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Lymphomatoid granulomatosis
!
Lymphomatoid granulomatosis Melinda M. Tong, MB, BS, Bridget Cooke, MB, BS, F R C P A , and Ross St.C. Barnetson, MD, F R C P , FRACP, F A C D Sydney, Australia Lymphomatoid granulomatosis or angiocentric T-cell lymphoma is a systemic disease that affects multiple organs. The histopathologic findings include a characteristic infiltrate that is both angiocentric and angiodestructive. The prognosis is poor but may be improved by early recognition and aggressive chemotherapy. We report a case of cutaneous lymphomatoid granulomatosis and emphasize that dermatologists play an important role in the early diagnosis of this disease. (J AM ACAD DERMATOL1992;27:872-6.) Lymphomatoid granulomatosis (angiocentric T-celI lymphoma) is characterized by an angiocentric lymphohistiocytic process that primarily involves the lung. It frequently shows extrapulmonary manifestations when first seen and is of great dermatologic interest because cut aneous lesions have been reported in as many as 40% to 45% of cases, l, 2 Because the diagnosis rests on histopathologic examination, a skin biopsy m a y spare the patient further invasive procedures. This report emphasizes that cutaneous lesions m a y often be the only apparent feature of lymphomatoid granulomatosis and that early recognition and treatment m a y lead to complete remission of tile disease)
Fig. 1. Red annular plaque in right preauricular region of face.
CASE REPORT
A 42-year-old Chinese man had a 2-year history of a red, mildly itchy annular plaque in the right preauricular region (Fig. 1). Eighteen months before examination he developed cicatricial alopecia of the scalp (Fig. 2), and 6 months later a red annular plaque appeared on his right upper back. The plaque on his face measured 5 cm across, and the plaque on his back was 3 cm across. The remainder of the physical examin ation was unremarkable except for a firm, mobile preauricular node (1 • 0.5 cm). The onlysignificant information from his past medical history was that he had pulmonary tuberculosis as a teenager. A chest x-ray film demonstrated a small, calcified lesion in the apex of the left lung. Results of a computerized tomographic scan of his chest and abdomen were normal, apart from one enlarged paraaortic node that was
From the Departments of Dermatology and Anatomical Pathology, Royal Prince Affred Hospital. Reprint requests: Ross St.C. Barnetson, MD, Department of Dermatology, Royal Prince Alfred Hospital, Camperdown 2050, Sydney, Australia. 161"4/36891
872
probably of no significance. Findings of skin biopsy specimens from the right preauricular region, scalp, and right upper back were consistent with a diagnosis of lymphomatoid granulomatosis. Results of a surgical biopsy specimen from the left postauricular lymph node showed only reactive follicular hyperplasia. A complete blood cell count demonstrated the trait of a-thalassemia. Electrolytes and results of renal and liver function tests were all normal. Sputum was negative for acid-fast bacilli, and results of a Mantoux test were positive and showed erythema and induration (1.5 • 1.5 cm). Findings of immunologic studies (immunoglobulins, complement levels, antinuclear antibody, DNA, and extractable nuclear antigens) were all normal. The ratio of T4 to T8 cells was normal. Because of the aggressive nature of lymphomatoid granulomatosis and its poor prognosis if left untreated, the patient was given oral cyclophospharnide, 100 mg daily, and prednisone, 40 mg daily. He was also given prophylactic treatment for tuberculosis with isoniazid, 300 mg daily, rifampicin, 600 mg daily, and pyridoxine, 50 mg daily, because of immunosuppression from the
Volume 27 Number 5, Part 2 November 1992
Lymphomatoid granulomatosis 873
Fig. 2. Erythematous areas of scalp with cicatricial alopecia.
Fig. 3. Dense mid-dermal infiltrate centered on and involving the walls of blood vessels. (Hematoxylin-eosin stain; •
chemotherapy. Three months after therapy he has had some hair growth on the scalp, and the facial lesion has regressed significantly.Filmfrom a repeat chest x-ray has revealed no change, and the patient has remained without symptoms. Formalin-fixed, paraffin-embedded hematoxylin and eosin-stained sections from two biopsy specimens were examined histologically. The first biopsy specimen, which was taken from the lesion on the face, showed a nodular perivascular infiltrate in the mid dermis (Fig. 3). The infiltrate was predominantly lymphocytic and included occasional large, atypical cells. Infiltration of blood vessel walls with involvement of the intima was discovered. In the second biopsy specimen, which was taken from the scalp, the infiltrate was much denser and was both perivascular and periadnexal with involvement of the pilosebaceous units. The infiltrate extended into the subcutis and was also predominantly lymphocytic. Large, abnormal lymphoid cells with vesicular nuclei, prominent nucleo[i, and a moderate amount of cytoplasm were more easily identified (Fig. 4). Angiocentricity was less apparent than in the first biopsy specimen. As no fresh tissue was received for marker studies, immunohistochemical tests were performed on formalinfixed sections of the second biopsy specimen. A pan-B
lymphocyte marker (L26, Dako Corp., Carpenteria, Calif.) was used, in addition to a pan-T lymphocyte marker (CD3, Dako Corp.), a T4 lymphocyte marker (OPD4, Dako Corp.) and leukocyte common antigen (Dako Corp.). A small number of the large abnormal cells stained weakly for the pan-T lymphocyte marker and for the T4 marker. These cells were negative for the pan-B lymphocyte marker. DISCUSSION Lymphomatoid granulomatosis was first described by Liebow et al. in 1972. l It is an uncommon systemic disease that usually appears in middle age (although it has been reported in a 7-year-old boy) 4 with bilateral pulmonary infiltrates. The most common symptoms are a cough, shortness of breath, and chest pain, which reflect the pulmonary involvement, and fever, weight loss, malaise, and myalgia. Extrapulmonary manifestations occur in the skin (45%), kidney (32%), and central nervous system (30%). The male to female ratio is 2 to 1. The prognosis is poor, and patients with this disease have a high mortality rate (70% to 90%), which is attributed most often to respiratory failure. 1,2
874
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Journal of the American Academy of Dermatology
Fig. 4. The infiltrate includes plasma cells, small and large irregular lymphocytes,and immunoblasts. (Hematoxylin-eosin stain; x480.) Skin lesions may be the first sign that is observed in up to 20% of cases, and skin lesions have been reported to occur before the development of lung lesions in I0% to 15% of cases. 5,6 The cutaneous manifestations are protean; papules, nodules, ulceration, vesicles, ichthyosis, alopecia, annular plaques with central clearing, anhidrosis, 5-8 and necrobiosis lipoidica-like lesions9 have all been reported. The differential diagnosis includes granuloma annulare, sarcoidosis, leprosy, cutaneous systemic lupus erythematosus, mycosis fungoides, and leukemia cutis.6. 8 Skin lesions may precede (by up to 9 years), occur simultaneously with, or follow pulmonary involvement; they may be transient, even when left untreated. 5 Skin involvement is usually asymptomatic and does not affect the prognosis. In one study 61% of the patients with skin lesions and pulmonary disease died; in comparison, 66% of the patients without skin involvement died. 2 This finding is in contrast to the implications of neurologic manifestations, which are a grave prognostic sign (86% of patients with central nervous system involvement died; the median time of survival was approximately 14 months, regardless of treatment). 2 Certain factors that are believed to be of prognostic value have been identified in a review of 152 cases by Katzenstein et al.2: disease onset at an early age (<25 years), increased white blood cell count, neurologic involvement, hepatomegaly, and large numbers of atypical lymphoreticular cells in biopsy Specimens are poor prognostic signs, whereas patients who have
unilateral, asymptomatic lung lesions and biopsy specimens that show few atypical cells have a favorable prognosis. 2 The question of whether lymphomatoid granulomatosis is a separate benign disorder that may be complicated by lymphoma or a lymphoma from inception has been much debated. The debate developed because it was observed that lymphomatoid granulomatosis apparently "evolved" into malignant lymphoma in 13% to 18% of patients, 1,2 whereas in others the simultaneous appearance of both was noted) It is currently believed that a continuum exists that ranges from the more benign Iymphomatoid granulomatosis to malignant lymphoma.3, 4 The term angiocentric immunoproliferative lesion or angiocentric T-cell lymphorna has been suggested by Jaffe 1~to cover the spectrum, and many consider lymphomatoid granulomatosis to be a histologic variant of cutaneous T-cell lymphoma. l l, 12 Architecturally a characteristic perivascular infiltrate invades and destroys both small veins and arteries, which leads to necrosis of normal tissue and of tumor. The cytologic features of the infiltrate are both polymorphic (including benign and malignant cells) and pleomorphic, which may obscure a diagnosis of malignancy.4, 6 Histologic grading has been performed by Lipford et al. 13on the basis of the degree of cytologic atypia and is of value in predicting outcome. Group I has little or no cell atypia, group II has moderate atypia, and group III has overt angiocentric lymphoma, which is subclassified
Volume 27 Number 5, Part 2 November 1992
into diffuse, mixed ceil, or large cell. 13 Monoclonal antibodies have demonstrated T cells in lymphomatold granulomatosis, particularly of the T4 subset,6, 14 and clonal rearrangement of the T-cell receptor B-chain gene has been reported. 15, 16 Donner et al. 17have recently reported the occurrence of a clone of chromosomally abnormal cells in a patient, which is further evidence of the neoplastic character of the disease; however, they were unable to establish the lineage of the lymphoproliferative process. Other clinical evidence for malignancy include the findings that lymphomatoid granulomatosis disseminates to multiple organs and that more than two thirds of patients have a poor prognosis, with a median survival of 14 months despite treatment. 2 The pathogenesis of lymphomatoid granulomatosis remains unclear. Abnormal immunoregulation and T-cell dysfunction in particular have been postulated, given the findings of abnormalities of serum immunoglobulins, decreased in vitro lymphocyte responsiveness to antigens and mitogens, and changes in T lymphocyte subset populations; however, it is not certain whether these findings are primary or secondary events. 18 In two patients lymphomatoid granulomatosis developed in the setting of long-term, iatrogenically-induced immune suppression: one patient had undergone a renal transplant,19 and one was being treated for pemphigus. 2~ Six cases of lymphomatoid granulomatosis have been reported in human immunodeficieney virusinfected patients, and two had painful, ulcer-like lesions of the oral and esophageal mucosa. 21 The possibility that an oncogenic viral infection such as the Epstein-Barr virus or the human T-lymphotropic virus type 1 is the etiologic agent has been postulated, but is difficult to substantiate. 22, 23 Retrospective studies have suggested a poor prognosis, particularly in patients who have systemic involvement. 1,2 In the study by Katzenstein et al. 2 94% of patients were dead within 3 years. 2 No conclusive treatment regime has been established, although a prospective study by Fauci et al.3suggested that prompt treatment with cyclophosphamide and prednisone in the early phases of the disease may lead to prolonged remissions) Others have reported the importance and success of aggressive combination chemotherapy. 16,24 Successful remission that was induced by adjunctive radiotherapy has been reported,16, 25 and Bernstein et al.26 have described a 16-year-old boy with tymphomatoid granuloma-
Lymphomatoid granulomatosis 875 tosis who was successfully treated by allogeneic bone marrow transplantation, which is the first such case to be reported. Patients who had extensive systemic disease at diagnosis had a rapid downhill course despite treatment; the common causes of death were respiratory failure, pulmonary hemorrhage, and central nervous system involvement) Lymphoma ultimately developed in approximately 20% of patients.2, 5 Early, aggressive therapy has an important role in improving prognosis)' 6, 16 Initial complete remission has been reported by Lipford et al) 6 to be the most important prognostic indicator. Recognition of lymphomatoid granulomatosis and prompt treatment of a patient with only cutaneous manifestations may spare the patient further invasive investigations and lead to complete remission and an improved opportunity for survival. REFERENCES 1. Liebow AA, Carrington CRB, Friedman PL Lymphomatold granulomatosis. Hum Pathol 1972;3:457-558. 2. Katzenstein A-LA, Carrington CB, Liebow AA. Lymphomatoid granulomatosis: a clinicopathologic study of 152 cases. Cancer 1979;43:360-73. 3. Fauci AS, Haynes BF, Costa J, et al. Lymphomatoid granulomatosis: prospective clinical and therapeutic experience over 10 years. N Engl J Meal 1982;306:68-74. 4. Scully RE, Mark E J, McNeely WF, et al. Case records of the Massachusetts General Hospital. N Engl J Med 1987; 317:879-90. 5. James WD, Odom RB, Katzenstein A-LA. Cutaneous manifestations of lymphomatoid granulomatosis. Arch Dermatol 198t;117:196-202. 6. Jambrosic J, From L, Assaad DA, et al. Lymphomatoid granulomatosis. J AM ACAD DERMATOL 1987;17:621-31. 7. Wood ML, Harrington CI, Slater DN, et al. Cutaneous lymphomatoid granulomatosis: a rare cause of recurrent skin ulceration. Br J Dermatol 1984;110:619-25. 8. BrodeU RT, Miller CW, Eisen AZ. Cutaneous lesions of lymphomatoid granulomatosis. Arch Dermatol 1986; 122:303-6. 9. Akagi M, Taniguchi S, Ozaki M, et al. Necrobiosis lipoidica-like skin manifestations in lymphomatoid granulomatosis (Liebow). Dermatologica 1987; 174:84-92. 10. Jaffe E. Pathologic and clinical spectrum of post-thymic T-cell malignancies. Cancer Invest 1984;2:413-26. 11. Weis JW, Winter MW, Phyliky RL, et al. Peripheral T-cell lymphomas:histologic, immunohistologic, and c[inicalcharacterization. Mayo Clin Proe 1986;61:411-26. 12. Colby TV, Carrington CRB. Pulmonary lymphomas: current concepts. Hum Pathol 1983;14:884-7. 13. Lipford E, Margofick J, Cossman J, et al. Lymphomatoid grannlomatosis and angiocentric lymphoma: a spectrum of post-thymic T-cell proliferations [Abstract]. Lab Invest 1986;54:37A. 14. Petras RE, Sebek BA, Tubbs RR. Irnmunomorphology of lymphomatoid granulomatosis [Abstract]. Am J Clin Pathol 1981;76:354. 15. Bleiweiss I J, Strauchen JA. Lymphomatoid granutomatosis of the lung: report of a case and gene rearrangement studies. Hum Pathol 1988;19:1 t09-12.
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Journal of the American Academy of Dermatology
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16. Lipford EH, Margolick JB, Longo DL, et al. Angiocentrie immunoproliferative lesions: a clinicopathologie spectrum of post-thymic T cell proliferations. Blood 1988;72:167481. 17. Donner LR, Dobin S, Harrington D, et al. Angiocentric immunoproliferative lesion (lymphomatoid granulomatosis): a cytogenetic,immunophenotypic,and genotypicstudy. Cancer 1990;65:249-54. 18. SordilloPP, Epremian B, Koziner B, et al. Lymphomatoid granulomatosis: an analysis of clinical and immunologic characteristics. Cancer 1982;49:2070-6. 19. Walter M, Thomson NM, DowlingJ, et al. Lymphomatoid granulomatosis in a renal transplant recipient. Aust N Z J Meal 1979;9:434-6. 20. Jauregui HO. Lymphomatoid granuloma•osis after imrnunosuppression for pemphigus. Arch Dermatol 1978; 114:1052-5.
21. Dover JS, Johnson RA. Cutaneous manifestations of human immunodeficiencyvirus infection. Arch Dermatol 1991;127:1549-58. 22. Veltri RW, Raich PC, McClung JE, et al. Lymphomatoid granulomatosis and Epstein-Barr virus. Cancer 1982; 50:1513-7. 23. McNutt NS, Smoller BR, Kline M, et al. Angiocentric T-cell lymphoma associatedwith human T-celllymphotropic virus type I infection. Arch Pathol Lab Med 1990; 114:170-5. 24. JenkinsTR, ZaloznikAJ. Lymphomatoidgranulomatosis: a casefor aggressivetherapy. Cancer 1989;64:1362-5. 25. Nair BD, JosephMG, Carton GE, et al. Radiation therapy in lymphomatoid granulomatosis. Cancer 1989;64:821-4. 26. Bernstein ML, Reece E, de Chadarevian J-P, et al. Bone marrow transplantation in lymphomatoid granulomatosis: report of a case. Cancer 1986;58:969-72. IIIIII
Human papillomavirus type 6 infection involving cutaneous nongenital sites Andrew Blauvelt, M D , Ana M. Duarte, M D , Chulaporn Pruksachatkunakorn, MD, Craig L. Leonardi, M D , and Lawrence A. Schachner, M D Miami, Florida Human papillomavirus (HPV) type 6 is classically considered a mucosatropic virus. Interestingly, clinical manifestations of HPV 6 infection that involve nonmucosal or nongenital sites have rarely been described. The reasons for this site specific infectivity ofHPV 6 are unknown. We describe a patient who had condylomata acuminata-like lesions that involved cutaneous nongenital sites; HPV 6 DNA was detected in skin biopsy specimens with use of the polymerase chain reaction, followed by hybridization with use of type-specific DNA probes. (J AM AeAD DERMATOL 1992;27:876-9.) The h u m a n papillomaviruses (HPVs) are speciesspecific, double-stranded D N A viruses. More than 66 H P V genotypes have been identified and cloned. Each type is classified into one of three distinct clinical groups: those that involve the mucosa, those that infect nongenital cutaneous sites, and those found in the setting of epidermodysplasia verruciforrnis. H P V type 6 is classically considered a mucosatropic virus. It is the most common H P V type found in condylomata acuminata (genital warts).1,2 In addition, H P V 6 has been isolated in papillomas that involve the conjunctivae, 3 oral mucosa, 4 and upper bronchopulmonary tract. 4,6 Interestingly, From the Department of Dermatologyand CutaneousSurgery,Universityof Miami Seheolof Medicine. Reprint requests: LawrenceA. Schachner, MD, Departmentof Dermatologyand Cutaneous Surgery, Universityof Miami School of Medicine,P.O. Box 016250, Miami, FL 33101. 16/4/36892
clinical manifestations of H P V 6 infection that involve nonmucosal or nongenital sites have rarely been described. 7 The reasons for this site specific infectivity of H P V 6 are unknown. W e describe a patient who had condylomata acuminata-like lesions that involved cutaneous nongenital sites; H P V 6 D N A was detected in skin biopsy specimens from this patient with use of the polymerase chain reaction (PCR), followed by dot-blot hybridization. CASE REPORT A 9-year-old black gir! had a 3-year history of asymptomatic growths on the arms and legs. Her medical history was significant fQr atopic dermatitis and asthma of many years' duration. The patient's mother died from complications that resulted from sickle cell disease, and the identity of the patient's father was not known. The girl was now living with her maternal grandmother, who reported no history of cutaneous or genital warts in friends or family members, although these close contacts had not
Lymphomatoid granulomatosis Melinda M. Tong, MB, BS, Bridget Cooke, MB, BS, F R C P A , and Ross St.C. Barnetson, MD, F R C P , FRACP, F A C D Sydney, Australia Lymphomatoid granulomatosis or angiocentric T-cell lymphoma is a systemic disease that affects multiple organs. The histopathologic findings include a characteristic infiltrate that is both angiocentric and angiodestructive. The prognosis is poor but may be improved by early recognition and aggressive chemotherapy. We report a case of cutaneous lymphomatoid granulomatosis and emphasize that dermatologists play an important role in the early diagnosis of this disease. (J AM ACAD DERMATOL1992;27:872-6.) Lymphomatoid granulomatosis (angiocentric T-celI lymphoma) is characterized by an angiocentric lymphohistiocytic process that primarily involves the lung. It frequently shows extrapulmonary manifestations when first seen and is of great dermatologic interest because cut aneous lesions have been reported in as many as 40% to 45% of cases, l, 2 Because the diagnosis rests on histopathologic examination, a skin biopsy m a y spare the patient further invasive procedures. This report emphasizes that cutaneous lesions m a y often be the only apparent feature of lymphomatoid granulomatosis and that early recognition and treatment m a y lead to complete remission of tile disease)
Fig. 1. Red annular plaque in right preauricular region of face.
CASE REPORT
A 42-year-old Chinese man had a 2-year history of a red, mildly itchy annular plaque in the right preauricular region (Fig. 1). Eighteen months before examination he developed cicatricial alopecia of the scalp (Fig. 2), and 6 months later a red annular plaque appeared on his right upper back. The plaque on his face measured 5 cm across, and the plaque on his back was 3 cm across. The remainder of the physical examin ation was unremarkable except for a firm, mobile preauricular node (1 • 0.5 cm). The onlysignificant information from his past medical history was that he had pulmonary tuberculosis as a teenager. A chest x-ray film demonstrated a small, calcified lesion in the apex of the left lung. Results of a computerized tomographic scan of his chest and abdomen were normal, apart from one enlarged paraaortic node that was
From the Departments of Dermatology and Anatomical Pathology, Royal Prince Affred Hospital. Reprint requests: Ross St.C. Barnetson, MD, Department of Dermatology, Royal Prince Alfred Hospital, Camperdown 2050, Sydney, Australia. 161"4/36891
872
probably of no significance. Findings of skin biopsy specimens from the right preauricular region, scalp, and right upper back were consistent with a diagnosis of lymphomatoid granulomatosis. Results of a surgical biopsy specimen from the left postauricular lymph node showed only reactive follicular hyperplasia. A complete blood cell count demonstrated the trait of a-thalassemia. Electrolytes and results of renal and liver function tests were all normal. Sputum was negative for acid-fast bacilli, and results of a Mantoux test were positive and showed erythema and induration (1.5 • 1.5 cm). Findings of immunologic studies (immunoglobulins, complement levels, antinuclear antibody, DNA, and extractable nuclear antigens) were all normal. The ratio of T4 to T8 cells was normal. Because of the aggressive nature of lymphomatoid granulomatosis and its poor prognosis if left untreated, the patient was given oral cyclophospharnide, 100 mg daily, and prednisone, 40 mg daily. He was also given prophylactic treatment for tuberculosis with isoniazid, 300 mg daily, rifampicin, 600 mg daily, and pyridoxine, 50 mg daily, because of immunosuppression from the
Volume 27 Number 5, Part 2 November 1992
Lymphomatoid granulomatosis 873
Fig. 2. Erythematous areas of scalp with cicatricial alopecia.
Fig. 3. Dense mid-dermal infiltrate centered on and involving the walls of blood vessels. (Hematoxylin-eosin stain; •
chemotherapy. Three months after therapy he has had some hair growth on the scalp, and the facial lesion has regressed significantly.Filmfrom a repeat chest x-ray has revealed no change, and the patient has remained without symptoms. Formalin-fixed, paraffin-embedded hematoxylin and eosin-stained sections from two biopsy specimens were examined histologically. The first biopsy specimen, which was taken from the lesion on the face, showed a nodular perivascular infiltrate in the mid dermis (Fig. 3). The infiltrate was predominantly lymphocytic and included occasional large, atypical cells. Infiltration of blood vessel walls with involvement of the intima was discovered. In the second biopsy specimen, which was taken from the scalp, the infiltrate was much denser and was both perivascular and periadnexal with involvement of the pilosebaceous units. The infiltrate extended into the subcutis and was also predominantly lymphocytic. Large, abnormal lymphoid cells with vesicular nuclei, prominent nucleo[i, and a moderate amount of cytoplasm were more easily identified (Fig. 4). Angiocentricity was less apparent than in the first biopsy specimen. As no fresh tissue was received for marker studies, immunohistochemical tests were performed on formalinfixed sections of the second biopsy specimen. A pan-B
lymphocyte marker (L26, Dako Corp., Carpenteria, Calif.) was used, in addition to a pan-T lymphocyte marker (CD3, Dako Corp.), a T4 lymphocyte marker (OPD4, Dako Corp.) and leukocyte common antigen (Dako Corp.). A small number of the large abnormal cells stained weakly for the pan-T lymphocyte marker and for the T4 marker. These cells were negative for the pan-B lymphocyte marker. DISCUSSION Lymphomatoid granulomatosis was first described by Liebow et al. in 1972. l It is an uncommon systemic disease that usually appears in middle age (although it has been reported in a 7-year-old boy) 4 with bilateral pulmonary infiltrates. The most common symptoms are a cough, shortness of breath, and chest pain, which reflect the pulmonary involvement, and fever, weight loss, malaise, and myalgia. Extrapulmonary manifestations occur in the skin (45%), kidney (32%), and central nervous system (30%). The male to female ratio is 2 to 1. The prognosis is poor, and patients with this disease have a high mortality rate (70% to 90%), which is attributed most often to respiratory failure. 1,2
874
Tong et al.
Journal of the American Academy of Dermatology
Fig. 4. The infiltrate includes plasma cells, small and large irregular lymphocytes,and immunoblasts. (Hematoxylin-eosin stain; x480.) Skin lesions may be the first sign that is observed in up to 20% of cases, and skin lesions have been reported to occur before the development of lung lesions in I0% to 15% of cases. 5,6 The cutaneous manifestations are protean; papules, nodules, ulceration, vesicles, ichthyosis, alopecia, annular plaques with central clearing, anhidrosis, 5-8 and necrobiosis lipoidica-like lesions9 have all been reported. The differential diagnosis includes granuloma annulare, sarcoidosis, leprosy, cutaneous systemic lupus erythematosus, mycosis fungoides, and leukemia cutis.6. 8 Skin lesions may precede (by up to 9 years), occur simultaneously with, or follow pulmonary involvement; they may be transient, even when left untreated. 5 Skin involvement is usually asymptomatic and does not affect the prognosis. In one study 61% of the patients with skin lesions and pulmonary disease died; in comparison, 66% of the patients without skin involvement died. 2 This finding is in contrast to the implications of neurologic manifestations, which are a grave prognostic sign (86% of patients with central nervous system involvement died; the median time of survival was approximately 14 months, regardless of treatment). 2 Certain factors that are believed to be of prognostic value have been identified in a review of 152 cases by Katzenstein et al.2: disease onset at an early age (<25 years), increased white blood cell count, neurologic involvement, hepatomegaly, and large numbers of atypical lymphoreticular cells in biopsy Specimens are poor prognostic signs, whereas patients who have
unilateral, asymptomatic lung lesions and biopsy specimens that show few atypical cells have a favorable prognosis. 2 The question of whether lymphomatoid granulomatosis is a separate benign disorder that may be complicated by lymphoma or a lymphoma from inception has been much debated. The debate developed because it was observed that lymphomatoid granulomatosis apparently "evolved" into malignant lymphoma in 13% to 18% of patients, 1,2 whereas in others the simultaneous appearance of both was noted) It is currently believed that a continuum exists that ranges from the more benign Iymphomatoid granulomatosis to malignant lymphoma.3, 4 The term angiocentric immunoproliferative lesion or angiocentric T-cell lymphorna has been suggested by Jaffe 1~to cover the spectrum, and many consider lymphomatoid granulomatosis to be a histologic variant of cutaneous T-cell lymphoma. l l, 12 Architecturally a characteristic perivascular infiltrate invades and destroys both small veins and arteries, which leads to necrosis of normal tissue and of tumor. The cytologic features of the infiltrate are both polymorphic (including benign and malignant cells) and pleomorphic, which may obscure a diagnosis of malignancy.4, 6 Histologic grading has been performed by Lipford et al. 13on the basis of the degree of cytologic atypia and is of value in predicting outcome. Group I has little or no cell atypia, group II has moderate atypia, and group III has overt angiocentric lymphoma, which is subclassified
Volume 27 Number 5, Part 2 November 1992
into diffuse, mixed ceil, or large cell. 13 Monoclonal antibodies have demonstrated T cells in lymphomatold granulomatosis, particularly of the T4 subset,6, 14 and clonal rearrangement of the T-cell receptor B-chain gene has been reported. 15, 16 Donner et al. 17have recently reported the occurrence of a clone of chromosomally abnormal cells in a patient, which is further evidence of the neoplastic character of the disease; however, they were unable to establish the lineage of the lymphoproliferative process. Other clinical evidence for malignancy include the findings that lymphomatoid granulomatosis disseminates to multiple organs and that more than two thirds of patients have a poor prognosis, with a median survival of 14 months despite treatment. 2 The pathogenesis of lymphomatoid granulomatosis remains unclear. Abnormal immunoregulation and T-cell dysfunction in particular have been postulated, given the findings of abnormalities of serum immunoglobulins, decreased in vitro lymphocyte responsiveness to antigens and mitogens, and changes in T lymphocyte subset populations; however, it is not certain whether these findings are primary or secondary events. 18 In two patients lymphomatoid granulomatosis developed in the setting of long-term, iatrogenically-induced immune suppression: one patient had undergone a renal transplant,19 and one was being treated for pemphigus. 2~ Six cases of lymphomatoid granulomatosis have been reported in human immunodeficieney virusinfected patients, and two had painful, ulcer-like lesions of the oral and esophageal mucosa. 21 The possibility that an oncogenic viral infection such as the Epstein-Barr virus or the human T-lymphotropic virus type 1 is the etiologic agent has been postulated, but is difficult to substantiate. 22, 23 Retrospective studies have suggested a poor prognosis, particularly in patients who have systemic involvement. 1,2 In the study by Katzenstein et al. 2 94% of patients were dead within 3 years. 2 No conclusive treatment regime has been established, although a prospective study by Fauci et al.3suggested that prompt treatment with cyclophosphamide and prednisone in the early phases of the disease may lead to prolonged remissions) Others have reported the importance and success of aggressive combination chemotherapy. 16,24 Successful remission that was induced by adjunctive radiotherapy has been reported,16, 25 and Bernstein et al.26 have described a 16-year-old boy with tymphomatoid granuloma-
Lymphomatoid granulomatosis 875 tosis who was successfully treated by allogeneic bone marrow transplantation, which is the first such case to be reported. Patients who had extensive systemic disease at diagnosis had a rapid downhill course despite treatment; the common causes of death were respiratory failure, pulmonary hemorrhage, and central nervous system involvement) Lymphoma ultimately developed in approximately 20% of patients.2, 5 Early, aggressive therapy has an important role in improving prognosis)' 6, 16 Initial complete remission has been reported by Lipford et al) 6 to be the most important prognostic indicator. Recognition of lymphomatoid granulomatosis and prompt treatment of a patient with only cutaneous manifestations may spare the patient further invasive investigations and lead to complete remission and an improved opportunity for survival. REFERENCES 1. Liebow AA, Carrington CRB, Friedman PL Lymphomatold granulomatosis. Hum Pathol 1972;3:457-558. 2. Katzenstein A-LA, Carrington CB, Liebow AA. Lymphomatoid granulomatosis: a clinicopathologic study of 152 cases. Cancer 1979;43:360-73. 3. Fauci AS, Haynes BF, Costa J, et al. Lymphomatoid granulomatosis: prospective clinical and therapeutic experience over 10 years. N Engl J Meal 1982;306:68-74. 4. Scully RE, Mark E J, McNeely WF, et al. Case records of the Massachusetts General Hospital. N Engl J Med 1987; 317:879-90. 5. James WD, Odom RB, Katzenstein A-LA. Cutaneous manifestations of lymphomatoid granulomatosis. Arch Dermatol 198t;117:196-202. 6. Jambrosic J, From L, Assaad DA, et al. Lymphomatoid granulomatosis. J AM ACAD DERMATOL 1987;17:621-31. 7. Wood ML, Harrington CI, Slater DN, et al. Cutaneous lymphomatoid granulomatosis: a rare cause of recurrent skin ulceration. Br J Dermatol 1984;110:619-25. 8. BrodeU RT, Miller CW, Eisen AZ. Cutaneous lesions of lymphomatoid granulomatosis. Arch Dermatol 1986; 122:303-6. 9. Akagi M, Taniguchi S, Ozaki M, et al. Necrobiosis lipoidica-like skin manifestations in lymphomatoid granulomatosis (Liebow). Dermatologica 1987; 174:84-92. 10. Jaffe E. Pathologic and clinical spectrum of post-thymic T-cell malignancies. Cancer Invest 1984;2:413-26. 11. Weis JW, Winter MW, Phyliky RL, et al. Peripheral T-cell lymphomas:histologic, immunohistologic, and c[inicalcharacterization. Mayo Clin Proe 1986;61:411-26. 12. Colby TV, Carrington CRB. Pulmonary lymphomas: current concepts. Hum Pathol 1983;14:884-7. 13. Lipford E, Margofick J, Cossman J, et al. Lymphomatoid grannlomatosis and angiocentric lymphoma: a spectrum of post-thymic T-cell proliferations [Abstract]. Lab Invest 1986;54:37A. 14. Petras RE, Sebek BA, Tubbs RR. Irnmunomorphology of lymphomatoid granulomatosis [Abstract]. Am J Clin Pathol 1981;76:354. 15. Bleiweiss I J, Strauchen JA. Lymphomatoid granutomatosis of the lung: report of a case and gene rearrangement studies. Hum Pathol 1988;19:1 t09-12.
876
Journal of the American Academy of Dermatology
Tong et al.
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Human papillomavirus type 6 infection involving cutaneous nongenital sites Andrew Blauvelt, M D , Ana M. Duarte, M D , Chulaporn Pruksachatkunakorn, MD, Craig L. Leonardi, M D , and Lawrence A. Schachner, M D Miami, Florida Human papillomavirus (HPV) type 6 is classically considered a mucosatropic virus. Interestingly, clinical manifestations of HPV 6 infection that involve nonmucosal or nongenital sites have rarely been described. The reasons for this site specific infectivity ofHPV 6 are unknown. We describe a patient who had condylomata acuminata-like lesions that involved cutaneous nongenital sites; HPV 6 DNA was detected in skin biopsy specimens with use of the polymerase chain reaction, followed by hybridization with use of type-specific DNA probes. (J AM AeAD DERMATOL 1992;27:876-9.) The h u m a n papillomaviruses (HPVs) are speciesspecific, double-stranded D N A viruses. More than 66 H P V genotypes have been identified and cloned. Each type is classified into one of three distinct clinical groups: those that involve the mucosa, those that infect nongenital cutaneous sites, and those found in the setting of epidermodysplasia verruciforrnis. H P V type 6 is classically considered a mucosatropic virus. It is the most common H P V type found in condylomata acuminata (genital warts).1,2 In addition, H P V 6 has been isolated in papillomas that involve the conjunctivae, 3 oral mucosa, 4 and upper bronchopulmonary tract. 4,6 Interestingly, From the Department of Dermatologyand CutaneousSurgery,Universityof Miami Seheolof Medicine. Reprint requests: LawrenceA. Schachner, MD, Departmentof Dermatologyand Cutaneous Surgery, Universityof Miami School of Medicine,P.O. Box 016250, Miami, FL 33101. 16/4/36892
clinical manifestations of H P V 6 infection that involve nonmucosal or nongenital sites have rarely been described. 7 The reasons for this site specific infectivity of H P V 6 are unknown. W e describe a patient who had condylomata acuminata-like lesions that involved cutaneous nongenital sites; H P V 6 D N A was detected in skin biopsy specimens from this patient with use of the polymerase chain reaction (PCR), followed by dot-blot hybridization. CASE REPORT A 9-year-old black gir! had a 3-year history of asymptomatic growths on the arms and legs. Her medical history was significant fQr atopic dermatitis and asthma of many years' duration. The patient's mother died from complications that resulted from sickle cell disease, and the identity of the patient's father was not known. The girl was now living with her maternal grandmother, who reported no history of cutaneous or genital warts in friends or family members, although these close contacts had not