http://www.enm-kes.org

Received: 19 June 2010, Accepted: 28 August 2010Corresponding author: Sung-Kil LimDepartment of Internal Medicine, Yonsei University College of Medicine, 250 Seongsan-ro, Seodaemun-gu, Seoul 120-752, KoreaTel: +82-2-2228-1948, Fax: +82-2-393-6884, E-mail: lsk@yuhs.ac

Primary Bilateral Adrenal Non-Hodgkin’s Lymphoma Presented with Adrenal Insufficiency: A Case Report Eun Young Lee, Kyoung Min Kim, Kwang Joon Kim, Songmi Noh1, Jin Seok Kim, Woo Ik Yang1, Sung-Kil LimDepartments of Internal Medicine and Pathology1, Yonsei University College of Medicine, Seoul, Korea

Primary adrenal lymphoma is a very rare disease and it is known to have a poor prognosis. We report here on a case of primary adre-nal insufficiency that was secondary to primary bilateral adrenal lymphoma. A 54-year old man was hospitalized because of easy fa-tigability, weight loss and consistent malaise for 6 months. The physical examination revealed hyperpigmentation on the anterior chest and hypotension. According these findings and symptoms, we did a rapid ACTH stimulation test with a clinical suspicion of adrenal insufficiency. He showed an inadequate adrenal response and so he was diagnosed with adrenal insufficiency. The abdom-inal CT images showed bilateral huge adrenal masses and increased uptake of the adrenal glands on PET. The pathologic diagnosis by ultrasound-guided gun biopsy of the right adrenal gland was diffuse large B cell lymphoma. The patient was administered combi-nation chemotherapy with the R-CHOP regimen, and after 8-cycles of chemotherapy, he achieved complete remission of tumor ac-cording to the image studies and he recovered his adrenal function. Primary adrenal lymphoma, although a rare disease, should be considered in patients with bilateral enlargement of the adrenal glands and when the adrenal glands show increased uptake on a PET scan, and especially there is adrenal insufficiency. (Endocrinol Metab 26:101-105, 2011)

Key Words: Adrenal insufficiency, Non-Hodgkin’s lymphoma

Endocrinol Metab 26(1):101-105, March 2011DOI: 10.3803/EnM.2011.26.1.101 CASE REPORT

INTRODUCTION

Non-Hodgkin’s lymphoma (NHL) refers to all malignancies of

the lymphoid system with the exception of Hodgkin’s lymphoma

and is around 90% of all malignant lymphomas [1]. Most patients

with NHL present with painless lymphadenopathy, commonly in

the cervical or supraclavicular regions [2]. However, extranodal

presentation of NHL occurs in 15% to 40% of patients at presenta-

tion and varies depending on immune status and geographic differ-

ences. The most common extranodal sites are the gastrointestinal

tract and nasopharynx. Other common sites include skin, bone,

brain, lung, thyroid, salivary glands, and testis [2-6]. Secondary in-

volvement of the adrenal gland with NHL has been reported to oc-

cur in up to 25% of patients during the course of disease [2,7].

However, primary adrenal lymphoma (PAL) is a very rare disease

and is often accompanied by adrenal insufficiency. The first case

of PAL with adrenal insufficiency was reported in 1970 and only

ten cases of PAL had been reported until the year 1989 [8]. The

prognosis of PAL is known as poor [8-10], but early diagnosis and

combination chemotherapy may improve not only the prognosis of

lymphoma, but also adrenal function [8].

PAL should be considered in patients with bilateral enlargement

of adrenal glands, especially with adrenal insufficiency [8]. We re-

port a case of PAL with primary adrenal insufficiency, which showed

early diagnosis and treatment could improve the prognosis.

CASE REPORT

A 54-year old man was hospitalized because of easy fatigability,

weight loss of 10 kg and consistent malaise for 6 months. On ad-

mission, his vital signs were as follows: body temperature, 36.7℃;

pulse rate 113 beats per minute; blood pressure 98/77 mmHg.

Physical examination revealed some pigmented spots on his upper

chest and face (Fig. 1). His tongue was dry and skin turgor was de-

creased. Neither lymphadenopathy or hepatosplenomegaly was

noted. Ascites and edema were not present.

A complete blood count showed hemoglobin 12.4 g/dL, hemato-

crit 35.2%, white blood cell count 8320/mL with 58.7% segmented

neutrophils, 24% lymphocytes, and 8.8% monocytes, and a platelet

count 234,000/mL. The serum sodium, potassium and chloride

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levels were 128, 4.7, and 91 mEq/L, respectively. The serum β2 mi-

croglobulin increased to 3.31 mg/L (normal, 0.0-2.71 mg/L). The

serum lactate dehydrogenase level increased to 285 IU/L (normal,

119-247 IU/L). The serum cortisol (8 AM) was 47.85 ng/mL (nor-

mal, 70-250) and the plasma adrenocorticotrophic hormone

(ACTH) (8 AM) increased to 147.29 pg/mL (normal, 10-60). Twenty

four-hour urine vanillylmandelic acid, epinephrine, metanephrine,

norepinephrine, and free cortisol were within normal. plasma re-

nin activity increased to 23.53 ng/mL/hr (normal, 0.15-2.23 ng/mL/

hr) and aldosterone level was 98.88 pg/mL (normal, 29.9-158.8 pg/

mL). We suspect adrenal insufficiency because of hyponatremia,

fatigability, weight loss, consistent malaise and hypotension. Clini-

cal suspicion of adrenal insufficiency was confirmed by the finding

of a low serum cortisol level of 47.85 ng/mL at 8 AM, a high plasma

ACTH level of 147.29 pg/mL at 8 AM, and low cortisol level of

100.14 ng/mL 1 hour after the rapid ACTH stimulation test.

The chest X-ray was normal without evidence of hilar lymphade-

nopathy. The patient was aged person with prominent weight loss,

so we took a computerized tomographic (CT) scan. A CT scan

showed large bilateral adrenal gland masses with poor enhance-

ment (Fig. 2). Right adrenal mass invaded S7 of liver and was adja-

cent to right diaphragm. There were no lymphadenopathy and as-

cites. Our impressions were lymphoma, metastasis, or adrenal car-

cinoma. Fludeoxyglucose positron emission tomography (FDG

PET)-CT scan was performed to identify the masses and showed

huge bilateral adrenal masses with intense FDG uptake and inva-

sion of right adrenal mass into the right hepatic lobe (Fig. 3). These

findings are consistent with malignancy. In the rest of the body,

there was no increased FDG uptake which suggests malignancy.

An ultrasound-guided percutaneous gun biopsy of the right adre-

nal mass was performed. The gun biopsied specimen showed dif-

fuse proliferation of large atypical cells without forming organoid

structures. The tumor cells showed folded nuclei with one or mul-

tiple prominent nucleoli and a variable amount of cytoplasm (Fig.

4A). They showed positive reactions with CD20 on immunohisto-

chemical stain (Fig. 4B), but negative reactions with CD3, CD10,

and cytokeratin. The final diagnosis was bilateral adrenal diffuse

large B cell lymphoma (DLBCL) with adrenal insufficiency, and the

clinical staging by the Ann Arbor system was ⅣB, and interna-

tional prognostic index was low intermediate risk group.

The patient received adrenal hormone replacement with Cor-

tico® (hydrocortisone) 30 mg daily. He also was administered com-

bination chemotherapy with R-CHOP regimen; rituximab, cyclo-

phosphamide, doxorubicin, vincristine, prednisolone. After 3 cy-

cles of chemotherapy, left adrenal mass was not visible and right

adrenal mass decreased in size from 6.4 cm to 3.7 cm by CT scan.

He received total 8 cycles of chemotherapy, because PET scan

showed mild hypermetabolism on right adrenal gland after sixth

Fig. 3. FDG-PET scan at diagno-sis showed huge bilateral adrenal masses with intense FDG uptake. Right adrenal mass invaded into the right hepatic lobe.

Fig. 2. Abdomen CT scan at diagnosis showed about 6.4 cm sized adrenal gland masses.

Fig. 1. Appearance of the patient: Hyperpigmentation on skin (A) face and the upper chest (B) back. Arrows: hyperpigmented spots.

A B

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cycle of chemotherapy. After 8 cycles of chemotherapy, right adre-

nal mass further decreased in size from 3.7 cm to 3.5 cm by CT

scan and there were no increased FDG uptake by PET scan (Fig.

5). He had taken a prednisolone 10 mg per day for 6 months. Clini-

cally adrenal insufficiency was also improved with disease remis-

sion, so the dose of steroid replacement was tapered off. This pa-

tient is continued to be followed up without any evidence of recur-

rence. Furthermore, he did not have any signs or symptoms of ad-

renal insufficiency for 1 year.

DISCUSSION

Adrenal glands are common metastatic site of primary cancers,

such as breast, lung, lymphoma, melanoma, leukemia, renal cell

and ovarian cancers [11]. In contrast to primary tumors, many me-

tastases tend to invade both adrenal glands. Primary malignant

lymphomas arising in endocrine organs are rare with representing

only 3% of extranodal lymphomas [8]. They are almost confined to

the thyroid gland [5,12] and primary lymphoma originated from

adrenal is extremely rare. The first case of PAL with adrenal insuf-

ficiency was reported in 1970 and only ten cases of PAL had been

reported until the year 1989. The development of imaging tech-

niques and immunostaining procedures makes the diagnosis of

PAL easier and so, about 120 cases of PAL have been reported in

the literature [9].

Adrenal insufficiency is rare because it becomes apparent when

approximately 90% of adrenal cortex is destructed [13]. And most

of adrenal insufficiency are believed to be associated with atrophy

of adrenal glands, secondary to autoimmune mechanisms [14]. Ap-

proximately 50% of patients with primary adrenal lymphoma pres-

Fig. 4. High-power view of the adrenal gland tumor (both, x 200). A. The gun biopsied specimen showed diffuse proliferation of large atypical cells, which had fold-ed nuclei with one or multiple prominent nucleoli (H&E staining). B. The tumor cells were positive to CD20 immunohistochemical staining.

A B

Fig. 5. Imaging studies after 8 cycle R-CHOP. A. Abdominal CT scan. B. FDG-PET scan.

A B

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ent with symptoms of adrenal insufficiency [9]. Our patient also

showed typical symptoms and sings of adrenal failure. In this pa-

tient, dehydration accompanied with by adrenal insufficiency may

cause to increase renin activity. Human adrenal glands contain no

lymphoid tissue, so PAL is believed to arise from previous autoim-

mune adrenalitis, which explain why adrenal insufficiency is com-

mon in PAL. The symptoms of adrenal insufficiency are general

weakness, fatigue, weight loss, hyperpigmentation, hypotension,

fever, and gastrointestinal symptoms such as anorexia, nausea,

vomiting and dyspepsia [9]. Among disease symptoms, hyperpig-

mentation is usually present with long term adrenal insufficiency.

Because DLBCL is aggressive disease, most PAL patients with adre-

nal insufficiency are not present with hyperpigmentation. How-

ever, our patient had some pigmented spots on his upper chest

and face (Fig. 1), which mean chronic progression of the disease.

Primary adrenal insufficiency can be confirmed by low basal se-

rum cortisol level, high ACTH level, and inadequate adrenal re-

sponse to the rapid ACTH stimulations [14].

In PAL, men are more frequently affected than women, with a

ratio of 3:1. The mean age at the time of diagnosis is 68 years (range

39-89). More than two-third of PAL are bilateral. Most common

histopathology is diffuse large cell lymphoma of B cell lineage [9].

These malignant cells express CD45, and antigens specific to B

lymphocytes, such as CD19, CD20, and CD79a [15]. About 10% of

de novo DLBCL cases express CD5 and CD5-positive DLBCL is

more common in older women, with extranodal involvement and

associated with a shorter survival [15]. T cell lymphoma, expressing

antigens specific to T lymphocytes, such as CD3, CD5, and CD7

[16] occupies less than 10% of PAL. In our case, the tumor cells

showed positive reactions with CD20 on immunohistochemical

stain, but negative reactions with CD3 and CD10. Less common

histopathology includes small-cell lymphoma, mixed small- and

large-cell lymphoma, undifferentiated lymphoma, anaplastic large-

cell and follicular lymphoma [9]. On CT scan, lymphomas usually

show complex masses with variable density and sometimes ac-

companied by necrosis and hemorrhage, but calcification is un-

common. The contour of the involved adrenal gland may be pre-

served. On MRI scan, lymphomas show low signal intensity on T1-

weighted images and heterogeneous high signal intensity on T2-

weighted images. However, CT and MRI finding of adrenal lym-

phoma are not specific [17]. In our case, CT scan showed large bi-

lateral adrenal gland masses with poor enhancement, and lym-

phoma, metastasis or adrenal carcinoma were included in the dif-

ferential diagnosis. FDG PET scan is useful for diagnosis of malig-

nancy. And if malignancy is diagnosed, FDG PET can be useful for

detecting tumor recurrences and response to treatment [8]. Percu-

taneous needle biopsy under CT or US guidance has been reported

as a safe and accurate diagnostic tool. Before a biopsy in patient

with adrenal masses, we must exclude pheochromocytoma to avoid

a hypertensive crisis.

The prognosis of PAL is known as poor, but early diagnosis of

the disease and combination chemotherapy may improve the

prognosis. Several poor prognostic factors of PAL are old age, adre-

nal insufficiency, large tumor size, elevated serum LDH level and

expression of CD5 [18,19]. The cause of death is severe infection,

pulmonary embolism, and tumor recurrence [20]. One study re-

ported that mean overall-survival rate is 15.3 months; 34 months of

the patients who achieve a partial or complete remission after che-

motherapy and 3.6 months of the patients who have no response

to chemotherapy [8]. The longest survival was 50 months in cases

of treating with CHOP chemotherapy [13]. The treatment of PAL is

not established, but recent studies show that chemotherapy includ-

ing CHOP can extend survival. The regimens of chemotherapy in-

clude CHOP (cyclophosphamide, doxorubicin, vincristine, and

prednisone), R-CHOP (adding rituximab to CHOP), CHO (cyclo-

phosphamide, doxorubicin, vincristine), CVP (cyclophosphamide,

vincristine, and prednisone) or MACOP (cyclophosphamide, doxo-

rubicin, prednisone, methotrexate, bleomycin) [9]. Surgical resec-

tion only is not recommended for PAL treatment because of a poor

outcome. The role of radiation therapy on PAL is unknown. But in

some cases, the patients with PAL had radiation therapy with che-

motherapy [9]. CNS prophylaxis with intrathecal methotrexate is

also considered in patients with high risk of CNS involvement. Risk

factors for CNS involvement are elevated serum LDH level, high/

intermediate or high International Prognostic Index and involve-

ment of more than one extranodal site including bone marrow [9].

In this case, the patient had taken abdomen ultrasonography and

CT at first visit of our hospital, and diagnosed of NHL by percuta-

neous gun biopsy. After pathologic diagnosis, he received combi-

nation chemotherapy without delay. After 8-cycle of chemotherapy,

he achieved complete remission clinically. Primary adrenal lym-

phoma, although a rare disease, should be considered in patients

with bilateral enlargement of adrenal glands, especially with adre-

nal insufficiency. And early diagnosis can lead to better prognosis

by early treatment.

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REFERENCES

1.Ekstrom-SmedbyK:Epidemiologyandetiologyofnon-Hodgkinlym-phoma-areview.ActaOncol45:258-271,2006

2.RosenbergSA,DiamondHD,JaslowitzB,CraverLF:Lymphosarcoma:areviewof1269cases.Medicine(Baltimore)40:31-84,1961

3.JonesSE,FuksZ,BullM,KadinME,DorfmanRF,KaplanHS,Rosen-bergSA,KimH:Non-Hodgkin’slymphomas.IV.Clinicopathologiccor-relationin405cases.Cancer31:806-823,1973

4.VegaF,LinP,MedeirosLJ:Extranodallymphomasoftheheadandneck.AnnDiagnPathol9:340-350,2005

5.AlShemmariSH,AmeenRM,SajnaniKP:Extranodallymphoma:acom-parativestudy.Hematology13:163-169,2008

6.SaidJ:DiffuseaggressiveB-celllymphomas.AdvAnatPathol16:216-235,2009

7.PalingMR,WilliamsonBR:Adrenalinvolvementinnon-Hodgkinlym-phoma.AJRAmJRoentgenol141:303-305,1983

8.KumarR,XiuY,MaviA,El-HaddadG,ZhuangH,AlaviA:FDG-PETimaginginprimarybilateraladrenallymphoma:acasereportandreviewoftheliterature.ClinNuclMed30:222-230,2005

9.OzimekA,DieboldJ,LinkeR,HeynJ,HallfeldtK,MussackT:Bilateralprimaryadrenalnon-Hodgkin’slymphomaandprimaryadrenocorticalcarcinoma-reviewoftheliteraturepreoperativedifferentiationofadrenaltumors.EndocrJ55:625-638,2008

10.WangJ,SunNC,RensloR,ChuangCC,TabbarahHJ,BarajasL,FrenchSW:Clinicallysilentprimaryadrenallymphoma:acasereportandreviewoftheliterature.AmJHematol58:130-136,1998

11.MansmannG,LauJ,BalkE,RothbergM,MiyachiY,BornsteinSR:Theclinicallyinapparentadrenalmass:updateindiagnosisandmanagement.

EndocrRev25:309-340,200412.KrolAD,leCessieS,SnijderS,Kluin-NelemansJC,KluinPM,Noordijk

EM:Primaryextranodalnon-Hodgkin’slymphoma(NHL):theimpactofalternativedefinitionstestedintheComprehensiveCancerCentreWestpopulation-basedNHLregistry.AnnOncol14:131-139,2003

13.KuyamaA,TakeuchiM,MunemasaM,TsutsuiK,AgaN,GodaY,Kane-tadaK:Successfultreatmentofprimaryadrenalnon-Hodgkin’slymphomaassociatedwithadrenalinsufficiency.LeukLymphoma38:203-205,2000

14.OelkersW:Adrenalinsufficiency.NEnglJMed335:1206-1212,199615.deLevalL,HasserjianRP:DiffuselargeB-celllymphomasandburkitt

lymphoma.HematolOncolClinNorthAm23:791-827,200916.LibeR,GiavoliC,BarbettaL,Dall’AstaC,PassiniE,BuffaR,Beck-Pec-

cozP,AmbrosiB:Aprimaryadrenalnon-Hodgkin’slymphomapresent-ingasanincidentaladrenalmass.ExpClinEndocrinolDiabetes114:140-144,2006

17.ZhangLJ,YangGF,ShenW,QiJ:Imagingofprimaryadrenallympho-ma:casereportandliteraturereview.ActaRadiol47:993-997,2006

18.YamaguchiM,SetoM,OkamotoM,IchinohasamaR,NakamuraN,Yo-shinoT,SuzumiyaJ,MuraseT,MiuraI,AkasakaT,TamaruJ,SuzukiR,KagamiY,HiranoM,MorishimaY,UedaR,ShikuH,NakamuraS:DenovoCD5+diffuselargeB-celllymphoma:aclinicopathologicstudyof109patients.Blood99:815-821,2002

19.SchreiberCS,SakonJR,SimiaoFP,TomarchioMP,HuayllasM,PereiraLC,StellaLC,SantomauroACJr,BuenoSS,FraigeFF:Primaryadrenallymphoma:acaseseriesstudy.AnnHematol87:859-861,2008

20.HsuCW,HoCL,SheuWH,HarnHJ,ChaoTY:Adrenalinsufficiencycausedbyprimaryaggressivenon-Hodgkin’slymphomaofbilateraladre-nalglands:reportofacaseandliteraturereview.AnnHematol78:151-154,1999