UPDATED APRIL 2015
1. GENERAL INFORMATION
1.1 What is the disease and how is it treated?
What is thymoma?
Thymoma and thymic carcinoma are tumours of the mediastinum, also called thymic epithelial tumours, since they develop from the thymic epithelium.
What are the causes of thymoma?
The causes of thymoma and thymic carcinoma are unknown to date, but understanding of the aberrant pathways involved is improving.
Is it a frequent type of cancer?
Thymic epithelial tumours are extremely rare.
How is it treated?
Surgery is the mainstay of treatment in the management of thymic tumours, as long as they are completely resected. Multimodality approaches with radiotherapy and/or chemotherapy before surgery (induction/neoadjuvant therapy) and/or after surgery (adjuvant therapy) are used in selected cases: generally:
- when surgery is not possible or
- when after surgery there is a tumour residual.
The rarity of this tumour has precluded it from the last phase of large clinical trial investigations, and new drugs are slow in development.
2. THYMOMA: WHAT IS IT, HOW DOES IT OCCUR, HOW IS IT DIAGNOSED?
2.1 What are thymomas and thymic carcinomas?
Thymomas and thymic carcinomas are uncommon primary tumours of the mediastinum, originating from the thymic epithelium. Thymoma is the most common primary anterior mediastinal mass, whereas thymic carcinoma is much rarer, but much more likely to spread.
The thymus is the site of maturation for T cells, playing a central role in the immune system defences. Systemic autoimmune syndromes, including myasthenia gravis, pure red cell aplasia, and hypogammaglobulinaemia are usually seen in patients with thymic epithelial tumours.
The majority of thymic tumours have non-malignant appearing thymic epithelial cells mixed with variable proportions of lymphocytes. Prognosis and behaviour of thymic epithelial tumours are difficult to predict. As a result of the complexity of these tumours, many different classifications for thymic neoplasms have been described in the literature, based on the characteristics of the cells in the tumour, benign and malignant type, etc.
The cause of thymomas and thymic carcinomas (thymic epithelial tumours) are unknown to date, but understanding of the aberrant pathways involved is improving.
2.1.1 Disease stats
Figures refer to tumours diagnosed in Europe in 2000-2007.
Frequency. Epithelial tumour of the thymus is extremely rare. In Europe, in one year less than 2 persons out of 1 million are diagnosed with this disease (rate: 1.7/1,000,000).
Gender. Incidence for thymus cancer is the same in men and women.
Age. In the oldest age group of patients (65 years old and older), incidence is higher (rate: 4.2); in the 25-64-year age group, the incidence rate is 1.9; in adolescents and young adults (<25 years of age) it is 0.4 per million per year.
Geographical distribution. The occurrence of the disease is lower in Northern and Eastern Europe, UK, and Ireland (≈1), and higher in Central and Southern Europe (≈2).
Survival. There has been a substantial improvement in European survival figures since the end of the Nineties. The percentage of patients alive 1 year after the diagnosis increased from 81% to 84%, and that of patients alive 5 years after the diagnosis from 58% to 65%.
There is no difference in survival between men and women.
Patients older than 65 years have a 5-year survival rate of 60%, compared to 78% in the youngest age group (<25 years of age). Five-year survival is higher for thymoma (69%) than squamous cell carcinoma (36%), undifferentiated carcinoma (12%), and adenocarcinoma (34%). Lymphoepithelial carcinoma has an intermediate 5-year survival (50%). Patients older than 65 years had the worst prognosis: 5-year survival was 55%, compared to 72% in the 25-54-year age group.
Prevalence. In Europe about 7,000 people are living with a diagnosis of epithelial tumour of thymus. The figure includes patients who are cured, under treatment, or in clinical follow-up. Long-term survivors may be estimated to account for about 50% of the complete prevalence.
You can find out more about the frequency of rare cancers in Europe by visiting the RARECAREnet projects website.
2.2 What are the symptoms of thymoma?
The natural history of the disease is usually unpredictable, including asymptomatic, incidentally-discovered disease with an indolent course, and aggressive malignant tumours. Approximately one third of patients with a thymic tumour are asymptomatic. Among symptomatic patients, 40% present chest pain, cough, hoarseness, and dyspnoea (less frequently superior vena cava syndrome, for obstruction or narrowing of this vessel) caused by the intra-thoracic mass, 30% have systemic symptoms (weight loss, rarely fever and night sweats), making it difficult to differentiate from lymphoma, and the rest have neurological symptoms linked to myasthenia gravis.
2.2.1 Parathymic syndromes
Thymomas are associated with several syndromes, generally autoimmune conditions. Abnormal regulation of lymphocytes within the thymus gland can result in autoimmunity and/or immunodeficiency. As a result, several organs may be affected and more than one immunologic disorder may be present in any given patient diagnosed with a thymoma.
Myasthenia gravis is the most common, occurring in approximately 45% (range 30%-65%) of patients with thymoma. Conversely, approximately 10%-15% of patients with myasthenia gravis will have a thymoma.
Myasthenia gravis is usually diagnosed by history: patients commonly present with ptosis, or drooping eyelids, double vision, drooling, dysarthria, difficulty climbing stairs, easy fatigability, muscular weakness, hoarseness, dyspnoea, or generalised fatigue, particularly one that gets worse late during the day, and they will require neurological treatment. Neurologic consultation should be considered if there is suspicion of myasthenia gravis, particularly for any patient being evaluated for surgical intervention, as severe respiratory risks can be minimised with appropriate perioperative management.
Pure red cell aplasia and adult-onset hypogammaglobulinaemia are the next most common conditions associated with thymoma, each occurring in 2% to 5% of patients.
Other less commonly associated conditions include: chronic ulcerative colitis, regional enteritis, systemic lupus erythematosus, sarcoidosis, scleroderma, rheumatoid arthritis, polymyositis, dermatomyositis, pericarditis, Sjogren’s syndrome, Raynaud’s disease, thyroiditis, parathyroid adenoma, T-cell deficiency syndrome, pemphigus, alopecia, chronic candidiasis, Cushing’s syndrome, hypopituitarism, Addison’s disease, hypertrophic osteoarthropathy, macrogenitosomia praecox, nephrosis, minimal change nephropathy, red cell hypoplasia, pernicious anaemia, erythrocytosis, agranulocytosis, multiple myeloma, haemolytic anaemia, acute leukaemia, and T-cell lymphocytosis.
Many studies have also noted that 17%-28% (higher than expected) of patients with thymoma present with a second synchronous or non-synchronous primary malignancy, including lung, thyroid, gastrointestinal, prostate, lymphoma, brain, sarcoma, and leukaemia, especially non-Hodgkin lymphoma.
Diagnosis is based on clinical features (reported above, symptoms of thymoma) and diagnostic testing and imaging.
WHO histologic classification divides thymic tumors in:
- thymomas (Ts – A, A/B, B1, B2, B3 subtypes);
- thymic carcinomas (TCs – C) depending on microscopic features.
- Contrast-enhanced chest computed tomography (CT) scan is the best test for the evaluation of anterior mediastinal masses, providing information on size, characteristics, and relationship to surrounding intra-thoracic organs and, if present, identifying pleural metastasis.
- Magnetic resonance imaging (MRI) of the chest can be used for patients who cannot receive iodinated contrast.
- Positron emission tomography (PET) scan is currently being evaluated to assess its efficacy for some types of thymoma, metastatic disease, and to ascertain response to non-surgical therapy.
- Combined PET-CT scans may play a role in determining whether distant metastases are present; combining these modalities may provide diagnostic value before considering biopsy (see below).
A definitive tissue diagnosis obtained by biopsy is needed when:
- clinical presentation and imaging only lead to suspect the disease;
- the patient requires a non-operative approach or preoperative chemotherapy or chemo-radiotherapy;
- lymphoma is considered to be a strong possibility;
- metastatic lesion is suspected.
If core needle biopsy is not possible or is non-diagnostic, then surgical options exist for further evaluation.
2.3.4 Differential diagnosis
Thymic tumours account for approximately 50% of anterior mediastinal masses, whereas lymphomas (25%) and various other tumours comprise the remainder. Treatment options are radically different and differential diagnoses can be made with the aid of the patient’s age, gender, clinical history, physical examination, associated symptoms, CT scan appearance, blood test, and biopsy.
3. HOW IS THYMOMA TREATED?
3.1 General information
Surgery is the mainstay of treatment in the management of thymic tumours, as long as they are completely resected.
Induction/adjuvant radiotherapy or chemotherapy in case of partial resection or when surgery is not possible should be based on multidisciplinary evaluation.
The rarity of this tumour has precluded it from the last phase of large clinical trial investigations, and new drugs are slow in development.
3.2.1 When is surgery appropriate?
Surgery is the mainstay of treatment in the management of thymic tumours, as long as they are completely resected.
Once staging work-up has been completed, decision on surgical treatment should be based mainly on two elements: the risk of incomplete resection and the surgical risk for the patient.
- In case of resectable disease, surgery is usually the first step of treatment, once concomitant diseases such as myasthenia gravishave been stabilised. As previously reported, neurologic consultation should be considered if there is suspicion of myasthenia gravis, particularly for any patient being evaluated for surgical intervention, as severe respiratory risks can be minimised with appropriate perioperative management.
- When the risk of incomplete resection of the tumour with surgery exceeds 30%, a neoadjuvant treatment can be proposed in order to improve the resection rate in low-risk (A, AB, B1 subtypes) patients.
- Incomplete resection of the tumour with surgery in high-risk (B2, B3 and C subtypes) patients should be avoided, as debulking procedures are useless.
3.2.2 What is the difference among surgery procedures?
Surgery with resection should be tailored according to the extent of the disease, which may be preoperatively classified as falling into one of two situations:
- presence of a small, clinical stage I or II tumour with radiological characteristics of thymoma or
extended tumours suggesting stage III-IV disease and/or thymic carcinoma (for staging, please see below).
These two situations differ in the preoperative, intraoperative, and postoperative management.
3.2.3 Surgery management
18.104.22.168 Preoperative management
In the presence of an isolated mass within the anterior mediastinal space with a radiological appearance suggesting clinical diagnosis of thymoma and without involvement of surrounding organs, a preoperative diagnosis is useless. Preoperative diagnosis is mandatory in case of unresectable disease, need for neoadjuvant treatment, and uncertain differential diagnosis with lymphoma.
22.214.171.124 Intraoperative management
- Stage I and II thymic tumour: the standard surgical procedure is thymectomy. The type of thymectomy may range from complete thymectomy (complete removal of the thymic gland with surrounding fatty tissue, in patients without myasthenia gravis) to extended thymectomy (removal of mediastinal pleura and all the adipose tissue, the fat, in mediastinal and pericardiophrenic areas), suggested in patients with myasthenia gravis. This attitude is justified by the frequent presence of thymic tissue within the mediastinal fat, which may be responsible for lack of myasthenia gravis remission or late myasthenia gravis occurrence after surgery.
- Stage III thymic tumours infiltrating surrounding structures: there is no place for minimally invasive techniques. In this setting, multidisciplinary evaluation is crucial to decide whether a neoadjuvant treatment should precede surgery. Surgery should require resection of/intervention on surrounding structures infiltrated by the tumour or with metastasis, such as phrenic nerve, section of the superior vena cava, lung, pleura, with related postoperative disturbances.
- Suspicious lymph nodes should be dissected, because of the risk of nodal metastases.
- Radicality of the resection and stage are the main prognostic factors after surgery for thymic tumours. Additionally, most decisions on postoperative adjuvant treatment will be made based on these elements. For these reasons, every effort should be made to improve precision of pathological assessment of the resected tissues.
126.96.36.199 Postoperative management
After surgical resection, three issues should be addressed:
- proper definition of pathological staging (see below);
- the need for adjuvant treatment: to define the need for adjuvant treatment, in deciding for adjuvant radiotherapy, radicality of the resection, stage, and histology are usually considered;
- the type of required follow-up (see below).
188.8.131.52 Surgical treatment of recurrence
A certain proportion of patients may experience recurrence of the tumour after surgical resection. In stage I thymoma, recurrence is a rare event (3%), occurring after a mean time of 10 years. As stage increases, the risk of recurrence increases (11% in stage II and 30% in stage III) while time to recurrence shortens (3 years). The most frequent sites of intrathoracic recurrence are the mediastinum, pleura and/or diaphragm and the lung. In many cases, treatment options are limited, because radiotherapy has already been administered in an adjuvant setting after the first resection. In select cases, these recurrences may be considered for surgery, as long as a radical resection can be anticipated. When a radical resection is achieved (50%), good results can be obtained in terms of long-term survival.
3.3.1 General information
Adjuvant treatment radiotherapy has been widely adopted in advanced stage disease mainly when the disease invades surrounding tissues or when surgery has resulted in only partial resection. The role of radiotherapy remains quite controversial as adjuvant treatment in radically resected patients according to low or high risk.
Present and future efforts should classify patients according to class of risk, adapting adjuvant treatment according to surgery extension, stage, and tumour histology.
With a more advanced disease, where complete resection is not achievable, patients should refer to multimodality treatment (with chemotherapy and radiotherapy) in order to undergo radical surgery (type C evidence).
Where surgery is not recommended, a personalised approach including radiotherapy and/or chemotherapy should be discussed with individual patients and by a Multidisciplinary Disease Team, where available.
3.3.2 When is radiotherapy employed?
o Excellent long-term results are obtained with complete surgical thymectomy for stage I and II thymoma patients, and no adjuvant therapies should be proposed following a complete resection.
o Adjuvant radiotherapy may be proposed as individualised therapy in patients with stage II disease with positive or close margins, as determined by both pathological and/or intraoperative findings.
o Stage III thymoma may be difficult to identify prior to surgery, as invasion of adjacent structures may only be identified at the time of surgery. These patients often receive aggressive surgical resection including wide surgical margins, with consideration of adjuvant radiation therapy.
o If invasion of local organs is apparent on pre-treatment imaging as stage III or IV disease, a multimodality approach including induction therapy followed by surgery may be proposed.
o Finally, treatment options for recurrent disease should be defined according to the possibility of eventually being able to receive radical surgery, previous oncological treatment, site of recurrence, and time from initial treatment to failure.
- Thymic carcinoma. Treatment should be tailored to individual patients and managed mostly in a multimodality setting.
o Adjuvant radiotherapy should be considered in stage II disease, and applied as adjuvant treatment in patients with stage III disease either with complete or grade I partial resection;
o stage IV disease should be managed in a multimodality setting.
The observations about advanced disease and multimodality approach stated above for thymoma should be applied in thymic carcinoma, as well.
3.4 Medical therapy
3.4.1 When is chemotherapy used?
o Chemotherapy drugs are not recommended for patients with radically resected (R0) stage I-II thymic epithelial tumours.
o Chemotherapy may be employed in combination with radiotherapy or not as induction/neoadjuvant treatment in case radiological evidence of invasion of neighbour organs.
o Patients with advanced and/or not resectable disease (stage III o IV) are candidates for chemotherapy with or without radiotherapy.
New biological drugs are being studied such as immunotherapy or targeted therapies (to inhibit the growth of the tumours with substances against growth factors/enzymes, receptors).
3.4.2 How does chemotherapy works and how is given?
Chemotherapy drugs act killing malignant cells. Chemotherapeutic agents may be by mouth (orally) or by injection (intravenously) into a vein using a syringe or an infusion. Various drugs may be given singularly or in combination. When administered chemotherapeutic drugs are carried in the blood, they may reach all parts of the body. For this latter mechanisms, chemotherapy is defined systemic therapy.
3.4.3 Side effect of chemotherapy
The side effects of chemotherapy depend on the type of drug and the type of combinations. Generally, we may have:
- Nausea and vomiting caused by systemic action of chemotherapy or by specific radiotherapy field. To prevent these side effects there are:
o several antiemetic agents that oncologist will add to chemotherapy and will prescribe for the following days after infusion;
o some daily precautions: to avoid large meals or fried, to eat and to drink slowly and to chew long aiding digestion, do not lie down right after meals, to prefer still water.
- Alopecia: hair loss may occur throughout the body, including the head, face, arms, legs, underarms, and pubic area; hair loss may fall out entirely, gradually, or in sections. To reduce intensity the patient should:
o use soft brushes, avoid hair dye or permanent and use warm air to dry hair.
- Anaemia, infections and/or bleeding can occur when blood cells (red and white blood cells, platelets ) reduce due to chemotherapy effect on bone marrow. For this, periodic haematological controls will be made. Blood transfusion or drugs stimulating the growth of bone marrow cells would be used.
- Diarrhea and constipation could be caused by direct effect of chemotherapy or by antiemetic drugs administration:
o all drugs blocking side effects should be prescribed by your doctor.
o dehydration should be avoid by drinking plenty of water and integrating with minerals.
- Peripheral neuropathy: some drugs could cause burning, tingling (“pins and needles” feeling) or electric/shock-like pain, loss of feeling (can be numbness or just less ability to sense pressure, touch, heat, or cold), trouble using your fingers to pick up or hold things. There are few antidotes to revert these symptoms, but chemotherapy may be reduced or interrupted.
- Cardiac toxicity: some drugs could determine heart failure due to direct action of over dosage of chemotherapy. Ecocardiography will be performed if necessary.
4. STAGES OF THYMIC TUMOURS
Thymic tumours can rarely present as primary lesions outside the anterior mediastinum, such as the middle and posterior mediastinum, pleura, neck, and as intra-thyroidal lesions. At presentation, approximately 40% of thymic tumours are stage I, stage II and stage III, each account for 25%; 10% are stage IVa; only 1% to 2% are stage IVb.
It is uncommon for patients with thymoma to have metastatic disease at presentation, with the pleura being the most frequent site and extra-thoracic disease accounting for <10% of cases.
Thymic carcinomas present with distant metastasis more frequently than thymomas.
4.1 How is the stage of thymic tumours determined?
There are a number of staging systems.
The most widely accepted was proposed by Masaoka (see Table 4 in Professional Area). It was proposed in 1981 as a surgical and pathologic staging system based on the extent of the disease, focusing on the integrity of the thymic capsule, the presence of micro/macroscopic invasion into adjacent mediastinal structures, and metastatic spread by lymphatic and blood vessels.
In 1994, a staging modification was proposed by Koga (see Table 7 in Professional Area), and the Masaoka classification with Koga modification has been adopted by the International Thymic Malignancy Interest Group (ITMIG), with further definition (see Table 8 in Professional Area).
The TNM system (1991) closely parallels the Masaoka one, but is less commonly used and in 2004 the World Health Organization proposed a new system of TNM classification and staging (see Table 9 in Professional Area).
4.2 Treatment of thymoma depending on the stage
- Stage I: thymectomy, the removal of the entire thymus gland en bloc with the tumour (complete or extended thymectomy); radiotherapy is controversial as adjuvant treatment in radically resected patients.
- Stage II: thymectomy, the removal of the entire thymus gland en bloc with the tumour (complete or extended thymectomy); adjuvant radiotherapy is considered.
- Stage III: multidisciplinary evaluation to decide whether a neoadjuvant treatment should precede surgery; surgery should require resection of/intervention on surrounding structures infiltrated by the tumour or with metastasis; no place for minimally invasive techniques; consideration of adjuvant therapies.
- Stage IV: multimodality approach.
5.1 General information
Prognosis indicates the probability of survival and recovery from the disease, that is statistical data obtained from several studies that observe the progress of the disease in a significant number of patients. These statistics merely provide an indication: it is not possible to define exactly what the treatment outcome will be in a particular patient, nor to quantify survival.
Few studies have addressed recurrence of the disease as an outcome for thymic malignancies.
Overall survival has been the most commonly used endpoint; nevertheless, it is not an ideal endpoint, because many patients die of unrelated causes, and patients may survive for many years with recurrent disease.
Frequency of relapse is different depending on the stage of the tumour, increasing from stage I to stage III (3% for stage I, 16% for stage II, and 26% for stage III), while it is variable for stage IV.
Ten-year overall survival and disease free survival rates are 90% and 94% for stage I; 70% and 88% for stage II; 55% and 56% for stage III; and 35% and 33% for stage IV, respectively.
Local recurrence is more common. It usually presents as a pleural or pericardial nodule. Distant metastasis is usually found in lung, liver, and bone. Factors associated with a lower rate of recurrence are Masaoka stages I and II, histologic type (especially thymoma versus thymic carcinoma), a complete resection, and smaller tumours.
5.2 Prognosis of thymic tumours
Several factors need to be considered for patient prognosis:
- tumour stage is the single most important prognostic factor;
- a combination of stage and histologic subtype should be considered in predicting survival;
- completeness of resection is extremely important for prognosis;
- myasthenia gravis used to be associated with worse prognosis, but advances in managing this disease have led to most patients being diagnosed as stage I and II, and having a better outcome;
- hypogammaglobulinaemia and pure red cell aplasiaare associated with worse prognosis;
- early recurrence has also been reported to be a poor prognosis indicator of overall survival;
- there is some suggestion that patients with smaller tumours have a better prognosis;
- there is some suggestion that patients younger than 30 to 40 years have a better prognosis.
6. WHAT TO DO AFTER TREATMENT
6.1 General information
Follow-up after treatment consists of a series of visits and additional tests to monitor the effects of treatment and make sure that the tumour does not recur. No standard duration of follow-up or timetable of visits have been established; international guidelines recommend surveillance for recurrence with CT scan every 6 months for the first 2 years, then annually for 5 or 10 years in case of thymic carcinoma and thymoma, respectively.
6.2 Follow-up of thymic tumours
Follow-up should take into account that thymomas are indolent tumours that may develop recurrence many years after resection. An annual CT scan is therefore proposed for the first 5 years after surgical resection of stage I-II thymoma. CT is alternated with chest X-ray for the next 5 years, followed by an annual chest X-ray afterwards.
In case of higher stages, incomplete resection, or thymic carcinoma, a CT scan is proposed every 6 months for the first 3 years.
An alternative strategy is to maintain lifelong annual CT scans, the rationale being the peculiar risk (15%-20%) for thymoma patients of developing second tumours, and very late recurrence.