Lymphoma and Disseminated Castleman's Disease

OVERVIEW: What every practitioner needs to know

Are you sure your patient has lymphoma and disseminated disease? What should you expect to find?

Lymphoma in HIV-infected (and other) patients can present with a localized mass (Figure 1) or with general symptoms (called “B” symptoms) such as fever, pruritus or weight loss. In the context of HIV infection, lymphomas are frequently extranodal, located in particular in the abdomen (Figure 2, Figure 3), liver (Figure 4, Figure 5) or central nervous system (Figure 6). Definite diagnosis is provided by biopsy, which may reveal one of several types of (non-Hodgkin’s) lymphoma:

Figure 1.

Large B-cell lympoma, involving right axilla and thoracic wall

Figure 2.

A 17 year old girl with congenitally acquired HIV infection, and a mass infiltrating the rectum(left picture, arrows). A remission was attained after treatment with rituximab (anti-CD20 antibodies, right picture). She refused further treatment, and was lost to follow-up.

Figure 3.

A year later, she relapsed with a mixed retroperitoneal/abdominal mass (arrow), infiltrating the duodenum. Dilated intrahepatic bile ducts are shown on the right. Treatment with high-dose steroids was followed by intestinal perforation and peritonitis, and the patient died.

Figure 4.

A 2 year old child with HIV infection, failure to thrive, and protuberant abdomen. The abdominal cavity is filled by a massively enlarged liver and spleen. Biopsy: Malignant lymphoma, Burkitt-type. V. Sirisanthana

Figure 5.

Rapidly progressing mass in an HIV/HCV co-infected former drug user. Biopsy: Diffuse large-cell lymphoma

Figure 6.

Brain lymphoma showing irregular uptake of gadolinium in the MRI scan (right)

  • Diffuse, large-cell lymphoma

  • Immunoblastic lymphoma

  • Burkitt’s lymphoma which has a particularly rapid doubling time and frequent gastro-intestinal involvement

  • Castleman’s disease (Figure 7, Figure 8) deserved special mention, because of its prominent “B” symptoms, especially fever, spontaneous remissions and relapses, and histologic peculiarities with characteristic “onion-skin” appearance, but without clear signs of malignancy.

  • Body-cavity lymphoma, often associated with Kaposi’s sarcoma and Castleman’s disease, presents with malignant pleural, peritoneal, or pericardial exudates (Figure 9).

Figure 7.

A patient with long-standing extensive cutano-mucosal Kaposi’s sarcoma developed fever, thrombocytopenia, and lymphadenopathy. The CT scan shows massive enlargement of spleen and liver

Figure 8.

Lymph-node biopsy coloured with antibody to CD23, showing the typical “onion-skin” appearance of Castleman’s disease

Figure 9.

Two-dimensional echocardiogram, showing a large pericardial effusion (arrows)

Hodgkin’s disease was falsely thought not to be associated with HIV, but it is indeed much more frequent than would be expected in age-matched HIV-negative persons. In contrast to non-Hodgkin’s lymphoma, its frequency appears little changed after the introduction of HAART (Figure 14).

How did the patient develop lymphoma and disseminated disease?

Environmental and virus(es) both play a role. Epstein-Barr-Virus (EBV) is involved in many lymphomas, and practically always present in brain lymphomas. Castleman’s disease is more frequent in those with Kaposi’s sarcoma, and is associated with both EBV and human herpes virus 8 (HHV8).

Which individuals are of greater risk of developing lymphoma and disseminated disease?

As a rule, non-Hodgkin lymphomas occur in the context of immunosuppression. This is particularly true of brain lymphomas, almost never seen in patients with CD4 counts above 100. Exceptionally, Burkitt-type lymphomas may occur with higher CD4 counts. In Hodgkin’s disease, the relation to immune deficiency is much less definite. In patients treated with HAART, total lymphocyte and CD4 counts often decline in the months before diagnosis of Hodgkin’s.

Beware: there are other diseases that can mimic lymphoma and disseminated disease:

  • In immune suppressed patients with B symptoms such as weight loss and fever, many opportunistic diseases enter into the differential: tuberculosis (TB), mycobacteria other than TB, disseminated histoplasmosis, bacillary angiomatosis, Leishmaniasis, and others. The origin of the patient needs to be carefully considered; a presumptive diagnosis of TB may be reasonable in an African, but less so in a homosexual man who has not traveled outside of the United States.

  • A particular problem is the differential between cerebral toxoplasmosis and brain lymphoma. Relative arguments in favor of lymphoma are (1) one, as opposed to several, masses seen in NMR scans, (2) irregular uptake of contrast medium (Figure 10), and (3) presence of EBV DNA, as opposed to toxoplasma DNA after gene amplification in the cerebrospinal fluid (CSF).

Figure 10.

The discovery of a large solitary mass in an immunosuppressed patient speaks in favor of lymphoma

What laboratory studies should you order and what should you expect to find?

Laboratory findings are usually non-specific. Anemia, leukopenia, and abnormal liver tests are frequent in the context of AIDS; with lymphoma, these abnormalities may also indicate involvement of the liver and bone marrow. As mentioned, gene amplification in the cerebrospinal fluid is of value when the CNS is involved. In some cases, malignant lymphocytes invade the CSF (see Figure 11).

Figure 11.

Malignant lymphocytes with basophil cytoplasm and large nucleoli from a HIV-positive patient with brain lymphoma

Results that confirm the diagnosis

Diagnosis of lymphoma requires a biopsy. This is relatively straightforward if an accessible lymph node is involved, but more difficult in a case of cerebral or abdominal disease. The usual structure of the lymph node disappears, and is replaced by sheets of lymphocytes or lymphocyte precursors (see Figure 12). Definite diagnosis of the particular type of lymphoma at hand results from examining the shape, size and arrangement of the cells, and from staining with antibodies to particular cellular differentiation (CD) antigens (Figure 13).

Figure 12.

Burkitt-like lymphoma in a lymph node biopsy: The predominant malignant lymphocytes have little cytoplasm and appear blue, interspersed with macrophages with more cytoplasm. This aspect has been compared to a « starry sky ».

Figure 13.

High-power view, immunoperoxidase stain with anti-CD 20 antibodies

Figure 14.

The patient was on HAART, with undetectable viremia and a CD4 count of 560 when he developed a right cervical mass. The PET scan shows that this mass is metabolically active (left). Excellent response to MOPP chemotherapy.

What imaging studies will be helpful in making or excluding the diagnosis of lymphoma and disseminated disease?

Computed tomography (CT) scans and nuclear magnetic resonance (NMR) scans are helpful to show the extent of the disease (staging). Positron emission tomography (PET) scans show metabolically active tissue and therefore distinguish lymphoma (positive scan) from abscesses (negative center with positive rims, see Figure 14). However, imaging studies cannot usually provide a definitive diagnosis without a biopsy.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

Consultation with oncology is necessary, particularly in view of treatment.

Key principles of therapy

Before the advent of highly active anti-retroviral therapy (HAART), prognosis was dismal with or without therapy. Therapeutic nihilism appeared logical in view of the side effects of oncologic treatment, and the difficulty of administering such treatment in patients who were already immune suppressed to start with. However, with HAART, treatment of concomitant lymphoma is now the same as treatment of lymphoma in HIV-negative patients. Here, I provide a summary of relevant principles, with an overview of initial regimens see Table I for a listing of regimens, and Table II for details on the drugs. A detailed discussion of treatment of lymphoma, and of treatment options in case of resistant or recurrent disease, is beyond the scope of this chapter, please refer to the oncology section.

  • As mentioned, long-term success of anti-lymphoma treatment is contingent upon successful anti-HIV treatment. Many regimens used in HAART have important drug-drug interactions, e.g. profound inhibition of cytochrome P450 3A by ritonavir, or induction by efavirenz. Raltegravir, a HIV integrase inhibitor without significant drug-drug interaction and few side effects may present an advantage when cytostatic therapy is considered. However, it should be noted that despite this potential problem, many different HAART regimens have been administered successfully and contemporaneously with cytostatic therapy.

  • In the context of HIV, virtually all malignant non-Hodgkin lymphomas are generalized at presentation. Localized treatment therefore has only a minor role to play.

  • The CD4 count declines further during chemotherapy. Prevention against opportunistic infections, in particular low dose cotrimoxazole, should be continued. Further preventive treatment by antibiotics, acyclovir, fluconazole or voriconazole may be necessary.

  • Most HIV-associated lymphomas express the CD-20 antigen. Because it has little overlapping toxicity, addition of rituximab to established chemotherapy is an attractive option. However, rituximab does not “come for free”, and controlled studies show an increase in septicemia. This is of particular concern in patients with very low CD4 counts (<50 per μL), where the decision to use rituximab needs to be individualized.

  • For most patients with diffuse large-B-cell lymphoma, or with Hodgkin’s lymphoma, CHOP (see Table I) is the initial regiment. Rituximab is added to CHOP if the tumor is CD-20 positive. In general, 6 to 8 cycles are administered. In the rare cases with localized disease, abbreviated chemotherapy followed by radiation therapy may be appropriate. Dose-adjusted EPOCH (intravenous etoposide, vincristine, doxorubicin, cyclophosphamide and rituximab, plus oral prednisone, is an alternative for patients with high-risk disease.

  • In patients with Burkitt-like lymphoma/leukemia, CHOP is less effective. Short-duration chemotherapy with CNS prophylaxis is preferred, for instance the CODOX-M/IVAC regimen (see Table II).

  • CNS involvement is frequent: Approximately 30% in Burkitt-type lymphoma, as opposed to 10% in patients with diffuse large-B-cell lymphoma. All patients should undergo lumbar puncture, and have the cerebrospinal fluid examined with cytology and flow cytometry. In cases of leptomeningeal involvement, intrathecal chemotherapy, or systemic treatment with anti-neoplastic agents that cross the blood-brain barrier is indicated.

  • If clinical response is satisfactory, patients should be further evaluated approximately one month after completion of planned therapy by PET/CT. The combination of PET and CT has the advantage of excellent spatial resolution, and can also distinguish fibrosis, with negative PET scan, from residual disease (positive PET). Note that earlier PET may produce unduly alarming results due to inflammatory responses to treatment.

  • Primary cerebral lymphomas (PCL) had a particularly dismal prognosis before HAART, with median survival measured in weeks rather than months. After HAART was introduced, PCL became rare. As a consequence, optimal therapy is ill-defined. High-dose methotrexate therapy (3g/m
    2) has produced remissions lasting for more than a year. Others have used the same regimens as in non-HIV-related PCL, i.e. methotrexate/temozolomide/rituximab. Concurrent control of HIV with HAART is essential.

  • As noted, multicentric Castleman’s disease has an unpredictable course, including spontaneous remissions. Case reports and small case series suggest that rituximab may be particularly effective. Single-agent chemotherapy with etoposide or vinblastine, or CHOP has also produced lasting remissions.

What should you tell the family about the patient's prognosis?

AIDS-associated lymphoma is a serious disease with significant mortality. However, with chemotherapy and HAART, there is a chance of complete remission and probable cure which, in recent studies, has surpassed 50% overall. Hodgkin’s disease has the best prognosis, followed by large-B-cell lymphoma and Burkitt-type lymphoma.

How do you contract lymphoma and disseminated disease and how frequent is this disease?

In the absence of HAART, approximately 10% of HIV patients developed a non-Hodgkin lymphoma. All HIV risk groups seem to be similarly affected. Compared to age- and sex-matched HIV-negative controls, the incidence of lymphoma was increased more than a 100-fold for diffuse large-B-cell lymphoma and Burkitt-type lymphoma. Since the advent of HAART, the incidence of non-Hodgkin’s lymphoma has greatly declined, although it remains above the incidence in HIV-seronegatives.

Hodgkin’s disease deserves special mention. Although it is not an AIDS-defining neoplasm, it is much more frequent in HIV-positives, with standard incidence ratios above 10. In contrast to non-Hodgkin’s lymphoma, Hodgkin’s disease appears to be little impacted by HAART. As a consequence, Hodgkin’s has become relatively much more frequent in recent years (see Figure 14).

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Mantina, H, Wiggill, TM, Carmona, S, Perner, Y, Stevens, WS. “Characterization of Lymphomas in a high prevalence HIV setting”. J Acquir Immune Defic Syndr. vol. 53. 2010 Apr. pp. 656-60. (A study of almost 2000 cases of lymphoproliferative disease with statistical power to show which types are, and which are not associated with HIV)

Carbone, A, Cesarman, E, Spina, M, Gloghini, A, Schulz, TF. Blood. vol. 113. 2009 Feb 5. pp. 1213-24. (HIV-associated lymphomas and gamma-herpesviruses. An overview of the complicated interplay between Epstein-Barr virus, Kaposi's sarcoma herpesvirus, and HIV in the pathogenesis of HIV-associated lymphomas)

Noy, A. “Curr Opin Oncol. Controversies in the treatment of Burkitt lymphoma in AIDS.”. vol. 22. 2010 Sep. pp. 443-8. Burkitt's lymphoma has so far defied standard treatment approaches. This review provides perspectives when faced with difficult therapeutic decisions)

Kaplan, LD, Lee, JY, Ambinder, RF, Sparano, JA, Cesarman, E, Chadburn, A, Levine, AM, Scadden, DT. “Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010”. Blood. vol. 106. 2005 Sep 1. pp. 1538-43.

Sparano, JA, Lee, JY, Kaplan, LD, Levine, AM, Ramos, JC, Ambinder, RF, Wachsman, W, Aboulafia, D, Noy, A, Von Henry, DH, Roenn, J, Dezube, BJ, Remick, SC, Shah, MH, Leichman, L, Ratner, L, Cesarman, E, Chadburn, A, Mitsuyasu, R;. “AIDS Malignancy Consortium”. Blood. vol. 115. 2010 Apr 15. pp. 3008-16. (Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma)

Barta, SK, Lee, JY, Kaplan, LD, Noy, A, Sparano, JA. “Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma”. Cancer. vol. 118. 2012 Aug 15. pp. 3977-83. (Articles 4 to 6 provide perspective on the advantages and risks of adding rituximab to standard chemotherapy regimens such as CHOP)

Coté, R, Biggar, RJ, Rosenber, PS, Devesa, SS, Percy, C, Yellin, FJ, Hardy, C, Goedert, JJ, Blattner, WA. “NonHodgkin's lymphoma among people with AIDS: incidence, presentation and public health Burden.”. Int J Cancer. vol. 73. 1997. pp. 645

Barta, SK1, Xue, X, Wang, D, Tamari, R. “Treatment factors affecting outcomes in HIV-associated non-Hodgkin lymphoma: a pooled analysis fo 1645 patients.”. Blood. vol. 122. 2013. pp. 3251-62. (Solid statistical evidence for improved outcomes in intensively treated patients with regimens including rituximab.)