latent inherited disorder or if porokeratoses are acquired marrow transplantation (BMT) for .... paraneoplastic syndrome or associated with immune lesions of ...
Bone Marrow Transplantation, (1997) 19, 77–79 1997 Stockton Press All rights reserved 0268–3369/97 $12.00
Case report Disseminated superficial porokeratosis after autologous bone marrow transplantation B Rio1, C Magana2, A Le Tourneau3 , C Bachmeyer2, V Le´vy1, N Hamont3, J Diebold3 and R Zittoun1 1
Service d’He´matologie; 2Centre de Diagnostic; and 3 Service Central d’Anatomie Pathologique, Hoˆtel-Dieu de Paris, Paris, France
Summary: A case of disseminated superficial porokeratosis (DSP) is reported in a black man 5 years after autologous bone marrow transplantation (BMT) for acute promyelocytic leukemia. Porokeratosis is a rare hyperkeratotic disorder arising from clonal keratinocytes with a high potential to develop squamous cell carcinoma. Inherited forms are classical but recent observations of acquired porokeratosis have been reported in immunocompromized patients (AIDS, immune disorders, immune suppressive drugs or organ transplantation). Two cases of DSP have been reported after allogeneic BMT in patients treated for chronic GVHD. Our case is the first one after autologous BMT, in a black man, on no immunosuppressive drug at the time of diagnosis of DSP. Hematopoietic and immune reconstitution was apparently complete. The cancer-prone character of porokeratosis could be favored by total body irradiation used in conditioning regimen. Thus, porokeratosis has to be associated with other late effects after BMT such as HCV seropositivity, cataract and infertility that were observed in this patient. Keywords: bone marrow transplantation; late effect; secondary malignancy; porokeratosis
The porokeratoses are a group of rare disorders of keratinization, characterized by centrifugally enlarging annular or linear hyperkeratotic plaques. Five clinical variants are recognized: porokeratosis Mibelli, disseminated superficial actinic porokeratosis, porokeratosis palmaris, plantaris and disseminata, linear porokeratosis and punctate porokeratosis.1 The histological hallmark of the different varieties is the cornoid lamella,2 ie a column of parakeratotic cells arising over a shallow depression in the epidermis. Porokeratosis could originate from an abnormal clone of either skin fibroblasts or epidermal keratinocytes,3 with a high potential for malignant transformation into squamous cell carcinoma.4–7 The pathogenesis is not well understood. An autoCorrespondence: Dr B Rio, Service d’He´matologie Hoˆ tel-Dieu, 1 place du Parvis Notre-Dame, 75 004 Paris, France Received 28 December 1995; accepted 17 June 1996
somal dominant mode of transmission has been initially established.1 However, acquired immune deficiency has been associated with porokeratosis8 and can account for 50% of new cases.9 Whether immune deficiency reveals a latent inherited disorder or if porokeratoses are acquired diseases is unknown. In large surveys of organ transplant recipients, porokeratoses developed in 0.65 and 3.5% of patients.10,11 After bone marrow transplantation (BMT), porokeratosis has been reported in two patients who received allogeneic transplants.9,12 We report the first case of disseminated superficial porokeratosis after autologous BMT. Case report Acute promyelocytic leukemia was diagnosed in October 1990, in a 36-year-old black man. The patient gave informed consent to be included in AML8 protocol of the European Organization for Research and Treatment of Cancer (EORTC). The induction course (daunorubicine 3 days and cytosine-arabinoside 7 days) started on 24 October. Complete remission was achieved on 22 November, followed by consolidation course with intermediate doses of cytosine-arabinoside (days 1–6) and amsacrine (days 5–7). The patient was randomized for autologous BMT. Bone marrow was infused on 14 March 1991 after a conditioning regimen combining cyclophosphamide 120 mg/kg and total body irradiation at 10 Gy. Recovery was slow: WBC .1 × 109/l at day +52; ANC .0.5 × 109/l at day +63; platelet .50 × 109/l at day +358. During induction and consolidation courses, the patient developed systemic infection with Clostridium perfringens and Candida tropicalis. After transplant, fever of unknown origin needed empiric antibiotic, antifungal and antituberculosis treatment because of an earlier history of tuberculosis. Hepatitis C virus-associated hepatitis occurred at 3 months post-BMT and resolved in 1 month. At 1 year after transplant, complete remission was effective and the patient returned to Mali in October 1991. Yellow fever antibody titer, induced by vaccination 5 years before BMT, remained efficient. The patient stayed in Africa for 2 years and was lost to follow-up until May 1995. By this time, the patient had developed post-radiation cataracts and infertility. Complete continuous remission was confirmed by blood and marrow
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examination. Transaminases and alkaline phosphatase levels were in the normal range. Hepatitis C virus antibodies were positive for c33c and c22 viral proteins. Antibodies directed against hepatitis B virus, Epstein–Barr virus and cytomegalovirus were positive, whereas serologies for human immunodeficiency virus type 1 and 2 and human Tlymphotropic virus type I were negative. Serum ferritin level was increased at 2446 ng/ml. Immunoglobulin levels were IgG:15.8 g/l, IgA:2.01 g/l, IgM:1.8 g/l without monoclonal component. Lymphocyte count was 1.3 × 109/l and subsets: CD20: 9%, (6% kappa and 3% lambda), CD3: 60% (CD3 +DR+: 8%), CD4: 22%, CD8: 38%. Skin multitests indicated a good response with positivity for candida, tetanus, diphtheria and tuberculus. However, the presence of six asymptomatic superficial lesions 5 mm diameter with a slightly depressed center and a keratotic ridge in the periphery of lesions on each leg led us to suspect a disseminated superficial porokeratosis (Figure 1). Histologic and immunohistochemical studies were processed on a 0.4-cm punch biopsy obtained under local anesthesia. For light microscopy the biopsy was fixed in Bouin’s solution. Paraffin sections were stained with hematoxylin and eosin. Immunohistochemistry was performed with antibodies directed against CD1A (monoclonal antibody (mAb); Immunotech, Marseille, France) and S100 protein (polyclonal antibody, Dako, Trappes, France)
to recognize Langerhans cells, vimentin (mAb; Immunotech) to recognize fibroblasts, Kl1 (mAb; Immunotech) and EMA (mAb; Dako) to recognize epithelial cells, BNH9 (mAb; Immunotech) to recognize endothelial cells, CD30 (mAb; Dako) to recognize ‘activated’ cells and Mib1 (mAb; Immunotech) to identify cycling cells. Histological examination showed the characteristic features of porokeratosis (Figure 2). However, no specificity was observed after immunohistochemistry. Keratinocytes or fibroblasts did not express active proliferation. Langerhans cells were scarcely observed. No important inflammatory infiltrate was found. In December 1995, two lesions occurred on the lumbar region which was not exposed to the sun, and acquired a tumoral appearance. Biopsies confirmed features of intra-epithelial carcinoma.
Figure 1 Three characteristic annular lesions 5 mm diameter on the left leg, with hyperkeratotic ridges and slightly depressed centers.
Figure 2 Skin biopsy: invagination of the epidermis with thin parakeratotic column (haematoxylin-eosin ×100).
Discussion We report the first case of disseminated superficial porokeratosis occurring after autologous BMT. Actinic induction cannot be ruled out. 13–15 The patient has stayed in Mali but the lesions occurred either on sun-exposed or on unexposed areas. However, disseminated superficial porokeratosis is considered as extremely rare in blacks.1,16 The relationship with his underlying disease or its treatment has to be considered. Porokeratosis has been described in patients with hemopathies,8,17–19 either as
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paraneoplastic syndrome or associated with immune depression. When porokeratosis was diagnosed in our patient, blood and bone marrow examination confirmed the continuous complete remission. Immunodeficiency is frequently found as a prelude to the development of porokeratosis. 8 Some reports describe exacerbation associated with immune depression related to chronic lymphocytic leukemia20 and others the complete remission of porokeratosis after withdrawing corticosteroids given for dermatomyositis.21 The two patients observed after allogeneic BMT developed porokeratosis during the treatment of chronic graft-versus-host disease (GVHD).9,12 Five years after autologous BMT, immune reconstitution can be considered as nearly complete. In our patient, immunoglobulin levels and skin multi-tests were in the normal range. Peripheral lymphocyte subsets were characterized by a slightly decreased level of CD4 positive cells. Moreover, active protection against yellow fever was observed without vaccination since the time of BMT. HIV infection has been associated with porokeratosis because of acquired immune deficiency.22 A hypothetical infectious agent has been suggested to be the etiological factor for acquired porokeratoses.23,24 However no report on transmissibility of porokeratosis has been published. Neither donor follow-up nor HIV serology in recipients were available in the two cases of porokeratosis observed after allogeneic BMT.9,12 With immunohistochemistry, Jurecka et al25 recognized many intra-epidermal Langerhans cells in lesions from immunocompromised or nonimmunocompromised patients with porokeratosis. Manganoni et al11 and Kanitakis et al22 demonstrated a complete absence of Langerhans cells. In our patient, Langerhans cells were normally present. We could not observe cycling keratinocytes or fibroblasts. The conditioning regimen before BMT included total body irradiation. Only one patient has been reported to develop porokeratosis after electron beam radiation.26 Xray treatment does not appear to be responsible for the occurrence of porokeratosis. However, X-ray treatment of porokeratosis seems to promote development of squamous cell carcinoma in lesions. 4–7 The risk of second malignancy observed in long-term survivors after BMT is known, particularly basal cell carcinoma of skin.27 The cancer-prone character of porokeratosis means that this disease should be considered to be a premalignant lesion. References 1 Wolff-Schreiner EC. Porokeratosis. In: Fitzpatrick TB, Eisen AZ, Wolff K et al (eds). Dermatology in General Medicine, 4th edn. McGraw-Hill: New York, 1993, pp 565–571. 2 Wade TR, Ackerman AB. Cornoid lamellation: a histologic reaction pattern. Am J Dermatopathol 1980; 2: 5–15. 3 Reed RJ, Leone P. Porokeratosis – a mutant clonal keratosis of the epidermis. Arch Dermatol 1970; 101: 340–347. 4 Taylor A, Harnden D, Fairburn E. Chromosomal instability associated with susceptibility to malignant disease in patients with porokeratosis of Mibelli. J Natl Cancer Inst 1973; 51: 371–378. 5 Schrum JR, Cooper PH, Greer KE et al. Squamous cell carcinoma in disseminated superficial actinic porokeratosis. J Am Acad Dermatol 1982; 6: 58–62.
6 Chernosky ME, Rapini RP. Squamous cell carcinoma in lesions of disseminated superficial actinic porokeratosis. Arch Dermatol 1986; 122: 853–854. 7 Otsuka F, Shima A, Ishibashi Y. Porokeratosis as a premalignant condition of the skin, cytologic demonstration of abnormal DNA ploidy in cells of the epidermis. Cancer 1989; 63: 891–896. 8 Lederman JS, Sober AJ, Lederman GS. Immunosuppression: a cause of porokeratosis. J Am Acad Dermatol 1987; 13: 75–79. 9 Raychaudhuri SP, Smoller BR. Porokeratosis in immunosuppressed and nonimmunosuppressed patients. Int J Dermatol 1992; 31: 781–782. 10 Komorowski RA, Clowry LJ. Porokeratosis of Mibelli in transplant recipients. Am J Clin Pathol 1989; 91: 71–74. 11 Manganoni AM, Faccheti F, Gavazzoni R. Involvement of epidermal Langerhans cells in porokeratosis of immunosuppressed renal transplant recipients. J Am Acad Dermatol 1989; 21: 799–800. 12 Ghigliotti G, Nigro A, Gambini C et al. Porokeratose de Mibelli apre`s une greffe de moelle. Ann Dermatol Venereol 1992; 119: 968–970. 13 Bencini PL, Crosti C, Sala F. Porokeratosis: immunosuppression and exposure to sunlight. Br J Dermatol 1987; 116: 113–116. 14 Neumann RA, Knobler RM, Jurecka W, Gebhart W. Disseminated superficial actinic porokeratosis: experimental induction and exacerbation of skin lesions. J Am Acad Dermatol 1989; 21: 1182–1188. 15 Reymond JL, Beani JC, Amblard P. Superficial actinic porokeratosis in a patient undergoing long-term PUVA therapy. Acta Derm Venereol (Stoch) 1980; 60: 539–540. 16 de Oliveira Filho J, Cutin SL, Cuce LC. Disseminated superficial actinic porokeratosis in a black patient. Arch Dermatol 1986; 122: 852–853. 17 Vire G, Latour D, King LE. Porokeratosis and immunosuppression. J Am Acad Dermatol 1986; 14: 683–684. 18 Nicolas JF, Fauvet N, Kanitakis J et al. Poroke´ratose ‘actinique’ superficielle dissimine´e et immunosuppression: a` propos de deux cas. Nouv Dermatol 1990; 9: 187–188. 19 Luelmo-Aguilar J, Gonzalez-Castro U, Mieras-Barcelo C, Catells-Rodellas A. Disseminated porokeratosis and myelodysplastic syndrome. Dermatology 1992; 184: 289 (letter). 20 Zenarola P, Melillo L, Lomuto M et al. Exacerbation of porokeratosis: a sign of immunodepression. J Am Acad Dermatol 1993; 29: 1035–1036. 21 Tsambaos D, Spiliopoulos T. Disseminated superficial porokeratosis: complete remission subsequent to discontinuation of immunosuppression. J Am Acad Dermatol 1993; 28: 651–652. 22 Kanitakis J, Misery L, Nicolas JF et al. Disseminated superficial porokeratosis in a patient with AIDS. Br J Dermatol 1994; 131: 284–289. 23 Macmillan AL, Roberts SOB. Porokeratosis after renal transplantation. Br J Dermatol 1974; 90: 45–51. 24 Foulds IS, Slater DN. Porokeratosis of Mibelli and immune complex glomerulonephritis. Clin Exp Dermatol 1983; 8: 69–75. 25 Jurecka W, Neumann RA, Knobler RM. Porokeratoses: immunohistochemical, light and electron microscopic evaluation. J Am Acad Dermatol 1991; 24: 96–101. 26 Halper S, Medinica M. Porokeratosis in a patient treated with total body electron beam radiation. J Am Acad Dermatol 1990; 23: 754–755. 27 Socie´ G, Ko¨lb HJ on behalf of the EBMT Late-Effects Working Party. Malignant diseases after bone marrow transplantation: the case for tumor banking and continued reporting to registries. Bone Marrow Transplant 1995; 16: 493–495.
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