Cutaneous granulomas as the first manifestation of Hodgkin’s disease

ARTICLE

Auteur(s) : A. MACAYA, O. SERVITJE, A. MORENO¹, J. PEYRÍ

Dermatology Service, Ciutat Sanitària i Universitària de Bellvitge, Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Barcelona, Spain. 
¹ Pathology Service L’Hospitalet de Llobregat, Barcelona, Spain

Article accepted on 14/02/2003

Hodgkin disease (HD) may be associated with cutaneous manifestations that may be specific or non-specific. The latter include cutaneous granulomas. Both specific and non-specific manifestations of HD initially seen in the skin are extremely rare, and are associated with a poor prognosis. 
We describe a patient with familial HD that presented with fever, hepatomegaly and cutaneous epithelioid non-caseating granulomas. Final diagnosis of HD was achieved by hepatic percutaneous biopsy, which showed typical Reed-Sternberg cells (RS). Sarcoidosis, mycobacterial infections and other causes of granulomas were ruled out.
Polychemotherapy achieved complete remission of fever, cutaneous lesions, hepatomegaly and lymphadenopathy. Eighteen months later, a cutaneous rash identical to the previous one reappeared, with no evidence of systemic lymphoma.

Report

In March 1999 a 64-year-old male presented to the emergency department of our hospital with a five day history of weakness, arthralgia, fever and cutaneous rash.
His medical history included a left nephrectomy in 1992 because of nephrolythiasis.
His father died of HD in 1982. His brother had required splenectomy because of HD in 1968. Recently HD relapsed with multiple cervical and thoracic lymphadenopathy.
Our patient had a body temperature of 38 °C. Physical examination showed erythematous maculopapules on the trunk and extremities (Fig. 1) and a palpable liver edge 2 cm below the right costal margin. No splenomegaly nor lymphadenopathy were palpable. Routine laboratory examinations and chest X-ray examination in the emergency department were normal. A clinical diagnosis of tick typhus was made, and treatment with doxicycline (100 mgr twice daily for 4 days) was started.
Five days later, he returned to our hospital because of persistent fever and cutaneous rash. Full blood count, renal and hepatic profiles were normal. Serological tests for HIV, hepatitis B and C virus, Ebstein-Barr virus, cytomegalovirus, human T-cell lymphotropic virus (HTLV-1), syphilis, Lyme disease, Brucella and Rickettsia Conori were negative. Repeated mycobacterial cultures of urine and sputum were negative. Serum and urinary calcium level and serum angiotensin converting enzyme activity were normal. A gallium scan showed normal uptake. The Kveim test was not performed.
Biopsy specimens of the cutaneous papules disclosed a dense lymphohistiocytic infiltrate with a granulomatous pattern (Fig. 2). No Reed-Sternberg cells (RS) were identified. The biopsy was examined under polarised light to exclude presence of foreign bodies. Stains for bacteria, acid-fast organisms and fungi were negative. Fungal and mycobacterial cultures of the skin were also negative. Immunophenotype of the lymphocytes was CD3+/CD4+ /CD5+/CD45RO+/CD30–.
A computed tomography scan of the chest, abdomen and pelvis revealed homogeneous hepatosplenomegaly and very small retroperitoneal lymphadenopathy. An iliac crest bone marrow biopsy specimen was normal. An hepatic percutaneous biopsy was performed revealing granulomatous infiltration with typical RS cells (Fig. 3). The immunophenotype of these cells was CD30+/CD15–/CD20–/EMA–.
The diagnosis of Hodgkin lymphoma (unclassificable, stage IVb) was made.
He received Stanford V chemotherapy schema (adriamicine, vinblastine, VP16, vincristine and bleomicine). On completing the course of chemotherapy, fever and cutaneous lesions resolved, and CT examination showed complete resolution of the lymphadenopathy and hepatosplenomegaly.
Eighteen months later, a cutaneous rash identical to the previous one reappeared. Our patient had no fever nor hepatomegaly. Exhaustive investigations including bone marrow biopsy and computed tomography of the chest, abdomen and pelvis could not demonstrate any evidence of systemic lymphoma nor hepatomegaly.

Discussion

The family of our patient has several members affected by HD. It has been estimated that 4.5% of HD cases occur as familial HD. Etiology remains unknown but a chronic infectious process due to Epstein-Barr virus and genetic causes like DRB1*1501-DQA1*0102-DQB1*0602 haplotype have been implicated [1].
Cutaneous involvement in HD may occur in 17-53% of cases [2].
Skin signs at the time of initial diagnosis are very rare, and they have been related to poor prognosis.
The most common cutaneous manifestations are pruritus, hyperpigmentation, urticaria, erythroderma, erythema multiforme and erythema nodosum. These manifestations do not reflect cutaneous infiltrations by neoplastic cells, and they can be classified as “unspecific cutaneous signs”.
“Specific” cutaneous manifestations occur in only 0.5% to 7.5% of cases [3-5]. They appear in the setting of advanced disease and are associated with a poor prognosis. Papules, plaques, nodules, tumors, ulcers or erythroderma, alone or in combination have been described in the literature. Cerroni et al. found RS cells in 4/7 cases of cutaneous HD and Hodgkin cells in all cases. The immunophenotype of neoplastic cells is CD30+/CD15+/CD45–. However, CD15 negativity of RS cells can be observed in up to 28% of cases of cutaneous infiltrate of HD [6].
The mechanisms behind the formation of these lesions are believed to be due to direct extension or retrograde lymphatic spread from affected lymph nodes, or haematogenous spread.
Cutaneous granulomas associated with HD are a nonspecific sign. Sarcoid, tuberculoid and granuloma annulare-like cutaneous granulomas have been reported in association with HD.
Sarcoid-like granulomas at uninvolved sites may occur in 11.9% of patients with HD [7]. In a study about the value of staging laparotomy in 60 patients with HD, Whittaker et al. [8] observed sarcoid-like granulomas in the skin in only one patient. There have been also reports of granuloma annulare associated with HD and other lymphomas [9, 10].
Granulomatous infiltration of the skin as the first manifestation of lymphoma as in our patient is a very rare feature. It has been reported associated with several cases of HD, in one case of diffuse large cell lymphoma and in one case of large cell lymphoma affecting the central nervous system [11, 12].
We have not found any case described presenting with fever and cutaneous rash.
Farrell et al. [13] reported a 50-year-old man with a high-grade T-cell non-Hodgkin’s lymphoma who developed sarcoid-like cutaneous granulomas.
The pathogenic mechanism of skin granulomas in HD and other lymphomas is not clear. Some authors think that granulomas may arise as a local-tissue response to cytokines produced by neoplastic cells. Others suggested mechanisms that include sarcoid-like reactions to foreign bodies or against disintegration products from the tumor or against microorganisms such as fungi or mycobacteria.
Another mechanism may be oportunistic infections or reactions to chemotherapy. Although it is highly improbable, some cases may occur because of coincidence in the same patient of HD and a granulomatous disease. None of the mechanisms mentioned is clear in our case.
Non-necrotic epithelial cell granulomas in tissues affected by HD have been related to a more favorable prognosis. At present, however, the prognostic implication of cutaneous granulomas without direct involvement of lymphoma cells is uncertain, because of the few published cases [13].
Cutaneous sarcoid granulomas must be considered as a rare, nonspecific sign of an underlying lymphoma, specially when sarcoidosis and mycobacterial infections have been ruled out. n

References

1. Harty LC, Yin Y, Goldstein AM, Jaffe ES, et al. HLA-DR, HLA-DQ, and TAP genes in familial Hodgkin disease. Blood 2002; 99 (2): 690-3.

2. Hayes TG, Rabin VR, Rosen T, Zubler MA. Hodgkin’s disease presenting in the skin: case report and review of the literature. J Am Acad Dermatol 1990; 22: 944-7.

3. Smith HL, Butler JJ. Skin involvement in Hodgkin’s disease. Cancer 1980; 45: 354-61.

4. White RM, Patterson JW. Cutaneous involvement in Hodgkin’s disease. Cancer 1985; 55: 1136-40.

5. Tassies D, Sierra J, Montserrat E, et al. Specific cutaneous involvement in Hodgkin’s disease. Hematol Oncol 1992; 10: 75-9.

6. Cerroni L, Beham-Schmid C, Kerl H. Cutaneous Hodgkin’s disease: an immunohistochemical analysis. J Cutan Pathol 1995; 22: 229-35.

7. Brincker H. Sarcoid reactions in malignant tumours. Cancer Treat Rev 1986; 13: 147-56.

8. Whittaker JA, Slater A, Al-Ismail SAD, et al. An assessment of laparotomy in the management of patients with Hodgkin’s disease. Q J Med 1978; 47: 291-301.

9. Setoyama M, Kerdel FA, Byrnes JJ, Kanzaki T. Granuloma annulare associated with Hodgkin disease. Int J Dermatol 1997; 36: 435-42.

10. Barksdale SK, Perniciaro C, Halling KC, Stricker JG. Granuloma annulare in patients with malignant lymphoma: clinicopathologic study of thirteen new cases. J Am Acad Dermatol 1994; 31: 42-8.

11. Randle H, Banks PM, Winkelmann RK: Cutaneous granulomas in malignant lymphoma. Arch Dermatol 1980; 116: 441-3.

12. Diette KM, Caro WA, Roenigk HH. Malignant lymphoma presenting with cutaneous granulomas. J Am Acad Dermatol 1984; 10: 896-902.

13. Farrell AM, Henry K, Woodrow D, et al. Cutaneous granulomas associated with high-grade T-cell non-Hodgkin’s lymphoma. Br J Dermatol 1999; 140: 145-9.