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Table : AIDS-Related Neoplasms in Children

Non-Hodgkin's lymphoma Burkitt's lymphoma (B-cell, small non-cleaved) Immunoblastic lymphoma (B-cell, large cell) Central nervous system lymphomas Mucosa-associated lymphoid tissue (MALT) type Leiomyosarcoma and Leiomyoma Kaposi's sarcoma Leukemias

Non-Hodgkin's lymphoma

Non-Hodgkin's lymphoma (NHL) is the most common malignancy secondary to HIV infection in children. It is usually of B-cell origin as in Burkitt's (small non-cleaved cell) or immunoblastic (large cell) NHL.

The mean age of presentation of malignancy in congenitally transmitted disease is 35 months, with a range of 6 to 62 months. In transfusion-transmitted disease, the latency from the time of HIV seroconversion to the onset of lymphoma is 22-88 months. The CD4 lymphocyte count is less than 50/mm3 at the time of diagnosis of the malignancy.

The presenting manifestations include :

• Fever
• Weight loss
  
  

Extranodal manifestations (e.g. hepatomegaly, jaundice, abdominal distension, bone marrow involvement, or central nervous system [CNS] symptoms

Some patients will already have had lymphoproliferative diseases such as lymphocytic interstitial pneumonitis or pulmonary lymphoid hyperplasia. These children usually have advanced (stage III or IV) disease at the time of presentation.

Central nervous system lymphomas. Children with CNS lymphomas present with:

• Developmental delay or loss of developmental milestones
• Encephalopathy (dementia, cranial nerve palsies, seizures, or hemiparesis)

Differential diagnosis include infections such as toxoplasmosis, cryptococcosis, or tuberculosis. Contrast-enhanced computed tomography (CT) studies of the brain show hyperdense mass lesions that are usually multicentric or periventricular. CNS lymphomas in AIDS are fast growing and often have central necrosis and a "rim of enhancement" as in an infectious lesion. A stereotactic biopsy will give a definitive diagnosis

Treatment of HIV infection-related lymphomas :Treatment consists of a standard protocols as described for Non-Hodgkin's lymphoma. Treatment of CNS lymphomas is more difficult. Intrathecal therapy is indicated even for those without evidence of meningeal or mass lesions at diagnosis of NHL. Radiation therapy may be a helpful adjunct for CNS involvement.

The following are more favorable prognostic features in NHL secondary to AIDS:

• CD4 lymphocyte count above 100/mm3
• Normal serum LDH level
• No prior AIDS-related symptoms
• Good Karnofsky score (80-100)
  
  

Proliferative lesions of mucosa-related lymphoid tissue (MALT) :

MALT shows reactive lymphoid follicles with prominent marginal zones containing centrocyte-like cells, lymphocytic infiltration of the epithelium (lymphoepithelial lesion), and the presence of plasma cells under the surface epithelium. These lesions may be associated with the mucosa of the gastrointestinal tract, Waldeyer's ring, salivary glands, respiratory tract, thyroid, and thymus. Proliferative lesions of MALT can be benign or malignant (such as lymphomas).

The proliferative lesions arising from MALT form a spectrum or a continuum extending from reactive to neoplastic lesions. The neoplastic lesions are usually low grade but may progress into high-grade MALT lymphomas (as shown in following table). MALT lymphomas characteristically remain localized, but if dissemination occurs, they are usually confined to the regional lymph nodes and other MALT sites. MALT lesions represent a category of pediatric HIV-associated disease that may arise from a combination of viral etiologies, including HIV, EBV, and CMV.

Table : Spectrum of Systemic Lymphoproliferation in Children with AIDS

Follicular hyperplasia (lymph nodes, gastrointestinal tract) Lymphoid follicles / nodular (liver, thymus) Thymitis and multilocular thymic cyst PLH / LIP complex, typical and atypical Polyclonal polymorphic B-cell lymphoproliferative disorder Myoepithelial sialoadenitis Myoepithelial sialoadenitis with lymphoma MALT lymphoma (involving lungs, tonsils and salivary glands) Non-MALT lymphoma (involving nodal and extranodal sites)

Treatment of low-grade MALT lymphoma

• Alpha Interferon: 1,000,000 units/m2 SC 3 times a week (continued until regression of disease or severe toxicity occurs).
• Rituxan (monoclonal antibody-anti-CD20) 375 mg/m2 IV weekly for 4 weeks (courses may be repeated as clinically indicated).
  
  

Some patients may not require any treatment because of the indolent nature of the disease.

Leiomyosarcomas and leiomyomas

Malignant or benign smooth muscle tumors, leiomyosarcoma (LS) and leiomyoma (LM), are the second most common type of tumor in children with HIV infection. The incidence in HIV patients is 4.8% (in non-HIV children , it is 2 per million). The most common sites of presentation are the lungs, spleen, and gastrointestinal tract. Patients with endobronchial LM or LS often have multiple nodules in the pulmonary parenchyma. Bloody diarrhea, abdominal pain, or signs of obstruction may signal intraluminal bowel lesions. These tumors are clearly associated with EBV infection. In situ hybridization and quantitative polymerase chain reaction studies of LM and LS demonstrated that high copy numbers of EBV are present in every tumor cell. The EBV receptor (CD21/C3d) is present on tumor tissue at very high concentrations but it is present at lower concentrations in normal smooth muscle or control leiomyomas / leiomyosarcomas that had no EBV DNA in them. In AIDS patients, the EBV receptor may be unregulated, allowing EBV to enter the muscle cells and cause their transformation.

Treatment involves:

• Chemotherapy, including doxorubicin or alpha-interferon
• Radiotherapy
• Complete surgical resection prior to chemotherapy, where feasible
  
  

Despite surgery and chemotherapy, the disease tends to recurr.

Kaposi's sarcoma (KS) is rare in children and constitutes the third most malignancy in pediatric AIDS patients; it occurs in 25% of adults with AIDS. KS occurs only in those HIV-infected children who were born to mothers with HIV. The lymphadenopathic form of KS is seen mostly in Haitian and African children and may represent the epidemic form of KS unrelated to AIDS. The cutaneous form is a true indicator of the disease related to AIDS. Visceral involvement has not been pathologically documented in children with AIDS.

Leukemias Almost all leukemias are of B-cell origin. They represent the fourth most common malignancy in children with AIDS. The clinical presentation and biologic features are similar to those found in non-HIV children. Treatment involves chemotherapy designed for B-cell leukemias and lymphomas.

Miscellaneous tumors There is no increase of Hodgkin's disease in children with AIDS as compared to adult patients. Children with AIDS rarely develop hepatoblastoma, embryonal rhabdomyosarcoma, fibrosarcoma, and papillary carcinoma of the thyroid. The occurrence of these tumors is probably unrelated to HIV infection.