Once distant metastases have been identified during staging, further radiographic staging studies are necessary only if dictated by a clinical protocol or as necessary to evaluate a symptomatic complaint (. Because many of these patients have poor functional status and other adverse prognostic factors, less aggressive chemotherapy programs are acceptable and may provide comparable palliation with less toxicity. Because relapse invariably occurs, enrollment on an investigational study evaluating new targets designed to impair tumor growth is warranted if available. When disease progression does occur, additional chemotherapy should be offered to most patients with a good functional status. Successive large studies by the Southwest Oncology Group also confirm that although thoracic radiotherapy can substantially reduce the frequency of initial relapse at the primary tumor site, there is no apparent effect on survival. Overt intracranial metastases appear to be more difficult to sterilize than intrathoracic disease. Chemotherapy is also a therapeutic option for brain metastases, perhaps because the bloodbrain barrier is disrupted in the setting of macroscopic metastatic disease. Small series of patients in whom brain metastases were present at diagnosis have been treated with standard chemotherapy regimens without radiation, and the majority have demonstrated both clinical and radiographic improvement. These approaches include increasing the number of active agents used in the treatment program, often by the use of cyclic alternation between two combination regimens, increasing the dose intensity, often with the support of hematopoietic growth factors or blood progenitor cells, and weekly chemotherapy regimens, which increase the dose intensity by shortening the interval between treatment rather than increasing the dose. The somatic mutation model developed by Goldie and Coldman provided a theoretical underpinning to this approach, as this model predicted that the best probability of cure was achieved by the earliest possible introduction and most rapid alternation of all active agents. Although it did not reach its planned accrual, it still had sufficient power to have detected a 2-month increase in median survival time with alternating therapy, had it existed. These studies, therefore, do not support the superiority of an alternating chemotherapy combination in patients with extensive disease. Alternating noncross-resistant chemotherapy has also been investigated in patients with limited disease. Patients with extensive disease who responded to chemotherapy continued treatment for 1 year. No differences in survival based on treatment were noted in the patients with extensive disease. Additional studies have evaluated alternating chemotherapy introduced after achieving a response to an induction regimen. No difference in outcome was noted based on treatment arm in either limited or extensive disease. Other studies have compared alternating regimens that were designed based on the suggestion of in vitro synergy349 or have compared an alternating multidrug combination with a different standard regimen. These include dose intensification without or with hematopoietic growth factor support, dose intensification with marrow or peripheral blood stem cell support, and compression of the time in which chemotherapy is delivered using a weekly schedule. Hryniuk and Bush developed a methodology that expresses dose intensity as the drug dose administered per meter squared per week. Nevertheless, this method has been used to demonstrate a positive correlation between dose intensity and treatment outcome in advanced breast cancer and ovarian cancer. More recently, several investigators evaluated whether increasing the dose of drugs beyond the dose used in current regimens improves survival. Most of these studies were conducted in patients with extensive disease 364,365,366,367 and 368 (Table 31. Neither of these studies used a hematopoietic growth factor in the intensified arm. Although the planned cumulative doses of chemotherapy were equivalent for three of the drugs, the intensified arm actually received a lower total dose because of toxicity. The only study that has suggested that the administration of higher drug doses within a standard regimen was beneficial was conducted in patients with limited disease. This French study randomized 105 patients with limited disease to a higher dose of cisplatin (100 vs. These studies indicate that a modest intensification of the dose of the commonly used agents does not improve outcome for patients with extensive disease and may even compromise survival by producing excessive toxicity. Whether a modest increase in the dose of drugs improves the outcome of patients with limited disease should be confirmed, and this question should probably be addressed in randomized trials that include either growth factor or stem cell support to maximize the delivered dose.
Long-term survival is rare for patients who have not undergone a successful resection. Surgical considerations are complex and best addressed by surgeons intimately familiar with hepatic anatomy and resection. For successful resection, perfusion and drainage for an anatomic segment of the liver must be preserved. The liver lobes are perfused by the two divisions of the hepatic artery and the portal vein, with one branch to each lobe. The left and right lobes are divided along a plane between the bed of the gallbladder and the anterior aspect of the vena cava. The liver is drained by three veins into the vena cava at the most superior aspect of the liver. The right hepatic vein drains the major portion of the right lobe (the posterior segment and a portion of the anterior segment of the lobe). The left hepatic vein, arising from a short common trunk with the middle vein in 50% of cases, travels along the umbilical fissure of the liver and primarily drains the lateral segment of the left lobe. In a right or left lobectomy, the left or right branches of the hepatic artery and portal vein are preserved, along with the left and middle or right and middle hepatic veins. In an extended right or left hepatectomy (also referred to as a trisegmentectomy), the same inflow vessels are removed, along with the middle and left or right hepatic veins. A much greater portion of the hepatic parenchyma is removed in this type of resection (. Relation between hepatic anatomy and nomenclature for various types of hepatic resection. It defines the critical relationship between the tumor and associated vasculature. Historically, most children underwent angiography to facilitate surgical planning before hepatic resection. When angiography is not performed, the surgeon must be aware of the frequent anomalies of the hepatic artery. The right hepatic artery may arise from the superior mesenteric artery, while the left hepatic artery may arise from the celiac axis. These variations, if present, must be identified before division of any vessels in the hepatic porta. Factors that render a liver tumor unresectable include involvement of both lobes of the liver and lymph node involvement in the porta hepatis or mediastinum. Additional features that preclude resection include direct extension into the inferior vena cava, a central lesion that involves both the left and right hepatic arteries or the portal vein, or lesions that involve all branches of the hepatic vein. A large hepatoblastoma grossly distorts the normal anatomy and relationships of the vessels. It is as if a balloon is placed within the liver parenchyma and is progressively inflated. The vessels to the uninvolved segments may be tightly drawn over a massively enlarged segment, making safe dissection and preservation difficult. As the tumor responds to chemotherapy, it does not regress from areas of involvement, although its decreased volume permits identification of the normal uninvolved segments. Treatment with chemotherapy before definitive surgery has permitted complete resections in children whose hepatoblastomas were initially deemed unresectable. Although complications from hepatectomy persist, perioperative mortality has significantly decreased. Bile leaks, strictures, subphrenic or subhepatic abscesses, and intraoperative hemorrhage are the most frequent complications. Major postoperative complications have occurred more frequently in children undergoing resection after chemotherapy (25%) than in children resected at presentation (8%). The distribution between lobectomies and trisegmentectomies was similar for children undergoing primary resections and resections following several course of induction chemotherapy. Lymph node involvement is a contraindication for efforts at resection and transplantation. Cryoablation or radiofrequency ablation of hepatic malignancies has been increasingly used in adults, particularly for metastatic lesions in the liver.
Diseases
Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo. Interferon-inducible protein-10 identified as a mediator of tumor necrosis in vivo. Effects of the Th1 and Th2 stimulatory cytokines interleukin-12 and interleukin-4 on human immunodeficiency virus replication. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Time course of induction of metabolism of all- trans-retinoic acid and the up-regulation of cellular retinoic acid-binding protein. J Acquir Immune Defic Syndr Hum Retrovirol Vol 17, Lippincott, Williams & Wilkins. Current trends revision of the case definition of acquired immunodeficiency syndrome for national reportingUnited States. Role of zidovudine antiretroviral therapy in the pathogenesis of acquired immunodeficiency syndrome-related lymphoma. The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression. Epstein-Barr virus strain type and latent membrane protein 1 gene deletions in lymphomas in patients with rheumatic diseases. Post-transplantation lymphoproliferative disorder of donor origin in a sex-mismatched renal allograft as proven by chromosome in situ hybridization. Low dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone with zalcitabine in patients with acquired immunodeficiency syndrome-related lymphoma. Evidence for early B-cell activation preceding the development of Epstein-Barr virus-negative acquired immunodeficiency syndrome-related lymphoma. Polyclonal polymorphic B-cell lymphoproliferative disorder with prominent pulmonary involvement in children with acquired immune deficiency syndrome. Human immunodeficiency virus-associated systemic lymphomas may be subdivided into two main groups according to Epstein-Barr viral latent gene expression. Relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Epstein-Barr and human immunodeficiency viruses in acquired immunodeficiency syndrome-related primary central nervous system lymphoma. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. Low-grade monoclonal Epstein-Barr virus-associated lymphoproliferative disorder of the brain presenting as human immunodeficiency virusassociated encephalopathy in a child with acquired immunodeficiency syndrome. Accessing Epstein-Barr virus-specific T-cell memory with peptide-loaded dendritic cells. Induction of bcl-2 expression by Epstein-Barr virus latent membrane protein 1 protects infected B cells from programmed cell death. Histogenetic correlations between subcategories of small noncleaved cell lymphomas. Selection of immunoglobulin diversity gene reading frames in B cell lymphoproliferative disorders. Human herpesvirus-8-associated body cavity-based lymphoma in human immunodeficiency virus-infected patients: a unique B-cell neoplasm. Guidelines for prophylaxis against Pneumocystis carinii pneumonia for persons infected with human immunodeficiency virus type 1. Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: results of a tree-structured survival analysis. American Society of Clinical Oncology35th Annual Meeting, Atlanta, May 1518, 1999. Epidemiology of brain lymphoma among people with or without acquired immunodeficiency syndrome. Experience with brain biopsy in acquired immune deficiency syndrome-related focal lesions of the central nervous system. Intracranial mass lesions in acquired immunodeficiency syndrome: using decision analysis to determine the effectiveness of stereotactic brain biopsy.
The emphasis on defining real disease entities, rather than focusing on subtleties of morphology or immunophenotype or primarily on patient survival, represented a new paradigm in lymphoma classification. This consensus approach represented the second major departure from previous classifications, most of which represented the work of one or a few individuals. Although its initial publication incited considerable controversy, experience over the intervening years has shown that it can be used by most pathologists, and that the entities it describes have distinctive clinical features, making it a useful and practical classification, despite its apparent complexity. Thus, it will represent the first true international consensus on the classification of hematologic malignancies. It recognizes that all of these criteria are at best approximations, and that continued research and experience will be needed to continue to improve the definition of these diseases. Morphology remains the first and most basic approach and is sufficient for both diagnosis and classification in many typical cases of lymphoma. Immunophenotyping and, particularly, molecular genetic studies are not needed in all cases; however, they are useful in difficult cases and improve interobserver reproducibility. It is the availability of these more objective methods that make a consensus on lymphoma classification possible now, while it was impossible in the 1970s, when classification was based purely on subjective morphologic features. Both lymphomas and lymphoid leukemias are included, since both solid and circulating phases are present in many lymphoid neoplasms, and distinction between them is artificial. Immunodeficiency-associated lymphomas are classified according to the basic lymphoma classification; a separate classification of the posttransplant lymphoid proliferations that do not fulfill criteria for lymphoma is also given (Table 45. Many of the neoplasms recognized in the classification have morphologic variants, clinical subtypes, or both. This study convincingly demonstrated that the classification could be used by expert hematopathologists: Over 95% of the cases with adequate material could be classified into one or another of the categories. The interobserver reproducibility was substantially better than that for other classifications and was better than 85% for most diseases (Table 45. Immunophenotyping was helpful in some diseases, such as mantle cell lymphoma and diffuse large B-cell lymphoma, in which it improved accuracy by 10% to 15% and was essential for all types of T-cell lymphoma, improving reproducibility from approximately 50% to over 90%. The most common lymphoma was diffuse large B-cell lymphoma, followed by follicular lymphoma; together, these accounted for 50% of the lymphomas in the study. These results are reassuring, confirming that the majority of the cases that will be encountered by oncologists and pathologists will be only a few subtypes, with which they are already familiar. However, they also underscore the need for recognizing the more recently described entities, which although less common, have important clinical differences. The study also found differences in geographic distribution of the lymphoma types, with follicular lymphoma being more common in North America and western Europe, T-cell lymphomas more common in Hong Kong, and both mediastinal large B-cell lymphoma and mantle cell lymphoma more common in Ticino (the Italian-speaking canton), Switzerland. Presenting Features of Common B- and T-Cell Neoplasms the different entities recognized by the classification had significantly different clinical presentations and survivals. For example, diffuse aggressive lymphomas, which would be lumped as intermediate or high grade in the Working Formulation, include diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, peripheral T-cell lymphoma, and anaplastic large T/null-cell lymphoma. The clinical features at presentation were strikingly different, with a younger age group for mediastinal large T-cell lymphoma and anaplastic large T/null-cell lymphoma, and striking differences in male to female ratios, suggesting that these are distinctive biologic entities (see Table 45. When overall survivals were analyzed, entities that would have been lumped together as low grade or intermediate/high grade in the Working Formulation showed marked differences in survival, again confirming that they need to be recognized and treated as distinct entities. A critical finding in this study was that classification is not the only predictor of clinical outcome. Patients with any of these diseases could be stratified into better and worse prognostic groups according to the International Prognostic Index. In lymph nodes or other tissues, the most important distinguishing features include effacement of the architecture and the presence or absence of pseudofollicles. Although the cells in the peripheral blood may resemble hairy cells, the nuclei are usually smaller, with more condensed chromatin, and the villi are polar and less conspicuous than those of hairy cell leukemia. The marrow infiltrate is usually sparse and nodular, in contrast to hairy cell leukemia. In this situation, if morphologic criteria are insufficient, staining for Ig light-chains is the most useful test to determine clonality. Histologically, the presence of a dense, diffuse infiltrate of marginal zone B cells, with destruction of glands and prominent lymphoepithelial lesions is required for a confident diagnosis. Antibiotic therapy often causes the lymphoma to regress, but the long-term outcome of these patients is not known, and therefore it is important to know before treatment, whether the patient has lymphoma or just gastritis. The major differential diagnosis, both clinically and pathologically, for follicular lymphoma is with reactive follicular hyperplasia.
In a series of reports, we have documented a high overall response rate and long-term disease-free survival in a minority of such patients. Most of the patients in this group did not have clinical characteristics strongly suggestive of extragonadal germ cell tumor. However, involvement of the mediastinum, retroperitoneum, and peripheral lymph node groups was relatively common. Later, as etoposide replaced vinblastine, these patients received cisplatin and etoposide with or without bleomycin. All patients received an initial treatment trial of two courses of therapy, and responding patients received a total of four treatment courses. Major tumor responses were seen in 138 of 220 patients (62%), and 58 patients (26%) had complete response to treatment. Clinical Characteristics of 220 Patients with Poorly Differentiated Carcinoma of Unknown Primary Site Our most recent update of this initial group of patients shows the following: 12% (26 patients) of the entire group has remained alive and free of tumor at a minimum follow-up of 6 years, with a range of 6 to 17 years (median, 11 years). Fourteen patients who were relapse-free at a minimum of 11 months at the time of our original report 141 cannot be documented now as alive and free of the original tumor. Six patients are lost to follow-up, though each was known to be alive and relapse-free at 1, 2. Four patients died with progressive carcinoma of unknown primary site (two at 1 year and two at 7 years after initial chemotherapy). Three patients developed new cancers: one brain tumor, one pancreatic carcinoma, one lymphoma (two at 9 years and one at 17 years, respectively, after the initial therapy). The survival curves for the entire group of 220 patients and for the subset of 58 (26%) who had a complete response to chemotherapy are shown in Figure 48-5 and Figure 48-6. Of the 58 complete responders, 22 patients remain alive and relapse-free (38%), representing 10% of the entire group of 220. Four additional patients were treated in an "adjuvant setting" after resection of all gross tumor and all remain alive, bringing the total to 12% of all patients relapse-free. Patients who are lost to follow-up (six), died of second unrelated cancers (three), or died of other causes (one) are included as deaths on the curves. It is of note that 50 of the 220 patients were treated by oncologists outside our center, and their long-term results are equivalent. These results in a large series of patients support the notion that these poorly differentiated histologic types, as a whole, represent more sensitive tumors than well-differentiated adenocarcinoma, and substantial prolongation of life is possible for some of these patients, with the expectation of cure for a small minority. Survival curve for all 220 patients with poorly differentiated carcinoma (12% at 17 years). In only 32 of the 220 patients (14%) was the primary site or specific tumor type eventually identified (Table 48-5). In 19 of these 32 patients, the definitive diagnosis was made at repeat biopsy later during the course of the disease or at autopsy. In the remainder, retrospective specialized pathology studies provided the basis for diagnosis. All six lymphomas were identified retrospectively: four by immunoperoxidase staining, one by repeat biopsy at the time of tumor relapse, and one by genetic analysis (detection of an immunoglobulin gene rearrangement). However, only 30 autopsies were performed, and in only 11 (37%) was a primary site identified. In the remainder, metastatic, poorly differentiated carcinoma or poorly differentiated adenocarcinoma with no primary site was found. This observation is nearly opposite for those patients with well-differentiated adenocarcinoma; in nearly 80% of them, a primary tumor was found at autopsy. In addition, nine patients were thought to have melanoma on the basis of pathologic review or special pathologic studies; however, none of these patients had a known primary site, and none had typical light-microscopical findings of melanoma. Specific Pathologic Diagnoses Confirmed Since 1989, we have either seen or collected clinical and pathologic data from 700 additional patients with carcinomas of unknown primary site. Before 1997, the majority of these patients with poorly differentiated carcinomas received cisplatin plus etoposide with or without bleomycin, and the results are similar to those of the 220 previously reported patients. In the last 5 years, we have treated most patients with carboplatin and etoposide, with or without a taxane (paclitaxel or docetaxel), either as initial therapy or after first relapse. Furthermore, we have explored the paclitaxel-based 100 and docetaxel-based chemotherapy (unpublished data) in this group, in addition to the well-differentiated adenocarcinoma group, and found these regimens useful. We are attempting to confirm that taxane-based chemotherapy is superior to other chemotherapy regimens. At present, the treatment for most patients with poorly differentiated carcinoma (with or without features of adenocarcinoma) is controversial, but we think that they should be treated initially with a regimen containing paclitaxel, carboplatin, and oral etoposide.
Syndromes
La Radiotherapie des mesotheliomes pleuraux malins: a propos de 14 cas irradies a dose elevees. Clinical applications of high energy electron beams: the pancreas, pleura, and spine. Radiotherapy in the treatment of malignant mesothelioma of the pleura, with special reference to its use in palliation. Factors influencing the outcome of radiotherapy in malignant mesothelioma of the pleuraa single-institution experience with 189 patients. The treatment of malignant mesothelioma of the pleura: review of a 5-year experience, with special reference to radiotherapy. Radiographic chest assessment of lung injury following hemithorax irradiation for pleural mesothelioma. Changes in surfactant in bronchoalveolar lavage fluid after hemithorax irradiation in patients with mesothelioma. The role of computed tomography scanning in the initial assessment and the follow-up of the malignant pleural mesothelioma. Physical aspects of external beam radiotherapy for the treatment of malignant pleural mesothelioma. The value of Adriamycin in the treatment of diffuse malignant pleural mesothelioma. Ifosfamide and mesna with doxorubicin have activity in malignant mesothelioma [letter; comment]. Therapeutic intraperitoneal 32P: a clinical assessment of the dynamics of distribution. Mesothelioma of the abdomen in women; monitoring of therapy by peritoneal fluid study. Treatment of diffuse pleural malignant mesothelioma by cis dichloro diammine platinum in nine patients. Treatment of diffuse pleural malignant mesothelioma by cis-diaminedichloroplatinum: preliminary results in eleven patients. Recombinant interferon alpha-2b in the treatment of diffuse malignant pleural mesothelioma. Intrapleural treatment with recombinant gamma-interferon in early stage malignant pleural mesothelioma. Randomized comparison of cyclophosphamide, imidazole carboxamide, and adriamycin versus cyclophosphamide and adriamycin in patients with advanced stage malignant mesothelioma: a Sarcoma Intergroup Study. Intrapleural cisplatin and mitomycin for malignant mesothelioma following pleurectomy: pharmacokinetic studies. Activity of doxorubicin and cisplatin combination chemotherapy in patients with diffuse malignant pleural mesothelioma. High dose doxorubicin plus cisplatin in the treatment of unresectable mesotheliomas: report of four cases. Combination chemotherapy with cisplatin-vinblastine in malignant mesothelioma [see comments]. Weekly systemic combination of cisplatin and interferon alpha 2a in diffuse malignant pleural mesothelioma. Higher doses of alpha-interferon do not increase the activity of the weekly cisplatin-interferon combination in advanced malignant mesothelioma Eur J Cancer 1997;33:1900. Mitomycin C and cisplatin in human malignant mesothelioma xenografts in nude mice: clinical correlation. Cisplatin, mitomycin, and interferon-alpha2a combination chemoimmunotherapy in the treatment of diffuse malignant pleural mesothelioma. Treatment of malignant pleural mesothelioma with cisplatin, mitomycin C and alpha interferon. High-dose methotrexate in combination with interferons in the treatment of malignant pleural mesothelioma. Malignant pleural mesothelioma: a disease unaffected by current therapeutic maneuvers. Phase I study of paclitaxel as a radiation sensitizer in the treatment of mesothelioma and non-small-cell lung cancer. Pleurectomy and intraoperative brachytherapy and postoperative radiation in the management of malignant pleural mesothelioma.
Symptomatic treatment of recurrent malignant pleural effusions with intrapleurally administered Corynebacterium parvum. Clinical response is not associated with evidence of enhancement of local cellular-mediated immunity. A randomized trial of intracavitary bleomycin and Corynebacterium parvum in the control of malignant pleural effusions. Intrapleural natural beta interferon in the treatment of malignant pleural effusions. Intrapleural immunotherapy with escalating doses of interleukin-2 in metastatic pleural effusions. Intrapleural application of recombinant interleukin-2 in patients with malignant pleurisy due to lung cancer. Cisplatin and cytarabine administered intrapleurally as treatment of malignant pleural effusions. Intrapleural cisplatin and cytarabine in the management of malignant pleural effusions: a Lung Cancer Study Group trial. Intracavitary Adriamycin nitrogen mustard and tetracycline in the control of malignant effusions: a randomized study. Pleurectomy/decortication for palliation in malignant pleural mesothelioma: results of surgery. Video-assisted thoracoscopic pleurectomy in the management of malignant pleural effusion. Early experience with videothoracoscopic hydrodissection pleurectomy in the treatment of malignant pleural effusion. Case report: malignant pericardial effusion as the initial manifestation of malignancy. Pericardial effusion and tamponade: evaluation, imaging modalities, and management. Unsuspect malignant pericardial effusion causing cardiac tamponade: rapid diagnosis by computed tomography. Echocardiographic and surgical correlation of pericardial effusions in patients with malignant disease. The differentiation of malignant from idiopathic and radiation-induced pericarditis. Pericardial effusion: subxiphoid pericardiostomy versus percutaneous catheter drainage. Thoracoscopic management of effusive pericardial disease: indications and technique. Pericardioperitoneal shunt: an alternative treatment for malignant pericardial effusion. Pericardiocentesis for symptomatic malignant pericardial effusion: a study of 36 patients. Two-dimensional echocardiographically guided pericardiocentesis: experience in 117 consecutive patients. Pericardial sclerosis as the primary management of malignant pericardial effusion and cardiac tamponade. Prospective comparison of the sclerosing agents doxycycline and bleomycin for the primary management of malignant pericardial effusion and cardiac tamponade. Percutaneous balloon pericardiotomy for the treatment of cardiac tamponade and large pericardial effusions: description of technique and report of the first 50 cases. Percutaneous balloon pericardial window for patients with malignant pericardial effusion and tamponade. Thoracoscopic talc insufflation versus talc slurry for symptomatic malignant pleural effusion. Cardiac tamponade caused by primary lung cancer and the management of pericardial effusion.
By obtaining information from the history and physical examination, one assesses the risk of malignancy in that individual. In general, there is a 5% to 10% chance of malignancy in all thyroid nodules for the total population 11; however, men and patients at the extremes of age are at higher risk for malignancy. Nodules found in a patient with a history of childhood neck irradiation carry a 33% to 37% chance of malignancy. Tender nodules are more often associated with thyroiditis and are likely to be benign. On examination of the neck, attention to the firmness, mobility, and size of the nodules, their adherence to surrounding structures, and the presence of adenopathy are important clues to the presence of carcinoma. However, these features, with the exception of cervical lymphadenopathy, lack specificity for malignancy. In this case, one determines whether the nodule is functional with a radionuclide scan by iodine uptake. Tests of serum thyroglobulin (Tg) levels are not helpful in distinguishing benign from malignant thyroid nodules. Radionuclide scans are also helpful in determining the functional status of nodules in patients with multinodular thyroid disease to focus a biopsy on cold nodules. Cysts larger than 4 cm in size and having a partially solid component and those that recur after three aspirations may warrant biopsy, as these conditions are more likely to be associated with malignancy. The impact this procedure has had on clinical practice is reflected by a reduction of the total number of thyroid surgeries performed, a greater proportion of malignancies removed at surgery, and an overall reduction in the cost of managing patients with nodules. Reviews of this technique provide insight into the results typically obtained at the time of fine-needle biopsy of the nodules: 70% are classified as benign (range, 53% to 90%), 4. The cells from follicular adenomas and follicular carcinomas appear identical; only by identifying capsular or vascular invasion can cancer be diagnosed. Malignancy is found in 10% to 20% of follicular nodules that are classified as indeterminateon biopsy. Sampling error occurring during biopsy of large, cystic hemorrhagic nodules or simple misdiagnosis account for many of the false-negative results. The creation of a subclinical hyperthyroid state by suppressive doses of thyroxine increases the incidence of osteoporosis. One significant difference in the incidence in terms of race is that the proportion of well-differentiated thyroid carcinomas that are follicular is increased greatly in blacks as compared to whites. It is reported that follicular carcinoma accounts for 15% of all well-differentiated tumors in whites as compared to 34% in blacks. One is medically administered external-beam irradiation, and the second is environmental exposure, previously related to nuclear weapons attacks or weapons testing and, more recently, from nuclear power plant accidents. Internal exposure occurs by ingestion of radioisotopes of iodine that concentrate in the thyroid gland from either medical treatment with radioactive iodine or by ingestion of these radioisotopes from the fallout from nuclear weapons explosions or power plant accidents. The relative risks of radiation exposure from these different sources has been well studied, and variables, such as age at exposure, radiation dose, and latent period to developing cancers, have been defined. Relative risk is also linearly related to exposure dose, at least up to 2000 rads. They have intensively analyzed more than 3000 patients who were irradiated between 1939 and 1962. More than one-third of these patients developed thyroid nodules, and 318 patients were documented to have thyroid cancer. However, even after 40 years, the relative risk as compared to a nonirradiated population was still increased. Although the use of radiation for benign conditions has not been practiced since the 1960s, there is increased use of radiation treatments for neoplastic conditions, including infants, children, and young adults. A large study of more than 150,000 women treated with radiation for cervical cancer had an estimated thyroid exposure of 11 rads, with a relative risk of 2. These isotopes come from two sources: medical administration either for diagnostic or therapeutic purposes using radioactive iodine, 57 and environmental exposure to fallout from nuclear weapons or nuclear accidents. The most common exposure is due to 131I administered for diagnostic thyroid scans. A typical nuclear medicine study exposes the thyroid to the equivalent of approximately 50 rads of external-beam radiation exposure. A more dangerous type of ingestion of radioisotopes of iodine comes from exposure to nuclear fallout. The natural history and pathology of radiation-associated thyroid cancer has been well documented in the aforementioned epidemiologic studies.
Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders. Posttransplant lymphoproliferative disorders: summary of Society for Hematopathology Workshop. Posttransplant lymphoproliferative disease in thoracic organ transplant patients: ten years of cyclosporine-based immunosuppression. Durable remission after aggressive chemotherapy for post-cardiac transplant lymphoproliferation. Autologous lymphokine-activated killer cell therapy of Epstein-Barr virus-positive and -negative lymphoproliferative disorders arising in organ transplant recipients. I nfusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation [see comments]. Human immunodeficiency virus-related lymphoma treatment with intensive combination chemotherapy. High-dose methotrexate for the treatment of primary cerebral lymphomas: analysis of survival and late neurologic toxicity in a retrospective series. Therapeutic management of primary central nervous system lymphoma in immunocompetent patients: results of a critical review of the literature. Primary central nervous system lymphoma: age and performance status are more important than treatment modality. Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the treatment of patients with malignant brain tumors. Testicular lymphoma: a population-based study of incidence, clinicopathological correlations and prognosis. Testicular lymphoma: late relapses and poor outcome despite doxorubicin-based therapy. The value of magnetic resonance imaging and two-dimensional echocardiography at disease presentation. Intracardiac malignant lymphoma detected by gallium-67 citrate and thallium-201 chloride. Sick sinus syndrome with seroconstrictive pericarditis in malignant lymphoma involving the heart: a case report. Primary cardiac lymphoma in immunocompetent patients: diagnostic and therapeutic management. Lymphoid lesions of the thyroid: review in light of the revised European-American lymphoma classification and upcoming World Health Organization classification. Primary lymphoma of the thyroid: clinical features, prognostic factors, and results of treatment. A 30-year clinicopathologic experience and an evaluation of the presence of Epstein-Barr virus. Clinical aspects of primary thyroid lymphoma: diagnosis and treatment based on our experience of 119 cases. Clinically silent primary adrenal lymphoma: a case report and review of the literature. Diversity of organ site involvement among malignant lymphomas of mucosa-associated tissues. Histology according to the Revised European-American Lymphoma Classification significantly predicts the prognosis of ocular adnexal lymphoma. Lymphoid hyperplasia and malignant lymphoma occurring in the ocular adnexa (orbit, conjunctiva, and eyelids): a prospective multiparametric analysis of 108 cases during 1977 to 1987 [see comments]. Immunohistologic features predict clinical behavior of orbital and conjunctival lymphoid infiltrates. Primary low-grade B-cell lymphoma of the conjunctiva: a mucosa-associated lymphoid tissue type lymphoma. Primary intraocular lymphoma (ocular reticulum cell sarcoma) diagnosis and management. Clinical features, laboratory investigations, and survival in ocular reticulum cell sarcoma. Primary lymphoma of bone: experience of 39 cases at the Tata Memorial Hospital, India.
These modalities comprise three broad categories: systemic therapy, radiation therapy, and surgery. Until the development of bisphosphonates, no specific drugs were directed to the general entity of bone metastases. Bisphosphonates have shown great utility in the management of patients with metastatic bone lesions, most notably in cases of breast cancer and multiple myeloma. Bisphosphonates Bisphosphonates are stable analogs of naturally occurring inorganic pyrophosphate. They inhibit the precipitation of calcium phosphate in vitro and biologic calcification in vivo. They also inhibit bone resorption, particularly that occurring in certain metastatic lesions of bone. The mechanism by which bisphosphonates inhibit bone resorption is inhibition of osteoclasts by interruption of the mevalonate metabolic pathway and, possibly, by causing osteoclast apoptosis as well. First-generation bisphosphonates such as clodronate and etidronate, second-generation drugs such as tiludronate and pamidronate, and third-generation medications such as ibandronate and zoledronate, have differing potencies and effects. The drugs are not metabolized in the human body, with 50% to 60% of each dose rapidly absorbed by bone, followed by slow renal elimination; the other 40% to 50% is rapidly excreted by the kidneys. The skeletal morbidity was significantly reduced in the patients receiving pamidronate; however, there was no significant difference in survival or objective bone response rate. Again, a significantly decreased risk of bone lesion complications was seen in the pamidronate group as compared to the placebo group. There was a significant reduction in skeletal events in the pamidronate group, although survival was not different between the pamidronate and placebo patients. Again, the skeletal event curves of the pamidronate and placebo groups diverged, in this instance from the initiation of the study. Although bisphosphonates have not been proven to be efficacious in managing bone metastasis due to other tumors, theoretically these compounds should be of value in all cancers causing lytic bone lesions. There is also evidence that bisphosphonates may actually prevent the development of bony metastases. In several animal models, injected tumor cells failed to establish colonies in bone that had been pretreated with bisphosphonate. When a more rapid response is needed, radiation therapy or surgery (or both) still are required. Chemotherapy and Hormone Therapy Because of the significant percentage of patients with breast cancer who develop metastatic bone lesions, the effects of chemotherapy and hormone therapy on these lesions have been investigated. The goals of chemotherapy and hormone therapy in patients with metastatic disease involving bone are pain control, disease stabilization, and reduction of the risk of morbid skeletal events. Anderson Cancer Center who were treated with 5-fluorouracil, doxorubicin, and cyclophosphamide, bone lesions showed an 18% complete and a 65% partial response to the regimen. Hormone-sensitive breast carcinoma has a predilection to metastasize to bone; therefore, hormone therapy can be effective in these cases. As with other therapies, a peritreatment lesion "flare" may occur that makes the evaluation of overall response difficult. However, the use of chemotherapy and hormone therapy in metastatic breast cancer has been shown to prolong survival and can render patients better able to respond to bone lesionspecific therapy such as bisphosphonates or systemic radionuclides, reducing overall skeletal morbidity. The indications for radiation therapy are pain relief and suppression of local tumor growth. Suppression of local tumor growth is important in the treatment of impending fractures, after surgical fixation of metastatic lesions, and in the treatment of neural compression. Tumor reduction and pain relief can begin immediately, particularly for very radiosensitive round cell tumors. Thoughtfully planned treatment with high-energy radiation causes minimal morbidity, and the benefits far exceed the risks in most situations. Radiation is of therapeutic value in patients with localized symptomatic lesions and should be considered in all but the few cases in whihc either the disease is very responsive to systemic treatment. The radiation oncologist must collaborate with the medical oncologist and surgical personnel to optimize treatment. This interdisciplinary cooperation is critical in the management of an impending fracture. Occasionally, a lesion will heal with radiation therapy, especially if it is mechanically protected.
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