Clinical presentation and management of thymoma and thymic carcinoma INTRODUCTION — The thymus, derived from the Greek word meaning life-force or soul, is a unique anterior mediastinal organ that weighs 12 to 15 grams at birth, reaches its maximum weight of 40 grams at puberty, then involutes and persists in an atrophic state into old age. It is derived embryonically from the third pharyngeal pouch and is composed of an outer cortex consisting primarily of epithelial cells, degenerated keratinized epithelial cells (Hassall's corpuscles), myoid cells, thymic lymphocytes ("thymocytes"), and B-lymphocytes, which form rare germinal centers. The thymus is primarily involved in the processing and maturation of lymphocytes which become T-lymphocytes upon release into the circulation. Thymomas are the most common neoplasms affecting the thymus, although other tumors can arise from this organ, including thymic carcinoma, carcinoid tumors, germ cell tumors, and lymphomas. The histologic distinction of thymoma from other tumors may be difficult. Physicians may have to rely upon the clinical presentation and course of the disease. The clinical presentation and management of thymoma are reviewed here. The pathology and classification of mediastinal tumors and tumors of the thymus other than thymoma are discussed separately. PATHOLOGY — Ninety percent of thymomas arise in the anterior mediastinum; in rare cases origin in the pleura or lung has been documented. Classification — The original 1961 classification of Bernatz classified thymomas according to the dominant cell type. If more than two-thirds were polygonal cells, they were categorized as epithelial; if more than two-thirds were lymphocytes, they were classified as lymphocytic; if the two cell types were present in equal proportions, they were called mixed thymomas. A fusiform morphology in more than two-thirds of the epithelial cells led to its designation as a spindle cell thymoma. Some series suggest biologically more aggressive behavior with epithelial and mixed thymomas , and others associate lymphocytic or spindle cell subtype with a favorable outcome Other classification schema, such as the Marino and Muller-Hermelink (MM-H) classification, have been developed based upon the presumed origin of the malignant cell. The medullary thymomas are thought to represent the neoplastic equivalents of normal thymic medullary cells, and have a more favorable prognosis than cortical thymomas, in which the neoplastic cells have the appearance of having arisen from the cortex of the normal thymus . Spindle-shaped cells predominate in the medullary area while the cortex contains predominantly round to oval cells. The World Health Organization Committee on the Classification of Thymic Tumors adopted a new classification system for thymic neoplasms which recognizes that cytologic similarities between normal thymic epithelial cells and neoplastic cells is of prognostic significance in patients with thymoma. As a result, five types of thymomas are recognized. The classification scheme has demonstrated prognostic significance. This topic is discussed in detail elsewhere (see below). Histology — Grossly, thymomas are yellow-gray with a fleshy lobulated appearance; intratumoral hemorrhage, cystic spaces, and calcifications may be present. Histologically, thymomas are composed predominantly of thymic epithelial cells although a variable proportion of infiltrating nonneoplastic lymphocytes and interdigitating reticular cells are also present. Tumors are usually subdivided by fibrous bands . Morphologically, the most common epithelial cell type is a plump polygonal cell; others are spindle-shaped with elongated nuclei. The epithelial neoplastic cell usually grows slowly and lacks cytologic characteristics of malignancy. Despite their cytologically bland appearance, thymomas are considered to be malignant neoplasms because of their invasive potential In contrast, the rare thymic carcinomas (classified as a type C thymoma in the WHO consensus classification, see above) have overtly malignant cytologic characteristics (eg, anaplasia, cellular atypia, and increased proliferative activity) and capsular invasion. The majority are histologically undifferentiated, and lack the features of a normal thymus. The revised histologic classification for thymic carcinomas divides these tumors into low-grade (well differentiated squamous cell carcinoma, metaplastic, mucoepidermoid, and basaloid carcinoma) and high-grade (lymphoepithelioma-like carcinoma, small cell, undifferentiated, sarcomatoid, and clear cell) subtypes. Low-grade tumors are characterized by a relatively favorable clinical course, and a low incidence of local recurrence and distant metastases, while those in the high grade group are associated with advanced disease at presentation, high rates of metastases and a poorer prognosis (median survival 15 months) Cytokeratin staining is a useful diagnostic marker; immunostaining of the epithelial cells helps distinguish thymomas from nonepithelial malignancies, such as lymphomas or sarcomas. The immunohistochemical typing of the lymphocytic components is not usually diagnostically helpful. The lymphocytes present in thymomas usually have a mixture of immunophenotypes corresponding to normal thymocytes. In some series, thymic carcinomas have been associated with Epstein-Barr virus (EBV), although a causative relationship is not proven. Many of these tumors show increased expression of CD70, a surface marker that is found in other neoplasms associated with EBV, and CD70 positivity may be a useful means of differentiating thymic carcinoma from other mediastinal neoplasms. STAGING — Staging of thymomas is based upon clinicopathologic criteria, especially the presence of invasion. Masaoka staging system — The most widely used staging system is that defined by Masaoka, which incorporates the presence of invasion and the anatomic extent of involvement, as defined both clinically and histopathologically Staging by the Masaoka system correlates well with five year survival rates
The presence of invasion is an important prognostic factor. In multiple series, noninvasive thymomas have a very low or virtually absent relapse rate GETT staging system — The extent of surgery is a prognostic factor of major importance. The French Study Group on Thymic Tumors (GETT) developed a staging system based predominantly upon the extent of surgical resection Comparison of staging systems — There are several differences in the Masaoka and GETT staging classifications. As an example, contiguous spread to the pericardium is stage III in the Masaoka system, and if it can be completely resected, stage II in the GETT system. In contrast, an encapsulated, totally resected GETT stage I tumor is designated stage II-2 in the Masaoka system if there is microscopic invasion of the capsule Nevertheless, staging is comparable in approximately 90 percent of cases. The relative utility of both staging systems was compared in a series that included 163 patients with thymic neoplasms . Staging was concordant in 88 percent of the cases using both staging systems. The Masaoka system tended to upgrade GETT stage I and II tumors; 61 and 20 percent of GETT stage I and II tumors were classified as Masaoka stage II and III tumors, respectively, and analysis of disease-free survival (DFS) showed that the Masaoka II-GETT I patients had a better DFS than the Masaoka II-GETT II patients. A good correlation between the WHO classification and the Masaoka staging system has also been shown in terms of long-term outcome For these reasons, we typically use the Masaoka system. EPIDEMIOLOGY — Thymomas represent 20 percent of all mediastinal neoplasms in adults; they are the most common anterior mediastinal primary neoplasm in adults but are less commonly seen in children. The incidence of thymoma is 0.15 cases per 100,000, based upon data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program . Most patients are between 40 and 60 years of age, and there is slight male predominance. There are no known risk factors. Thymic carcinomas account for less than 1 percent of thymic malignancies CLINICAL PRESENTATION — Up to one-half of thymomas may be found as an incidentally detected radiographic abnormality in an asymptomatic patient. When present, clinical signs and symptoms are related to the size of the tumor and effects on adjacent organs (eg, chest pain, shortness of breath, cough, phrenic nerve palsy, superior vena cava obstruction) or, less commonly, "B" symptoms (fever, weight loss, and night sweats). Other tumors may be identified because the patient is being investigated for an associated systemic syndrome, such as myasthenia gravis (see below). Most patients with thymic carcinoma present initially with cough, chest pain, phrenic nerve palsy, or superior vena cava syndrome; further exploration usually reveals a mediastinal mass. Evidence of invasion of mediastinal structures is present in the majority of patients. Radiographically, thymic carcinomas commonly contain necrotic, cystic, or calcified areas. The tumor contour is often irregular compared to thymoma, which tends to be smooth. Distinct differences in MRI signal pattern and PET scan appearance have been described between thymomas and thymic carcinomas Pleural or pericardial effusion represents the most common form of metastatic involvement. Extrathoracic metastases occur in less than 7 percent, most commonly to the kidney, extrathoracic lymph nodes, liver, brain, adrenals, thyroid and bone. They are most common in patients with thymic carcinoma. Metastases to the ipsilateral lung are unusual. Paraneoplastic disorders — Thymomas are associated with a variety of paraneoplastic disorders, many of which are autoimmune or endocrine in nature. The most clinically important of these are myasthenia gravis, pure red cell aplasia, and hypogammaglobulinemia. These striking systemic syndromes associated with thymoma can be anticipated in 50 to 60 percent of affected patients; more than one disorder may be present. Myasthenia gravis — Myasthenia gravis (MG) is a neuromuscular junction disorder caused by the autoimmune destruction of the acetylcholine receptors in the postsynaptic villi of voluntary muscle . Symptoms include diplopia, ptosis, dysphagia, weakness and fatigue. Approximately 30 to 50 percent of patients with thymoma have MG; men and women are equally affected. The pathogenesis of MG in patients with thymoma is unknown, but it may involve the production of humoral or cytokine factors by the tumor, or cell-mediated cytotoxicity. The majority of patients with MG have thymic abnormalities: hyperplasia in 60 to 70 percent and thymoma in 10 to 12 percent. The normal thymus is responsible for the maturation of T cells that mediate immune protection without promoting an autoimmune response. The thymus contains B cells, T-helper cells, and antigen-presenting cells, all of the elements needed for production of antibodies. The thymus also contains a small number of "myoid" cells, which are distinguished by striations and by the presence of acetylcholine receptors on their surface. The availability of these acetylcholine receptors in the thymus may play a role in the pathogenesis of MG by acting as antigenic peptide sequences on the surface of antigen presenting cells. Patients with thymoma-associated MG produce autoantibodies to a variety of neuromuscular antigens, particularly the acetylcholine receptor and titin, a striated muscle antigen. It has been suggested that the concurrent presence of striational antibodies directed against titin are predictive of a thymic epithelial tumor in patients with MG (sensitivity 69 percent and specificity 100 percent in one series)
It is unclear whether these antibodies play a role in the pathogenesis of MG. Other data suggest an association between certain HLA loci and thymic pathology in patients with MG. In one study that included 95 patients undergoing thymectomy for MG, the presence of HLA A24 and HLA B8 were significant predictive factors for the presence of thymoma, while other HLA types were correlated with other thymic lesions such as hyperplasia, atrophy or thymolipoma Patients with MG and thymoma usually present with less advanced thymomas than those without MG, as the presence of neuromuscular symptoms favors earlier tumor detection In patients with both conditions, thymectomy usually results in an attenuation of the severity of MG, although some degree of MG persists in most patients and most remain dependent on immunosuppressive therapy Pure red cell aplasia — Pure red cell aplasia results from an autoimmune-mediated hypoproliferation of erythrocyte precursors in the bone marrow. This paraneoplastic disorder occurs in 5 to 15 percent of patients with thymoma, particularly in older women. Up to 50 percent of patients with acquired erythrocyte hypoplasia have thymoma, usually of spindle cell morphology. The etiology of this association is unclear; T-cell mediated suppression of erythropoiesis has been suggested by in vivo studies. Thymectomy may result in normalization of the marrow in up to 40 percent of cases Immunodeficiency
— Hypogammaglobulinemia and pure white cell aplasia are present in less
than 5 percent of patients with thymoma, most commonly in older women.
However, up to 10 percent of patients with acquired hypogammaglobulinemia
have an associated thymoma (Good syndrome), typically of spindle cell
histology. Patients usually have recurrent infections, diarrhea, and
lymphadenopathy. In a review of 51 cases, 19 patients had recurrent
sinopulmonary infection, 12 candidiasis (including one with candidemia), 7
bacteremia (including two with Campylobacter spp.), 12 CMV (only five with
clinical manifestations), 6 diarrhea, and
PROGNOSIS — Thymomas are usually slow-growing tumors, and the presence of invasion is an important adverse prognostic marker The overall five-year survival is 70 percent (50 percent with local invasion, 75 percent without invasion), and the 10-year survival is 50 percent (30 percent with invasion, 60 percent without invasion) A number of adverse predictors have been identified:
Although initially described as a negative prognostic factor, the presence of an associated paraneoplastic syndrome is not associated with inferior outcome, possibly because of earlier detection. In several large series, patients with thymoma presenting with MG had a similar or in some cases improved prognosis following surgery compared to those without MG The long term outcome correlates with the pathologic classification. Inferior outcomes in particular are seen for patients with thymic carcinomas. Survival rates according to WHO classification at five and ten years were as follows [
Second primary cancers — The prognosis of patients with thymoma may also be impacted by the development of second malignancies, which develop in 17 to 28 percent of patients following thymectomy. Second malignancies of varying histologic types were reported among 136 patients seen at a single institution, in whom 28 percent developed a second cancer, usually outside of the radiation port . However, in a series of 849 cases of thymoma collected through the SEER database, compared to the number of cases expected in the general population, standardized incidence ratios (SIR) were only significantly higher for B cell non-Hodgkin's lymphoma (SIR 4.7), digestive system cancers (SIR 1.8), and soft tissue sarcomas (SIR 11.1) PRIMARY TREATMENT — Attempted surgical excision is the treatment of choice for nonmetastatic thymoma and thymic carcinoma (type C thymoma), even if locally advanced; radiation therapy and chemotherapy may have adjunctive roles. Some patients with locally advanced or bulky lesions may benefit from preoperative chemotherapy Surgery — The extent of surgical resection for malignant thymomas and thymic carcinomas is dictated by the degree of invasion and/or adhesion of the tumor to contiguous structures. Resection of the pericardium as well as accompanying lung parenchyma is often required to accomplish complete resection with histologically negative margins. Tumor may be adherent to adjacent structures but not necessarily invasive. Thymomas may sometimes be adherent to adjacent structures without invasion. In such cases, the surgeon should designate the site of adhesion on the specimen, so the pathologist can take careful sections from that area. An inflammatory fibrous reaction can grossly lead to the false impression of tumor invasion. Surgeons are often faced with the dilemma of resecting tumor that extends along one or both phrenic nerves, with the probability of impaired respiratory function if the nerve is divided. Preoperative pulmonary function studies should be obtained in all patients so that resultant respiratory compromise following division of the phrenic nerve can be estimated. Resection of one involved phrenic nerve followed by dissection of the other nerve out of the surrounding tumor is usually recommended, if possible, to reduce postoperative respiratory disability. The most common operative approach is to enter the pericardium from the inferior position and utilize the free pericardial space to define the anterior mediastinal anatomy for resection. Along with the pericardium, the innominate vein may be resected with the tumor, and ligature of the left subclavian vein may be carried out with minimal and acceptable morbidity. Outcome is dependent on the extent and completeness of surgical resection. In one series that included 241 patients with thymoma, the seven year survival rate was 82, 71, and 26 percent in patients undergoing complete resection, subtotal resection, and biopsy alone, respectively While complete resection is ideal, debulking or biopsy may be the only option with acceptable morbidity if invasion is extensive. In such cases, debulking followed by postoperative radiotherapy may result in high survival rates Radiation therapy — Radiation therapy may be considered in the following circumstances:
After subtotal resection — Adjuvant radiation or chemoradiotherapy is beneficial when the tumor is incompletely resected or if the resection margins are microscopically positive. Local control rates in such patients range from 50 to 80 percent, with more local failures among those undergoing biopsy alone. In one series, 70 percent of patients undergoing subtotal resection followed by radiation were still alive at seven years After complete resection — Some reports suggest benefit for postoperative radiation in patients with completely resected invasive thymomas. Overall, in patients with completely resected stage II or III thymomas, adjuvant radiotherapy reduces the rate of local recurrence from approximately 28 to 5 percent. Moreover, at least in one small series of 36 patients undergoing surgery for stage II through IVa thymoma, adjuvant RT was associated with a higher five-year disease-free survival (62 versus 18 percent) In contrast, there appears to be no specific benefit for adjuvant radiation following resection of encapsulated noninvasive tumors. However, some recommend the use of postoperative irradiation for large completely resected GETT stage I-B tumors in whom pleural or pericardial adhesions are suspected during surgery The dose of radiation is quite variable in the adjuvant setting. Generally, 45 to 50 Gy are administered to the tumor bed and adjacent mediastinum by external beam techniques. Principal radiation-related toxicities include pulmonary fibrosis, pericarditis, and radiation myelitis. With three-dimensional treatment planning, these toxicities can potentially be reduced, permitting the administration of higher doses. Palliative radiation therapy — Although surgical resection, even if incomplete, is the treatment of choice for invasive thymoma, some patients may not be candidates because of the presence of extensive metastatic disease, or their overall medical condition. Others may have recurrent disease following primary surgical management. Such patients may benefit from palliative radiation therapy. Neoadjuvant chemotherapy — In patients with locally invasive tumor (particularly thymic carcinoma) or large bulky masses, initial combination chemotherapy with cisplatin-based regimen followed by radical resection with or without postoperative radiotherapy may offer the greatest potential for improved disease-free survival . However, this approach should only be undertaken in suitable patients who can tolerate aggressive management Thymomas are chemotherapy-sensitive malignancies. Several different chemotherapeutic regimens have been employed for induction therapy, including cisplatin, etoposide and epirubicin, cisplatin, doxorubicin, vincristine and cyclophosphamide (ADOC), and cisplatin, doxorubicin, and cyclophosphamide (PAC) with or without prednisone, with objective response rates ranging from 70 to 100 percent, and resectability rates from 36 to 69 percent In one report, 23 patients with locally advanced unresectable disease underwent three courses of induction cisplatin (30 mg/m2 per day by continuous infusion days 1 to 3), doxorubicin (20 mg/m2 per day by continuous infusion days 1 to 3), cyclophosphamide (500 mg/m2 on day 1) with prednisone (100 mg per day for five days). The objective response rate was 77 percent (3 complete and 14 partial responses). Of the 21 patients who underwent attempted resection, four had a pathologic complete response or tumor necrosis in >80 percent of the surgical specimen. Postoperative radiation (50 to 60 Gy) and adjuvant chemotherapy (three cycles of the same chemotherapy) was administered following resection, and 19 patients completed the entire course of treatment. The seven year disease-free and overall survival rates were 77 and 79 percent, respectively. Similar benefit was noted in a second series, in which 16 patients with stage III and IVa thymoma received doxorubicin (40 mg/m2 on day 1), cisplatin (50 mg/m2 on day 1), vincristine (0.6 mg/m2 on day 2) and cyclophosphamide (700 mg/m2 on day 4) (ADOC), repeated every three weeks. Two complete responses and 11 partial responses were observed, yielding an overall response 81 percent. Nine patients were radically resected, and median time to progression and overall survival were 33.2 and 47.5 months respectively. Three patients were alive and free of recurrence after more than five years. Thus, multimodality therapy may offer the opportunity for improved local control and better long-term survival for patients with locally advanced lesions. However, at least one series suggests that nonoperative therapy may provide similar long term benefit as induction chemotherapy followed by resection. In a United States Intergroup trial, 26 patients with unresectable locally advanced disease underwent two to four cycles of cisplatin (50 mg/m2 on day 1), doxorubicin (50 mg/m2 on day 1), and cyclophosphamide (500 mg/m2 on day 1) followed by 54 Gy to the primary tumor and regional nodes in those with stable disease or an objective response to chemotherapy Treatment was well tolerated, and 70 percent had an objective response to induction chemotherapy. The median time to treatment failure and median survival were each 93 months, and 53 percent were still alive at five years. Although these results compare favorably to those obtained with neoadjuvant chemotherapy followed by resection with or without postoperative radiation, further confirmation is needed. Recommendation — We choose patients for aggressive management with trimodality therapy when they are deemed unresectable. The combined neoadjuvant regimen we use is either cisplatin plus doxorubicin and cyclophosphamide (PAC) or the ADOC regimen followed by radiation therapy, and reassessment for resectability. In our personal experience (AT Skarin and R Salgia, unpublished observations, 2001), thymomas are also responsive to combined carboplatin and paclitaxel. In a research setting, we are studying two cycles of carboplatin (AUC=6) plus paclitaxel (200 mg/m2) every three weeks, followed by radiation therapy and concomitant weekly carboplatin (AUC=2) plus paclitaxel (50 mg/m2), and reassessment for resectability. CHEMOTHERAPY FOR METASTATIC OR RECURRENT DISEASE — Chemotherapy has traditionally been used for patients with unresectable or metastatic thymoma and for thymic carcinoma. Various single agents and combination regimens have been investigated, however, although no large randomized trials have been conducted because of the rarity of the disease. Although the majority of regimens are cisplatin-based, there is no single regimen that is considered standard for this disease. Response rates vary from 20 to 60 percent, particularly for regimens that include cisplatin and prednisone. Single agent therapy — Active single agents include cisplatin, ifosfamide, and corticosteroids. Cisplatin as a single agent (100 mg/m2 every three weeks) has resulted in complete responses (CR) lasting up to 30 months, but reducing the dose to 50 mg/m2 produces a response rate of only 11 percent. In one report, the response rate with single agent ifosfamide (1.5 g/m2 per day for 5 days every three weeks) was 40 percent, with a 39 percent CR rate (duration 25 to 87 months) Corticosteroids can also result in brief responses up to 77 percent of patients had an objective response in one report Octreotide — Thymic malignancies that express somatostatin receptors (ie, that are Octreoscan-positive) can also demonstrate meaningful responses to octreotide (500 µg SQ three times daily), with or without prednisone . In one multicenter phase II trial, the response rates with and without prednisone were 13 and 30 percent, respectively . Combination chemotherapy — Combination chemotherapy generally produces higher response rates than single agents . Cisplatin-containing regimens appear to be the most active, with overall response rates of 70 to 80 percent, one-half of which are complete. The three most popular regimens are PAC, ADOC, and EP. Most reported series are small, and there are no randomized comparisons between these regimens. Thus the choice of regimens is empiric. The following are representative of published results:
Recommendation — For recurrent or metastatic disease, we encourage patients to enroll on active clinical trials, if available. If unsuitable, we use combinations such as PAC, ADOC, and or etoposide and cisplatin. If cisplatin is not well tolerated, we have substituted carboplatin chemotherapy. As noted above, the combination of carboplatin and paclitaxel is active in thymoma, and we also using this regimen in a research setting. |
4
with a variety of other infections (including three with Pneumocystis
carinii pneumonia). In contrast to other paraneoplastic disorders
associated with thymoma, thymectomy does not reliably lead to the return
of normal immunoglobulin levels. (