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Primary Adrenal Lymphoma: presentation, management & prognosis
C. LAURENT1, O. CASASNOVAS2, L. MARTIN3, A. CHAUCHET4, H. GHESQUIERES5, G. AUSSEDAT5, L. FORNECKER6, S. BOLOGNA7, S. BOROT8, K. LAURENT9, B BOUILLET1, B. VERGES1, J-M. PETIT1.
Department of Endocrinology, University Hospital of DIJON, 2 Department of Hematology, University Hospital of DIJON, 3 Department of Pathology, University Hospital of DIJON, 4 Department of Hematology, University Hospital of BESANCON, 5 Department of Hematology, Centre Leon Berard, University Hospital of LYON, 6 Department of Hematology, University Hospital of STRASBOURG, 7 Department of Hematology, University Hospital of NANCY, 8 Department of Endocrinology, University Hospital of BESANCON, 9 University of Science and Technology of Nancy.
Key words: primary adrenal lymphoma; adrenal insufficiency; FDG PET; MRI.
Corresponding authors:
LAURENT C., Service de Diabétologie et d’Endocrinologie, CHU du Bocage, BP 77908, 21079 Dijon cedex, France.
Tel: 33 3 80 29 34 53
Fax: 33 3 80 29 35 19
E-mail: claire.laurent@chu-dijon.fr
Dr PETIT J-M., Service de Diabétologie et d’Endocrinologie, CHU du Bocage, BP 77908, 21079 Dijon cedex, France. Tel: 33 3 80 29 34 53 Fax: 33 3 80 29 35 19
E-mail: jean-michel.petit@chu-dijon.fr
@ The Author 2016. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com
ABSTRACT
Aim
This study aimed to identify the clinical, radiological and prognostic features of primary adrenal lymphoma (PAL) in order to diagnose the disease more accurately.
Materials and methods
A retrospective multi-centre study was conducted on the clinical, biological and radiological features as well as the treatment and overall survival outcomes in PAL.
Results
Between 1994 and 2014, 28 patients from five regions of eastern France were diagnosed with primary adrenal lymphoma. The revealing symptoms were a worsening general state (77%), weight loss (77%), and abdominal pain (42%). Biological features of PAL were almost omnipresent: increased LDH, ß2 microglobulin, CRP or ferritinaemia levels. The PAL was bilateral in 20 cases (71%), adrenal insufficiency was searched for in 11 patients and found in eight (73%). CT-scans showed masses of various size measuring up to 180 mm. On MRI, the lesions were hypointense in T1 and hyperintense in T2. When done, FDG-PET showed locations not seen on the CT, and revealed extra-adrenal locations in 70% of examinations. Adrenalectomy brought no benefit. The overall survival rate was poor (61.9% at 2 years) despite polychemotherapy.
Conclusion
The clinical presentation of PAL comprised major general symptoms. Adrenal insufficiency was very common in patients with bilateral involvement but was not systematically tested. PET was an efficient examination to visualize extra-adrenal locations. The preliminary results of MRI to distinguish between PAL and adrenocortical carcinoma should be confirmed. Further studies are needed to establish an optimal strategy for the management of these primary adrenal lymphomas.
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INTRODUCTION
Primary adrenal lymphoma is a rare entity accounting for less than 1% of non-Hodgkin lymphomas (1). Few clinical series have been reported.
The initial clinical presentation tends to take multiple forms, which makes diagnosis difficult. Most often, patients present general symptoms with worsening of the general state, weight loss and abdominal pain. Sometimes, symptoms linked with adrenal insufficiency are encountered. There are frequent in patients with bilateral adrenal disease (2,3) and must therefore be investigated. Adrenal tumours are rarely found incidentally. Clinicians may face difficulties when they discover large adrenal masses, as, the differential diagnosis with adrenocortical carcinoma or adrenal metastasis is not always easy. The initial examination varies depending on whether management takes place in an endocrinology or haematology care unit. Adrenal insufficiency is not systematically investigated. As primary adrenal lymphoma is an aggressive disease, it must be diagnosed quickly so that treatment can be started as early as possible. Given the rarity of PAL, the fact that patients are treated by different teams and the absence of guidelines, diagnosis may be delayed or the care inadequate.
This led us to carry out a study to identify the clinical, biological and morphological features, treatment and survival in 28 patients suffering from PAL in the Eastern region of France in order to help to characterize this disease.
MATERIALS AND METHODS
Study population:
This was a retrospective study covering the period from 1994 to 2014. The information was collected at five University Hospitals. The list of patients was obtained from the Pathology Departments of the different hospitals. Cases were selected on the basis of histological reports that confirmed an adrenal site of non-Hodgkin lymphoma.
PAL is defined by histologically-proven lymphomatous involvement of one or both adrenal glands in patients with no prior history of lymphoma. When the adrenal glands and other associated organs are involved, the adrenal lesions must be unequivocally dominant to confirm PAL.
Patients with secondary adrenal involvement because of an already-acknowledged lymphoma were not included. The study included only patients over 18. The medical records, either computer or paper records, were obtained mostly from haematology or endocrinology departments or from other departments involved in the initial diagnosis.
For each patient we collected the following information:
- demographic features,
- personal medical history,
- circumstances of the discovery of the disease,
- endocrine examination,
- initial biological examination,
- staging evaluation,
- interest of different radiological investigations (CT-scans, MRI, PET),
- treatment and initial response.
We referred to the 2011 WHO criteria for the histological classification of the lymphoma (3). The date of the diagnosis refers to the date the histological samples leading to a diagnosis PAL were delivered to the pathology departments. The response to the first line of treatment was defined according to the 1999 and 2007 Cheson criteria (‘4,5,6).
Diagnosis of adrenal insufficiency:
A short corticotropin test (250 µg) was used to establish the diagnosis of adrenal insufficiency. A peak cortisol level below 500 nmol/L (18 µg/dL) at 60 minutes indicates adrenal insufficiency. When a short corticotropin test was not performed, a morning cortisol level <140 nmol/L (5 ug/dL) in combination with a high ACTH level was also suggestive of adrenal insufficiency.
Statistical Analysis
The date of the last followed patient is provided. The duration of follow-up refers to the period between the date of diagnosis and the date of death, or the date of the last follow-up consultation.
Overall survival refers to the period between the date of the diagnosis and the date of death, whatever the cause. Progression-free survival refers to the period between the date of diagnosis and death by lymphoma or progression / relapse of the disease. Comparisons between groups were made using Student’s t test, or the Mann-Whitney U test and the chi 2 or Fisher’s exact probability test was used for categorical data. Statistical correlations were determined by the non-parametric Spearman test. Probability levels lower than 0.05 were considered significant. The survival curves were created with the Kaplan Meier method (R software).
RESULTS
In our study 28 patients were included in five centres from 1994 to 2014, (the characteristics are summarized in table 1).
Our cohort comprised 20 men (71%) and 8 women (29%), giving a sex ratio of 2.5. Their ages ranged from 25 to 88 years with a median age at diagnosis of 66 years. The median BMI was 26.4 kg/m2. None of our patients had a history of auto-immune disease. Four had a history of another cancer when the adrenal lymphoma was diagnosed, two prostate adenocarcinomas, one basal cell carcinoma and one chronic lymphoid leukaemia. One patient had immunosuppression (chemotherapy for chronic lymphoid leukaemia with hypogammaglobinaemia).
Departments responsible for the diagnosis
In 18 patients, the diagnosis was made by a haematology department (patients with extra- adrenal locations), in five patients by an endocrinology department and in the other five patients by other departments (infectious diseases for an initial suspicion of tuberculosis, internal medicine for two patients, dermatology and surgery departments). For the latter, immediate adrenalectomy led to the diagnosis.
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Histology
In 86% (24 of 28 patients) of the patients, the diagnosis was made on an adrenal biopsy with no failures. Only four patients underwent initial unilateral adrenalectomy (one intratumoral haemorrhage and one initial suspicion of adrenocortical carcinoma; two not known). Biopsies at other sites were performed as a complementary examination in six patients: four biopsies were positive for lymphoma.
The most frequent histology was a diffuse large B cell lymphoma (DLBCL) diagnosed in 78.6% of the patients (n = 22/28). One patient had mantle B cell lymphoma, one patient follicular lymphoma and three patients had T cell lymphoma. In one patient, the histology was mixed and showed B and T clonal populations (composite lymphoma).
Diagnosis
Clinical examinations
At the time of the diagnosis, the most frequent symptoms (figure 1) were worsening of the general state (77%, n = 20/26), weight loss (77%, n = 20/26) and anorexia (58%, n = 15/26). Abdominal pain was present in 11 patients (42%, n = 11/26). Neurological symptoms led to the diagnosis in two cases: headache with disorientation in one case and paralysis of several motor nerves in the other case. However, in the second case, the adrenal masses had been identified 6 months earlier, with no central nervous system involvement (normal MRI). PAL was discovered incidentally in only two patients (7%) during an examination for suspected pericarditis. A palpable mass (adenopathy, splenomegaly, hepatomegaly) was found retrospectively in only 18% (n = 5), 14% (n = 4), and 11% (n = 3) of patients.
Endocrinology examination
Adrenal insufficiency was confirmed in eight patients. Ten patients received Hydrocortisone®. Of the 20 patients with bilateral involvement, endocrinology investigations were done in 11 (55%). Signs likely to reveal adrenal insufficiency (hypotension, vomiting, hyponatremia) were found in 12 patients. Adrenal insufficiency was confirmed in 8 of the 11 tests (73%). Nine patients did not have an endocrinology evaluation, even though four of these had clinical signs
compatible with adrenal insufficiency. Skin hyperpigmentation linked to adrenal insufficiency was not reported in any of the files.
Biological examinations
Lactate deshydrogenase (LDH) levels were elevated in 20 out of the 27 patients tested (74%). It was over 2 N in 60% of those tested (n = 12). §2 microglobulin was elevated in 15 of 21 tested patients (71%), with a level over 3.5 mg/l (1.5 N) in 60% (n = 9/15) of cases. C-reactive protein (CRP) was elevated in 75% of patients (n = 21/28) with a rate over 50 mg/l (5 N) in 67% of patients (n = 14). Ferritinaemia was elevated in 74% of patients (n = 14/21), and 57% of the patients had levels over 1000 mg/l (3 N) (n = 8/14). In three patients, the cerebrospinal fluid was positive.
Imaging
CT-Scan
A CT-scan was performed in all patients (Fig 2). Bilateral adrenal involvement was present in 71% of the patients (n = 20/28). The median largest dimension of the mass was 80 mm (minimal value = 40 mm, maximal value = 180 mm). The median Hounsfield density (n = 6) was 35 Hounsfield units. The mass appeared homogeneous in five cases, heterogeneous in seven cases, invaded the inferior vena cava, the renal vessels or splenic vessels in five cases.
FDG-PET
Positron emission tomography with fluorodeoxyglucose (18FDG-PET) was performed in 10 patients (35.7%). The SUV (Standard Uptake Value) of the adrenal glands was high (median 17.24, minimal value = 9.5, maximal value = 48) and often more intense than the SUV of the other hypermetabolic foci (median 11.3, maximal value = 15.2). In addition, it seemed higher in bilateral PAL (n=5, median SUV = 19) than in unilateral PAL (n = 1, SUV = 9.5).
MRI
An MRI scan was performed in six patients (Fig 2). A hyposignal in T1 was found in the adrenal glands in three patients, an isosignal in T1 was present in one patient (two patients not known). A hypersignal in T2 was found in five patients (not known for one patient). There was no difference between homogeneous and heterogeneous lesions.
Extension
On the CT-scan, adrenal lesions alone were found in nine patients. In the other patients (n = 19), extra-adrenal locations were also described (seven had adenopathy, six had organ locations and six patients had both adenopathy and one or more other sites of their lymphoma). FDG uptake was confined to the adrenal glands in three of the ten patients who had a PET assessment, even though splenomegaly and a lung lesion had been found on the CT-scan in one patient. In the remaining seven patients assessed by PET, other hypermetabolic lesions in addition to the adrenal sites were found (70%) : organ involvement alone in two cases, and another organs associated with adenopathy in five cases.
In these 10 situations, FDG-PET gave a more precise work-up of the extension of the PAL in seven patients: by eliminating locations visualised on the CT-scan in two patients and by revealing new lesions in five patients. In three patients, the extension revealed by PET was similar to that revealed by the CT-scan. Three patients had initial neuro-meningitis involvement and two patients developed the condition subsequently.
Only six patients (21%) had an exclusively adrenal condition with no other locations (lymph nodes or organ) (Table 2). The main extra-adrenal locations are described in Table 3. They were mainly lymph nodes (68%). Extra-lymph node locations were present in 82% of patients, and mainly involved bones, the spleen, the lungs and bone marrow.
The largest diameter, the cumulative size (in patients with bilateral masses) and laterality were not significantly associated with the presence of extra-adrenal locations or biological parameters.
Treatment
The treatment was based on polychemotherapy associated with Rituximab (anti-CD20) in 17 patients (61%). Eighteen patients (64%) were given CHOP cures: cyclophosphamide, doxorubicin, vincristine and prednisone. Fourteen patients were given R-CHOP (50%), while 18% (n = 5) had chemotherapy by ACVBP (doxorubicin, cyclophosphamide, vincristine, bleomycin, prednisone). No patients had complementary radiotherapy.
After the first line treatment, 12 patients (43%) were in complete remission and 10 in partial remission (36%). Four responding patients (two in complete remission and two in partial remission) received high dose therapy followed by autologous stem cell transplantation (ASCT) as the consolidation treatment. ASCT was performed 4 months (n = 1) and 5 months (n = 3) after diagnosis. With a medium follow-up of 36.3 months, six patients (21%) showed disease progression during the first line of chemotherapy, and five patients relapsed after achieving a first response. Ten patients died during the study period: seven deaths were caused by the lymphoma, one by treatment toxicity, one by angiocholitis and one unknown. No death were caused by adrenal insufficiency. The median PFS and OS were 49.9% and 61.6% respectively, for the whole population and 100% for patients who received ASCT consolidation (Figure 3)
DISCUSSION
Our study included 28 patients with this rare disease in France. The initial clinical presentation varied, which led to heterogeneity in the medical care and treatment. Lesion were rarely restricted to the adrenal glands, and adenopathy or the involvement of other organs was frequently found. The main difficulties concern the diagnosis of PAL rather than adrenal cortical carcinoma and the standardization of extension investigations.
Primary adrenal lymphoma is a rare form of non-Hodgkin lymphoma (< 1%) and represents about 3% of extranodal lymphomas (1). Two hundred patients have been described in the literature (5).
The characteristics of our population correspond to the data found in the literature. PAL mainly affects men over 65 (7-9) (whereas adrenocortical carcinoma principally affects women aged
between 15 and 50 years) (6). One possible presentations is a clinical picture of adrenal insufficiency (7), often in patient with bilateral adrenal involvement (8). In our population, 13 patients showed signs of adrenal insufficiency. These signs may be non-specific and linked to the evolution of the lymphoma, which explain why one patient with unilateral adrenal lymphoma was described as having symptoms of adrenal insufficiency. However, adrenal insufficiency could be acute and in such case it is a critical situation. All suspicions of adrenal insufficiency should be investigated. Of the 20 patients with bilateral adrenal masses, nine were not tested for adrenal insufficiency (45%). Four patients with bilateral involvement and signs of adrenal insufficiency were not tested either. These patients were not managed by an endocrinology department. When endocrinology tests were performed, adrenal insufficiency was confirmed in 73% of patients with bilateral involvement and in 88% of patients with clinical or biological signs of adrenal insufficiency. All eight patients with confirmed adrenal insufficiency had bilateral masses. No patients with unilateral involvement showed adrenal insufficiency. Skin hyperpigmentation was not reported in any of the medical records, possibly because there were few endocrinology consultations. Consequently, an endocrinology evaluation appears necessary and should be systematic in patients with bilateral adrenal masses and/or clinical symptoms of adrenal insufficiency.
The initial examination in patients with adrenal lesion only should aim to orientate the diagnosis with the help of clinical, biological and imaging explorations. The worsening of the general state with weight loss were almost constant features in our PAL population. However these signs are not very discriminating as they can be found in other malignant diseases (adrenocortical carcinoma and adrenal metastases) (6). An inflammatory syndrome with high CRP and high ferritin levels associated with high levels of LDH and ß2 microglobulin can be observed in primary adrenal lymphoma. The same anomalies are described in patients with adrenocortical carcinoma (6) or metastases. The specificity of ß2 microglobulin orients the diagnosis towards a haematological disease, but, once again, there is no real difference allowing an easy diagnosis.
The contribution of the imaging examination is thus primordial (9-11). The CT-scan is essential to characterize the adrenal mass. However, in patients with PAL, the aspect is not very specific. Most of the time, the mass is hypodense, homogeneous or heterogeneous, of variable density
(often > 30 UH) with moderate enhancement after injection of a contrast agent. It can look like necrosis or suggest a cystic component (5,11,12). The tumour looks hypointense with T1-weighted MRI and hyperintense in T2 (5,11,12). Only six patients underwent MRI. However, the hyposignal in T1 could be discriminating compared with malignant adrenocortical carcinoma, in which T1 shows a hypersignal caused by haemorrhage or necrosis (6,10, 13,14). The lesions in our population were haemorrhagic in only one patient. As there were few patients in our study, the results must be interpreted with caution. More studies are necessary to confirm our findings. Primary adrenal lymphoma is mostly associated with extra-adrenal locations (lymph nodes or organs). The extension work-up essentially rests on the combination of a CT and FDG-PET-scan. PET was used in a small number of patients (n = 10). This could be explained by the fact that some records dated back to the pre-PET era. However, 12 patients diagnosed in the 2000s (1995-2005) did not benefit from a PET- scan at the initial investigation, which possible reflects local practices in the use of this examination. FDG-PET allowed a more precise evaluation of the PAL extension in seven of the 10 patients who underwent PET (by eliminating sites seen on the CT-scan in two patients and by revealing new sites in five patients). In three patients, the extension in the PET was comparable to that in the CT-scan. Given the interest of FDG-PET in the extension work-up of an adrenal mass, it should perhaps be used systematically. In patients with a suspected neoplastic disease or an adrenal mass, FDG-PET makes it possible to refine the diagnosis and to identify the initial site. In PAL, hyperfixation and SUV in the adrenal gland are high, and higher than the SUV of other associated sites, thus orienting the diagnosis towards primary adrenal lymphoma. FDG-PET is part of the initial examination of a malignant adrenocortical carcinoma to allow staging of the disease, but it is not indicated in the characterization of adrenal incidentaloma (11). Nonetheless, in patients with a large adrenal mass, it seems important to differentiate between benign and malignant disease (12). FDG-PET is indispensable for PAL staging, for supervision and for the evaluation of treatment response (4,13).
Clinicians may face difficulties when they discover heterogeneous masses with a differential diagnosis of adrenocortical carcinoma. In the absence of orienting signs in imaging examinations, the diagnosis is not easy, especially so if lesions are confined to the adrenal glands with no other locations. In our population, exclusive adrenal masses were unilateral in three patients and bilateral in
three other patients. Adrenal insufficiency was confirmed in two of these patients. The diagnosis was made by an adrenal biopsy in four cases and by surgery with adrenalectomy in two cases. This shows the importance of imaging examinations, especially CT-scan, MRI and FDG-PET-scan to obtain orienting elements in addition to biological and adrenal insufficiency evaluation.
In patients with suspected PAL or adrenal metastases, the definitive histological diagnosis is based on a fine needle biopsy under CT-scan control. No failures were observed in our population (14). Despite the large size of the adrenal masses (> 6 cm), which in theory is an indication for adrenalectomy, this procedure brings no additional benefit in PAL. Adrenalectomy is therefore useless.
Neurological symptoms led to the diagnosis in two patients: headache and disorientation for one patient and paralysis of several motor nerves for the other patient. Secondary neuromeningitis is a major negative prognostic factor (2% to 10% of DLBCL), (15). The risk factors are a high LDH level, old age, Ann-Arbor stage IV and a high IPI score (16). A adrenal lymphoma is therefore related to a high risk of CNS involvement and requires either an appropriate treatment strategy with systemic high dose methotrexate or cytarabine and intrathecal chemotherapy for patients with documented baseline CNS involvement, or chemoprophylaxis with intrathecal injections of methotrexate or cytarabine for the remaining patients (17).
As for other nodal or extra nodal lymphomas, the treatment of adrenal lymphoma is based on polychemotherapy. The reference chemotherapy regimen for DLBCL is R-CHOP (18)(19) but R- ACVBP could be preferred for young patients with risk factors (20,21). Radiotherapy is not advised and seems ineffective (16). Adrenalectomy preceding the chemotherapy adds no benefit to survival (18). The prognosis remains poor with a high risk of relapse, occurring within 2 years after the diagnosis. Thereafter a plateau is observed on the PFS and OS curves with few additional events. In the present study, 2 year overall survival and progression-free survival were 61.6% and 49.9% respectively and were comparable to those reported in the Kim study (18). Survival is longer if complete remission is obtained after the first line of chemotherapy (18) and ASCT consolidation could prolong survival (22).
Several limitations of the current study need to be considered. First, it was a retrospective study. Second, the number of patients was fairly small. We are aware that our results need to be confirmed in larger cohorts. Third, there is no standardisation of management procedures (endocrine examination, imaging) which makes it more difficult to extrapolate the results. However, our study considered a population of 28 patients included according to clinical information. The literature mainly considers case-reports or studies with small populations.
In conclusion, primary adrenal lymphoma is a rare disease. The clinical presentation of PAL includes major general symptoms, often associated with abdominal pain. Only half of the patients with bilateral masses were screened for adrenal insufficiency. The initial care needs to be codified and should include endocrinology examination in patients with bilateral adrenal masses and/or symptoms of adrenal insufficiency. FDG-PET appears to be more discriminating than a CT-scan and was an efficient examination to reveal extra-adrenal locations. The preliminary results of MRI to distinguish between PAL and adrenocortical carcinoma should be confirmed.
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| Sexe | F | 8 (29%) |
| M | 20 (71%) | |
| Age of diagnosis (years) | 66 | |
| Unilateral PAL | 8 (29%) | |
| Bilateral PAL | 20 (71%) | |
| Size (mm) | 80 | |
| DLBCL | 22 (79%) | |
| Other histology | 6 (21%) | |
| Adrenal biopsy | 24 (86%) | |
| Adrenalectomy | 4 (14%) | |
| N (%) ☒ | |
|---|---|
| Exclusive Adrenal Localisation | 6 (21 %) |
| 1 Extra-Adrenal Localisation | 4 (14 %) |
| 2 Extra-Adrenal Localisation | 9 (32 %) |
| ≥ 3 Extra-Adrenal Localisation | 9 (32 %) |
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| Lymph Node Localisations | Abdominal | 11 |
|---|---|---|
| Mediastinal | 7 | |
| Cervical / Axillary | 3 | |
| Extra-Lymph Node Localisations | Bones | 6 |
| Lung | 3 | |
| Osteomedullary cells | 4 | |
| Skin | 1 | |
| Ovary / Testis | 1 / 1 | |
| Thyroid | 1 | |
| Digestive | 2 | |
| Pericardium / Pleura | 2/ 1 | |
| Spleen | 5 | |
| Liver | 2 | |
| Kidney | 1 | |
| Meningal / Cerebral | 2/ 1 |
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Figure 1: Symptoms revealing primary adrenal lymphoma.
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Figure 2: Imaging of primary adrenal lymphoma . A-B -C: Right unilateral primary adrenal lymphoma 14.1 cm; (A - CT scan), (B-MRI scan), ( C- Positron emission tomography with fluorodeoxyglucose with a Standard Uptake Value of right adrenal tumor = 9.5). D - CT scan of a bilateral primary adrenal lymphoma (right 12X7 cm; Left 13X10 cm).
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Figure 3: Overall and Progression-free survival.
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Conflict of Interest: The authors declare that they have no conflict of interest.
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ABBREVIATIONS
PAL = Primary Adrenal Lymphoma
LDH = Serum Lactate Dehydrogenase
CRP = C Reactive Protein
CT = Computed Tomography
MRI = Magnetic Resonance Imaging
PET = Positron Emission Tomography
WHO = World Health Organization
BMI = Body Mass Index
IU = International Unit
N = Normal
FDG = FluoroDeoxyGlucose
SUV = Standard Uptake Value
DLBCL = Diffuse Large B Cell Lymphoma
R-CHOP = Rituximab, Cyclophosphamide, Doxorubicin, Oncovin, Prednisone
ACVBP = Doxorubicin, Cyclophosphamide, Vincristine, Bleomycin, Prednisone HU = Hounsfield Unit
IPI = International Prognosis Index
REVEALING SYMPTOMS
90
80
77
77
70
60
58
50
42
40
38
30
27
23
20
19
10
8
7
0
WORSENING of the GENERAL STATE
WEIGHT LOSS
ANOREXIA
ABDOMINAL PAIN
FEVER
DIGESTIVE DISORDERS
BACK PAIN
SWEAT
NEUROLOGIC SYMPTOMS
INCIDENTALOMA
[R]
[L]
C40
OMNIPAQUE
[P]
W400
R
P.
R
R
R
R
F
F
F
F
F
F
0
1
1
R
R
R
R
R
R
S
F
F
F
F
F
F
0
9
O
R
R
R.
R
F
R
R.
0
F
F
F
F
F
F
Im: 13
Study Date:
Study Time: IPP:
[R]
[L]
C353
[P]
VV848
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B
[R]
[L]
C40
IOMERON 400
[P]
W350
1.0
0.8
Survival
0.6
+
0.4
0.2
Overall Survival Almost Population
Progression Free Survival Almost Population
0.0
0
20
40
60
80
100
120
140
Tracking Duration (months)
Figure 3 174x153mm (96 x 96 DPI)