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Primary Adrenal Natural Killer/T-Cell Nasal Type Lymphoma: First Case Report in Adults
Michael A. Thompson,1* Mouhammed A. Habra,2 Mark J. Routbort,3 F. Christopher Holsinger,4 Nancy D. Perrier, Steven G. Waguespack,2 and Maria A. Rodriguez6
1 Division of Medical Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas
2 Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas
3 Department of Hematopathology, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas
4 Department of Head and Neck Surgery, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas
5 Department of Surgical Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas
6 Department of Lymphoma/Myeloma, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas
We report the first case of a primary adrenal natural killer (NK)/T-cell nasal type lymphoma in adults. The patient presented with an enlarging left adrenal mass and the initial concern was for adrenocortical carcinoma. Surgical resection revealed NK/T-cell lymphoma. Rapid recurrence in the contralateral adrenal gland was treated with a single cycle of chemother- apy before he died due to infectious complications and progressive disease. This case dem- onstrates the aggressive presentation of a novel subset of primary adrenal lymphoma that should be considered in the differential diagnosis of a rapidly enlarging adrenal mass. Am. J. Hematol. 82:299-303, 2007. @ 2006 Wiley-Liss, Inc.
Key words: extranodal lymphoma; natural killer; nasopharynx; adrenal mass; Epstein Barr virus; adrenal tropism
INTRODUCTION
Primary adrenal lymphoma (PAL) is a rare disease that may present with adrenal insufficiency, fever of unknown origin, or it can also be discovered inci- dentally on abdominal imaging [1-3]. The vast ma- jority of the reported PAL cases are B cell lympho- mas and, to our knowledge, this is the first reported case of a primary adrenal natural killer (NK)/T-cell lymphoma in adults [4]. Recently, the first case of NK/T-cell PAL was reported in an adolescent [5]. NK/T-cell lymphoma is an aggressive, rare form of lymphoma that is associated with Epstein Barr virus (EBV) [6]. It usually originates in the nasal cavity/ nasopharynx and invades the surrounding tissues; less often, it can arise in other organs including the skin, testicles, or the GI tract. This case demonstrates the aggressive presentation of a novel subset of a rare disorder that should be considered in the differential diagnosis of a rapidly enlarging adrenal mass.
CASE REPORT
A 35-year-old white man presented with urinary symptoms in October 2003. A computed tomogra- @ 2006 Wiley-Liss, Inc.
phy (CT) scan revealed a 4-mm ureteral stone with no hydronephrosis; the adrenal glands were normal in appearance (Fig. 1). He passed the kidney stone test but low back pain continued. In March 2004, he had increased low back pain and an intravenous pyelogram was negative for kidney stones. On August 27, 2004, the patient was evaluated for shortness of breath, chest pain, and palpitations. CT of the abdomen showed a new 5-cm left adrenal mass. The result of evaluation for a functioning adrenal neoplasm was negative. Past medical history was significant for hypertension, appendicitis, ob-
The material in this manuscript has previously been presented in part in abstract form at the Endocrine Society’s 87th Annual Meeting.
*Correspondence to: Michael A. Thompson, M.D., Ph.D., M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 10, Houston, TX 77030. E-mail: micthompson@mdanderson.org
Received for publication 8 June 2006; Accepted 28 August 2006
Published online 8 November 2006 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/ajh.20811
40
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esity, and obstructive sleep apnea. Family history was negative for lymphoma. At initial evaluation at M. D. Anderson Cancer Center, a September 24, 2004 CT of the abdomen and pelvis indicated a fur- ther enlarged left upper quadrant mass (Fig. 2). There was no evidence of liver metastasis, regional adenopathy, or other primary cancers. Because of a concern for a primary adrenal malignancy he under- went left open adrenalectomy on September 27, 2004.
Pathology indicated extranodal natural killer (NK)/ T-cell lymphoma, nasal type, extensively involving the adrenal gland (Fig. 3). Left para-aortic tissue American Journal of Hematology DOI 10.1002/ajh
Positive
Negative
biopsy was negative for lymphoma. Immunophe- notyping by immunohistochemical analysis re- vealed: Ki-67 of 75%, CD56 (NK antigen) with strong, uniform membranous positivity; T cell intra- cellular antigen-1 (TIA-1) and granzyme B with strong uniform granular perinuclear positivity (cyto- toxic granules); CD3 with dim heterogeneous cyto- plasmic positivity; and CD2 and CD20 with dim cytoplasmic positivity. The following markers were negative on immunohistochemical stains: CD5, CD7, CD8, CD10, CD79, Pax-5, bcl-2, bcl-6, cytokeratin, and lysozyme. Epstein Barr virus (EBV)-encoded RNA (EBER) staining by chromogenic in situ hybridization showed strong and uniform nuclear positivity in the neoplastic population (Fig. 4). T-cell receptor and im-
munoglobulin clonality studies were not performed, as the combination of NK-lineage antigens (TIA-1, gran- zyme B, CD56) with EBV-expression was diagnostic of extranodal NK/T-cell lymphoma.
At that point, he was referred to the Lymphoma department. The patient had no B symptoms of fever, chills, or night sweats; however, he had lost 25 pounds since the time of surgery. Physical exami- nation was remarkable for obesity, no peripheral lymphadenopathy, no abnormal oral, oropharyngeal, or anterior nasal lesions. A postsurgical abdominal drain was in place without abdominal organomegaly. Laboratory tests were significant for normocytic anemia and mildly elevated ALT and AST, which normalized after an antibiotic was discontinued. Ad- ditional studies included: ß-2-microglobulin 3.0 mg/L, LDH 666 IU/L, normal cortisol level, and negative HIV and hepatitis panels. Bilateral bone marrow biopsy was negative for lymphoma. CT and otorhi- nolaryngology examination were negative for naso- pharyngeal lymphoma. However, a October 21, 2004 PET/CT scan revealed a new right adrenal mass with intense FDG uptake (maximum SUV of 37) (Fig. 5). Therapy options discussed included cyclo- phosphamide, doxorubicin, vincristine, prednisone (CHOP) as standard of care versus an aggressive phase II clinical trial of modified hyper-CVAD (hyper-CVID/Doxil) with alternating cycles 1 and 2 as follows: Cycle 1: cyclophosphamide every 12 hr for 6 doses, mesna, vincristine, dexamethasone, and pegylated liposomal doxorubicin (Doxil); Cycle 2: methotrexate, citrovorum, and cytarabine. The patient elected to proceed with the phase II clinical trial; however, chemotherapy initiation was delayed twice for upper gastrointestinal bleeding and then a fever and abdominal abscess. The abdominal abscess was drained percutaneously. A CT of the abdomen and pelvis on November 9, 2004 indicated that the right adrenal gland had significantly increased in size measuring 11 x 8 cm2. Due to rapidly increas- ing tumor size, CHO(P) chemotherapy was initiated off protocol on November 13, 2004 with prednisone not given due to his active infection. In December 2004, a second cycle of chemotherapy was delayed due to abscess recurrence requiring IV antibiotics and drainage. Subsequently, he developed tachyp- nea, shortness of breath, abdominal and back pain, fever, and diarrhea. On December 25, 2004, an ab- dominal abscess was positive for Serratia marcescens and progressive adrenal lymphoma. He underwent abdominal exploration and placement of large bore catheters in the left retroperitoneum for continuous irrigation on December 26, 2004. Stress dose ste- roids were administrated for a low random cortisol level. His condition remained poor and he died on
R
A
R
B
December 27, 2004. At autopsy, disseminated lym- phoma was found in the right adrenal gland, liver, spleen, lymph nodes, and serosal surfaces.
DISCUSSION
This is the first report of an NK/T-cell, nasal type PAL in adults, which presented as a rapidly enlarg- American Journal of Hematology DOI 10.1002/ajh
302 Case Report: Thompson et al.
ing homogenous adrenal mass. After surgical re- moval of the left adrenal gland, a large right adrenal mass quickly appeared, indicating an extremely aggressive lymphoma biology. NK/T-cell lymphoma is an extranodal lymphoma with a predilection for the nasal cavity, nasopharynx, skin, and other extra- nodal sites. The initial presentation of our patient’s tumor in the adrenal gland is extremely rare. Often these tumors present in patients who are immuno- suppressed or who have had solid organ transplan- tation; there is no history in this case of either. NK/ T-cell lymphoma is strongly associated with EBV, suggesting a pathogenic role for the virus [7,8]. The patient’s adrenal gland was positive for EBV. Un- fortunately, this disease pursues an aggressive course and many of the patients succumb to disseminated disease. The optimal treatment is not established [9]. Novel therapies in NK/T-cell lymphomas have been reviewed [10]. Li et al. reported a 5 year overall survival of 36% in 77 patients with NK/T-cell sino- nasal lymphoma [11]. They found combined chemo- therapy and radiation to be beneficial. Kim and col- leagues reviewed their retrospective experience with CEOP-B (cyclophosphamide, epirubicin, vincristine, prednisolone, bleomycin) chemotherapy in 43 newly diagnosed extranodal NK/T-cell lymphoma patients [9]. Patients had either nasal cavity or upper airway involvement. The CR/unconfirmed-CR rate was 44% and overall response rate was 67%. The median overall survival was 27.9 months and the median disease-free survival was 15.3 months [9]. No clinical or laboratory factors were predictive of survival, except age. Radiation did not show a survival bene- fit. Lee et al. recently proposed an extranodal NK/ T-cell, nasal type lymphoma prognostic model from a multicenter retrospective study of 262 patients [12]. Prognostic factors included B symptoms, stage, LDH level, and regional lymph node involvement.
PAL has been defined as the presence of adrenal lymphoma without other nodal or organ involvement and the absence of leukemia [13,14]. Others have defined it as the dominant site of disease without HIV involvement [15]. Adrenal masses are commonly found as “incidentalomas” on imaging [16]. PET imaging to follow PAL treatment has recently been reviewed [17]. CT findings for PAL have been des- cribed as complex cystic due to necrosis and hemor- rhage; whereas, secondary lymphoma involvement of the adrenal is more likely to be a homogeneous mass [18]. The adrenal gland is involved in ~25% of diffuse lymphoma patients [19,20]. PAL has been the subject of recent reviews [1,15]. In the review of 100 PAL cases, including 84 cases with reported pathology, only 5 were of T-cell origin and no cases had NK/T-cell histology [1]. The PAL tropism for
the adrenal gland is incompletely understood. Re- cently, the first case of NK/T-cell PAL was reported in an adolescent [5]. That patient presented with bilateral NK/T-cell PAL associated with an EBV infection, normal cortisol level and hemophagocytic lymphohistiocytosis (HLH). He was treated for HLH with steroids, cyclosporine A, and plasmapheresis, which did not alter PAL progression. EBV was de- tected in 9 of 20 patients in a series from Japan [13]. The incidence of central nervous system (CNS) involvement in PAL is not clear. Only one case has been reported with CNS disease at diagnosis and that patient had T-cell histology [21]. Patients may develop CNS disease at relapse and a summary of six cases of relapse in addition to the one case of CNS disease at diagnosis were reported by Grigg and Connors [15]. Bilateral adrenal involvement is found in 79% of cases and is associated with adre- nal insufficiency in two-thirds of cases [1]. Our patient did not have adrenal insufficiency on initial evaluation but appeared to have developed adrenal insufficiency, which was treated with stress dose steroids, before his death. Treatments for PAL have included various combinations of surgery, chemo- therapy, and radiation. The long-term prognosis in PAL has not been determined. For patients treated with curative intent the complete remission rate was 46% and the disease-free survival for 6 months was 34% [1]. In a review of 83 cases of PAL the survival rate at 1 year was 17.5% [22]. Remaining questions in PAL include the optimal combination of chemo- therapy, radiation, and surgery; the role of CNS prophylaxis; and the mechanism for adrenal tro- pism. The rapid deterioration in our patient is simi- lar to that described in other studies.
In conclusion, we present the first case of a pri- mary adrenal NK/T-cell nasal type lymphoma in an adult. PAL, although a rare entity, should be considered in the differential diagnosis for a rapidly enlarging adrenal mass, especially if it lacks the characteristic radiographic appearance of adrenocor- tical carcinoma.
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