, which suggests that the skin lesions may be primary. Although the biologic role of 'YO TCR+ cells has not been demonstrated definitively, the limited diversity of the gene l 3, 14 and the unique anatomic distribution 15, 16 suggest that the 'YO TCR+ cells may participate in host defense against the invasion of various pathogens. 17 This is supported by recent reports that 'YO TCR+ cells participate in the immune response to mycobacterial antigens. 1S- 24 However, other studies indicate that 'YO TCR+ cells increase not only in mycobacterial infections, but also in the synovial fluid of patients who have rheumatoid arthritis" and in the gut epithelium of patients who have coeliac disease. 25, 26 The phenotypes of these 'YO TCR+ cells are V02+, V'Y9+ in mycobacterial infection/" and rheumatoid arthritis,21 which is similar to that of most peripheral blood 'YO TCR+ cells, but they are vsr-, vor, V'Y9- in coeliac disease.i" which is consistent with that in the small intestine. The 'Yo TCR+ cells in normal human skin also express VO 1-, V 02+, V'Y9+. 27 In our case, however, the V region gene was V 01-, V V1'9+, which is not consistent with these phenotypes. Possible explanations include the existence of another new phenotype of 'Yo TCR+ cells and a phenotypic change in 'Yo TCR+ cells when they are transformed. In addition, the phenotype in our case was not the same as the two previously reported cases of 'YO T-cell malignancy of the skin" 7
or,
We thank Dr. L. E. Golitz, Denver General Hospital, for his helpful comments about the histologic findings of the patient. We also thank Dr. Koh Nakata for providing monoclonal antibodies, Ms. Fumiko Owatari for technical assistance, and Mr. Arimitsu Hasegawa for photographic works.
Cutaneous T-cell lymphoma expressing 'YO TCRs 359 REFERENCES
1. Raulet DH. The structure, function, and molecular genetics ofthe-y/ 0T cell receptor. Ann Rev Immunol1989;7:175207. 2. Picker LJ, Brenner MB, MichieS, et al. Expression ofT cell receptor delta chains in benign and malignant T lineage lymphoproliferations. Am J Patho11988;132:401-S. 3. Champagne E, Takihara Y, Sagman U, et al, The isolation of the human 'Y chain gene and its expression in normal T cells and T cell leukemias. Leukemia 1988;2:717-2L 4. Griesinger F, Greenberg IN, Kersey 1H. T cell receptor 'Y and {j rearrangements in hematologic malignancies: relationship to lymphoid differentiation. J Clin Invest 1989; 84:506-16. 5. Falini B, Flenghi L, Fagioli M, et aL T-lyrnphoblastic lymphomas expressing the non-disulfide-linked form of the T-cell receptor 'Ylo: characterization with monoclonal antibodies and genotypic analysis. Blood 1989;74:2501-7. 6. Gaulard P, Bourquelot P, Kanavaros P, et al. Expression of the a/f3 and 'Ylf3 T-cell receptors in 57 cases of peripheral T-celllyrnphomas: identification of a subset of "f15 T-cell lymphomas. Am J Pathol /990;137:617-28. 7. Berti E, Cerri A, Cavicchini S, et al. Primary cutaneous 1'/5 T-cell lymphoma presenting as disseminated pagetoid reticulosis. J Invest DermatoI1991;96:718-23. 8. Fujita M, Furukawa F, Horiguchi Y, et aL Regional development of Langerhans cells and formation of Birbeck granules in human embryonic and fetal skin. J Invest DermatoI1991;97:65-72. 9. Southern EM. Detection of specificsequences among DNA fragments separated by gel electrophoresis. J Mol BioI 1975;18:503-17. 10. BurkeJS, Hoppe RT, Cibull M, et al. Cutaneous malignant lymphoma: a pathologic study of 50 cases with clinical analysis of 37. Cancer 1981;47:300-10. 11. Knowles DM II, Halper 1P, Jakobiec FA. The immunologic characterization of 40 extranodallyrnphoid infiltrates: usefulness in distinguishing between benign pseudolymphoma and malignant lymphoma. Cancer 1982;49:232135. 12. Wood GS, Burke JS, Horning S, et al. The immunologic and clinicopathologic heterogeneity of cutaneous lymphomas other than mycosis fungoides. Blood 1983;62:464-72. 13. Saito H, Kranz DM, Takagaki Y, et aL Complete primary structure of a heterodimeric T-cell receptor deduced from cDNA sequences. Nature 1984;309:757-62. 14. Heilig JS, Tonegawa S. Diversity of murine gamma genes and expression in fetal and adult T lymphocytes. Nature 1986;322:836-40. 15. Stingl G, Konig F, Yamada H, et al. Thy1+ dendritic epidermal cells express T3 antigen and the T-cell receptor 0 chain. Proc Nat! Acad Sci USA 1987;84:4586-90. 16. Goodman T, Lefrancois L. Expression of the 'YO T cell receptor on intestinal CD8+ intraepithelial lymphocytes. Nature 1988;336:479-81. 17. Janeway CA, Jones Jr. B, Hayday A.Specificityand function of T cells bearing 'YO receptors. Immunol Today 1988;9:73-6. 18. Janis EM, Kaufmann SHE, Schwartz RH, et aLActivation of T cells in the primary immune response to Mycobacterium tuberculosis. Science 1989;224:713-6. 19. Kabelitz D, Bender A, Schondelmaier S, et al. A large fraction of human peripheral blood 'Y/ 0+ T cells is activated by Mycobacterium tuberculosis but not by its 65-kD heat shock protein. J Exp Med 1990;171:667-79. 20. Happ MP, Kubo RT, Palmer E, et al. Limited receptor
Fujita et al. repertoire in a mycobacteria-reactive subset of "(D T lymphocytes. Nature 1989;342:696-8. 21. Holoshitz H, Konig F, Coligan lE, et al. Isolation ofCD4-, CDS- mycobacteria reactive T lymphocyte clones from rheumatoid arthritis synovial fluid. Nature 1989;339: 226-9.
22. Modlin RL, Pirmetz C, Hofman FM, et al. Lymphocyte bearing antigen-specific 'YO T-cell receptors accumulate in human infectious disease lesions. Nature 1989;339: 544-8. 23. Inoue T, Yoshikai Y, Matsuzaki G, et al. Early appearing 'Y/o..bearing T cells during infection with Calmette Guerin Baccilus. J Immunol1991;146:2754-62. 24. Kabelitz D, Bender A, Prospero T. The primary response of human 'Y/o+ T cells to Mycobacterium tuberculosis is
Journal of the American Academy of Dermatology February 1993
restricted to V'Y 9-bearing cells. J Exp Moo 1991; 173:1331-8. 25. Spencer J, Isaacson PG, Diss TC, et a!. Expression of disulfide-linked and non-disulfide-linked forms of the T cell receptor 'Y/o heterodimer in human intestinal intraepitheliallymphocytes. Eur J Immuno11989;19:1335-8. 26. Trejdosiewicz LK, CalabreseA, Smart CJ, et al. 'YO T cell receptor-positive cells of the human gastrointestinal mucosa: occurrence and V region gene expression in Heliobacter pylori-associated gastritis, coeliac disease and inflammatory bowel disease. Clio Exp Immunol 1991; 84:440-4. 27. Dupuy P, Heslan M, Fraitag S, et a1. T-cell receptor-v/f bearing lymphocytes in normal and inflammatory human skin. J Invest Dermatol 1990;94:764-8.
Necrosis of the hand after extravasation of intravenously administered phenytoin Anne G. Hayes, MD, and Thomas McC. Chesney, MD
Memphis, Tennessee
Extravascular escape of intravenously administered phenytoin can result in serious local soft tissue complications. Injury can range from simple phlebitis to chemical cellulitis or, in extreme cases, frank tissue necrosis that necessitates amputation. The histopathologic findings include extensive necrosis and sloughing of epidermis, widespread necrosis of dermis, subcutaneous tissue, muscles and nerves, and extensive thrombotic occlusion of vessel lumens. Results ofelastic tissue stains reveal thatthe thrombosed vessels are exclusivelyveins and venules. Vascular fibrinoid necrosis, leukocytoclasis, and true inflammatory vasculitis are not features. This is the first detailed report of the histopathologic alterations associated with this therapeutic misadventure. (J AM ACAD DERMATOL 1993;28:360-3.) Although seemingly a simple method of drug delivery, intravenous therapy requires specialized equipment, experienced personnel, and careful observation, 1,2 One risk is the chance misdirection of intravenous infusions. Brown et aP estimated that extravasation occurs in 11% of intravenous infusions in children. Riyami" reported that as many as 22.8% From theDepartments of Pathology and Medicine-Dermatology, University of Tennessee at Memphis and Baptist Memorial Hospital. Partially presented as a poster at theAnnual Meeting oftheAmerican Society of Dermatopathology, Dallas, Tex. Dec. 4-6, 1991. Reprint requests: Thomas McC. Chesney, MD, Baptist Memorial Hospital, Department of Pathology, 899 Madison Ave., Memphis, TN 38146. Copyright @ 1993 by the American Academy of Dermatology. 0190-9622/93 $1.00 +.10 16/4/39626
360
of intravenous infusions in adults result in extravascular escape. Fortunately, most of these incidents are recognized immediately and have little or no ill effect. However, serious local soft-tissue complications can ensue. In extreme cases, extensive tissue necrosis may occur. 1-8 At this time phenytoin is perhaps the most widely used intravenous anticonvulsant agent. Severe extravasation injury from this agent has been reported9- 12 and is mentioned in the Physician's Desk References? Although previous case reports have thoroughly described the clinical findings associated with phenytoin extravasation, the histopathologic features have not been elaborated. A patient at our institution recently developed severe tissue necrosis of the hand as a consequence of