Introduction

There are three general categories of thymic tumours: thymoma, thymic carcinoma and tumours of other thymic elements (Classification). They share many features of presentation and investigation but their behaviour and treatment varies widely.

Thymoma

Thymomas are of particular fascination because of their unusual para-neoplastic associations. The best known of these is myasthenia gravis but the number of syndromes associated with thymoma is extensive (Parathymic syndromes). The tumour contains both epithelial and lymphocytic elements which can also make differentiation from lymphoma difficult.

Aetiology and epidemiology

There is no known aetiology for thymoma or thymic carcinoma. Therefore prevention and screening are not feasible.

There is no relationship between thymoma and gender, sex or race though the peak incidence is in the fifth and sixth decades. While myasthenia gravis presenting in adolescence is usually associated with thymic hyperplasia, later onset is associated with thymic neoplasm. Other conditions such as thymo-lipoma which may be a an abnormality of thymic involution tend to occur in adolescence or early adulthood.

The genetic expression of thymomas is unlike other epithelial tumours with abnormal expression of p16, p53, pRB, and cyclin D1 being less frequent and alterations of the p53 genes and overexpression of cyclinD1 may not play a significant role in tumorigenesis of thymomas. On the other hand, the inactivation of CDKN2/p16 gene or pRB may play a significant role in the tumorigenesis and the progression of thymomas and thymic carcinomas.

Pathology

Most thymomas occur in the anterior mediastinum though five per cent occur in the neck and others in the posterior mediastinum, left hilum and pulmonary parenchyma.

As benign thymoma is cured by surgery without adjuvant therapy the two-fold aim of the pathologist is to determine whether the tumour iscomposed of thymic epithelial elements and to assess the degree of malignancy. The malignant potential is frequently suggested by the clinical behaviour of the tumour as assessed by the surgeon at the time of operation. A diffuse lesion, invading surrounding structures making radical clearance difficult is suggestive of malignancy. Most well defined lesions tend to follow a benign course whereas the prognosis of thymic carcinoma is stage related.

There is a spectrum of malignant change in thymoma which has led to a number of attempts at classification. The classification we use is a compromise between the Masoaka staging system, which categorises thymoma purely on encapsulation and invasion of local tissues, and the Muller-Hermelink morphological classification. Attempts have also been made to differentiate the malignant potential according to histological subtypes (predominantly lymphocytic, mixed lymphoepithelial, predominantly epithelial and spindle cell). Others propose a subdivision into cortical and medullary. While these classifications have been shown to correlate with survival, the differences do not become apparent till 5 to 10 years after diagnosis. Thus thymic carcinoma tends to run an indolent course, though most patients with stage IV tumours will eventually die of their disease.

Marino and Muller-Mermelink (Marino M, Muller-Mermelink HK: Thymoma and thymic carcinoma. Relation of thymoma epithelial cells to the cortical and medullary differentiation of thymus. Virchows Arch [A] 407:119,1985) proposed a subclassification into "cortical" and "medullary" based on light microscopy. While some pathologists find the criteria for distinguishing these subclasses vague and subjective (Close PM, Kirchner T, Uys CJ, Muller-Hermelink HK: Reproducibility of a histogenetic classification of thymic epithelial tumours. Histopathology 1995 Apr;26(4):339-43), statistically significant relationships between histologic results and age, surgical stage, and prognosis were demonstrated by Pescarmona et al. (Pescarmona E, Rendina EA, Venuta F, et al.: The prognostic implication of thymoma histologic subtyping: a study of 80 consecutive cases. American Journal of Clinical pathology 93(2):190-195, 1990.) Cortical cells have malignant potential and are more likely to be associated with myasthenia gravis, whereas those of medullary epithelial cell origin are completely benign and show no potential for recurrence or myasthenia.

A comparison of Masaoka and Muller-Hermelink appears in the Annals of Thoracic Surgery May 2000 (Prognostic relevance of Masaoka and Muller-Hermelink classification in patients with thymic tumors. Didier Lardinois, MD, Renate Rechsteiner, MD, R. Hubert Lng, MD, Matthias Gugger, MD, Daniel Betticher, MD, Christian von Briel, MD, Thorsten Krueger, MD, Hans-Beat Ris, MD Ann Thoracic Surg 2000;69:1550-5) This is available online on CTSNet at http://ats.ctsnetjournals.org/cgi/content/full/69/5/1550 with my own discussion of the paper.

Presentation

Many thymomas are assymptomatic and are noticed incidentally on a chest Xray taken for other purposes. Others present with general symptoms aof malaise, lethargy, non-productive cough or dyspnoea. Fifty per cent of patients with thymic neoplasms present with myasthenia gravis. A further 10 - 20% will have features of other paraneoplastic syndromes while a small percentage will have a combination of myasthenia and other syndromes. In some patients the parathymic syndrome does not reveal itself till after surgical thymectomy. Invasive tumours and thymic carcinomas may cause pain due to chest wall, pleural or pericardial invasion. SVC obstruction, phrenic nerve palsy, recurrent laryngeal nerve palsy and dysphagia can all occur.

Parathymic conditions

The conditions which have been described in association with thymic pathology are known as parathymic syndromes. They generally fall into the categories of neuromuscular dysfunction, haematologic disorders, immune drficiencies, endocrinopathies and auto-immune or collagen disorders. The most important are myasthenia gravis, pure red cell aplasia, acquired agammaglobulinaemia and systemic lupus erythematosus. Some of the other syndromes have been described so rarely that a causative relationship has not been confirmed.

Examination

Generally the examination findings will relate to the para-thymic conditions. Rarely are there clinical signs of the tumour itself. However, malignant thymomas may show signs of SVC obstruction, phrenic nerve palsy or pleural effusion.

Diagnosis

Myasthenia gravis

The diagnosis of myasthenia gravis can point one to a thymoma. However, it can occur in the presence of other thymic neoplasms. Myasthenia is due to circulating antibodies to the acetylcholine receptor sites of the neuro-muscular end-plate. Diagnosis is usually clinical with fatiguing of striated muscle involved in repeated or "maintenance" functions. Drooping of eyelids, double vision and dysphagia are common symptoms as the facial, oculomotor, laryngeal and pharyngeal muscle are frequently involved.

Response to neostigmine is indicative of the diagnosis. More commonly used for diagnostic purposes is "Tensilon" (Edrophonium chloride) which has a more rapid action, less side effects and the action dissipated within a few minutes. The response to an intravenous injection of edrophonium is almost instantaneous.

Thymic mass

The differential diagnosis of thymoma without myasthenia gravis is that of any anterior mediastinal mass. The important diagnoses to consider are thymoma, thyroid (retrosternal), teratoma and lymphoma (The four "T’s": thymoma, teratoma, thyroid and terrible lymphoma!) Also to be considered are metastases from other neoplasms, frequently lung or breast. Benign lymphadenopathy such as sarcoidosis and Castleman’s disease can occur in this area. Simple cysts of the thymus are also common. A CT scan or MRI scan will outline the exact site of the lesion and will give clues to the diagnosis, a variegated appearance suggesting teratoma. These scans will also give an indication of malignant invasion of adjacent structures and pleural metastases with there typical "droplet" pattern.

Haematological markers of teratoma (beta-HCG and alpha feto-protein) should be sought and other manifestations of lymphoma excluded. Attempts should be made to avoid surgery to the anterior mediastinum in cases of lymphoma and germ cell tumours as the definitive radiotherapy and chemotherapy may be unnecessarily delayed. The presence of a surgical wound in a radiation field can also lead to troublesome complications (the author has seen two young adults die of the complications of radiation induced fistula with no viable tumour detectable at post mortem).

While it is a principle of oncological surgery that the tumour capsule should not be broached as it may theoretically allow dissemination of a thymoma, routine use of radical thymectomy as a diagnostic procedure is impractical. Fine needle aspiration cytology is frequently inadequate to differentiate thymoma from lymphoma and almost never provides enough tissue to differentiate between types of lymphoma, an important consideration as Hodgkin’s and non-Hodgkin’s lymphoma are treated by different modalities in the first instance. A core biopsy is sometimes safe and productive though the proximity of the aorta dissuades some radiologists. Mediastinoscopy, mediastinotomy via anterior mini-thoracotomy or thoracoscopy may be required to provide enough issue for the pathologist to make a full diagnosis.

Staging

As extra-thoracic disease is rarely present a CT or MRI of the thorax and upper abdomen usually suffices for routine staging of a thymic neoplasm. Attention should be given to mediastinal sites other than the anterior compartment and also to the pleura and pericardial fat.

Treatment

Treatment of thymoma involves two aspects: treatment of the para-thymic symptoms, and extirpation of all tumour. Frequently it is necesary to control the parathymic symptoms before surgery can be contemplated. Of importance for subsequent surgery is the development of shortness of breath on exertion as respiratory muscle become involved. Also of interest to the anaesthetist is the fact that fatiguability is often exacerbated by sedative drugs and some antibiotics.

Medical

Medical treatment is only aimed at treating the parathymic conditions rather than the thymoma itself. Usually coordinated by a neurologist it involves an appropriate combination of anti-cholinergic drugs (pyridostigmine or neostigmine), steroids, plasma-pheresis or intravenous immunoglobulin (IVIg). Although the mechanism of action for IVIg is not known, it is likely to produce a downregulation of antibody production.

As a single treatment modality it is only suitable if CT scanning has excluded the presence of a thymoma. Medical therapy is an intricate part of the workup for surgery and in most cases has to be continued post-operatively. It is usual that a neurologist supervises the medical care and a neurology opinion is wise in all cases of thymoma as thymectomy can precipitate crises.

Anti-cholinergic drugs

Neostigmine analogues provide the backbone of treatment for myasthenia. While neostigmine itself is used for acute crises, pyridostigmine (Mestinon) is more commonly used for longterm control as the concurrent administration of atropine is not usually required.

Steroids

The para-thymic effects of thymic neoplasms, being mediated by the associated hyperplastic lymphoid tissue can, be ameliortaed by the administartion of steroids. Tumours can actually shrink in size as the lymphoid elements react to the steroids leaving the epithelial neoplastic elements intact. Steroids are generally used in all but the mildest cases of myasthenia.

Plasmapheresis

Acute myasthenic crises have more recently been treated with immune plasmapheresis which removes anticholinesterase antibodies from the plasma. This has also been a useful adjunct to optimising of patients for surgery.

Gamma globulins

In recent years gamma globulins (IVIg) can be injected to mimic the effect of plasmapheresis. Their administration is simpler, safer and less draining on the patient.

Other para-neoplastic syndromes

Steroids may help treat other para-thymic conditions. However, transfusion of blood products may be required. Immunoglobulin infusions may also be required during exacerbations of deficiency.

Surgery

Radical surgery is the only kown cure for thymoma be it encapsulated, invasive or frankly malignant thymic carcinoma. Classically surgery is via median sternotomy though unilateral disease or the presence of associated pleural disease may be better approached by a lateral thoracotomy. The aim of surgery is to remove all the thymic tissue and surroundingmediastinal fat including, where necessary, pericardium and pericardial fat. Care must be taken to preserve at least one phrenic nerve.

Repeat surgery for recurrent disease may be appropriate for diagnostic or cytoreductive effect as part of a multi-modality approach.

Radiotherapy

Radiotherapy to the thymus has in the past been used to control myasthenia gravis. This role is rarely used today. It is generally accepted that post-operative irradiation to the thymic bed following excision of Stage 2 and 3 disease, either where there has been extracapsular invasion or where there has been gross fixation of tumour even in the absence of microscopic invasion, reduces local recurrence. (Nakahara K. Ohno K, Hashimoto J et al: Thymoma Results with complete resection and adjuvant post-operative irridation in 141 consecutive cases. J Thorac Cardiovasc Surg 95:1041,1998.)

Chemotherapy

Invasive thymoma is responsive to platinum based chemotherapy which is usually reserved for treating relapses.

Prognosis

Complete excision of a non-invasive stage 1 thymoma is curative. Recurrence of stage 2 tumours can be reduced from 45% to 25% by post-operative radiotherapy. For more advanced disease multi-modality therapy (cyto-reductive surgery, post-operative radiotherapy and adjuvant chemotherapy) can result in significant long-term survival. (Shin Dm, Walsh GL, Komaki R Putnam JB et al: A multidisciplinary approach to therapy for unresectable malignant thymoma. Ann Intern Med 1998;129(2):100-4) The influence of radiotherapy and chemotherapy on prognosis is difficult to gauge as, even with incomplete resection, 5 year survivors are not uncommon. The differences in survival will only become truly apparent with assessment of 10 year survival.

 

Thymic Carcinoma

Thymic carcinoma is exceedingly rare once it has been established that the tumour is not a metastasis from a tumour elsewhere. Most thymic carcinomas are of squamous histology and most have metastases at the time of diagnosis and follow an aggressive course.

Treatment consists of chemotherapy and radiotherapy appropriate to the corresponding histological type.

Thymic tumours composed of other elements

Tumours have been described arising from virtually all tissues found within the thymus but not from thymic epithelial cells. Some like thymolipoma and its sarcomatous form are probably a subset of thymomas as they share parathymic, pathological and prognostic features.

Lymphomas and germ cell tumours are frequently found in the thymus. It is not always clear whether they have arisen within the thymus, they have metastasised to the thymus or whether they are in fact in anterior mediastinal lymphatic tissue. The treatment is that of the underlying histology.

Similarly carcinoid tumours are known to arise from the neuroendocrine elements of the thymus. As these tumours are often more aggressive locally than elsewhere the term thymic neuro-endocrine carcinoma is more appropriate. In addition to local symptoms many are associated with Cushing’s syndrome, inappropriate ADH (anti-diuretic hormone) secretion, and MEN-1 syndrome (multiple endocrine neoplasia type 1). They are resistant to current conventional chemotherapy and radiotherapy but local resection and medical treatment of associated syndromes can lead to relatively good survival.