Esophageal actinomycosis after allogeneic peripheral blood stem cell transplantation for extranodal natural killer/T cell lymphoma, nasal type

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Summary:

We report a 19-year-old man with extranodal natural killer (NK)/T cell lymphoma, nasal type treated by allogeneic peripheral blood stem cell transplantation (allo-PBSCT). His lymphoma was chemoresistant, and disseminated during local radiotherapy. The patient received allo-PBSCT from his HLA-1 locus mismatched sister using busulfan (BU), cyclophosphamide (CY) and VP-16 as the conditioning regimen. His course was complicated by esophageal actinomycosis 9 months after transplantation, which resulted in the rupture of the right common carotid artery. These observations suggest that actinomycosis should be monitored carefully after transplantation in patients who have received local radiation therapy before the procedure.

Main

Extranodal natural killer (NK)/T cell lymphoma, nasal type (nasal NK/T cell lymphoma) is rare in Western countries, but common in Asia. It is highly associated with Epstein–Barr virus (EBV), and it usually affects the midline nasal cavity.1 Various chemotherapies, including radiotherapy, are usually provided for patients with localized disease. Once it disseminates to other parts of the body, its prognosis is extremely poor and it is inevitably fatal.

Actinomycosis is a rare infectious disease caused by anaerobic or microaerophilic bacteria that normally colonize the mouth, colon and vagina. Classic features include spread to contiguous structures by crossing natural anatomic boundaries and the formation of fistulae and sinus tracts.2 There are some reports of actinomycosis developing after organ transplantation,3 but there are no cases of this condition described after hematopoietic stem cell transplantation.

We report a patient with advanced nasal NK/T cell lymphoma which was treated by allogeneic peripheral blood stem cell transplantation (allo-PBSCT) using busulfan (BU), cyclophosphamide (CY) and VP-16 as the conditioning regimen. This patient developed esophageal actinomycosis 9 months after transplantation, which caused the rupture of the right common carotid artery.

Case report

A 19-year-old man was referred to us for further treatment of a primarily, chemoresistant nasal NK/T cell lymphoma. He had presented with a perforated soft palate on 5 February, 2001 and had been admitted to a nearby hospital. Biopsy of the soft palate showed infiltration of small to large atypical lymphocytes and necrosis. Immunohistochemical staining revealed that the tumor cells were positive for CD56, Granzyme B and T cell intracellular antigen-1 (TIA-1), but negative for surface-CD3, CD8, CD20 and perforin. In situ hybridization showed the presence of EBV-encoded small nuclear RNA (EBER) in the tumor cells. The diagnosis of nasal NK/T cell lymphoma was made, and staging confirmed that the disease was localized in the soft palate and nasal cavity. Although combination chemotherapy with MACOP-B was started, the tumor grew bigger while the patient was receiving chemotherapy (total dose of methotrexate 600 mg, doxorubicin 150 mg, cyclophosphamide 1100 mg and vincristine 2 mg; the daily dose of prednisolone was 1 mg/kg p.o.). Consequently, he was transferred to our hospital.

On admission, physical examination revealed a large defect in the palate, a tumor in the inferior wall of the left nasal cavity and an ulcerated nasal septum. Neither the liver nor the spleen was palpable. There was no peripheral lymphoadenopathy. Laboratory studies revealed a WBC count of 3.71 × 109/l, Hb 13.1 g/dl and platelets count of 176 × 109/l. Aspartate aminotransferase (AST), alkaline phosphatase, lactate dehydrogenase (LDH), serum amylase, total bilirubin, blood urea nitrogen (BUN), creatinine, C-reactive protein (CRP) and soluble IL-2 receptor were within the normal range (NR). Levels of alanine aminotransferase (ALT) 67 U/l (NR 4–44) and leucine aminopeptidase (LAP) 85 U/l (NR 30–70) were slightly elevated. Serological tests for EBV antibodies showed the following titers: EBV viral capsid antigen (VCA), immunoglobulin G (IgG) 1:320, IgM <1:10 and IgA 1:40; EBV early antigen (EA), IgG 1:40 and IgA <1:10, and EB nuclear antigens (EBNA), 1:20. Bacterial culture of stools and throat swabs revealed the presence of methicillin-resistant Staphylococcus aureus (MRSA). Magnetic resonance imaging (MRI) of the nasal cavity showed involvement of the posterior wall of the pharynx, but other imaging examinations and bone marrow biopsy did not reveal tumor metastasis.

Local radiotherapy (total 50 Gy) was started; however, the lymphoma spread to the shoulders bilaterally, forming subcutaneous lesions. At the time of dissemination, peripheral CD56+ cells (NK cells) obtained by flow cytometry were analyzed for the presence of EB viral DNA by polymerase chain reaction (PCR). This examination revealed the presence of EB viral DNA in CD56+ cells. The patient underwent allo-PBSCT using cells from his HLA-1 locus mismatched sister (donor HLA type: A(11, 24) B(51, 55) DRB1(0405, 0803) recipient type: A(24, -) B(51, 55), DRB1(0405, 0803)) on 1 August 2001. The conditioning regimen consisted of BU 4 mg/kg p.o., in divided doses, daily, for 4 days (from −8 day to −5 day, total dose 16 mg/kg), CY 60 mg/kg once daily, i.v., for 2 days (from −3 day to −2 day, total 120 mg/kg) and VP-16, 10 mg/kg once daily, i.v., for three consecutive days (from –4 day to –2 day, total 30 mg/kg). GVHD prophylaxis consisted of a short course of methotrexate and 3 mg/kg cyclosporin A(CsA) twice daily, p.o., beginning 1 day before PBSCT. The patient received G-CSF (filgrastim 300 μg/m2 once daily, i.v.) from day 5 to day 13. However, he developed hyperbilirubinemia without weight gain or hepatomegaly on day 7. The concentration of total bilirubin rose to 8.5 mg/dl on day 12, and gradually decreased to levels within NR without specific therapy. The patient made an excellent hematologic recovery. Signs of acute cutaneous GVHD (grade II) were noted on day 89, but it responded well to a short course of prednisolone and an increase in CsA dosage. After PBSCT, both the nasal tumor and sub-cutaneous metastatic lesions gradually regressed and complete remission was achieved. He was discharged on day138.

At 9 months after transplantation, he was admitted to the ENT department of a nearby hospital because of pharyngeal pain and dyspnea. Bilateral recurrent laryngeal nerves palsy and an ulcer of the cervical part of the esophagus were diagnosed; thus, he was transferred to our hospital. On admission, physical examination revealed stridor and mild chronic GVHD of the oral mucosa. Laboratory studies revealed a WBC count of 14.0 × 109/l, Hb 14.0 g/dl and platelets of 194 × 109/l. CRP levels (NR<0.3) were slightly elevated at 2.19 mg/dl but other laboratory data were within NRs. Three biopsies of the esophageal ulcer revealed tissue inflammed with actinomycotic colonies. There was no evidence of lymphoma cells. Bacterial culture of the throat revealed the presence of MRSA and Candida species. The patient was therefore started on ampicillin, arbekacin sulfate and fluconazole. As a result of mixed infection by Pseudomonas aeruginosa, piperacillin sodium was substituted for ampicillin on the 17th hospital day. WBC and CRP decreased to values within NR; however, the esophageal ulcer did not improve significantly. On the 60th hospital day, sudden rupture of the right common carotid artery caused hematemesis and hypovolemic shock. An emergency operation (interposition of the right common carotid artery with a saphenous vein graft) was performed and he survived with a left hemiplegia. A biopsy of the ruptured carotid artery revealed the presence of actinomycetes. At present, that is 18 months after PBSCT, he is alive without symptoms of recurrence of the lymphoma.

Discussion

Nasal NK/T cell lymphoma is rare in the United States and Europe but common in Asia.1 At a workshop held in Hong Kong in 1994, the clinicopathological characteristics of this lymphoma were confirmed: (1) high association with EBV, (2) broad cytologic spectrum ranging from small or medium cells to large transformed cells, (3) constant presence of necrosis, (4) angioinvasion by tumor cells, (5) a CD2+, CD56+ and surface CD3− immunophenotype and (6) no rearrangement of T cell receptor genes.1 The prognosis of nasal NK/T cell lymphoma is generally very poor. Kwong et al4 reported that the median survival of patients with localized disease was 12 months, and that of patients with multiorgan involvement was only 2 months.

In our patient, lymphoma was a localized nasal lesion on admission, but it was primarily chemoresistant and disseminated forming subcutaneous lesions during radiotherapy. He thus required a more intensive therapy. We examined peripheral CD56+ cells, which were sorted by flow cytometry, to look for the presence of EB viral DNA by PCR analysis at the time of dissemination.5 Although we confirmed the presence of EBV-infected NK cells in his peripheral blood, it was unclear whether these NK cells were neoplastic, because we did not clarify their clonality by terminal repeat sequencing. There have been some reports of patients who were successfully treated by autologous transplantation.6 However, we thought it was safer to avoid reinfusion of these EBV-infected NK cells and, thus, we used allo-PBSCT, and we expected to observe a graft-versus-lymphoma (GVL) effect.

No ideal conditioning regimen for nasal NK/T cell lymphoma has been established. Makita et al7 reported the case of a patient who was successfully treated with allo-PBSCT using CY+TBI as the conditioning regimen. This case underwent early tapering of CsA and DLI in an attempt to induce a GVL effect. We could not use TBI because in our patient the nasopharyngeal region had already been irradiated with 50 Gy. We added VP-16 to the standard BU/CY conditioning regimen because VP-16 is considered to be an effective drug for hemophagocytic lymphohistiocytosis which is also associated with EBV infection.8 After transplantation, the size of the lymphomas gradually decreased, and he has already been in complete remission for 18 months. These observations suggest that allo-PBSCT using this conditioning regimen may be effective for disseminated nasal NK/T cell lymphoma.

Actinomycosis is an indolent, slowly progressive infection caused by anaerobic or microaerophilic bacteria that normally colonize the mouth, colon and vagina. It is most commonly caused by Actinomyces israelii. Other species of actinomyces are established, but less common, causes of the disease. Classic features of actinomycosis include spread to contiguous structures by crossing natural anatomic boundaries and the formation of fistulae and sinus tracts.2 Some cases of actinomycosis occuring after radiation therapy9 and organ transplantation3 have been described, but there has been no report of this disease after hematopoietic stem cell transplantation. Actinomycosis most commonly occurs in the oral–cervicofacial regions and esophageal actinomycosis is rare in the general population, except for HIV-infected patients.10 It is supposed that, in our patient, disruption of the mucosal barrier resulting from prior radiation therapy and chronic GVHD enabled actinomyces to enter the deep layer of the esophagus. Actinomycosis generally responds well to prolonged antibiotic therapy. The treatment of choice is penicillin and other alternative regimens include erythromycin, tetracycline, doxycycline, and clindamycin.2 In our patient, antibiotic therapy improved the systemic inflammatory response; however, the esophageal ulcer expanded and caused rupture of the right carotid artery. The obliteration of small blood vessels caused by prior radiation therapy may have interfered with the distribution of antibiotics and resulted in a poor response.

In summary, we suggest that a strategy consisting of allo-PBSCT and BU/CY/VP-16, as the conditioning regimen, should be considered for the treatment of a primarily chemoresistant, disseminated nasal NK/T-cell lymphoma. Moreover, it is important to bear in mind the possibility of actinomycosis developing in patients with chronic GVHD or a history of local radiation therapy.

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Acknowledgements

We thank Dr Takayuki Okamura, Dr Emiko Satou and Dr Keisei Kawa (Department of Pediatrics, Osaka Medical Center and Research Institute for Maternal and Child Health) for performing the PCR analysis of EBV.

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Correspondence to T Yagi.

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Yagi, T., Fujino, H., Hirai, M. et al. Esophageal actinomycosis after allogeneic peripheral blood stem cell transplantation for extranodal natural killer/T cell lymphoma, nasal type. Bone Marrow Transplant 32, 451–453 (2003) doi:10.1038/sj.bmt.1704161

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Keywords

  • actinomycosis
  • nasal NK/T cell lymphoma
  • allo-PBSCT
  • BU/CY/VP-16

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