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experience. Ann Surg Oncol 1995;2:524–529.

Thymic Carcinoma in a Child With HIV Infection

Morgan McDonald, MD,1 Thomas McLean, MD,2 Thomas Belhorn, MD,3 Scott Victor Smith, MD,4

Lynn Ansley Fordham, MD,5 Charles Woods, MD,6 and Julie Blatt, MD1*

INTRODUCTION

HIV infection predisposes to cancer during childhood, although

the prevalence is lower than in HIV-infected adults [1–6]. As with

adults with HIV, the majority of cases are non-Hodgkin lymphoma

(NHL). Hodgkin disease (HD), leiomyosarcoma, and B-cell acute

lymphoblastic lymphoma (B-ALL) also are well described.

The major diagnostic considerations for anterior mediastinal

masses in the setting of HIV infection are NHL and HD. Malignant

thymoma has been described in a small number of adults with HIV

[7,8]. There have been several dozen reports of malignant thymoma

in children thought to be immunocompetant [9]. To our knowledge,

malignant thymoma has not been reported previously in HIV

infected children.

Adistinct pathologic entity ofmultilocular thymic cysts has been

described in adults and childrenwithHIV [10–13]. A report of eight

HIV-positive children with multilocular thymic cysts suggests that

the natural history of these lesions is one of slow resolution [12].We

describe the first case of thymic carcinoma in an HIV-infected child

with a history of regressing multilocular thymic cysts. The tumor

expressed CKIT but failed to respond to imatinab mesylate after a

transient response to multi-agent chemotherapy. This case extends

the spectrum of pediatric malignancy in the setting of HIV and

suggests that patients with presumed benign thymic cysts require

ongoing surveillance.

CASE REPORT

A 10-year old biracial male with perinatally acquired HIV

infection presented with a several month history of cough and

progressive chest pain. He had no fevers, sweats, or weight loss.

Chest radiograph (Fig. 1a) showed a large right-sided multi-

lobulated superior mediastinal mass. Computed tomographic scan

(CT) (Fig. 1b) also showed a multi-lobulated heterogeneous mass

measuring 8.8� 6.8� 6.7 cm with central necrosis and a small

ipsilateral pleural effusion. The mass was gallium-avid.

Biopsy of the mediastinal mass and a separate diaphragmatic

nodule (Fig. 2) showed cohesive groups of atypical large malignant

cells with moderate nuclear pleomorphism, prominent central

macronucleoli, and a sheet-like highly infiltrative growth pattern

within a fibrous stroma. The stroma contained abundant lympho-

cytes, admixed plasma cells, and a few scattered eosinophils.

Scattered mitotic figures and apoptotic cells were identified. The

HIV infection predisposes to cancer during childhood. Inaddition to the AIDS-defining non-Hodgkin lymphoma (NHL) andKaposi sarcoma, a range of other lymphoid malignancies and solidtumors have been described. We report the first case of an HIV-positive child with thymic carcinoma in the setting of regressingthymic cysts. The tumor expressed CKIT but failed to respond to

imatinab mesylate after a transient response to multiagent chemo-therapy. This case extends the spectrum of pediatric malignancy inthe setting of HIV and suggests that patients with presumed benignthymic cysts require ongoing surveillance. Pediatr Blood Cancer2007;49:1004–1007. � 2005 Wiley-Liss, Inc.

Key words: AIDS; HIV; KIT; Thymic carcinoma; Thymic cysts

——————1Division of Pediatric Hematology-Oncology, The University of North

Carolina, Chapel Hill, North Carolina; 2Section of Pediatric

Hematology-Oncology, Wake Forest University School of Medicine,

Winston-Salem, North Carolina; 3Division of Pediatric Infectious

Diseases, The University of North Carolina, Chapel Hill, North

Carolina; 4Department of Pathology and Laboratory Medicine,

Division of Hematopathology, The University of North Carolina,

Chapel Hill, North Carolina; 5Division of Pediatric Imaging, Dept. of

Radiology, The University of North Carolina, Chapel Hill, North

Carolina; 6Section of Pediatric Infectious Diseases, Wake Forest

University School of Medicine, Winston-Salem, North Carolina

*Correspondence to: Julie Blatt, M.D., Division of Pediatric

Hematology-Oncology, CB 7220, The University of North Carolina,

Chapel Hill, NC 27599-7220. E-mail: jblat@med.unc.edu

Received 17 September 2005; Accepted 12 October 2005

� 2005 Wiley-Liss, Inc.DOI 10.1002/pbc.20694

1004 Brief Reports

atypical large cells displayed moderate pleomorphism with

prominent central macronucleoli, and showed diffuse intense

staining with EBV-LMP, EBV-ISH, BerEP4, and AE1/AE3 cyto-

keratin. EMA stained a diffuse subset of tumor cells and CAM5.2

cytokeratin was focally positive. Immunohistochemical stains were

negative for CD3, CD20, CD15, CD30, CD45, Pax5, and PLAP. The

histopathologic and immunohistochemical features were consistent

with a diagnosis of lymphoepithelioma-like carcinoma of the

thymus. Metastatic work-up was negative, including bilateral bone

marrow aspirates in biopsies, brain MRI, CT of the abdomen and

pelvis, and gallium scan.

Past medical history was significant for a multilocular thymic

cyst (Fig. 1c). This was first noted at 3½ years of age, and had

Pediatr Blood Cancer DOI 10.1002/pbc

Fig. 1. a: Chest radiograph, (b) chest CT scan showing tumor mass at

time of present illness; (c) chest radiograph showing thymic cyst 5 year

prior to cancer diagnosis.

Fig. 2. Thymic carcinoma histopathology and EBV infection. Biopsy

of the mediastinal mass showed cohesive groups of atypical large

malignant cells with sheet-like growth pattern and highly infiltrative

growth within a desmoplastic stroma with a lymphoplasmacytic

infiltrate (a) (H&E stain, 400�). The large malignant cells showed

intense positivity for EBV by in situ hybridization studies (b) (EBVEBER ISH stain, 400�).

Brief Reports 1005

decreased in size on repeat CT scans and chest radiographs,

including at the time of the present illness. Though adherence was

not always certain, the patient had been treated with antiretroviral

therapy for 9 years prior to cancer diagnosis. This included four

different clinical trial-driven regimens. The first three included the

following alone or in combination: stavudine (zerit), zidovudine

(retrovir), didanosine (videx), nevirapine (viramune), and lamivu-

dine (epivir). The most recent regimen which was initiated 5 years

prior to diagnosis of thymic carcinoma, included zidovudine,

didanosine, nelfinavir (viracept), and ritonavir (norvir). His CD4

counts had remained stable above 1,000 cells/ml in the 2½ years

prior to cancer diagnosis. HIV viral load had peaked at 38,000

copies/ml 2 years prior to cancer diagnosis and generally trended

downward so that it was less than 400 copies/ml for nearly a year

prior to diagnosis. Prior documented infections included adenovi-

rus, herpes zoster, RSV, and Pneumocystis carinii pneumonia at

6 months of age. He had no history of lymphoid interstitial

pneumonitis (LIP) or oral candidiasis.

He was treated with ADOC chemotherapy modified from a

published report [14]. This included doxorubicin 40 mg/m2 and

cisplatin 50 mg/m2 (day 1), vincristine 0.6 mg/m2 (day 2), and

cyclophosphamide 700mg/m2 (day 3).ART, consisting of nelfinavir

and zidovudine, continued concurrent with ADOC. He had

approximately 50% reduction in tumor size. After three courses of

ADOC, he underwent surgical excision of the mass. Pathology

showed clear margins, but metastatic tumor was present in one of

six lymph nodes. He was treated with one more course of ADOC

(four courses total), and was then treated with 5,400 cGy radiation

therapy to the tumor bed. Just prior to chemotherapy, his CD4 count

was 560 cells/ml. It dropped to 110 cells/ml after chemotherapy. His

HIV viral load continued to be undetectable.

Seven months after completing therapy, a new liver lesion was

biopsied and found to be recurrent disease. The tumor strongly

expressed CKIT. He was treated with imatinib mesylate (Gleevec),

300 mg daily. Approximately 4 months into treatment, a chest

radiograph showed new nodular opacities, one measuring 5� 5 cm

in the left lower lobe of the lung, indicating progression of disease

despite targeted therapy.

DISCUSSION

HIV infection predisposes to cancer. In contrast to HIV-infected

adults, in whom the incidence of malignancy is 4% per year [4], the

incidence of malignancy in children with HIV has been estimated to

range from 0.66 to 4.18 cases/1,000/year [1,2]. The relative risk for

all cancer subtypes within 2 years of AIDS diagnosis in children has

been estimated at 40–100 [1,3]. All of these figures reflect

experience before the availability of highly active antiretroviral

therapy (HAART). Among adults with HIV, the incidence of

opportunistic infections and Kaposi sarcoma has declined since the

widespread use of HAART, but the incidence of NHL and other

cancers has not [15].

As in adults with HIV, the majority of pediatric cases are NHL.

The risk of primary brain lymphomas is particularly high with

relative risk of >7,000. HD, leiomyosarcoma, and B-ALL also are

well described. Case reports and series have shown the occurrence

of chronic myelogenous leukemia [16], hepatoblastoma, schwan-

noma [3], and MALToma [4] in the setting of pediatric HIV

infection. The incidence of Kaposi sarcoma has been debated but

appears to be rare in children with HIV outside of Africa [4,6].

Invasive cervical carcinoma and squamous cell carcinoma of the

anus have not been linked to AIDS in children, presumably

reflecting their association with sexual transmission.

The immediate cause of malignancy in the setting of HIV is

incompletely understood. One case-controlled study from the

Pediatric Oncology Group (POG) of 43 patients with HIV and

new malignancies diagnosed 1992–1998 identified high Ebstein

Barr virus (EBV)DNAviral load as an independent risk factor [3]. It

has been hypothesized that T cell suppression allowed for

unregulated growth of EBV-infected cell lines over other cell lines.

However, low CD4 cell count was not an independent risk factor for

malignancy in this study, and the authors hypothesized that there is a

critical level of lymphopenia belowwhichEBV replication and viral

load decreases. Other associations, not clearly independent risk

factors in the POG study, included LIP and oral candidiasis, perhaps

as indicators of severity of immunosupression.

There may be a causative role for HIV infection or coinfection

with EBVin the development of cancer. For example, EBV seems to

play a particularly strong role in the development of leiomyomas

and leiomyosarcomas in children with HIV, but not in children who

do not haveHIV [17].However, there is still a substantial percentage

of patients with HIV-related malignancy who do not express EBV

and many more with HIV/EBV co-infection who do not develop

cancer.

The major diagnostic considerations for anterior mediastinal

masses in an HIV-positive patient are NHL and HD. Other

diagnostic considerations include germ cell tumors, soft tissue

neoplasms, lipomas, thyroid neoplasms, thymic cysts, thymoma,

and thymic carcinoma [9]. Benign thymomas are not uncommon

in the adult population. Malignant thymoma has been described

rarely in adults with HIV [7,8]. There have been several dozen

reports of malignant thymoma in children thought to be immuno-

competant [9].

A distinct clinico-pathologic entity of massive thymic enlarge-

ment secondary to lymphoid hyperplasiawithmultilocular cysts has

been described in HIV infected adults and children [10–12]. A

report of eight HIV-positive children with multilocular thymic cysts

suggests that the natural history of these lesions is one of slow

resolution [12]. Of note, samples from four of eight cases were

positive for EBV. It is of interest that our patient developed biopsy-

proven thymic carcinoma even as his thymic cysts continued to

decrease in size. His malignant cells expressed EBV DNA. His

carcinoma was not AIDS defining, and became evident during a

period of normal CD4 counts.

Limited data on chemotherapy in patients with HIV suggest that

responses are poor, survival time short, and toxicity greater than in

HIV-negative hosts [18,19]. In one series, chemotherapy with two

drugs (cyclophosphamide and methotrexate; ifosfamide and

cytarabine; cisplatin and etoposide) did not appear to induce HIV

or EBV viral replication, and it has been suggested that one may be

able to decrease concurrent retroviral therapy in order to deliver

more myelosuppressive chemotherapy. In contrast, for malignant

thymomas in patients not infected with HIV, including children,

long-term remissions appear to be achievable with multimodal

therapy [20,21]. Our anecdotal experience suggests that thymic

carcinomas in the setting of HIV may be initially responsive to

ADOC or related therapies. Although chemotherapy did lower the

patient’s CD4 count, it did not interfere with the effectiveness of

antiretroviral therapy in sustaining nondetectable viral load.

Importantly, therewere no apparent adverse effects from continuing

Pediatr Blood Cancer DOI 10.1002/pbc

1006 Brief Reports

ART.Based on a recent report of response to imatinabmesylate in an

HIV-negative patient with thymic carcinoma and mutated CKIT

[22], we were hopeful that the expression of CKIT in our patient’s

tumor cells would provide a successful target for his recurrence.

This lack of response to targeted treatment may reflect the absence

of a sensitive mutation, something which we did not examine.

This case extends the spectrum of pediatric malignancy in the

setting of HIV and suggests that patients with presumed benign

thymic cysts require ongoing surveillance.

Thymic carcinomas in the setting of pediatric HIV can be

responsive to traditional multimodal treatment although long-term

benefit seems less likely. Further investigation will be needed to

establish whether there is a rationale for therapy targeted against

tyrosine kinase pathways.

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