104 - Radiologic Evaluation of Lung Cancer
Editors: Shields, Thomas W.; LoCicero, Joseph; Ponn, Ronald B.; Rusch, Valerie W.
Title: General Thoracic Surgery, 6th Edition
Copyright 2005 Lippincott Williams & Wilkins
> Table of Contents > Volume II > Section XVII - Other Tumors of the Lung > Chapter 121 - Lung Tumors in the Immunocompromised Host
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Chapter 121
Lung Tumors in the Immunocompromised Host
Joseph LoCicero III
Philip G. Robinson
Several situations may lead to the development of an immunocompromised state that could last for life or for extended periods of time. Iatrogenic immunosuppression, such as solid organ transplantation or autoimmune diseases; chronic infections, such as with human immunodeficiency virus (HIV); and even other malignancies or anticancer therapy may cause altered immunocompetence (Table 121-1). Patients with these altered states have a greater incidence of certain malignancies than does the general population. In some cases, immunocompromised patients may develop pulmonary neoplasms that are not necessarily related to their immune status but may be the result of other influences. Autoimmune diseases do not cause immunosuppression, but many of these patients are treated with immunosuppressive agents to control the inflammatory response. Each specific situation has been analyzed individually by various investigators. Some of the mechanisms of malignancy development now appear to be similar. To show the significance of lung tumors in the immunocompromised host, we review the broader spectrum of tumor biology in these patients.
POSTTRANSPLANT MALIGNANCIES
Patients on immunosuppression drugs for organ transplantation have a higher incidence of certain malignancies. This observation was made within a few years of the routine use of cadaver renal transplantation for renal failure. Since then, multiple reports have confirmed this fact. Penn (1988) noted the staggering increase in transplant cancers compared with that in the general population (Table 121-2). He found that uterine cervical cancers increased 14 times, skin cancers increased 21 times, lung cancers increased 29 times, non Hodgkin's lymphoma increased 50 times, carcinoma of the anus and vulva increased 100 times, and Kaposi's sarcoma increased up to 500 times over expected rates. Penn (1994) pointed out that these neoplasms may develop a short time after transplantation. Kaposi's sarcoma appeared at an average of 21 months after transplantation, and non Hodgkin's lymphomas appeared at an average of 32 months. The International Society of Heart and Lung Transplantation (2003) listed cumulative 15-year data from the International Transplant Registry. In 5,104 lung transplant recipients who have been followed for at least 1 year, the incidence of new malignancies is 3.9%, down from 4.5% 5 years ago. The majority of these tumors (52.1%) were labeled lymphoproliferative disorders or T-cell lymphomas. Skin tumors were the second most common, at 21%. A variety of other tumors accounted for 17.9% of the cancers. Statistics are available now on 5-year survivors; 886 patients who survived 5 years or more have a 13.1% chance of having cancer, with skin cancers the most common at 45.5% and lymphomas second at 15.6%. In a single-institution series, Mihalov and associates (1996) reported on 674 recipients, including 305 renal, 307 heart, 54 lung, and 8 heart and lung transplants. They noted a 3.7% incidence of cancer in lung transplants. They also noted that thoracic organ transplant recipients, in contrast to renal transplant recipients, had a significantly higher rate of lymphomas. Spiekerkoetter and colleagues (1998) reported one patient who developed pulmonary squamous cell carcinoma out of 219 patients who underwent lung transplantation. However, the chance for developing lung cancer after solid organ transplantation as reported by De Perrot and associates (2003) is very low (0.3%) and usually occurs in continuing smokers.
The International Society of Heart and Lung Transplantation (2003) has assessed risk factors for the development of posttransplantation malignancies. Risk factors include double-lung transplantation (odds ratio = 0.63), female recipient (odds ratio = 0.69), and induction chemotherapy for other malignancies (odds ratio = 0.67). Recipients' age over 45 years is associated with increased risk (Fig. 121-1). Donors show a bell-shaped curve with the greatest risk for developing a later malignancy at 35 years (Fig. 121-2).
Table 121-1. Common Thoracic Malignancies in Immunocompromised Hosts | ||||||||||
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Approaching this problem from a different perspective, End and associates (1995) looked at pulmonary nodules in 64 lung transplant recipients. Nodules developed in eight patients (12.5%) an average of 5.8 months after transplantation. In two patients, the nodules spontaneously resolved over 3 weeks. Of the remaining six patients, three had posttransplantation lymphoproliferative disorder (PTLD), two had aspergillosis, and one had a mixed bacterial abscess. Diagnoses were made by computed tomography (CT)-directed needle aspiration.
Proposed Causal Mechanisms of Posttransplantation Malignancies
Concepts about the development of posttransplantation tumors have varied over the years. Penn (1977) described the early theories. Tumors were thought either to be carried into the host in the transplanted tissue or to develop de novo in patients who were cancer free at the time of transplantation. The tumors in the latter scenario were thought to result in some way from the immunosuppression.
As more experience was gained over the years and immunosuppression became better understood, theories became more focused. One popular theory was that the immune system provides a feedback loop to regulate the production of lymphoid tissue. When this loop is suppressed, there could be uncontrolled lymphoid proliferation. Chronic antigenic stimulation by the graft could cause lymphoid hyperplasia and somehow lead to lymphomas. A possibility also considered was that the immunosuppressive drugs might have a direct oncogenic effect on the host.
Table 121-2. Incidence of De Novo Tumors in Transplant Patients Compared with the General Population | ||||||||||||||||
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Fig. 121-1. Demonstration of positive correlation of increased risk with increasing age of the recipient. Courtesy of International Society of Heart and Lung Transplantation registry (2003). |
Speculation on analysis of anogenital cancers in transplant recipients has led to the development of one current theory about at least some posttransplantation malignancies. Penn (1986) noted that among 65 female transplant patients with cancers of the vulva, vagina, uterine cervix, or anus, several had a history of condyloma acuminatum or herpes genitalis. He suggested that these viruses might be contributing to cancer development. Subsequently, other viruses were implicated (Table 121-3): Epstein-Barr virus (EBV) and lymphoma; papillomavirus and carcinoma of the vulva, perineum, and uterine cervix; human herpesvirus and carcinoma of the vulva, uterine cervix, lips, and skin; human herpesvirus 8 (HHV-8) and Kaposi's sarcoma; and hepatitis and hepatocellular carcinoma.
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Fig. 121-2. Demonstration of increased risk from donor age. Risk is highest for donors near 35 years of age. Courtesy of International Society of Heart and Lung Transplantation registry (2003). |
Table 121-3. Viruses Implicated in the Development of Cancers in Transplant Recipients | ||||||||||||
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A concentrated effort has been made to delineate the role of the EBV in the collection of lymphoid conditions now known as PTLDs. Although the B lymphocyte is the usual host for EBV, T lymphocytes also may become infected. Infections in either cell line may lead to PTLD. The exact mechanism for the development of PTLD from EBV is unclear. Most PTLDs contain the EBV genome. Berger and Delecluse (1993) have postulated that PTLD is the result of the interaction between the virus and the host cells. After infection, there is a primary response, which is initially mediated by natural killer cells and CD4 suppressor T cells. Later, the secondary immune response is mediated by human leukocyte antigen (HLA)-restricted CD8 cytotoxic T cells, which are specific for EBV. Also, there is an immunoglobulin M (IgM) and later an IgG response to the viral capsid antigen, early antigen, and EBV nuclear antigens. When the EBV-infected B cells escape the cytotoxic T cells, other EBV products, such as EBV nuclear antigens and latent membrane proteins, upregulate a series of genes, leading to proliferation and transformation of EBV-infected cells. This enlarged pool of proliferating cells carries an additional risk for mutation of an oncogene or a tumor suppressor gene. In an immunosuppressed patient, the EBV-infected cells are not controlled; this leads to the spectrum of PTLD, which ranges from hyperplasia to lymphoma (Fig. 121-3). The pathologic classification of PTLD is discussed later in this chapter.
Mathur and associates (1994) contend that unbalanced lymphokine production contributes to the development of PTLD. They found that levels of interleukin-4 (IL-4) were significantly elevated in patients with PTLD and in healthy immunosuppressed organ transplant recipients compared with normal healthy individuals. They also found that patients with PTLD exhibited significantly lower levels of interferon- (IFN- ) and higher levels of IgE than either healthy EBV-seropositive individuals or healthy immunosuppressed organ recipients. These findings suggest that a circulating imbalance of cytokines may contribute to PTLD. Along similar lines, Birkeland and co-workers (1995) described four patients with elevated levels of IL-10 in patients with PTLD. In one patient, the level decreased to zero after treatment with acyclovir. They also pointed out that the coding sequence for the IL-10 gene is highly homologous to the EBV open reading frame, BCRF1. Expression of this gene produces a viral IL-10, which has the same activities as natural IL-10. This cytokine, IL-10, is a potent suppressor of macrophages. Interestingly enough, Zhang and colleagues (2001) noted that patients in chronic rejection exhibited high levels of both IFN- and IL-10, suggesting the importance of these cytokines in the modulation of PTLD.
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Fig. 121-3. A schematic representation of the multiple steps for B-cell lymphomagenesis in immunodeficient hosts. Epstein-Barr virus (EBV) most likely plays a direct role in the proliferation of B cells, which leads to additional mutations or oncogene activation. CD21, EBV receptor; CTL, cytotoxic T cell. |
Both Montone (1996) and Mentzer (1996) and their colleagues reported PTLD in lung transplant recipients. Montone's group found the incidence of PTLD in lung transplantation to be an astonishing 20%. Using in situ hybridization techniques, they found that all patients had EBV-related polymorphous B-cell lesions. Most lesions were hyperplasia, but two of nine had lymphoma. Schwend and associates (1994) described a non Hodgkin's lymphoma occurring in the lung of a patient 8 weeks after undergoing heart transplantation. Immunostaining of the high-grade B-cell lymphoma revealed the latent membrane protein of EBV in the tumor cells. They suggested that immunosuppression permits an uncontrolled proliferation of EBV-infected B lymphocytes, resulting in a lymphoma. Marchioli and colleagues (1996) also have implicated HHV-8 in body cavity lymphomas.
Dockrell and colleagues (1998) examined their series at the Mayo Clinic, noting that only 1 of 61 cases of PTLD were restricted to the T-lymphocyte line. They specifically studied 21 cases, finding 38% to be induced by EBV. Haque and associates (1996) found that EBV-seronegative recipients can develop PTLD from a seropositive organ.
Boyle and colleagues (1997) studied 120 children receiving thoracic organ transplants and found a 19.5% incidence of PTLD in heart-lung and lung recipients and only a 7.7% incidence in heart recipients. They also discovered that recipients who were EBV positive before transplantation did not develop PTLD. Only those who developed a primary EBV infection developed PTLD. Because of this, Verschuuren and associates (2001) suggest that an EBV polymerase chain reaction test be administered to patients before and after lung
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transplantation. Wong and co-workers (2001) suggested that recipients and donors should be matched in a similar manner as they are matched for HLA and cytomegalovirus status.
AUTOIMMUNE DISEASES
Autoimmune diseases do not produce a compromised immune system until they are treated. Patients with these diseases are usually treated with steroids and anticancer agents, such as azathioprine or cyclophosphamide. Mellemkjaer (1997) and Ramsey-Goldman (1998) and their associates have both reported an increased incidence of the usual types of lung carcinomas in patients with systemic lupus erythematosus. Mellemkjaer and colleagues (1996) also described a similar increase of lung carcinomas in patients with rheumatoid arthritis. Quismorio (1996) reviewed the subject of pulmonary complications in Sj gren's syndrome. He found an increased risk for developing pulmonary lymphomas. In a study from the Mayo Clinic, Hansen and co-workers (1989) described 10 of 50 patients with Sj gren's syndrome who had pulmonary lymphomas. The lymphomas ranged from low to high grade, with the high-grade ones being associated with increased mortality. Nicholson and co-workers (1996) described six cases of primary pulmonary B-cell non Hodgkin's lymphomas in patients with autoimmune diseases who were receiving immunosuppressive drugs. The patients had rheumatoid arthritis, polymyositis, cryptogenic fibrosing alveolitis, mixed connective tissue disease, and Sj gren's syndrome. Only the patient with Sj gren's syndrome was not receiving immunosuppressive therapy. He developed a low-grade lymphoma. The other five patients were receiving immunosuppressive therapy, and they all developed high-grade lymphomas. In conclusion, patients with autoimmune diseases who may be immunosuppressed can develop carcinomas and lymphomas of the lung. The relationship between these autoimmune diseases and pulmonary neoplasms is unclear.
Kamel (1997) reviewed iatrogenic lymphoproliferative disorders. The most frequent setting is in patients with rheumatoid arthritis who are receiving methotrexate. He did not specifically discuss lung involvement. He cited a case of a 15-year-old girl with juvenile dermatomyositis being treated with methotrexate who developed a lymphoproliferative disorder in the lung and died. Consequently, the diagnosis of a lymphoproliferative disorder should be considered in patients with autoimmune diseases who are receiving immunosuppressive therapy.
HUMAN IMMUNODEFICIENCY VIRUS RELATED MALIGNANCIES
Patients with the archetypal infectious immunodeficiency acquired immunodeficiency syndrome (AIDS) have an increased incidence of three malignancies: Kaposi's sarcoma, intermediate- or high-grade lymphoma, and uterine cervical cancer. Within the very recent past, there has been speculation that primary lung cancer also may have an increased incidence in patients infected with HIV. Alshafie and associates (1997) reviewed the patients with lung cancer at the Harlem Hospital in New York. Eleven patients had HIV infection, and 116 cases were classified as HIV indeterminate. The HIV patients were younger and had shorter life expectancies than those without HIV, but no conclusion could be reached. Parker and colleagues (1998) discovered a more convincing link when they evaluated the state of Texas database of patients with HIV-AIDS and lung cancer diagnosed between 1990 and 1995. Of 26,181 HIV-positive patients with or without AIDS, they found 76 cases of lung cancer. This was a 6.5-fold increased incidence over the general U.S. population. Further data are necessary to establish a firm link.
In 1992, Fraire and Awe reported a case of pulmonary adenocarcinoma occurring in a 34-year-old HIV-positive man with a past history of intravenous drug abuse and smoking. At the time of diagnosis, he was at stage IV and was treated with radiation therapy. He was alive 17 months after diagnosis but had progressive disease. In their review of the literature, Fraire and Awe (1992) found 22 patients who had lung cancer and were HIV positive. In general, the patients were young, with a median age of 38 years. There were 20 men and two women, for a male-to-female ratio of 10:1, in contrast to the usual ratio of 2:1. Most patients were smokers. Eleven of the patients had adenocarcinomas (50%), six had small cell carcinomas (27.3%), three had squamous cell carcinomas (13.5%), and one had adenosquamous carcinoma (4.5%). They pointed out that, in general, younger patients tend to have adenocarcinomas more frequently than do older patients, which may partly explain the high percentage of adenocarcinomas in this population.
In 1993, Karp and colleagues described seven HIV-positive patients with lung adenocarcinoma and compared them with a control group. Their findings were similar to those of Fraire and Awe (1992), except that they described their patients as having a rapidly progressive course. In 1995, Flores and associates reported another 19 patients. Vyzula and Remick (1996) reported another 16 patients and reviewed the literature. In summary, HIV-positive patients with lung cancer tend to be younger and have a higher percentage of adenocarcinomas than do other patients. Most of them have a history of smoking. They usually present at a higher stage and have a more rapidly progressive course than do control groups. Whether there is a true increased incidence of lung cancer in HIV-positive patients is not clear, although the report of Parker and colleagues (1998) suggests that there is. The Italian Group on AIDS and Tumors (GICAT) reported by Tirelli and colleagues in 2000 found 102 HIV-positive patients with lung cancer. They were younger and smoked more than the other patients with AIDS. The patients have a worse prognosis than age-matched controls with lung cancer. In one case reported by Aviram and associates (2001), a
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patient lived long enough to develop a second lung cancer. White and co-workers (2001) reported on a patient whose lung cancer was the presenting feature of AIDS. The prognosis for these patients is poor but may be improving. In comparing stage-matched HIV-negative controls to patients with HIV and lung cancer treated with highly active antiretroviral therapy, Powles and coinvestigators (2003) noted similar survival rates. This could imply that patients with major advanced therapy and controlled HIV may benefit from the same aggressive therapy as other healthy, noninfected patients.
Proposed Causal Mechanisms of Human Immunodeficiency Virus-Related Malignancies
The HIV-infected patient has disease-related mechanisms that increase the risk for developing cancer. In the case of Kaposi's sarcoma, several mechanisms may be at work. Beral and associates (1992) noted an increased incidence of Kaposi's sarcoma among homosexual and bisexual men. Lassoued and colleagues (1991), however, found a low incidence of Kaposi's sarcoma in HIV-infected women. In Africa, where HIV is spread mainly by heterosexual contact, the incidence among the sexes is more closely aligned. Regulatory proteins, such as oncostatin M and HIV-TAT, may play a role. Vogel and co-workers (1988) demonstrated that HIV-TAT can initiate cell transformation and stimulate the proliferation of Kaposi's sarcoma spindle cells. Miles and associates (1992) discovered that oncostatin M functions as both a primary growth factor and a stimulator of IL-6, which serves the same purpose.
Speculation about the etiology of Kaposi's sarcoma has abounded over the years. In Africa, it has a similar distribution to Burkitt's lymphoma, which suggests viral origin. Cytomegalovirus and HIV have been suggested as etiologic agents. In 1994, Chang and colleagues described DNA sequences in Kaposi's sarcoma tissue that were similar to herpesvirus. This virus is now known as HHV-8, or Kaposi's sarcoma associated herpesvirus. A subsequent study by Moore and Chang (1995) found the HHV-8 DNA sequence in 20 of 21 tissue samples (95%) of Kaposi's sarcoma but in only 1 of 21 control samples (5%). The same sequence was identified from Kaposi's sarcoma tissue in AIDS patients (the classic patient) and in HIV-negative homosexual men. Kennedy and associates (1998) detected HHV-8 in early lesions of Kaposi's sarcoma. They concluded this virus had a role in the pathogenesis of Kaposi's sarcoma, although the exact mechanism is not clear. In 1995, Karcher and Alkan confirmed this finding in several of their patients and also noted an association in Castleman's disease. In 1998, Jones and associates discovered an associated HHV-8 infection in an immunosuppressed, HIV-negative cardiac transplant patient who developed Kaposi's sarcoma. This strong association suggests that human herpesvirus is an initiator of the process leading to the development of Kaposi's sarcoma. In addition, Cesarman and co-workers (1995) identified an HHV-8 DNA sequence in eight of eight effusion lymphomas, which strongly suggests a link between HHV-8 and effusion lymphomas (effusion lymphomas are discussed in greater detail under Primary Effusion Lymphomas, later in this chapter).
Besides the EBV theory of the etiology of lymphoma described previously, HIV itself exerts a strong influence on the lymphatic system. In Knowles' (1997) review of HIV lymphomagenesis, he concluded that HIV is not directly involved in the malignant transformation of B cells, nor, consequently, in the induction of B-cell lymphomas. Both functional and quantitative defects can be measured in the CD4 T cells. Pantaleo and colleagues (1993) described the expansion of the B-cell population induced by a variety of factors, including IL-1, IL-2, IL-4, IL-6, IL-7, IL-10, and tumor necrosis factor- . This stimulation leads to generalized lymphadenopathy and monoclonal hypergammaglobulinemia. Such intense stimulation magnifies the DNA rearrangements. Pelicci and associates (1986) reported on the multiple clonal rearrangements, espousing the theory that subsequent selection and growth advantage goes to the eventual development of a monoclonal B-cell malignancy. Finally, translocations, particularly of t(8;14), t(8;2), and t(8;22), result in the deregulation of C-myc present on chromosome 8. Laurence and Astrin (1991) showed that HIV infection of immortalized B-cell lines results in upregulation of C-myc. Lombardi and associates (1987) demonstrated that increased activity of C-myc resulted in transformation of B cells.
Chronic B-cell stimulation is present in HIV-infected patients, as manifested by polyclonal hypergammaglobulinemia and the persistent generalized lymphadenopathy syndrome. This may be another factor contributing to the development of lymphomas in HIV-positive patients. Pelicci and colleagues (1986) postulated that HIV immunosuppression allows an EBV infection, which results in polyclonal B-cell activation. Because the B-cell regulation is now aberrant, it allows some EBV-infected, immortalized B cells to undergo C-myc gene rearrangement and become lymphomas. This does not completely explain the pathogenesis of their lymphomas because, as Hamilton-Dutoit and co-workers (1989, 1991) have pointed out, only about half of AIDS lymphomas contain EBV.
SECOND NEOPLASM SYNDROMES
During the 1970s, transplantation was offered to patients who had a history of a malignancy or who were receiving chemotherapy for existing cancers. Penn (1976) found that there was a 4% incidence of new malignancies in the group with a preexisting malignancy, which was not different from the 6% incidence of de novo cancer development in patients with no evidence of cancer before transplantation. However, he found that 166 new malignancies began in 160
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patients receiving chemotherapy for 161 tumors. This striking occurrence was blamed directly on the combination of immunosuppression and anticancer chemotherapy. Today, strict criteria are used for selecting cancer patients for possible transplantation; cancers must have been low-grade malignancies, and the patients must be disease free for at least 5 years.
A special group of patients is the group who survived aggressive chemotherapy 20 or more years previously only to develop second cancers. The patients who have received recent attention are survivors of Hodgkin's disease. Most of these patients were children treated between 1970 and 1990. This was first reported by Sont and colleagues (1992) from Leiden, the Netherlands. Tucker, of the U.S. National Cancer Institute, acknowledged this serious problem in 1993. In a follow-up study, van Leeuwen and associates (1994) reviewed the statistics from the Netherlands Cancer Center, discovering a 3.5-fold increased rate of cancer among 1,939 Hodgkin's patients over that expected in the general population. They found that the second cancers, in decreasing frequency, were leukemia, non Hodgkin's lymphoma, lung cancer, gastrointestinal cancers, urogenital cancers, melanoma, and soft tissue sarcoma. By contrast, Wolden and colleagues (1998) of Stanford studied 694 treated patients, finding that the most common solid tumors were breast cancer and sarcoma. Oddou and associates (1998) described six patients (of 171) who developed second neoplasms after treatment of their lymphomas with chemotherapy and autologous stem cell transplantation. One of these patients was a 55-year-old man who developed a squamous cell carcinoma of the lung. He was a cigarette smoker.
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Fig. 121-4. Radiograph of a patient with lung cancer that developed 20 years after mantle radiation therapy for Hodgkin's lymphoma. The lesion appears as a deepening density in the area of the scar from the previous irradiation. |
Analysis by van Leeuwen's group (1994) found that risk factors for the development of second cancers in Hodgkin's disease included chemotherapy during the first year, follow-up chemotherapy, age greater than 40 years at first diagnosis, splenectomy, and advanced stage. Earlier forms of chemotherapy led to a higher risk for developing leukemia. Women under 20 years of age when treated with mantle radiation had a 40-fold increase in breast cancer. Risk for developing lung cancer was strongly related to treatment with thoracic irradiation (Fig. 121-4). These patients usually have lesions in the apex of the lung, which could be bilateral in those who had mantle radiation.
PULMONARY TUMORS PRODUCED BY IMMUNOSUPPRESSION
In HIV-positive patients, the most common tumors are non Hodgkin's lymphomas and Kaposi's sarcoma. Transplant patients develop PTLD. More recently, smooth muscle tumors have been described as a rare complication after transplantation. Many tumors presenting in immunosuppressed patients look and act the same as they would in an immunocompetent patient, but stage for stage, the prognosis is worse. Pham and colleagues (1995) evaluated 608 cardiac transplant recipients, of whom 10 developed lung cancer. Eight of the 10 patients had stage III disease at the time of diagnosis. All patients had a poor prognosis. Taniguchi and co-workers (1997) subsequently reported on four patients with bronchial carcinoma. The morphologies were diverse. Three patients died at 1, 6, and 11 months after diagnosis. Only one survived to live 15 months after multimodality therapy.
Kaposi's Sarcoma
Recognized and studied most thoroughly in the AIDS population, Kaposi's sarcoma is of uncertain cellular origin and does not fulfill all the criteria for a true cancer. As reviewed by Levine (1993), it has not been demonstrated that this sarcoma possesses clonality or clonal chromosomal abnormalities.
The incidence of pulmonary Kaposi's sarcoma is difficult to determine. The autopsy study of Meduri and associates (1986) found Kaposi's sarcoma in the lungs of 47% of patients with cutaneous lesions. The lesions are purple, reddish, or brown macules or patches. The most common presenting lesions are in the genital area, followed by the gastrointestinal tract. When the gastrointestinal tract is involved, the oral cavity is involved 50% of the time. Occasionally, patients develop involvement of lymph nodes and may present with lymphedema. Pulmonary or pleural involvement, or both, is serious and is a harbinger of short life expectancy.
Mitchell (1992) and Miller (1992) and their associates reviewed the subject of pulmonary involvement by Kaposi's
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sarcoma. All 48 of their patients were men, with ages ranging from 24 to 55 years. Their main presenting symptoms were cough and shortness of breath. A rare patient complained of chest pain or hemoptysis. On physical examination, all patients had cutaneous Kaposi's sarcoma, and most also had oral lesions. Pulmonary function studies showed normal values for peak flow, forced expiratory volume in 1 second, and functional vital capacity in patients with localized disease but reduced values in patients with widespread disease. In both groups of patients, the carbon monoxide transfer factor and the transfer coefficient were reduced.
Radiographically, pleural effusions are common. The chest radiographs vary in their findings, depending on whether the lesions are localized or widespread. In localized disease, they may be normal or they may show bilateral interstitial patterns and, rarely, a bilateral coarse reticulonodular pattern or lobar consolidation. Patients with widespread disease can have chest radiographs that show a normal pattern, perihilar infiltrates, bilateral interstitial shadows, bilateral coarse reticulonodular shadows, or lobar consolidation. Parenchymal lesions are best seen on CT scan and appear as discrete, low-attenuation nodules or as an infiltrate.
Pulmonary Kaposi's sarcoma is usually diagnosed bronchoscopically. However, lesions can be seen on the visceral or parietal pleura. In the airway, the lesions may be submucosal patches or heaped-up mucosa with a red color. They may be friable and bleed when examined via biopsy. The patients in the studies of Mitchell (1992) and Miller (1992) and their colleagues were subjected to biopsy because of the concern about bleeding. Intrathoracic lesions look like skin lesions and are usually limited in size.
On microscopic examination, the early stage of the disease shows a proliferation of thin-walled vessels around larger vessels (Fig. 121-5). They also usually have a sparse surrounding infiltrate of lymphocytes and plasma cells (Fig. 121-6). The more mature lesions are composed of plump, bland spindle cells with slitlike spaces filled with red blood cells (Fig. 121-7). Hemosiderin as well as some lymphocytes and plasma cells are seen around the periphery of the lesion.
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Fig. 121-5. Kaposi's sarcoma in the lung. The interstitial and peribronchial areas of the lung are thickened by cells with bland spindle-shaped nuclei. |
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Fig. 121-6. Kaposi's sarcoma in the lung. In the center and the lower right, the interstitium is thickened by abundant spindle cells. |
Although single-agent chemotherapy has been used, combination therapy is best for patients with pulmonary Kaposi's sarcoma. Gill and colleagues (1991) gave what is now known as ABV chemotherapy [adriamycin (20 mg/m2), bleomycin (10 mg/m2), and vincristine (2 mg)] every 2 weeks to patients with widely disseminated gastrointestinal Kaposi's sarcoma. They observed an 88% response rate with ABV chemotherapy, a 38% response rate with adriamycin alone, and a 20% opportunistic infection rate. The ABV regimen is now used for patients with pulmonary Kaposi's sarcoma.
Shepherd and associates (1997) at Toronto Hospital treated biopsy-proven Kaposi's sarcoma in 12 transplant patients. They initially reduced or withdrew immunosuppression
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and used local radiation therapy. This was sufficient therapy in seven of the patients. They gave ABV therapy to the remaining five, who either had disseminated Kaposi's sarcoma or who did not respond to immunomodulation. Four of five responded, two with complete remission. The last patient was given third-line chemotherapy of cisplatin and etoposide, with a response. Only grade 1 toxicities were encountered. In the report of Mitchell and co-workers (1992), all 19 of their patients died, with a median survival of 7 months.
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Fig. 121-7. Kaposi's sarcoma in the lung. The bland spindle-shaped nuclei of Kaposi's sarcoma with adjacent slitlike spaces containing red blood cells (arrow). |
Lymphoma
Non Hodgkin's lymphomas occur in all groups of immunosuppressed patients. As a whole, the lymphomas are different from the non Hodgkin's lymphomas found in the general population (Fig. 121-8). B-cell lymphomas are the most common and are intermediate or high grade in type. Some large cell types have been reported in transplant and AIDS patients. T-cell lymphomas also have been encountered. Kohler and colleagues (1995) described an HIV-positive patient with a primary T-cell lymphoma of the lung. The patient was an HIV-positive 32-year-old man. He presented with a right upper lobe mass that, on histologic examination, was an intermediate-grade, mixed small and large cell lymphoma of T-cell type. The patient refused treatment and died 19 months after diagnosis. Today, after histologic confirmation of lymphoma is made, the tumor is further classified by immunohistochemistry, flow cytometry, and DNA extraction to detect gene rearrangements.
Any anatomic site may be involved with non Hodgkin's lymphoma. Extranodal disease occurs in 75% of patients. The central nervous system (CNS) is involved nearly 50% of the time. Other areas include the gastrointestinal tract (40%), the bone marrow (33%), and the liver (26%). Involvement of the lung is unusual but significant.
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Fig. 121-8. Solitary nodular lymphoma in the right upper lobe of a patient with acquired immunodeficiency syndrome. This lesion is irregularly convex and homogeneous. |
In HIV-positive patients, the incidence of both non Hodgkin's and Hodgkin's lymphoma is greater than that in the general population. The non Hodgkin's lymphomas, according to Said (1997), are 70% to 90% high-grade immunoblastic or small noncleaved (Burkitt's-like). In AIDS-associated pulmonary lymphomas, the distinction must be made between a primary pulmonary lymphoma and secondary pulmonary involvement by a disseminated lymphoma.
Primary Pulmonary Lymphoma
Ray and associates (1998) described 11 men and 1 woman with AIDS who had primary pulmonary lymphomas. They ranged in age from 32 to 56 years. The main risk factors were homosexuality, with a few patients being intravenous drug users and one patient having had a blood transfusion. Most had a history of opportunistic infections or Kaposi's sarcoma. The interval from the diagnosis of HIV disease until the diagnosis of lymphoma ranged from 1 to 8 years, with an average of 5 years. The symptoms of these patients included cough, dyspnea, and chest pain, with most of them having systemic symptoms (B symptoms), including fever, weight loss, and, less commonly, night sweats. The mean CD4 cell count was 17 per microliter, with a range of 4 to 50 per microliter. The serum lactate dehydrogenase was 1.5 times normal in four patients. The most common finding on the chest radiographs was a well-defined nodule (#2 cm) or a mass (>2 cm) in the subpleural area. Occasionally, cavitary lesions developed. Lee and colleagues (1997) reviewed the chest radiographic findings in primary pulmonary lymphomas. Their most common finding was an area of opacification with poorly defined margins and an air bronchogram. Less common findings were nodules, diffuse bilateral air space consolidation, and segmental or lobar atelectasis. The chest CT scans showed no mediastinal lymph nodes exceeding 1 cm in diameter. Five of the patients showed cavitary lesions.
On gross examination, the lesions were white to yellow solid nodules that sometimes had soft central areas of necrosis. On microscopic examination, six cases were diagnosed as high-grade lymphoma, not otherwise specified. The others were mostly immunoblastic and centroblastic (large noncleaved cell) lymphomas. On immunophenotyping, 11 cases were B cell and one was null cell. All 12 cases had EBV latent membrane protein-1 by immunohistochemistry. Eleven patients, with one not tested, had EBV-encoded RNA transcripts by in situ hybridization. These findings strongly implicate EBV in the pathogenesis of these lymphomas. All except one patient were treated. The untreated patient died before therapy began. The other patients received various combinations of agents, which included CHOP (cyclophosphamide, adriamycin, vincristine, prednisone) or parts of CHOP as well as etoposide, bleomycin, cisplatinum, and novantrone. All patients died either from their lymphoma or intercurrent conditions. The median survival
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after diagnosis was 4 months, with a range of less than 1 month to 17 months.
Teruya-Feldstein and associates (1995) described a lymphoma of mucosa-associated lymphoid tissue (MALT) in the lung of a 7-year-old girl who had been HIV positive since she was 2 years old. In February 1992, she developed enlarged submandibular and submental lymph nodes. The following month, a chest radiograph showed a left upper lobe lung lesion. In August 1993, the patient's mother consented to removal of the lesion after it had grown on two consecutive CT scans. Grossly, it was a solid, white-tan mass that measured 4 cm in greatest dimension. On microscopic examination, the lesion was composed of a dense lymphoid infiltrate with germinal centers surrounded by monocytoid cells, small lymphocytes, and plasma cells. Lymphoepithelial lesions were present. The remaining lung tissue showed pulmonary lymphoid hyperplasia and lymphocytic interstitial pneumonitis. Immunohistochemical stains showed staining for l light chains but not for k light chains. EBV in situ hybridization was positive in a few background cells, thus suggesting that EBV was not an important factor in the development of this MALT lymphoma. Southern blot studies showed clonal immunoglobulin gene rearrangements. All these findings are consistent with a MALT lymphoma. The patient received no further treatment, and a CT scan performed in December 1993 showed no evidence of recurrent tumor.
Secondary Pulmonary Lymphoma
In contrast to primary lymphomas, the lung frequently is involved secondarily by lymphomas in AIDS patients. Eisner and colleagues (1996) reviewed 38 HIV-infected patients with pulmonary or pleural involvement by non Hodgkin's lymphoma. Their 38 patients were all men, with a mean age of 40.5 years and an age range of 28 to 61 years. The main risk factors were homosexuality and intravenous drug use, with a small percentage of patients having no known risk factors. Approximately one third of the patients had a history of an opportunistic infection, and one fourth had a history of Kaposi's sarcoma. Most had cough, dyspnea, or chest pain, and almost all had systemic symptoms (B symptoms), such as fever, weight loss, or night sweats. On physical examination, the patients had tachypnea (74%), crackles (37%), dullness to percussion (26%), decreased breath sounds (26%), and bronchial breath sounds (24%). Laboratory examination showed low CD4 counts (67 6.5 cells per microliter). The sedimentation rate and serum lactate dehydrogenase were usually elevated.
Almost all the chest radiographs were abnormal. The most common patterns were lobar consolidation (40%), nodules (40%), reticular infiltrates (24%), and masses (24%). Dodd and associates (1992) reviewed the chest radiographs of patients with AIDS-related lymphoma. Their most common abnormalities were pleural effusions (47%), reticulonodular infiltrates and alveolar consolidation (22%), hilar and mediastinal adenopathy (22%), pulmonary nodules or masses (17%), and pericardial effusions or masses (13%). Pleural effusions were present in many patients (44%). Lee and co-workers (1997) also reviewed the chest radiographic findings in AIDS patients with secondary pulmonary involvement. Their most common findings were thickening of bronchovascular bundles (41%), discrete pulmonary nodules (39%), and areas of consolidation (14%). Other findings include cavitated masses and bronchial masses. They also described CT scan findings of masses or masslike areas of consolidation larger than 1 cm (68%) and nodules smaller than 1 cm (61%). The CT scans described by Eisner and colleagues (1996) showed parenchymal nodules (50%), lobar consolidations (27%), and masses (19%). Pleural effusions were also present in many of the patients.
On microscopic examination, the lymphomas of Eisner and colleagues (1996) were immunoblastic (61%), large cell (18%), Burkitt's (5.3%), small noncleaved (2.6%), and undifferentiated high-grade lymphomas (13%). They found the lungs to be the most common extranodal site (71%) of involvement in patients with non Hodgkin's lymphoma. Unfortunately, studies for EBV were not reported for these cases. They suggested transbronchial biopsy, pleural fluid cytology, pleural biopsy, transthoracic needle biopsy, and open lung biopsy as the most useful methods of obtaining a diagnosis. In their series, they did not discuss treatment or survival of these patients. In additional studies by Hamilton-Dutoit and associates (1989, 1991), EBV was detected only in approximately 50% of these patients. Other studies have lower rates. This is in contrast to PTLD, in which EBV is detected in about 95% of cases.
The best therapy for lymphoma in patients who are not infected with HIV is CHOP chemotherapy. Attempts at more aggressive therapy did not result in greater response, as noted by Fisher and co-workers (1993). For HIV-associated lymphomas, various therapies have been tried. No specific regimen has emerged as the best. However, two seem to have a good response rate with fewer side effects. Kaplan and colleagues (1991) used CHOP with granulocyte-macrophage colony-stimulating factor, which kept the nadir granulocyte counts higher, thus decreasing the complication rate. Levine and associates (1991) used methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (M-BACOD) as a less is more therapy with success. Walsh of their group (1993) later reported use of M-BACOD with granulocyte-macrophage colony-stimulating factor, with a 67% complete response rate and only a 10% opportunistic infection rate.
Said (1997) discussed the relationship between Hodgkin's lymphoma and HIV-positive patients. The incidence of Hodgkin's lymphoma is increased in HIV-positive patients, but Hodgkin's lymphoma is not a defining criterion for AIDS. Hodgkin's lymphoma has a more aggressive course in HIV-positive individuals. A definite causal link between HIV, EBV, and Hodgkin's disease has not been established.
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Summary
HIV-positive patients have a high incidence of non Hodgkin's lymphoma. The lymphomas are usually of high grade and stage when they are diagnosed, and the patients have a short survival. The lymphomas may be primary pulmonary lymphomas or, more frequently, represent secondary pulmonary involvement. EBV may be detected in approximately 50% of these patients. This is in contrast to CNS lymphomas, which are almost all associated with EBV. MALT lymphomas, T-cell lymphomas, and Hodgkin's lymphoma may occur in HIV-positive patients, but they are far less common.
POSTTRANSPLANTATION LYMPHOPROLIFERATIVE DISORDERS
Thoracic organ transplant patients seem particularly susceptible to PTLD. The presentation ranges from asymptomatic pulmonary nodules to multiorgan failure. Symptoms are usually associated with enlarged lymph nodes.
PTLDs occur more frequently in patients who have lung, liver, and heart transplants than in those with kidney transplants. In kidney transplants, the clinician is more likely to temper the immunosuppression because the patient can always be returned to dialysis. With other organ transplants, this is not a viable alternative, and when rejection occurs, immunosuppression is usually increased. Morrison and colleagues (1994) described 26 patients with PTLD, some of whom had pulmonary involvement. Ferry and associates (1989) described a clinical series of PTLD, although none of their patients had pulmonary involvement. Hsi and co-workers (1998) described a patient with a PTLD of the natural killer cell type. Basgoz and Preiksaitis (1995) reviewed the subject of PTLD and described the clinical characteristics of the disease.
Clinical Presentation
The age and sex of the patients would depend on the transplantation recipient. The risk factors for the development of PTLD are listed in Table 121-4. They include the type of organ transplant, primary EBV infection, the type of immunosuppression (e.g., antilymphocyte antibody, cyclosporine A, FK-506), HLA mismatch, and cytomegalovirus disease. Kidney transplant recipients have a less than 1% chance for developing PTLD, whereas liver transplant recipients have a 4% chance, and heart-lung recipients have a 10% chance. The greater the degree of immunosuppression, the greater the risk for developing PTLD. A patient with a primary EBV infection after transplantation is more at risk than is a person who was EBV seropositive before receiving the organ. In bone marrow transplant recipients, the greatest incidence of PTLD occurred among patients with HLA mismatching. Patients with previous symptomatic infections of cytomegalovirus are also at increased risk for developing PTLD.
Table 121-4. Risk Factors for the Development of Posttransplant Lymphoproliferative Disorders | ||
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PTLDs may present in a variety of ways. Newly transplanted patients who develop a primary EBV infection may present with an infectious mononucleosislike illness. They have a febrile illness with leukopenia, pharyngitis, fevers, lymphadenopathy, and hepatosplenomegaly. Laboratory testing may not show atypical lymphocytosis, heterophile antibodies, or antibodies to specific EBV antigens. Patients who develop PTLD months or years after transplantation may present with persistent fever, malaise, and leukopenia without localizing signs. Therefore, any long-term transplant patient should be evaluated for PTLD as well as a variety of infectious agents, if they develop generalized symptoms. The CNS is a favored site. These patients may present with subtle alterations of mental status or advanced neurologic findings. If the gastrointestinal tract is involved, patients may present with abdominal pain, gastrointestinal bleeding, obstruction, or bowel perforation. PTLD may involve such organs as the lung, liver, kidney, allograft, lymph nodes, and bone marrow. Some patients, as reported by Muti and associates (2002), were found to be affected only on autopsy.
Radiographic Features
Rappaport and colleagues (1998) reviewed radiographic images of lymphoproliferative disorders in lung transplant patients. They presented data on 9 patients who developed PTLD of 246 transplant patients. Eight of the nine had only intrathoracic disease. The most common presentation was multiple, well-defined nodules with a basilar and peripheral prominence. Other presentations were mediastinal adenopathy, upper lobe consolidation, and a pleural mass. Dodd (1992) and Lee (1997) and their associates also reviewed the radiologic manifestations of thoracic PTLD. The radiologic findings are nonspecific and varied. They include multiple nodules scattered throughout the lungs ranging from 0.5 to 2.0 cm, solitary masses ranging up to 5 cm, an interstitial pattern of disease, and an alveolar disease pattern. These patients may or may not have hilar adenopathy (Fig. 121-9). Pleural effusions are common.
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Fig. 121-9. Posttransplantation lymphoproliferative disorder. This lesion is composed of a sheet of plasma cells with eccentrically placed nuclei. |
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Pathology
Because PTLD is a recently described disease, the pathology and nomenclature are undergoing an evolution. The origin of the disease appears to be an infection of lymphocytes by EBV that develops into a lymphoid proliferation (Fig. 121-10). The exact mechanism by which the transformation takes place is not completely understood, although various explanations have been put forward. Chadburn and associates (1995), using molecular analysis of involved and uninvolved recipient tissue, were able to determine that PTLD in solid organ transplant patients derives from the recipients' tissue. This is in contrast to bone marrow transplant patients, in whom the majority of PTLDs are of donor origin. The nomenclature used in the histologic classification of PTLD lesions varies in different medical centers. Unfortunately, morphologic appearances do not reliably predict ultimate clinical prognosis.
PTLD is the catch-all phrase used to describe a variety of lymphoid lesions, ranging from benign lymphoid proliferations to malignant lymphomas. Swerdlow (1992, 1997) reviewed the various classifications, and Harris and colleagues (1997) reviewed the morphology for the different categories of PTLD. Three published classifications exist for PTLD. The first is by Frizzera and colleagues (1981), which was later modified by Shapiro and co-workers (1988) with the help of Frizzera. The second is by Nalesnik and associates (1988), which was later modified by Wu and colleagues (1996). Knowles and co-workers (1995) published the third classification.
All three classifications have distinct merits, but the nomenclature is confusing. One reason for a classification is to determine treatment. In some cases, PTLD regresses if immunosuppression is stopped, whereas in others, PTLD progresses despite therapy. All three of these classifications use one or more of the terms atypical, polymorphic, and monomorphic. Before discussing the classifications, it is appropriate to define these terms. Atypical is defined as irregular or not conforming to type. In terms of a pathologic description, it can mean (a) a certain cell that is not in its proper location in the lymph node, (b) an abnormal increase of a certain type of cell, or (c) cells with an irregular nucleus, which gives them an atypical appearance. Polymorphous means that many different cell types are present, such as lymphocytes, plasma cells, and immunoblasts. It also suggests that, because the lesion is composed of different cell types, it is not yet a lymphoma. Monomorphic means only one cell type is present, such as immunoblasts. Because these lesions are of the same cell type, they are consistent with a lymphoma.
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Fig. 121-10. Chest radiograph of a liver transplant patient with posttransplantation lymphoproliferative disorder. Lesions are finely nodular and are present mainly in the lower lobe. |
Shapiro and co-workers (1988) modified the earliest classification of Frizzera and colleagues (1981) (Table 121-5). These researchers described five types of PTLD, which included atypical lymphoid hyperplasia, polymorphic diffuse B-cell hyperplasia, atypical polymorphic diffuse B-cell hyperplasia, polymorphic diffuse B-cell lymphoma, and immunoblastic sarcoma of B cells. They distinguished PTLD from reactive lymph nodes by their invasiveness, diffuse distribution of follicular center cells, architectural effacement, and a prominent large cell component mimicking malignant lymphoma. Invasiveness refers to infiltration of the vessel walls, nodal fibrous trabeculae, capsule, and extranodal tissues
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by lymphoid cells. Atypical lymphoid hyperplasia shows a polymorphic paracortical or interstitial proliferation that lacks invasiveness but has an abundance of immunoblasts as well as small lymphocytes with irregular nuclei. Polymorphic diffuse B-cell hyperplasia shows a diffuse proliferation of cells, resembling cleaved and noncleaved follicular center cells, small lymphocytes, plasma cells, and immunoblasts. Atypical polymorphic diffuse B-cell hyperplasia is similar to polymorphic diffuse B-cell hyperplasia, except that it has nuclear atypia and multinucleation of large cells. Polymorphic diffuse B-cell lymphoma shows extensive coagulative necrosis and atypical immunoblasts. The immunoblasts are atypical because of their nuclei. These nuclear changes include bilobulation or multilobulation, deep grooves, and irregular borders. The immunoblastic sarcoma of B cells is composed of cells that have enlarged oval nuclei with a vesicular appearance and nucleoli.
Table 121-5. Frizzera's Classification of Posttransplant Lymphoproliferative Disorders, as Modified by Shapiro | ||
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Wu and associates (1996) modified the second classification of Nalesnik and co-workers (1988) (Table 121-6). Their three categories are EBV-positive lymphadenitis resembling infectious mononucleosis, polymorphic PTLD, and monomorphic PTLD. EBV-positive lymphadenitis resembling infectious mononucleosis has polymorphic cells, but it lacks an invasive growth pattern, and there is partial or complete architectural retention. The cells are composed of a scattering of follicular cells with lymphocytes and plasma cells. Polymorphic PTLD includes both the polymorphic B-cell hyperplasia and polymorphic B-cell lymphoma of Frizzera and co-workers (1981). Monomorphic PTLD shows a population of lymphoid cells that are all at the same stage of differentiation. They can be either small or large noncleaved lymphocytes.
Table 121-6. Nalesnik's Classification of Posttransplant Lymphoproliferative Disorders, as Modified by Wu | ||
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Table 121-7. Knowles' Classification of Posttransplant Lymphoproliferative Disorders | ||
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Knowles and co-workers' (1995) classification of PTLD correlated morphology and clonality of the cells, clonality of EBV, and alterations in oncogenes or tumor-suppressor genes (Table 121-7). Their first category is plasmacytic hyperplasia. It is most commonly located in the oropharynx or the lymph nodes. It consists of an expansion of the interfollicular area of a lymph node by plasmacytoid lymphocytes, plasma cells, and sparse immunoblasts. Germinal centers may be hyperplastic, involuted, or absent. These are polyclonal, have only a minor cell population infected by a single form of EBV, and lack oncogene and tumor-suppressor gene alterations. The second category, polymorphic B-cell hyperplasia and polymorphic B-cell lymphoma, is the morphologic equivalent of polymorphic B-cell hyperplasia and lymphoma of Frizzera and co-workers (1981) and the polymorphic PTLD of Nalesnik and associates (1988). These PTLDs may arise in nodal and extranodal sites. They are monoclonal, contain a single form of EBV, but lack oncogene or tumor suppressor gene alterations. The last category is immunoblastic lymphoma or multiple myeloma. Immunoblastic lymphomas are composed of a monomorphic cell population that have either enlarged, bizarre pleomorphic nuclei or plasmacytoid nuclei. Multiple myeloma is composed of a dense infiltrate of atypical plasma cells. Both are generally widely disseminated at the time of presentation. They are monoclonal, contain a single form of EBV,
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and have alterations in one or more oncogenes (N-ras gene codon 61 point mutation or C-myc gene rearrangement) or tumor-suppressor genes (p53 mutation).
Table 121-8. Recognized Patterns of Posttransplant Lymphoproliferative Disorders (PTLDs) | ||
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Swerdlow (1997) summarized all the categories of PTLD (Table 121-8). In addition to the histology, these lesions should be evaluated for cellular monoclonality and oncogene or tumor suppressor gene mutations.
Treatment
Basgoz and Preiksaitis (1995) point out that the treatment varies for PTLD. It includes reduction in immunosuppression, surgical resection, antiviral treatment, radiation therapy, cytotoxic chemotherapy, IFN, and gamma globulin as well as a variety of experimental treatments. In 1984, Starzl and co-workers reported a regression of PTLD with a decrease in immunosuppression. Regression has been observed in localized or polyclonal lesions as well as some multifocal or monoclonal cases. Therefore, decreased immunosuppression is the first step in treatment. The next step may include resection or irradiation of a localized lesion. According to Morrison and co-workers (1994), more extensive disease may be treated with standard combination chemotherapy regimens, which include CHOP; CHOP-bleomycin; cyclophosphamide, vincristine, methotrexate, leucovorin, cytosine, and arabinoside; cyclophosphamide, vincristine, prednisone; M-BACOD; etoposide, doxorubicin, cyclophosphamide, vincristine, bleomycin, and prednisone; and ifosfamide and etoposide. Antiviral agents, such as acyclovir and ganciclovir, have been used to stop the replication of EBV. Their value in treating PTLD is in patients with polyclonal lesions rather than those with monoclonal ones. Malouf and colleagues (2002) advocate the use of antiviral agents as prophylaxsis in all EBV-negative patients. In their series, no patient on prophylaxsis who was EBV negative developed PTLD.
Mentzer and associates (1998) used a unique way to achieve success in controlling this disease. They began with the usual therapy for one of their lung transplant patients with posttransplantation lymphoma. As in other series, the therapy was ineffective. They established a cell line from the lymphoma and activated the virus by inducing the enzyme thymidine kinase with arginine butyrate. With this combination, the ganciclovir was effective and seemed to work synergistically with the chemotherapy to produce tumor necrosis.
The newest therapy involves the use of immunosuppression and humanized anti-CD20 monoclonal antibody (Rituximab-GENENTECH, South San Francisco, CA). Reynaud-Gaubert and associates (2000) reported that a patient with nasopharyngeal lymphoma following lung transplantation was treated successfully with anti-CD20 and radiation therapy, with long-term graft survival. Milpied and colleagues (2000) reported their experience in 32 patients with PTLD. They primarily treated 30 patients with anti-CD20 and gave rescue therapy to two additional patients. They had an overall response rate of 69%: 20 complete responses and 2 partial responses. The projected survival was 73%. The remaining patients received rescue therapy as outlined with good long-term results.
Prognosis
In the study by Morrison and associates (1994), 8 of 26 patients (31%) were rendered disease free by surgery or radiation therapy, or they achieved complete remission by chemotherapy. The remission duration ranged from 8 to 122 months. Of the 26 patients, 21 (81%) died. Their survival ranged from less than 1 month to 122 months, with a median of 14 months. In summary, the survival for patients who develop PTLD is not very good.
At this point, a strategy to prevent PTLD would be helpful. The objective would be to minimize the previously discussed risk factors associated with PTLD. Other strategies involve vaccinating EBV-seronegative recipients. The development of methods to determine viral load may indicate the patients who are more susceptible to developing PTLD and who may benefit from antiviral chemotherapy. Finally, because the EBV latency gene products play a major role in the transformation of cells, a method to inactivate these proteins might be useful in preventing PTLD.
Posttransplant Lymphoproliferative Disorders of T-Cell Origin
PTLDs of T-cell origin have also been described. Hsi and colleagues (1998) described the case of a 42-year-old man who underwent cadaveric renal transplantation for complete renal failure of unknown etiology. His immunosuppressive therapy consisted of cyclosporine, azathioprine, and prednisone. Eight years after transplantation, he developed a PTLD, which was diagnosed as a large cell malignant lymphoma. The immunophenotyping was consistent with a T-cell origin. The Southern blot studies did not show rearrangements of the heavy or light immunoglobulin genes or the T-cell receptor beta or gamma genes. The in situ hybridization for EBV-encoded RNA was negative. The polymerase chain reaction for detecting EBV genome was also negative.
The patient underwent an allograft nephrectomy as well as a nephrectomy of both native kidneys. Postoperatively, the patient was treated by a withdrawal of immunosuppression, acyclovir, and a single cycle of CHOP. The patient had a rapidly progressive disease and died 4 weeks after surgery. This case illustrates that not all PTLDs are of EBV-infected B-cell origin.
PRIMARY EFFUSION LYMPHOMA
Another lymphoma that occurs in HIV-positive patients is body cavity based lymphoma or, as it is now called, primary effusion lymphoma. These lymphomas were probably
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first described by Knowles and colleagues (1989). They occur in both HIV-positive patients and transplant recipients. Jones and associates (1998) have reported on this entity, as have Karcher and Alkan (1997). Primary effusion lymphomas are defined as lymphoma cells in body cavity effusions (pleural, pericardial, and peritoneal) with no identifiable contiguous tumor mass, lymphadenopathy, or organomegaly. These neoplasms are interesting because many of them contain both EBV and HHV-8. Cesarman and Knowles (1997) found HHV-8 in a significant proportion of patients with AIDS and in those with non-AIDS-related multicentric Castleman's disease.
Nador and colleagues (1996) described 19 cases of primary effusion lymphoma. Seventeen were in HIV-positive homosexual men who ranged in age from 31 to 58 years with a median age of 41 years; the other two were in HIV-negative men 79 and 85 years of age. Of the effusions, eight were in the pleural cavity, two in the pericardial cavity, seven in the peritoneal cavity, and one in both pleural and peritoneal cavities. The clinical symptoms of these patients are not described in the report. Morassut and co-workers (1997) described the radiologic findings in six patients with effusion lymphomas. The chest radiographs showed bilateral or unilateral pleural effusions with no evidence of pulmonary infiltrates or mediastinal enlargement. The CT scans confirmed the findings of the chest radiographs, and revealed a slight thickening of the parietal pleura in all patients and a pericardial thickening in four patients. They also revealed five patients with pericardial effusions and two patients with peritoneal effusions.
The pathologic features of these cases varied. In 15 cases, the malignant cells contained HHV-8, and in four they did not. Microscopic examination of the cells from the 15 HHV-8-positive cases revealed polymorphic large cells, which had features between a large cell immunoblastic lymphoma and an anaplastic large cell lymphoma. The four HHV-8-negative cases consisted of monomorphic medium-sized cells with round regular nuclei that resembled the cells of Burkitt's lymphoma. On immunophenotyping, 5 of the 19 cases had B-cell markers. The remaining 14 cases were indeterminate. The gene rearrangement studies were not performed on all cases. Sixteen of 17 cases had clonal heavy immunoglobulin gene rearrangement, 14 of 16 cases had clonal k light chain gene rearrangement, and 4 of 11 cases had clonal l light chain gene rearrangement. One case exhibited bigenotypism with clonal markers for both B and T cells. EBV was present in 18 of 19 cases, the exception being an HIV-negative, but HHV-8-positive, 85-year-old man. HIV was not detected in any of the 19 effusions. The C-myc protooncogene was germline in the 12 HHV-8-positive cases tested. In contrast, the four HHV-8-negative lymphoma effusions displayed a rearrangement of C-myc. No other consistent genotypic changes were detected in these neoplasms.
Nine of the patients were treated with chemotherapy, three patients received supportive care, and the treatment for six patients is unknown. All patients had a poor prognosis, with 18 of 19 patients dying 12 days to 14 months (median 5 months) after their diagnosis.
SMOOTH MUSCLE TUMORS
Benign and malignant smooth muscle tumors have been documented in posttransplant patients by Penn (1995) as well as by Lee (1995) and Timmons (1995) and their associates. In addition, these tumors have been reported in HIV-infected patients by van Hoeven and colleagues (1993). McClain and colleagues (1995) reported EBV infection in seven smooth muscle tumors (leiomyomas and leiomyosarcomas) from six children with HIV infection. In contrast, they found no evidence of EBV infection in normal muscle or tumors from HIV-negative children. They concluded that EBV had a role in the development of smooth muscle tumors in HIV-infected children.
Similar smooth muscle tumors have been described in liver transplant patients. Timmons (1995) and Lee (1995) and their co-workers found latent EBV in the neoplastic smooth muscle cells of transplant patients. One of the patients described by Lee and associates (1995) had multiple nodules of smooth muscle in the lung at the time of autopsy. In 1998, Somers and associates described a heart-lung transplant patient who developed multiple leiomyosarcomas in both the lung transplant and the host liver. The patient was a 15-year-old boy who underwent heart-lung transplantation for primary pulmonary hypertension at the age of 11 years. He was treated with cyclosporine, azathioprine, and prednisolone as well as a course of antithymocyte globulin to prevent rejection. He developed a chronic pulmonary infection with Pseudomonas aeruginosa that quickly became resistant to antibiotics. At 41 months after transplantation, he underwent a thoracic CT scan to evaluate bronchiectasis. He had multiple solid nodules approximately 0.5 cm in diameter throughout both lung fields. A CT scan of the abdomen did not show any abdominal disease. The patient was treated with decreased immunosuppression and intravenous ganciclovir, which was later changed to oral acyclovir. He eventually developed pneumonia and died 43 months after transplant. At autopsy, the patient had multiple nodules in both lungs as well as extensive suppurative bronchopneumonia. Two nodules were present in the liver. On histologic examination, the pulmonary and liver nodules were leiomyosarcomas. EBV DNA was extracted from lung tumor biopsy specimens but not from the autopsy lung and liver specimens. Somers and colleagues (1998) performed DNA amplification of microsatellite repeat polymorphisms. By this technique, they were able to demonstrate that the lung tumors arose from the donor tissue, whereas the liver lesions arose from host tissue. They postulated that the lack of detectable EBV DNA in the autopsy specimens was because of the treatment with ganciclovir and acyclovir. In conclusion, immunosuppressed patients can develop smooth muscle tumors
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of the lung. The evidence suggests that these smooth muscle tumors develop in a manner analogous to PTLD.
REFERENCES
Alshafie MT, Donaldson B, Oluwole SF: Human immunodeficiency virus and lung cancer. Br J Surg 84:1068, 1997.
Aviram G, Fishman JE, Schwartz DS: Metachronous primary carcinomas of the lung in an HIV-infected patient. AIDS Patient Care STDS 15:297, 2001
Basgoz N, Preiksaitis JK: Post-transplant lymphoproliferative disorder. Infect Dis Clin North Am 9:901, 1995.
Beral V, et al: Risk of Kaposi's sarcoma and sexual practices associated with faecal contact in homosexual or bisexual men with AIDS. Lancet 339:632, 1992.
Berger F, Delecluse HJ: Lymphomas in immunocompromised hosts. Rev Prat 43:1661, 1993.
Birkeland SA, et al: EBV-induced post-transplant lymphoproliferative disorder (PTLD). Transplant Proc 27:3467, 1995.
Boyle GJ, et al: Posttransplantation lymphoproliferative disorders in pediatric thoracic organ recipients. J Pediatr 131:309, 1997.
Cesarman E, Knowles DM: Kaposi's sarcoma-associated herpesvirus: a lymphotropic human herpesvirus associated with Kaposi's sarcoma, primary effusion lymphoma and Castleman's disease. Semin Diagn Pathol 14:54, 1997.
Cesarman E, et al: Kaposi's sarcoma-associated herpesvirus-like DNA sequences are present in AIDS-related body cavity-based lymphomas. N Engl J Med 332:1186, 1995.
Chadburn A, et al: Post-transplantation lymphoproliferative disorders arising in solid organ transplant recipients are usually of recipient origin. Am J Pathol 147:1862, 1995.
Chang Y, et al: Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266:1865, 1994.
DePerrot M, et al: Bronchogenic carcinoma after solid organ transplantation. Ann Thorac Surg 75:367, 2003.
Dockrell DH, Strickler JG, Paya CV: Epstein Barr virus induced T cell lymphoma in solid organ transplant recipients. Clin Infect Dis 26:180, 1998.
Dodd GD 3rd, Greenler DP, Confer SR: Thoracic and abdominal manifestations of lymphoma occurring in the immuno-compromised patient. Radiol Clin North Am 30:597, 1992.
Eisner MD, et al: The pulmonary manifestations of AIDS-related non Hodgkin's lymphoma. Chest 110:729, 1996.
End A, et al: The pulmonary nodule after lung transplantation. Cause and outcome. Chest 107:1317, 1995.
Ferry JA, et al: Lymphoproliferative disorders and hematologic malignancies following organ transplantation. Mod Pathol 2:583, 1989.
Fisher RI, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non Hodgkin's lymphoma. N Engl J Med 328:1002, 1993.
Flores MR, et al: Lung cancer in patients with human immunodeficiency virus infection. Am J Clin Oncol 18:59, 1995.
Fraire AE, Awe RJ: Lung cancer in association with human immunodeficiency virus infection. Cancer 70:432, 1992.
Frizzera G, et al: Polymorphic diffuse B-cell hyperplasias and lymphomas in renal transplant recipients. Cancer Res 41:4262, 1981.
Gill PS, et al: A systemic treatment of AIDS-related Kaposi's sarcoma: results of a randomized trial. Am J Med 90:427, 1991.
Hamilton-Dutoit SJ, et al: Identification of EBV-DNA in tumour cells of AIDS-related lymphomas by in-situ hybridisation. Lancet 1:554, 1989.
Hamilton-Dutoit SJ, et al: AIDS-related lymphoma: histopathology, immunophenotype, and association with EBV as demonstrated by in situ nucleic acid hybridization. Am J Pathol 138:149, 1991.
Hansen LA, Prakash UB, Colby TV: Pulmonary lymphoma in Sj gren's syndrome. Mayo Clin Proc 64:920, 1989.
Haque T, et al: Transmission of donor Epstein Barr virus (EBV) in transplanted organs causes lymphoproliferative disease in EBV seronegative recipients. J Gen Virol 77:1169, 1996.
Harris NL, Ferry JA, Swerdlow SH: Posttransplant lymphoproliferative disorders: summary of Society for Hematopathology Workshop. Semin Diagn Pathol 14:8, 1997.
Hsi ED, Pickens MM, Alkan S: Post-transplantation lymphoproliferative disorder of the NK-cell type: a case report and review of the literature. Mod Pathol 11:479, 1998.
International Society of Heart and Lung Transplantation: Registries Heart/Lung Registries. ISHLT website, accessed at www.ishlt.org/registries/heartLungRegistry.asp, 2003.
Jones D, et al: Primary-effusion lymphoma and Kaposi's sarcoma in a cardiac-transplant recipient. N Engl J Med 339:444, 1998.
Kamel OW: Iatrogenic lymphoproliferative disorders in nontransplantation settings. Semin Diagn Pathol 14:27, 1997.
Kaplan LD, et al: Clinical and virologic effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients receiving chemotherapy for human immunodeficiency virus associated non Hodgkin's lymphoma: results of a randomized trial. J Clin Oncol 9:929, 1991.
Karcher DS, Alkan S: Herpes-like DNA sequences, AIDS-related tumors and Castleman's disease. N Engl J Med 333:797, 1995.
Karcher DS, Alkan S: Human herpesvirus-8-associated body cavity based lymphoma in human immunodeficiency virus infected patients: a unique B-cell neoplasm. Hum Pathol 28:801, 1997.
Karp J, et al: Lung cancer in patients with immunodeficiency syndrome. Chest 103:410, 1993.
Kennedy MM, et al: Identification of HHV8 in early Kaposi's sarcoma: implications for Kaposi's sarcoma pathogenesis. Mol Pathol 51:14, 1998.
Knowles DM: Molecular pathology of acquired immunodeficiency syndrome related non Hodgkin's lymphoma. Semin Diagn Pathol 14:67, 1997.
Knowles DM, et al: Molecular genetic analysis of three AIDS-associated neoplasms of uncertain lineage demonstrates their B-cell derivation and the possible pathogenetic role of Epstein-Barr virus. Blood 73:792, 1989.
Knowles DM, et al: Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders. Blood 85:552, 1995.
Kohler CA, et al: Primary pulmonary T-cell lymphoma associated with AIDS: the syndrome of the indolent pulmonary mass lesion. Am J Med 99:324, 1995.
Lassoued K, et al: AIDS-associated Kaposi's sarcoma in female patients. AIDS 5:877, 1991.
Laurence J, Astrin SM: Human immunodeficiency virus induction of malignant transformation in human B lymphocytes. Proc Natl Acad Sci U S A 88:7635, 1991.
Lee ES, et al: The association of Epstein-Barr virus with smooth muscle tumors occurring after organ transplantation. N Engl J Med 332:19, 1995.
Lee KS, Kim Y, Primack SL: Imaging of pulmonary lymphomas. AJR 168:339, 1997.
Levine AM: AIDS-related malignancies: the emerging epidemic. J Natl Cancer Inst 85:1382, 1993.
Levine AM, et al: Low-dose chemotherapy with central nervous system prophylaxis and azidothymidine maintenance in AIDS-related lymphoma. A prospective multiinstitutional trial. JAMA 266:84, 1991.
Lombardi L, Newcomb EW, Dalla-Favera R: Pathogenesis of Burkitt lymphoma: expression of an activated c-myc oncogene causes the tumorigenic conversion of EBV-infected human B lymphoblasts. Cell 46:161, 1987.
Malouf MA, et al: Anti-viral prophylaxis reduces the incidence of lymphoproliferative disease in lung transplant recipients. J Heart Lung Transplant 21:547, 2002.
Marchioli CC, et al: Prevalence of human herpesvirus 8 DNA sequences in several patient populations. J Clin Microbiol 34:2635, 1996.
Mathur A, et al: Immunoregulatory abnormalities in patients with Epstein-Barr virus associated B-cell lymphoproliferative disorders. Transplantation 57:1042, 1994.
McClain KL, et al: Association of Epstein-Barr virus with leiomyosarcomas in children with AIDS. N Engl J Med 332:12, 1995.
Meduri GU, et al: Pulmonary Kaposi's sarcoma in the acquired immune deficiency syndrome. Clinical, radiographic, and pathologic manifestations. Am J Med 81:11, 1986.
Mellemkjaer L, et al: Rheumatoid arthritis and cancer risk. Eur J Cancer 32A:1753, 1996.
Mellemkjaer L, et al: Non Hodgkin's lymphoma and other cancers among a cohort of patients with systemic lupus erythematosus. Arthritis Rheum 40:761, 1997.
P.1878
Mentzer SJ, et al: Immunoblastic lymphoma of donor origin in the allograft after lung transplantation. Transplantation 61:1720, 1996.
Mentzer SJ, et al: Arginine butyrate-induced susceptibility to ganciclovir in an Epstein Barr virus associated lymphoma. Blood Cells Mol Dis 24:114, 1998.
Mihalov ML, et al: Incidence of post-transplant malignancy among 674 solid-organ-transplant recipients at a single center. Clin Transplant 10: 248, 1996.
Miles SA, et al: Oncostatin M as a potent mitogen for AIDS-Kaposi's sarcoma derived cells. Science 255:1432, 1992.
Miller RF, et al: Bronchopulmonary Kaposi's sarcoma in patients with AIDS. Thorax 47:721, 1992.
Milpied N, et al: Humanized anti-CD20 monoclonal antibody (Rituximab) in post transplant B-lymphoproliferative disorder: a retrospective analysis on 32 patients. Ann Oncol 11(suppl 1):113, 2000.
Mitchell DM, et al: Bronchopulmonary Kaposi's sarcoma in patients with AIDS. Thorax 47:726, 1992.
Montone KT, et al: Analysis of Epstein Barr virus associated posttransplantation lymphoproliferative disorder after lung transplantation. Surgery 119:544, 1996.
Moore PS, Chang Y: Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and without HIV infection. N Engl J Med 332:1181, 1995.
Morassut S, et al: HIV-associated human herpesvirus 8 positive primary lymphomatous effusion: radiologic findings in six patients. Radiology 205:459, 1997.
Morrison VA, et al: Clinical characteristics of post-transplant lymphoproliferative disorders. Am J Med 97:14, 1994.
Muti G, et al: Post-transplant lymphoproliferative disorders: improved outcome after clinico-pathologically tailored treatment. Haematologica 87:67, 2002.
Nador RG, et al: Primary effusion lymphoma: a distinct clinicopathologic entity associated with Kaposi's sarcoma associated herpes virus. Blood 88:645, 1996.
Nalesnik MA, et al: The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression. Am J Pathol 133:172, 1988.
Nicholson AG, et al: Pulmonary B-cell non Hodgkin's lymphoma associated with autoimmune disorders: a clinicopathological review of six cases. Eur Respir J 9:2022, 1996.
Oddou S, et al: Second neoplasms following high-dose chemotherapy and autologous stem cell transplantation for malignant lymphomas: a report of six cases in a cohort of 171 patients from a single institution. Leuk Lymphoma 31:187, 1998.
Pantaleo G, Graziosi C, Fauci AS: New concepts in the immunopathogenesis of human immunodeficiency virus infection. N Engl J Med 328: 327, 1993.
Parker MS, et al: AIDS-related bronchogenic carcinoma: fact or fiction? Chest 113:154, 1998.
Pelicci PG, et al: Multiple monoclonal B cell expansions and c-myc oncogene rearrangements in acquired immunodeficiency syndrome related lymphoproliferative disorders: implications for lymphomagenesis. J Exp Med 164:2049, 1986.
Penn I: Second malignant neoplasms associated with immunosuppressive medications. Cancer 37(2 suppl):1024, 1976.
Penn I: Malignancies associated with renal transplantation. Urology 10:57, 1977.
Penn I: Cancers of the anogenital region in renal transplant recipients. Analysis of 65 cases. Cancer 58:611, 1986.
Penn I: Development of new tumors after transplantation. In Cerilli GJ (ed): Organ Transplantation and Replacement. Philadelphia: JB Lippincott, 1988, p. 825.
Penn I: Malignancy. Surg Clin North Am 74:1247, 1994.
Penn I: Sarcomas in organ allograft recipients. Transplantation 60:1485, 1995.
Pham SM, et al: Solid tumors after heart transplantation: lethality of lung cancer. Ann Thorac Surg 60:1623, 1995.
Powles T, et al: Does HIV adversely influence the outcome in advanced non-small-cell lung cancer in the era of HAART? Br J Cancer 89:457, 2003.
Quismorio FP Jr: Pulmonary involvement in primary Sj gren's syndrome. Curr Opin Pulm Med 2:424, 1996.
Ramsey-Goldman R, et al: Increased risk of malignancy in patients with systemic lupus erythematosus. J Invest Med 46:217, 1998.
Rappaport DC, et al: Lymphoproliferative disorders after lung transplantation: imaging features. Radiology 206:519, 1998.
Ray P, et al: AIDS-related primary pulmonary lymphoma. Am J Respir Crit Care Med 158:1221, 1998.
Reynaud-Gaubert M, et al: Anti-CD20 monoclonal antibody therapy in Epstein-Barr virus associated B cell lymphoma following lung transplantation. J Heart Lung Transplant 19:492, 2000.
Said JW: Human immunodeficiency virus related lymphoid proliferations. Semin Diagn Pathol 14:48, 1997.
Schwend M, et al: Rapidly growing Epstein-Barr virus associated pulmonary lymphoma after heart transplantation. Eur Respir J 7:612, 1994.
Shapiro RS, et al: Epstein-Barr virus associated B-cell lymphoproliferative disorders following bone marrow transplantation. Blood 71:1223, 1988.
Shepherd FA, et al: Treatment of Kaposi's sarcoma after solid organ transplantation. J Clin Oncol 15:2371, 1997.
Somers GR, et al: Multiple leiomyosarcomas of both donor and recipient origin arising in a heart-lung transplant patient. Am J Surg Pathol 22: 1423, 1998.
Sont JK, et al: Increased risk of second cancers in managing Hodgkin's disease: the 20-year Leiden experience. Ann Hematol 65:213, 1992.
Spiekerkoetter E, et al: Prevalence of malignancies after lung transplantation. Transplant Proc 30:1523, 1998.
Starzl TE, et al: Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporine-steroid therapy. Lancet 1:583, 1984.
Swerdlow SH: Post-transplant lymphoproliferative disorders: a morphologic, phenotypic and genotypic spectrum of disease. Histopathology 20:373, 1992.
Swerdlow SH: Classification of the posttransplant lymphoproliferative disorders: from the past to the present. Semin Diagn Pathol 14:2, 1997.
Taniguchi S, et al: Primary bronchogenic carcinoma in recipients of heart transplants. Transplant Int 10:312, 1997.
Teruya-Feldstein J, et al: Pulmonary malignant lymphoma of mucosa-associated lymphoid tissue (MALT) arising in a pediatric HIV-positive patient. Am J Surg Pathol 19:357, 1995.
Timmons CF, et al: Epstein-Barr virus associated leiomyosarcomas in liver transplantation recipients. Origin from either donor or recipient tissue. Cancer 76:1481, 1995.
Tirelli U, et al: Lung carcinoma in 36 patients with human immunodeficiency virus infection. The Italian Cooperative Group on AIDS and Tumors. Cancer 88:563, 2000.
Tucker MA: Solid second cancers following Hodgkin's disease. Hematol Oncol Clin North Am 7:389, 1993.
van Hoeven KH, et al: Visceral myogenic tumors. A manifestation of HIV infection in children. Am J Surg Pathol 17:1176, 1993.
van Leeuwen FE, et al: Second cancer risk following Hodgkin's disease: a 20-year follow-up study. J Clin Oncol 12:312, 1994.
Verschuuren EA, et al: Patients at risk for post-transplant lymphoproliferative disease can be identified in the first months after lung transplantation by quantitative-competitive-EBV-PCR. J Heart Lung Transplant 20:199, 2001.
Vogel J, et al: The HIV tat gene induces dermal lesions resembling Kaposi's sarcoma in transgenic mice. Nature 335:606, 1988.
Vyzula R, Remick SC: Lung cancer in patients with HIV-infection. Lung Cancer 15:325, 1996.
Walsh C, et al: Phase I study of M-BACOD and GM-CSF in AIDS associated non Hodgkin's lymphoma. J AIDS 6:265, 1993.
White JD, Bowman CA, Woll PJ: Lung cancer as the presenting feature of AIDS. Lung Cancer 33:81, 2001.
Wolden SL, et al: Second cancers following pediatric Hodgkin's disease. J Clin Oncol 16:536, 1998.
Wong JY, et al: EBV mismatching and HLA matching post lung transplantation: key risk factors for post transplant lymphoproliferative disease (PTLD). J Heart Lung Transplant 20:199, 2001.
Wu T-T, et al: Recurrent Epstein-Barr virus associated lesions in organ transplant recipients. Hum Pathol 27:157, 1996.
Zhang QW, et al: Chronic rejection in H-2 matched cardiac allografts: early emergence of vasculopathy, alloantibody, and accumulation of IFN-gamma and IL-10 mRNA. Transplant Int 14:143, 2001.
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