History
A 23 year old male was referred to our intensive care unit from an outside hospital with hepatic and renal failure (serum bilirubin 41 mg/dl, International Normalized Ratio (INR) 1.7, Blood Urea Nitrogen (BUN) 108 mg/dl, serum creatinin 5.3 mg/dl).
Three weeks earlier the patient had presented to an outside hospital with increasing fatigue and cervical swelling over several weeks. Biopsy of the cervical lymph nodes had established the diagnosis of nodular sclerosing classical HL. Staging was done by whole body MRI scan (Figure 1) and revealed a large cervical lymph node bulk (8 × 3.3 cm) on the left side and slightly enlarged cervical, paratracheal and paraaortal lymph nodes on the right side. Moreover, there were two small masses in the left lung (13 mm and 7 mm in diameter, respectively) as well as multiple hepatic nodules. Further laboratoy work-up was notable for increased Erythrocyte Sedimentation Rate (ESR) of 96 mm/h, and immunodeficiency (lymphocytopenia, T helper cell and B cell count significantly decreased, IgG4 deficiency). Histological examination of the bone marrow showed no infiltration by HL.
The patient was also known to suffer from NBS. He was diagnosed at birth and registered in the NBS Registry as patient No. 45. In accordance with this diagnosis he displayed mild mental retardation (he had been working as an auxiliary cook up to this point), microcephaly, characteristic facial features as well as an immune defect. He was known to suffer from selective IgG4 deficiency and his fibroblasts and lymphocytes had been found to be hypersensitive to induction of DNA breaks (The International Nijmegen Breakage Study Group [7]). Up until this young adult age he had no history of severe infections.
During the initial evaluation the patient was withdrawn from further medical care by his parents. When he developed B symptoms and his condition rapidly deteriorated he was readmitted and transferred to our hospital. The patient measured 1,52 m with a weight of around 75 kg; he presented awake and oriented, but severely icteric, anuric and edematous. On admission, a little over two weeks after the diagnosis had been established, he was in acute renal and hepatic failure. Treatment with Prednisone 100 mg i.v. daily had been started.
Clinical course
Ultrasound-guided biopsy of liver nodules was performed immediately and showed multiple small nodular infiltrates of classical Hodgkins lymphoma (Figure 2). Therefore, diagnostic stage had to be corrected to IVB and systemic chemotherapy similar to CHOP schedule was started, however adapted to poor renal and hepatic function. He received reduced CHOP-like chemotherapy including cyclophosphamide 375 mg/qm (50%), doxorubicin 12.5 mg/qm (25%) and vincristin 2 mg abs. on day 3 of the hospital stay.
Citrate hemodialysis was initiated immediately and continued for the following four weeks. During this time renal function started to improve. Additionally, after application of the first cycle of chemotherapy, albumin dialysis was applied several times until hepatic function started to recover.
While organ functions were improving following application of chemotherapy, the patient developed aspergillus fumigatus and candida albicans pneumonia, confirmed by culture of bronchioalveolar fluid, and had to be ventilated for ten days. White blood counts were stimulated using granulocyte colony stimulating factor (G-CSF) starting on day 4 after chemotherapy application. Twenty-one days after the first chemotherapy, the patient received the second cycle, this time an attenuated ABVD schedule (adriamycin d1 75% and d15 100%, bleomycin d1 25% and d15 50%, vinblastin d1 75% and d15 100%, dacarbazin d1 50% and d15 75%). During the second cycle he again became septic from Candida urinary tract infection but recovered in due time with caspofungin treatment and G-CSF support to receive the next dose of chemotherapy on day 15. Overall, we applied four cycles of chemotherapy, three of them ABVD d1 and d15, and were able to escalate the doses of adriamycin, bleomycin and vinblastin to 100%, and of dacarbazin to 75% of the regular adult schedule. In detail, the following doses (given as total or per m2 body surface area) were applied. Cycle 1: cyclophosphamide 375 mg/m2, doxorubicin 12,5 mg/m2, vincristin 2 mg total dose; cyclophosphamide was reduced to limit hematotoxicity considering renal failure; doxorubicin dose was adjusted to poor liver function. Cycle 2 (3 weeks later), d1: doxorubicin 19 mg, bleomycin 2,5 mg, vinblastin 4,4 mg, dacarbazin 194 mg, all per m2. doxorubicin was still applied in a lower dose to account for hepatic dysfunction, bleomycin was thought to be particularly toxic since it induces DNA breaks, especially in kidney failure. Since the patient was still recovering from severe sepsis also vinblastin and dacarbazin were reduced to limit the risk of neutropenic infection. Pegylated G-CSF was given d4 and d19. Cycle 2, d15: doxorubicin 25 mg, bleomycin 5 mg, vinblastin 6 mg, dacarbazin 281 mg, all per m2. Cycle 3 and cycle 4, d1 and d15: doxorubicin 25 mg, bleomycin 10 mg, vinblastin 6 mg, dacarbazin 281 mg, all per m2.
However, the patient was affected with severe intensive care polyneuropathy leading to lower extremities paresthesias and paralysis. The situation was further complicated by grade IV anal ulcer and eventually a depressive episode. The resulting refusal to co-operate prevented mobilisation as well as implementation of supportive measures and staging procedures. Therefore, and in consideration of the dramatic clinical response already obtained it was decided together with his family to terminate chemotherapy. After fourteen days on an inpatient psychiatric ward undergoing intensive psychotherapy the patient was referred to a rehabilitation facility for the following eight weeks and then discharged home.
Follow-up MRI was performed at 3, 6, 12 and 18 months after initial diagnosis and continued to show complete remission. At 20 months after the initial diagnosis, the patient has now regained full mobility, does not exhibit any clinical sequelae of the disease and has started to work again as an auxiliary cook. His mental condition has returned to baseline without pharmacologic intervention.