Thymoma

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

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
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  • 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
    • 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

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)

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

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)
  • 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

HASSAL'S Body:

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  • 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

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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
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
  • 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

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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%

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%
  • 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