Ann Thorac Surg 2002;74:1733-1740
© 2002 The Society of Thoracic Surgeons
Review
Primary neuroendocrine tumors of the thymus
Rabih Chaer, MDa,
Malek G. Massad, MDa*,
Alexander Evans, MDa,
Norman J. Snow, MDa,
Alexander S. Geha, MDa
a Division of Cardiothoracic Surgery, Department of Surgery, The University of Illinois at Chicago, Chicago, Illinois, USA
* Address reprint requests to Dr Massad, University of Illinois at Chicago, Division of Cardiothoracic Surgery (MC 958), 840 South Wood St, CSB Suite 417, Chicago, IL 60612, USA.
e-mail: mmassad{at}uic.edu
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Abstract
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Primary neuroendocrine tumors of the thymus are highly aggressive tumors that rarely occur. A little more than 200 cases have been reported, many of which were single case reports. Only a few articles contained modest series from single centers for analysis. A review of 157 cases collected from the major series reported to-date show a clinical pattern with male preponderance (male:female ratio, 3:1) and a mean age of 54 years. Most patients presented with symptoms and signs of local compression. Almost 50% of these tumors were functionally active and were associated with endocrinopathies. Several histologic variants have been described, all with similar ultrastructural features. The biologic behavior of these tumors shows a direct relation to the degree of differentiation. Whenever possible, surgical resection is the treatment of choice as adjuvant therapy is controversial and has been used with variable success. Potential therapies exploit the presence of somatostatin receptors on a variety of these tumors. Use of radiolabeled Octreotide for radionuclide therapy has yielded tumor inhibition in animal models and may have clinical application. Fifty-one percent of the patients survived 3 years, 27% survived 5 years, and less than 10% survived beyond 10 years. Histologic grade, tumor extension, and early detection are the most important factors affecting survival. Other prognostic factors that impact outcome include presence of endocrinopathy, incomplete resectability, nodal status, and presence of distant metastasis.
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Introduction
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Primary neuroendocrine tumors of the thymus, previously known as carcinoid tumors of the thymus, are unusual tumors that account for less than 5% of all anterior mediastinal neoplasms [1, 2]. Originally, the term "carcinoid" was introduced in 1907 by Oberndorfer to identify a group of tumors in the small bowels that had a better prognosis than conventional carcinoma [3]. Given the aggressive behavior of these tumors, it has been proposed that the term, carcinoid, should be abandoned for designating these lesions in the mediastinum, because it misleadingly implies a benign or extremely low-grade neoplasm. Klemm and Moran [4] regard such tumors as part of a single spectrum of differentiation, ranging from well-differentiated to moderately-differentiated to poorly-differentiated neuroendocrine neoplasms. Unlike carcinoids arising from the gastrointestinal tract or the lungs, these tumors are highly aggressive [5]. It has been found that these tumors are malignant in approximately 82% of cases, as opposed to bronchial carcinoids, which are less aggressive and are malignant in approximately 26% of cases [4].
A comprehensive MEDLINE literature search, performed from 1966 to 2002, for universal articles pertinent to primary neuroendocrine tumors of the thymus produced slightly more than 200 reported cases confirming thymic carcinoid tumors. However these tumors remain to be unfamiliar to the practicing thoracic physician and surgeon. The majority of these reported cases are single case reports. Only a few articles contained modest series from single centers [6–13]. However the majority of these single center studies were too small to provide a uniform assessment of the various treatment modalities and factors that impact the long-term outcome of patients afflicted with this tumor.
In this article we review the natural history and clinical presentation of patients with primary neuroendocrine tumors of the thymus emphasizing the clinicopathologic findings, different treatment modalities, and long-term outcomes.
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Clinical features
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Primary neuroendocrine tumors of the thymus were first recognized in 1972 by Rosai and Higa [14]. They are predominantly located in the anterior mediastinum and show a predilection for men typically in their fourth and fifth decades of life, with a reported male to female ratio of approximately 3 to 1 [15, 16]. From our review of 157 cases collected from the major series reported to-date, the mean age was 54 years (range, 15 to 100 years). Men constituted 74% of the cases reviewed [6–13]. Clinically, these tumors manifest in one of four ways: (1) they may be asymptomatic, found incidentally on routine chest radiography, (2) they may produce symptoms of thoracic structure displacement or compression, (3) they may present with symptoms related to an associated endocrinopathy, or (4) they may present with symptoms and signs relating to a distant metastasis, most commonly to the liver, lung, pancreas, pleura, and bone [17]. It has been estimated that over one third of patients are asymptomatic and are incidentally discovered [18]. Most patients present with signs and symptoms related to a rapidly expanding mediastinal mass, such as cough, chest pain, and superior vena cava syndrome. At least 20% of affected patients have metastasis at presentation, with the frequency of extra-thoracic metastasis being as high as 20% to 30% [19–22]. A review of previously reported cases shows that almost 50% of thymic neuroendocrine tumors are functionally active and are associated with endocrinopathies, namely Cushing syndrome in 33% to 40% of affected patients, multiple endocrine neoplasia (MEN) type I (Wermer syndrome) in 19% to 25%, MEN type II (incomplete Sipple’s syndrome), and others [16, 19, 23–25]. Therefore it is prudent for these patients to be evaluated for presence of Cushing’s syndrome by measurement of cortisol levels in the serum or in the 24-hour urine collection. Elevated cortisol levels, if demonstrated, should be confirmed despite low-dose dexamethasone suppression test in order to exclude the possibility of an autonomous secretion of cortisol by an adrenal tumor. Other conditions that have been associated with these tumors include polyarthropathy, proximal myopathy, peripheral neuropathy, hypertrophic osteoarthropathy, and Eaton Lambert syndrome [20, 26]. Unlike carcinoid tumors of the gastrointestinal tract, thymic neuroendocrine tumors have rarely been associated with carcinoid syndrome (0.6%) [27].
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Pathologic features and clinical staging
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Thymic neuroendocrine tumors are usually located in the anterior mediastinum, but may rarely present in the middle or posterior mediastinum. Irrespective of their location, gross invasion of surrounding mediastinal structures may be apparent to the surgeon at the time of operation in more than half of the cases.
The differential diagnosis of primary neuroendocrine tumors of the thymus include multiple nonneoplastic and neoplastic lesions within the thymus gland or extra-thymic within the anterior mediastinum (Table 1).
Grossly, these tumors are large masses with an average size of about 11 cm [9]. Approximately 50% of the tumors are encapsulated. Most of the tumors are well circumscribed and, unlike true thymomas, regularly display foci of central necrosis and hemorrhage [16, 18]. These tumors also usually lack the internal fibrous septations seen in the thymus.
The clinical staging criteria of thymic tumors have been well described by Masaoka and associates [28]. These criteria are based on the extent of gross and microscopic spread of the tumor to the surrounding tissues and distant organs. This staging system has been used for the clinical staging of primary neuroendocrine tumors of the thymus and is illustrated in Table 2.
In 1991, Yamakawa and associates [29] proposed classifying these tumors according to the TNM classification suggested for thymomas, whereby T referred to the extent of tumor extension into the adjacent structures, N referred to the extent of lymph node involvement inside and outside of the thoracic cavity, and M referred to the presence or absence of hematogenous spread to other organs (Table 3).
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Light microscopic features
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Thymic neuroendocrine tumors are usually composed of an organoid array of uniform tumor cells. Their nuclei are oval or round with variable mitotic activity, inconspicuous nucleoli and evenly dispersed chromatin. The cytoplasm is granular and moderate in amount [20]. A characteristic feature of these tumors is the presence of "balls" of tumor cells that have detached from the surrounding stroma and contain areas of necrosis [14]. These can become calcified and account for their gross gritty consistency. True rosettes are often present in the latter lesions, as are perivascular pseudorosettes [30].
Several histologic variants have been observed on hematoxylin-eosin stain, including the spindle cell form, a diffuse subtype, a sclerotic form, a pigmented variant, and a subtype resembling medullary carcinoma of the thyroid [20, 31]. The spindle cell variant has the most resemblance to true thymomas and often requires electron microscopy or immunohistochemical studies for differentiation [31]. Well-differentiated thymic neuroendocrine tumors (low grade tumors) have less than 3 mitotic figures per 10 high power field (HPF), minimal atypia, small foci of necrosis, and good preservation of the classic organoid pattern. Moderately-differentiated thymic neuroendocrine tumors (intermediate grade tumors) lose this pattern and show more mitotic figures, between 4 to 9 per 10 HPF, and more areas of necrosis and cytologic atypia. Poorly-differentiated (high grade) tumors have a high mitotic activity (10 or more mitotic figures per 10 HPF), nuclear atypia, and extensive areas of necrosis [4]. Neuroendocrine tumors of the thymus have been classified, also according to their histologic characteristics and mitotic activity, into typical (low grade tumors with less than 10 mitoses/10 HPF) and atypical (high grade tumors with ten or more mitoses/10 HPF [32].
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Histochemical and immunohistochemical features
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The histochemical stains usually provide useful characteristic patterns for thymic neuroendocrine tumors. These lesions are argyrophillic with the Sevier-Munger and Gimelius techniques but lack argentaffinity [30]. The periodic acid-Schiff stain demonstrates a variable glycogen content; contents of the rosettes may be reactive with the alcian-blue stain, and the mucicarmine stain yields negative results. There is a relative absence of mast cells with the chloroacetate esterase (Van Leder’s) stain in contrast with true thymomas that contain a large number of such elements [30]. However, the presence and number of mast cells can hardly be regarded as an important feature in the differential diagnosis.
Thymic neuroendocrine tumors have been demonstrated to express reactivity for cytokeratins in virtually all cases [33]. Other immunohistochemical stains with antibodies for neuroendocrine markers are helpful in confirming the diagnosis. Chromogranin appears to be the most useful and reliable marker. However, other markers such as leu-7, neurospecific enolase, bombesin, and synaptophysin can also help to identify these lesions. Ultrastructurally, well-differentiated tumors may show dense core neurosecretory granules in their cytoplasm. These may be difficult to demonstrate in poorly-differentiated tumors.
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Electron microscopic features
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Ultrastructurally, all the tumor variants have common features regardless of their light microscopic appearance. The cells are polygonal or spindle, and as mentioned previously, their nuclei exhibit small nucleoli and evenly dispersed chromatin. The cytoplasm has a well-developed rough endoplasmic reticulum and contains a fair number of mitochondria [30]. An essential feature for the diagnosis of thymic carcinoid is the presence of cytoplasmic dense-core neurosecretory granules. These granules are sometimes difficult to demonstrate in poorly-differentiated tumors, as they are usually single or in small clusters and measure 80 to 400 nm in diameter. The granules are well preserved, even in paraffin blocks or formalin fixed specimens, and have been associated with the synthesis of several neuropeptides, such as somatostatin, met-enkephalin, leu-enkephalin, and ß-endorphin [20, 34, 35].
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Radiologic features
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Thymic neuroendocrine tumors manifest as large, lobulated and usually invasive anterior mediastinal masses that may exhibit areas of hemorrhage and necrosis [7, 30]. They are usually indistinguishable from thymomas on plain chest radiograms, although they are usually larger in size (Fig 1).
Computed tomographic scan and nuclear imaging are useful in making the diagnosis. The computed tomographic scan typically shows a lobulated thymic mass with heterogeneous enhancement and central areas of low attenuation secondary to necrosis or hemorrhage (Fig 2).
Punctate and dystrophic calcifications may also be seen with contrast enhancement [7, 36]. Because Octreotide accumulates in thymic neuroendocrine tumors and other primary and metastatic thymic neoplasms, it has been used for the anatomical localization of occult hormonally active tumors [37, 38].
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Fig 1. A plain chest roentgenogram of a 75-year-old human with a stage IVb primary thymic neuroendocrine tumor shows a large lobulated anterior mediastinal mass (posteroanterior [PA] view) (A) with anterior encroachment on the trachea (lateral view) (B). Presenting symptoms consisted of chest fullness, discomfort and weight loss.
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Fig 2. Computed tomographic scan of the chest (A) and abdomen (B) of the patient shown in Figure 1. (A) Contrast enhanced chest computed tomography (CT) shows a large heterogeneous anterior mediastinal mass and para-aortic lymphadenopathy. The tumor crosses the midline causing compression of the mediastinal structures. (B) Abdominal CT shows multiple areas of hepatic metastasis.
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Therapy
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Clinical experience from major series
The largest North American series of primary neuroendocrine thymic tumors was reported by Moran and Suster [6] and consisted of 80 cases that were identified from the records of the Armed Forces Institute of Pathology and the records of Mt. Sinai Medical Center (Miami, FL) during a 35-year period from 1960 to 1995. All patients underwent surgical resection followed by postoperative adjuvant therapy in an unknown number. Follow-up data was available on 50 patients (Table 4).
The overall survival rate for these patients was 29% at 5 years and 10% at 10 years (Table 5).
The disease-free survival correlated with tumor grade. Low-grade tumors (well-differentiated) had a 5- and 10-year disease-free survival of 50% and 9%, respectively. Intermediate-grade tumors (moderately differentiated) had a disease free survival of 20% at 5 years and none were disease-free at 10 years. None of the patients with high-grade tumors (poorly differentiated) were disease-free at 5 years.
At Henry Ford Hospital (Detroit, MI), 7 patients with thymic neuroendocrine tumors were seen over a span of 38 years [12], and all were resected. Adjuvant radiotherapy, consisting of 46 Gy in total, was initially given to 2 patients with evidence of invasion into the surrounding structures. One patient also received postoperative chemotherapy consisting of 5-fluorouracil and streptozocin. Recurrence developed in 5 patients at 1 to 9 years after the initial surgical excision and was treated with radiation therapy in 2. The remaining 3 patients with recurrence had re-excision of their recurrence and postoperative radiotherapy. One patient with recurrence also received chemotherapy with 5-fluorouracil, streptozocin, and carmustine. Brachytherapy with iodine 125 after tumor debulking was also used in 1 patient. Tumor recurrence was found at autopsy in 4 of 6 patients manifesting dissemination to the mediastinum, lungs, pleura, and abdomen. The median survival was 2 years and only 2 of 7 patients survived for 12 years.
In one of the larger single institutional series comprising 50 years of experience at the Mayo Clinic [7], metastasis occurred in 73% of all 15 patients, despite resection of the tumor in 11 patients, 9 of whom received chemotherapy and radiation therapy. Metastasis was delayed for as long as 8 years after the initial diagnosis. The mean survival after the appearance of extra-thymic tumor was 3 years. The longest survivors were 8 and 15 years after diagnosis. That series showed a much more dismal outlook for these tumors than a previous report from the same institution [2].
In another series of 15 patients by Fukai and colleagues [8] from Japan, 13 had total tumor resections and 1 had subtotal tumor resection. Distant metastasis developed in 10 patients. Only 2 patients became free of disease and 1 of them survived beyond 5 years. In a more recent report by Gal and associates [10], out of 10 patients with thymic neuroendocrine tumors, the overall mortality was 60%. Only 1 patient was alive without evidence of disease and 3 patients were alive with disease at a mean follow-up of 49 months.
Therapeutic recommendations
Primary neuroendocrine tumors of the thymus as a group appear to be highly aggressive neoplasms. Patients usually die as a result of locally invasive or distant metastatic disease. However, the biological behavior of these tumors may show a direct correlation with the degree of differentiation, with the well-differentiated lesions following a relatively indolent course. Preoperative biopsy information should be obtained in patients presenting with symptoms of local disease, or in asymptomatic patients who manifest rapid growth of a nonsuspicious anterior mediastinal mass, or those who show evidence of local invasion on computed tomography. In these instances, a preoperative needle biopsy may be attempted to confirm the diagnosis. The disadvantages of fine needle biopsy include complications such as bleeding, lung or tracheobronchial injury, inadequate tissue sampling for histologic and immunohistochemical analysis, and the possibility of missing the tumor mass. In these situations, a parasternal mediastinotomy or other biopsy techniques may prove to be more appropriate.
Whenever possible, complete surgical resection of the primary thymic tumor and its extension is the treatment of choice. Recurrent local disease is also addressed surgically. Palliative surgical resection or debulking of a large primary tumor causing compression symptoms is indicated in patients with tumor spread to the liver or other organs. Radiation therapy should be considered preoperatively and also following resection, particularly in patients with capsular invasion, because the behavior of these tumors is uncertain and recurrences have been detected several years after initial resection. Whereas the role of adjuvant radiation therapy and chemotherapy is controversial, they have been both used with variable success (Table 4) [9, 39]. Single agents or combination drug therapies with 5-flurouracil, streptozocin, carmustine, VP-16, Cisplatin, and others have been used previously without any significant impact on the recurrence rate or overall survival [6–13].
Therapeutic recommendations have also been made for thymic neuroendocrine tumors in multiple endocrine neoplasia type I [19]. Surgical excision remains the treatment of choice, whether complete excision or debulking, because it affords symptomatic relief and facilitates adjuvant treatment. Alpha interferons have been tried in this setting [19]. Nevertheless, almost all patients had metastatic disease (43%) or succumbed to their illness (39%) [40]. Adjuvant therapy does not seem to confer any survival advantage. It appears that late tumor detection may be responsible for the associated poor prognosis. A high degree of suspicion in families with MEN I syndrome and earlier detection of thymic neuroendocrine tumors may translate into better survival rates.
Because as many as 95% of MEN I patients present with hyperparathyroidism, a concurrent thymectomy at the time of cervical exploration may prevent recurrent disease from the supernumerary glands located in the thymus and may reduce the risk of thymic neuroendocrine tumors developing [19]. Indeed, some authors recommend a routine prophylactic thymectomy in patients with MEN I who undergo cervical neck exploration for hyperparathyroidism, especially men. Furthermore, cervical neck exploration should be considered in patients with hyperparathyroidism who are undergoing surgical excision of a thymic neuroendocrine tumor [40].
Other potential therapies exploit the presence of somatostatin receptors on a variety of neuroendocrine tumors, including carcinoid. At least five different human somatostatin receptors subtypes have been cloned [41]. They all bind somatostatin with high affinity, whereas their affinities to Octreotide differ significantly. Octreotide binds with high affinity to subtype 2 somatostatin receptors, which is the most frequently expressed subtype in carcinoids [42]. A number of observations have suggested an antiproliferative effect of somatostatin and its analogues [25, 43]. Clinical trials in patients with malignant midgut carcinoid tumors using Octreotide alone or in combination with interferon alpha have been rather disappointing [44, 45]. Yet, to the best of our knowledge, this chemotherapeutic approach has not been systematically used for treating neuroendocrine tumors of the thymus.
Another potential intervention is the use of radiolabeled Octreotide for radionuclide therapy. Systemic injection of (111 IN-DTPH 3) Octreotide has yielded tumor growth inhibition in animal models with somatostatin receptor positive tumors [46]. Gamma ray and electron emission with short- to medium-tissue penetration may confer therapeutic radiotoxicity to adjacent tumor cells [47]. The radionuclide could also be substituted with a chemotherapeutic agent targeting thymic neuroendocrine tumors; nevertheless the efficacy of this intervention has yet to be proven in clinical trials.
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Follow-up and prognosis
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Follow-up of the patient with a primary neuroendocrine thymic tumor usually consists of clinical examination, chest roentgenogram, computed tomography, and metastatic workup every 6 to 12 months [9, 48]. Patients should be monitored closely for 10 years or less after the time of diagnosis for late recurrence, because the fatal reappearance of these lesions after tumor-free intervals has been seen as long as 8 years after diagnosis [20]. Different survival rates have been quoted among centers and by each series [6–13]. In our review of 157 patients among the studies of major international series, 149 patients had some documentation of their treatment modalities that allowed analysis. One hundred and thirty-five patients had total or subtotal resection of their tumor followed in several patients by postoperative radiation and chemotherapy. In the series reviewed, follow-up data was not uniformly reported and in some, only survival figures at different follow-up periods were quoted. Of 108 patients who had some follow-up data available, 51% (26 of 51 patients with reported data) survived for 3 years, 27% (26 of 97 patients with reported data) survived for 5 years, and 9% (9 of 104 patients with reported data) survived 10 years or more (Table 5). Survivals as great as 12 and 15 years have been reported with aggressive surgical excision of the lesion and subsequent recurrences and metastases [7, 12]. Others stratify patients depending on the clinical context; thymic neuroendocrine tumors prove fatal in 30% of cases at 5 years in tumors unaccompanied by an endocrinopathy, whereas those associated with Cushing syndrome or MEN I have a 65% mortality at the same point [2].
The prognosis of patients with primary neuroendocrine thymic tumors remain poor because of the high incidence of local recurrence and metastatic disease after surgical excision. Prognostic factors that have been shown to impact long-term outcome include the histologic grade of the tumor, the mitotic activity, presence of associated endocrinopathy, capsular invasion, incomplete resection, lymph node status, and presence of metastasis at the time of diagnosis (Table 6).
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Comment
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In summary, primary neuroendocrine tumors of the thymus are aggressive tumors that are associated with poor survival. Surgical resection of the tumor and its extension remains the treatment of choice because the experience with adjuvant therapy has been unsatisfactory. Early detection remains the most important factor that determines outcome. Given the limited institutional experiences with thymic neuroendocrine tumors, a meta-analysis of the different reported series may shed some light on the behavior of these tumors and may provide prognostic stratification and limited information regarding different treatment strategy outcomes that have been used in the past.
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Abstract
Introduction
