Thymoma
Table of Contents
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Thymus Gland
- A bilobed lymphoepithelial organ
- Anterior mediastinum, behind the sternum & in front of the great vessels
- 12-15g @ birth —> 40gm @ puberty
Functions:
- In early life —> T-lymphocyte differentiation and maturation
- Outer cortex —>
- Primarily of epithelial cells
- Most tumours arise from epithelial cells
- Degenerated keratinized epithelial cells (Hassall’s corpuscles)
- Myoid cells
- Thymic lymphocytes (thymocytes)
- B lymphocytes
- Primarily of epithelial cells
Classification!
Historical classification:
- Cortical
- Arised from epithelial cells of cortex
- More aggressive
- Myastenia Gravis more!
- Mixed
- Medullary types
- Arised from medullary spindle cell
- سیر خوش خیم
- Thymic Carcinoma
WHO Classification:
- Based on the proportion of epithelial and lymphocytic cells
- RARE
- 50% of anterior mediastinal masses
- The most common:
- Thymoma
- Most common tumour found in ant mediastinum
- 90% in anterosuperior mediastinum
- usually associate with myriad neoplastic syndromes
- Exuberant lymphoid component composed of immature cortical thymocytes
- Benign histologically
- Invasive behaviour clinically
- Thymic carcinoma
- Type C thymomas
- Poorer prognosis
- 5%-36% of all thymic neoplasms
- Typically middle-aged/elderly
- Slightly —> M>F
- from thymic epithelium
- Capsular invasion
- Distant Metastases
- Specially high grade
- Histologic subtypes:
- High grade:
- Clear Cell Carcinoma
- Sarcomatoid Carcinoma
- Anaplastic Carcinoma
- Low-grade:
- Well-differentiated squamous cell carcinomas
- Basaloid carcinomas
- Mucoepidermoid carcinomas
- Lower incidence of local recurrence and metastasis
- High grade:
- Thymic carcinoids (neuroendocrine)
- < 5% of all neoplasms of the anterior mediastinum
- Middle-ages men
- Thought to originate from endodermal cell (or foregut cellular) precursors
- Unlike carcinoids in other locations, most thymic carcinoids behave aggressively
- Local invasion
- Distant metastases
- Endocrine abnormalities
- Thymoma
Etiology and Epidemiology
- Etiology unknown
- Reported association between Epstein-Barr virus (EBV)
- More common in Far Eastern countries
- High EBV infection
- Childhood thymus irradiation
- Familial ?
- Adult survivor of acute lymphoblastic leukaemia —> secondary Ca —> Thymoma
- Multiple endocrine neoplasia type 1 —> Thymic Carcinoid Tumours (30% of cases)
- Chromosomes 15 and 19 [t(15:19) (q15:p13)] abnormality in thymic carcinoma
- Particularly in young adults and pediatric patients with high-grade thymic carcinoma
- Deletion of the short arm of chromosome 6 —> benign thymomas
- Type B and C ( Carcinoma ) more associated with chromosome abnormality
- Loss of chromosome 6 and the gain of chromosome 1q
- The loss of chromosome 6
- Human leukocyte antigen locus and some of the tumor suppressor genes are on chromosome 6
- Gain of chromosome 1q
- Growth promoter genes on 1q
- These may have a role in paraneoplastic autoimmunity (characteristics of thymoma)
- The loss of chromosome 6
- Loss of chromosome 6 and the gain of chromosome 1q
Incidence
- Thymoma
- US —> 13-15 / 10,000,000 people
- Most patients are 40-60yrs
- Median Age —> 52
- M=F
- Most frequently diagnosed mediastinal masses
- 30% of anterior mediastinal lesions
- 20% of all mediastinal tumors in adults
- Less common in children:
- 15% of anterior mediastinal masses
- Less common in children:
Prevention and Early Detection
Mostly discovered incidentally through abnormal CXR.
Groups at risk:
- Thymic irradiation during childhood
- EBV infection
- Associated with lymphoepithelioid thymic carcinoma
- Familial cytogenetic abnormalities
- Associated with autoimmune disorders
- Myathenia Gravis (30-45% cases)
- Indolent growth pattern with a tendency toward local invasion
- Mets to regional lymph nodes & distant sites —> up to 30% of patients at diagnosis
Biologic Characteristics and Molecular Biology
THYMOMA:
Clinical Behaviour:
- Indolent natural history
- Histologically benign
- Direct extension
- Local & regional invasion
- Tendency for recurrence
- Mediastinum
- Pleura
- After complete surgical resection —> up to 40% of those with invasive disease still recur
- Complete resection in 50-70% of cases
- Late relapse is not uncommon
- Metastases
- Pleura
- Pericardium
- Diaphragm
- Nodal & hematogenous —> are rare
- An increased risk for second malignant tumours
- Up to 70% —> paraneoplastic syndromes
Physiologic Behaviour:
- Dysregulation of the lymphocyte selection process
- Abnormal proliferation
- Autoimmunity
- Alternation in circulating T-cell subsets
- Immunodeficiency
- B-cell lymphopenia
- Hypogammaglobulinemia (i.e., Good's Syndrome)
Thymoma:
- Altered TP53 expression
- If co-expressed with SRC Kinase ==> Worse OS!
- Increased expression of epidermal growth factor (EGF)
- Increased expression of epidermal growth factor receptor (EGFR)
- Deficiency in the autoimmune regulator (AIRE) gene
- 95% of thymomas
Thymic carcinomas:
- Higher propensity for capsular invasion and metastases than invasive thymomas
- If well-differentiated
- May see paraneoplastic syndromes
- Usually highly lethal
- Frequent metastases
- Regional lymph nodes
- Bone
- Liver
- Lung
- High EGFR expression
- BUT EGFR gene mutations are rare
- Elevation of serum VEGF
- Elevation of serum basic fibroblast growth factor (bFGF)
- Increased expression of:
- Epithelial membrane antigen
- Cytokeratin subtypes
- TP53 protein
- Somatic KIT gene mutations are present in some thymic carcinomas but not in thymomas
- Increased expression of CD70 may serve as a marker
- Recurrent Tumours and more aggressive tumours:
- Increased expression of:
- Cytoplasmic phosphorylated AKT serene
- Insulin-like growth factor-1 receptor (IGF-1R)
- Increased expression of:
- IGF-1R was associated with a worse progression-free survival time
How to differentiate from lung Ca?
- Negative expression of thyroid transcription factor
- Distinctly different cytokeratin profile
- Not likely TP53 gene mutation was not found in any of seven examined thymic carcinomas.110
- Cushing's Syndrome
- Endocrine Abnormality
- OS rates were only 28% and 10% at 5 and 10 years, respectively.
Pathology and Pathways of Spread
- If true malignant cytologic characteristics —> thymic carcinomas
- Malignant thymomas invade the capsule macroscopically or microscopically
- “bland” cytologic characteristics of thymic epithelial cells admixed with mature lymphocytes
- Invasive thymoma a better term rather than malignant thymoma
- Thymoma:
- Gross description:
- Nodular
- Multilobulated
- Firm
- Cystic spaces
- Calcification
- Hemorrhage
- May be neatly encapsulated
- Adherent to surrounding structures, or invasive
- Microscopic:
- Two cell types: epithelial and lymphatic cells
- Subtypes:
- Predominantly epithelial
- Predominantly lymphocytic
- Mixed lymphoepithelial
- Spindle cell type.
- Thymic neoplasms arise from epithelial cells
- Morphology:
- Large
- Round, oval, or spindle shaped
- Vesicular nuclei & small nucleoli
- Cyto- plasm is often eosinophilic or amphophilic
- Normal-appearing mature lymphocytes
- Hassall’s corpuscles (Thymic bodies or corpuscles)
- Structures found in the medulla of the human thymus
- Keratinizing squamous epithelium
- Rosettes, glands, cysts, papillary structures, and germinal centers
- Immunohistochemistry
- Positive for a number of thymic epithelial markers
- Cytokeratin, thymosin ß3 and α1, and epithelial membrane antigen
- Positive for a number of thymic epithelial markers
- Gross description:
HASSAL'S Body:
- Thymic carcinoma:
- Squamous cell histologic
- Other subtypes:
- Lymphoepithelioma-like
- Clear cell
- Sarcomatoid
- Adenosquamous
- Mucoepidermoid
- Adenocarcinomas
- Basaloid squamous cell
- Rarely encapsulated
- Immunohistochemically
- CAM positive
- Low-molecular-weight cytokeratins
- Chromogranins
- Synaptophysin
- Leucine-7
The degree of encapsulation and the invasion of adjacent tissues define malignancy for these tumors rather than the histologic appearance.
- About 50% are non-invasive locally.
Clinical Manifestations and Patient Evaluation
- 30-40% Asymptomatic
- Discovered incidentally
- Mediastinal mass
- Cough
- Chest pain
- Dyspnea
- Hoarseness
- SVCO
- Tumor hemorrhage
- Dysphagia
- Fever
- Weight loss
- Anorexia
- Symptomatic paraneoplastic syndromes)
- Myasthenia gravis(45%)
- Common with thymoma but rare in thymic carcinoma
- Increased operative mortality rate
- Mortality usually caused by complications of myasthenia gravis
- OS not different.
- After resection symptoms may get better but not completely resolved.
- Red cell aplasia
- About 50% of patients with pure red cell aplasia have thymoma
- Hypo gammaglobulinemia
'
Thymic Carcinoid:
- Cushing’s syndrome
- Eaton-Lambert syndrome
- SIADH
- Hypercalcemia
Prognostic Factors
Thymoma:
- Invasiveness (stage)
- Completeness of surgical resection
- happens in 50-70% of cases
- Tumor size (>10 cm)
- Presence of symptoms
- Red cell aplasia
- Hypogammaglobulinemia
- Lupus erythematosus
- WHO classification group
- A, AB and B1 may not need RT as DSS 100% with no RT
- Best prognosis
- Less Myastenia Gravis
- C has worst prognosis
- Subtypes of B no different in prognosis
- Mixed —> intermediate prognosis
- A, AB and B1 may not need RT as DSS 100% with no RT
Histologic Subtype | 10 year Survival |
---|---|
Cortical and Well differentiated | 45% |
Mixed | 76% |
Medullary | 100% |
Diagnostic Workup for Thymic Tumors
- History
- Physical examination
- Myasthenia gravis
- Fatigue
- Diplopia
- Ptosis
- Dysarthria
- Cushing's Syndrome
- Constitutional symptoms
- Suggestive of Lymphoma
- Fever
- Chills
- Weight loss
- Suggestive of Lymphoma
- Myasthenia gravis
- Routine Blood Work
- Serum alpha-fetoprotein and beta-human chorionic gonadotropin —> R/O nonseminomatous germ cell tumor
- CXR
- Hilar mass
- CT chest with contrast
- also shows degree of vascularity
- Usually homogeneous, well- demarcated lesions with a round or lobulated shape
- Vary in size
- Occasionally have calcification
- Presence of fat planes between the tumor and adjacent structures —> localized disease
- Check for drop metastases in pleura
- Thymic carcinomas
- Often alcifications, cysts, or necrosis
- Biopsy
- Sensitivity and specificity of > 90%
- The potential risk of breaching the capsule, leading to spillage and seeding of tumor cells during biopsy, has been debated and remains unsettled
Staging
Treatment
Surgery for Thymoma
- Mainstay of therapy in resectable cases
- Low risk of morbidity and mortality
- Chances of recurrence:
- If tumour encapsulated and no disturbance of capsule —> recurrence is rare
- Successful surgical treatment = Complete resection
- Phrenic nerve may be involved bilaterally —> resection of both ==> respirator morbidity
- Stage IVA —> 25% resectable
Radiation Therapy for Thymoma
- No prospective randomized study
- Retrospective studies —> improvement in local control
Indication for adjuvant RT:
- Encapsulated, noninvasive stage I & complete resection —> No RT
- Recurrence rate < 2%
- Stage II —> Contraversial
- Recurrence from 8-30%(?)
- Meta-analysis(retrospective) —> no benefit from RT
- Selection bias
- Fibrous adhesions of the tumor to the pleura —> increased chance of recurrence
- Stage III to IV disease
- RT decrease LR to half (from 50% to 25%)
- Pre-op RT for non-resectable lesions
- Definitive RT for non-resectable tumours
- Five-year survival rates of 53% to 87% and 10-year survival rates of 44%
- Intrathoracic recurrence
Chemotherapy for Thymoma
- Chemosensitive tumors
- Locally advanced
- Metastatic disease
- Platinum-based regimens
- Response rates : 24%-100%
- Cisplatin > RR > 50%
- Combinations of cisplatin, doxorubicin, and cyclophosphamide (PAC)> RR: 70%
- Response rates : 24%-100%
Combined-Modality Therapy for Thymoma
- Neoadjuvant chemotherapy and then surgery, followed by additional chemotherapy and irradiation, may improve the resectability and survival rates of the patients with locally advanced disease.
Results of Thymoma Treatment
Stage | 5yr survival |
---|---|
I | 83-100% |
II | 85-95% |
III | 70-90% |
IV | 50-70% |
- Encapsulated Thymoma; non-invasive; complete resection
- 5 & 10yr survival —> >90%
- Invasive; complete resection
- 5 & 10yr survival —> 50 and 30%
- The local control rates after a complete resection and adjuvant radiation therapy —> 65% to 100%
- Incomplete resection and radiation therapy —> Lower
- Stage II and III
- RT post-op —> 5% LR
- No RT —> 25% LR
- Post-op RT ==> Improved survival rates for patients with invasive thymomas after complete and incomplete resections
- 5yr survival:
- Stage II —> 92%
- Stage III 88%
- 5yr survival:
- Primary RT —> 2yr local control: ~50%
- Locally advanced —> Chemo-RT —> overall response rate : 60%
Treatment of Thymic Carcinoma
- Unclear
- Surgery is the mainstay
- Adjuvant RT
- 45-55 Gy
- 1.8-2 Gy per fraction
- 77% 5-year OS rate
- 82% if completely resected
- 66% if subtotally resected
- No survival benefit confirmed from adjuvant RT
- If non-resectabe —> Neoadjuvant platinum-based chemotherapy
Treatment of Thymic Carcinoid
- Surgery
- Recurrence and distant metastases are common
- Recurrence rate: ~60%
- DM: 30%
- Median survival time was 79 months
- 5-year survival rate was 84%
- Adj RT for non-complete resection
Techniques of Irradiation
- High energy X-ray
- CT-simulation
- Clips placed at the time of surgery denoting the extent of resection in completely resected tumors or outlining regions of residual disease are useful
- GTV
- CTV —> Tumour bed + Thymus if left any
- Areas of suspicious subclinical disease and regional lymphatics
- Treatment of the entire mediastinal and supraclavicular nodal basin prophylactically is not advised
- Low incidence of lymph node involvement
- Higher normal tissue complication rate when large target volumes are used
- PTV —> GTV + tumor bed with a 1.5- to 2-cm margin
- Dose > 40 Gy —> better local control
- Organs at risk:
- Spinal cord
- 45 Gy
- Lung
- Esophagus
- Heart
- Spinal cord
page revision: 69, last edited: 25 Mar 2013 19:42