Primary anaplastic large cell lymphoma of the adrenal gland

Primary anaplastic large cell lymphoma of the adrenal gland

Primary Anaplastic Large Cell Lymphoma of the Adrenal Gland Wendy L. Frankel, MD, Peter Shapiro, MD, and Noel Weidner, MD Primary adrenal lymphomas ...

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Primary

Anaplastic Large Cell Lymphoma of the Adrenal Gland

Wendy L. Frankel, MD, Peter Shapiro, MD, and Noel Weidner, MD Primary adrenal lymphomas are rare. Most reported cases are of B-cell phenotype and follow an aggressive clinical course. We report a case of primary anaplastic large cell, CD30+ adrenal lymphoma developing in a 62-year-old woman. The patient presented with fatigue and vague right upper quadrant pressure. Computed tomography revealed bilateral adrenal masses. A right adrenalectomy was performed. Histologic evaluation showed islands of large atypical cells surrounded by eosinophilic acellular material. The tumor cells stained positive for CD45, CD45R0, CD43, and CD30. Epstein-Barr virus genome was identified in tumor cells using in situ hybridization. The patient was treated with chemotherapy and a 23-month follow-up examination showed no change in the size of the opposite adrenal gland and no other evidence of lymphoma.

Ann Diagn Path01 4: 158-164,200O. Index positive

Words: Primary adrenal lymphoma, Epstein-Barr

Copyright

0 2000 by W.B. Saunders Company

lymphoma, anaplastic large virus-associated lymphoma

ECONDARY adrenal in\.ol\w~~ent bp non-Hodgkin’s l>mphomas is a relatively co~mnon finding.’ Ho~ve\rer, prima? adrenal l~mphomas are rare. At lcast 3 1 cases have been reported from Western countries”-‘“’ and 20 cases have been reported in the English literature from Japan. “’ The majority of patients did poorl) and many died from 1)mphoma. OnI>. four patients Ivith a kno\\n follo\v-up period of at least one-year sur-

S

cell

lymphoma,

CD30-

clinicopathologic fcaturcs in this patieni as \vell as the immunohistologic findings in the tuiiior ant1 re\ie\v the litcraturc on primal? adrenal l!mphomas. This is the first report providing detailed pathologic features of an anaplastic large ccl1 primay adrenal l~mphoma.

Case Report

,~\,ed~“;‘“;‘7,“U

.462-year-old \\oman xvith insulindepcndent diabetes mcllitus presented \tith the insidious onset of fatigue and right upper quadrant prrssure. She had no histor).of hcmatologic 01 chronic inllammaton. diseases. Her tra\,el histol? included

Most primaT adrenal l!mphomas are B-cell t)-pe. Four cases of adrenal I>mphoma with T-cell phenot)pe”.?“;27,3” and a single case of CD30+ l)mphoma’a have been reported. There is some evidence that adrenal lytnphomas are associated Ivith the presence of Epstein-Barr virus (EBV),j” and EBV has been associated in some studies \\ith anaplastic large cell l>mpho-

trips

tn

,\lesico

unrcmarkahlc. strated mately \\ithin

mas.31.3”

We recently studied a patient w-it11 primay anaplastic CD30+ large cell adrenal lymphoma. We discuss the

and

Bali.

Computed

The

examination

needle biopsies h>. a right adrenalectomy

\vas

(CT) scans demon-

hilatcral adrenal masses, the right measuring 15 cm and the left, 4 cm (Fig I). Endocrine normal limitsP’ 1 he patient undenvent three

tic percutaneous follo\ved

physical

tomography

apprositests \vere

nondiagnos-

of the right adrenal 6 months after

mass, initial

presentation. After

surgcn.

the patient

had

a staging

work-up

consisting

of follo\v-up chest, abdomen, and pelvic c?‘ scans that sho\ved no change in the left adrenal mass or other c\idcncc of tumor. Bone marrow aspirate and biopsy were negative for Iymphoma. The

patient

has been

suhscqucntly

treated

\\ith

six c).cles of

c!losan, dosorut~icin, lincristine, and prednisone. So clinical or radiologic evidence of recurrence or metastasis has been identified. Se\,entecn months after surgel)~ (23 months after presentation), she continues to do \vell. 158

Annals

of Diagnostic

Pathology,

Vol4.

No 3 (June),

2000:

pp 156-164

CD30+

Lymphoma

of the Adrenal

Gland

Figure 1. A CT scan of the abdomen before surgery. The right adrenal gland was 15 cm and the left. 4 cm.

Materials and Methods The hmalin.

adrenalectomy Sections were

Microscupic Findings

specimen ~~4s fiscd in IO% buffcrcd embeclclecl

in paraflin

and

routineI> mtlci-

processed. Sliclcs \vere stained \\ith llematos)lin-cosin, carmine. periodic a&-SchiK, Gomori’s mcthanc sihvr. acid lhst bacilli, ancl Gngo red. Immunoliistocliei~iist~ \\‘as pcrforniecl using the lollo\\ing prima? antibodies: cytokcratin cocktail (Ch\l 5.2 [BectonDickinson,San,Josc,CA], diluted 1:lW;~l/AE3 [BocrhingcrMannheim, Inclianapolis, IN], clilukcl I :600), \inientin (VY [Monosan Caltag, Burlingame, CA], dilutccl l:jO), CD68 (WI [Dako, Carpinteria, CA], diluted I: l,OOO), CD15 (1IMA [Bccton-Dickinson], diluted i:jO), CID3 (Dako, diluted I :300), CD20 (L26 [Dako], cliluted l:(jOO), CD-I-5 (2Bl I and PD7/ 2G/lti [Dako], diluted 1:IOO), CD45RO (.Mj [Z>-mccl, South San Francisco, CA], diluted l:500), CD43 (DF-1-I [Dako], dilutccl I :200), CD30 (Ber-HZ [Dako], dilutecl 1: I25), chromogranin A (LK2HIO [Biugcncs, San Ramon, CA], diluted 1: IO), kappa and lambda (Dako, cliluted 1:40,000), ALE;-I (Dako, diluted I:j), EBV LMP-I (CSl-4 [Dako], diluted l:(iO), S-100 (Dako, diluted I: l,OOO), and, using the Dako I,%~+ Kit, perosidase consisting of labeled strepta\idin biotin reagents. In situ hybriclization MYISperformed li)r EBV using the Super-Scnsiti\,e mlt\J.i\ Probe Kit (Biogenes). l’he EBER mRN.4 probe (Biogcnes) was used undiluted.

Results Gross Findings The adrenalectomy specimen iveighccl 710 g and measured 7 X 12 X 13.5 cm. It consisted of a unilocular thick-walled cystic mass containing friable, granular light brown material surrounded b>. a thin rim of residual adrenal tissue.

The majority of the mass was composed of cosinophilic acellular material encased b>r a fibrotic, inflamed, and hemorrhagic capsule. Focally, a rim of residual adrenal gland was present in this fibrotic shell. Scattered within the acellular eosinophilic debris were both ghost necrotic tumor cells and small islands of large, atypical, pleomorphic cells (Fig 2). The pleomorphic cells had variable nuclear to Lztoplasmic ratios, modcrate amounts of clear to cosinophilic qtoplasm, hlperchromatic nuclei, clumped chromatin, prominent nucleoli, ancl frequent mitotic ligures (Figs 3 and 4). Stains for mucicarminc, periodic acid-Schiff, acid fast bacilli, Gomori’s mcthanc sihrer, and Congo red \vere negative.

Immunohistochemical Findings The tumor cells stained strongI>, positive for CD30 (Ber-H2) (Fig 5), CD43, and limentin and were focall) positi\:c for CD45 and CD45RO. Tumor cells were negatilre for qtokeratin cocktail (CAM5.2 + AEl/AE3), ALK1, CD68, CD20, CD3, CDl5, chromogranin A, kappa, lambda, S-100 protein, ancl EBV.

In Situ Hybridization Tumor genome.

ccl1 nuclei

stained

strongI).

positi\re

for EBV

Discussion The aclrenal glands Hodgkin’s lymphoma.

arc frequently affected by nonIn an autopsy study, approxi-

160

Frankel,

Shapiro,

and

Weidner

Figure 2. The adrenal tumor consisting primarily of eosinophilic acellular material with a rim of residual adrenal gland (large arrow) and small islands of tumor cells (small arrows). mately 25% of the 1,269 patients with lymphoma had adrenal gland involvement.] By the time the adrenal glands are affected, most lymphomas are widespread and involve other organs and lymph nodes. Primary adrenal lymphoma is rare. Approximately 51 cases without initial involvement of any other sites than the adrenal glands have been reported from Western countries24g and from Japan in the English literature.30 Although the number of cases of primary adrenal lymphoma reported in the literature has been growing, the true incidence is difficult to determine because some studies have included patients with other organ involvement. In the reported cases of primary adrenal lym-

Figure 3. The adrenal

tumor consisting of large pleomorphic cells with hyperchromatic nuclei, prominent nucleoli, and frequent mitotic figures.

phoma, patient age ranges from 27 to 89 years and the male to female ratio is approximately 2: 1. Thirty-five tumors were bilateral, 12 were in the left adrenal, and four were in the right. Adrenal function was specified in 43 patients. It was normal in 25 patients, insufficiency was present in 17, and the syndrome of inappropriate antidiuretic hormone secretion was diagnosed in one. All patients with adrenal insufliciency had bilateral adrenal tumors2-30 The pathologic findings were varied in the reported cases and exact comparisons are difficult due to differences in lymphoma terminology and the use of different immunohistochemical markers for B and T cells. Most

CD30+

Figure

4.

Tumor cells with

Lymphoma

of the Adrenal

Gland

161

reniform

nuclei. tumors were diffuse and many were large cell type. Six were described as pleomorphic and one was categorized as undifferentiated. Immunohistochemistry demonstrated B-cell positivity in 33, T-phenotype in four, Band T-cell negativity in four, and not specified (or not done) in 1O.2-“0 The prognosis for patients with primaT adrenal Iymphoma is poor. Only four of the previously described patients with at least a l-year follovz-up period survived”~2”~2iJ~’ and all were treated with chemotherapy. Many others died before treatment or during the initiation of chemotherapy. Those treated with aggressive early chemotherapy seemed to do best.‘” The longest sunivor of those who clid not receive chemotherapy

survived only 9 months. 3o This patient had a diffuse large cell lymphoma that stained negatively for B- and T-cell markers. Primary adrenal lymphoma is an aggressive disease with only short-term survival reported in most cases. One patient recently reported survived for 8 years at the last follow-up visit.27 It is unclear why this patient has done so well. The tumor was T-cell type and adjuvant radiation therapywas performed after adrenalto other patients in whom no ectomy, in contrast radiation was used. Of the cases previously reported, only one tumor showed positive staining with CD30; this tumor was diagnosed as an anaplastic large cell 1ymphoma.t’ CD30 immunohistochemistry was not performed or not re-

.

\a



$

Figure 5. Tumor tively with CD30.

cells

staining

posi-

162

Franked,

Shapiro,

ported in any other cases. The prtxiously reported case of CD30+ IJmphoma failed to stain for an)’ B- or T-ccl1 marker evaluated (CD1 through CD5, CD7, CD8, CDl9, or CD20). The case of anaplastic large cell l~mphoma described in this report sho\\,ed positi\.e staining for CD30, CD-43, and CD-LSRO, supporting a T-cell lineage. Anaplastic large ccl1 1)mphoma esprcsscs “activation” antigen CD30 (K&l), Ivhich lvas first clcscribcd b> Stein et al”” in 1985. Anaplastic large cell 1)mphoma accounts for approsimately 5% of all non-Hodgkin’s (male to lymphomas. 34 There is a male predominance female ratio, 2:1) and patient ages range \\idcl!,. The clinical presentation is highly \.ariable, \\ith the lymph nodes, skin, bone, and gastrointestinal tract being the most commonly affected sites. Estranodal prcscntalion is common and virtually any body site can be in\rol\,cd. Anaplastic large cell l~ml~honia can clc\.clop de no\‘0 or follo\v other l)mphomas, such as m\.cosis frmgoidcs, peripheral T-cell l>mphomas. Hodgkin’s disease, and B-ccl1 l>-mphoma. 34 T-cell receptor genes ma\’ be rcarranged, but the tumor cells may be gcrmlinc:‘” Most anaplastic large cell ll-mphomas arc charactcrized b>. round to o\al large cells containing nuclei \\ith \.ariable profiles ranging from round to o\.al to kidne!. OI horseshoe shapes. Suclei contain clispcrscd chromatin and prominent nucleoli \\ith man!. mitotic ligurcs.:“lThc c!-toplasm is deeply amphophilic or basophilic and thcrc is frequentI>. a paranuclear pale “hof.” Some cases of anaplastic large cell lymphoma are composed ofsmallc1 cells, and the c)-toplasm ma). be lightI>. amphophilic ot pale cvith no paranuclear hof? Additionally, thcrc is a l>mphohistioc)Tic \.ariant of anaplastic large ccl1 l>mphoma composed of abundant admixed monotonous benign histioc)-tes \\-ith rare CDSO-p0sitit.e anaplastic cells, \vhich ma!. be some\\hat smaller than the classic anaplastic large cell l>mphoma ~~11s.‘” The tumor cells strongly express the CD30 (L-l) antigen.“,‘” The) espress leukocyte common antigen in approsimatel~ 80% of cases, epithelial membrane in approsimatcl~ 67%, CD15 in approsimatel!. 15%, CD68 in approsimately IO%, and c)-tokeratin in less than 30%.“’ Others ha\.e reported the incidence of kcratin-positi\,c anaplastic large cell l>mphoma to be 5% to IO%.“’ Sist). percent of anaplastic large cell l>mphomas are T-cell phenot)pc, 20% arc null-cell, and 20% arc B-cell lineage.“’ T- 01 null-cell prima7 systemic anaplastic large cell lymphomas hat-e been sho\\-n to be positive for the ALK antibody 60% to 85% of the time. The ALK antibody. infers the presence of the t(2;5) translocation, resulting

and Weidner

from fusion of the nucleophosniin (iLTM) gene with the anaplastic l!mphoma kinasc (ALE;) gene.” Thcrc has been some disagrccmcnt in the literature as to the outcome of patients \\ith anaplastic large ccl1 l!mphoma thought IO be secondal>. IO the lack of Carl>, diagnosis and prompt treatment in patients dcscribcd in the early literature.“’ Rcccnc studies ha\,c demonstrated that anaplastic large ccl1 l~mphonias arc scnsitivc to chemotherapy regimens used for other high-grade I>mp]lonlas,:3”m3 Those l>~mphomas prcscnting initially in the skin appear to follo~v a more variable course than those eventually developing or presenting predominantly systemicall>. with lymph nodal and/or visceral in\.ol\.ement. More estensi\re study is necessal>’ to determine Lvhcther the outcome of patients with primaq adrenal anaplastic large cell lymphoma differs significantly from those \\-ith other t!lxs of prima?, adrenal Iyllplloma.

Long-term follow,-up information is not a\.ailable for the pre\iousl!. reported patient \\ith CD30+ l)mphoma, but hc did respond to initial chemotherapy lvith methoIrcsatc, blcom!G, dosorubicin, c)clophosphamide, \-incristine, and desamcthasone.” Our patient has been trcatecl \\-ith six cycles of cytosan, closorubicin, Lincristine, and prcdnisone and continues to do IveIl 23 months after diagnosis. So evidence for discasc progression has been found on follo~v-up CT scans or bone marl-o\\ c\.aluations. The small mass originally identified in the left adrenal gland, Irhich \vas not resected, has not changed in size. B>, CT scan this mass was initially thought to bc tumor; since it has not decreased in six \\ith the chcmotherap)., it may consist primarily, of the acellular material idcntificd in the right aclrcnalectom). specimen. Epstein-Barr virus has been identified in some primal? adrenal 1)mphomas. The patients from the study performed in Japan lvere previously evaluated for the prcsencc of EBV genome using polymerase chain reaction, in situ hybridization, ancl immunoperosidase for latent membrane protein-l. Nine patients had EBV genomc identified with in situ hybridization.“” EpstcinBarr virus is thought by some to bc associated with anaplastic large cell l~ml~homa.j’~““~~X~‘” It was sho\\n that monoclonal EBV episomes arc present in 10% of anaplastic large cell lymphomas in a series of 22 cases.‘%’ Epstein-Barr virus-specific DNA sequences were detected by polymerase chain reaction in 15 of 47 patients \\ith anaplastic large cell l)mphomas, and in situ hybridization was positi\re for EBV RNA in nine of 11 of thcsc cases.” Epstein-Barr virus gcnome \vas identified using in situ hybridization in our patient.

CD30+

Lymphoma

of the Adrenal

Additional study and long-term follo\v-up periods arc necessaly to determine whcthcr the clinical outcome in patients with anaplastic large cell primary adrenal Iymphoma significantly differs from those \\ith the more common B-ccl1 phenotype and whether the presence of EBV influences the clinical course. Until more information is available on these patients, treatment \vith aggressi1.e chemotherap), seems to be warranted.

Gland

IX. F&hook (:utnptt

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20. B;udurr Iymphoma.

F. Delnwr

The authors Rosa Memorial for consultation.

thank Maui Arnold, MD, from Santa Hospital, for the material that \vas sent

entity.

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EBV and

164

Frankel,

Shapiro,

and Weidner