GOECP/SEOR radiotherapy guidelines for thymic epithelial tumours

Table 1 Levels of evidence and grades of recommendation

Levels of evidence
I	Evidence from at least one large RCT of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomised trials without heterogeneity
II	Small or large RCTs with suspicion of bias (lower methodological quality) or meta-analyses of such trials with demonstrated heterogeneity
III	Prospective cohort studies
IV	Retrospective cohort studies or case-control studies
V	Studies without control group, case reports, expert opinions
Grades of recommendation
A	Strong evidence for efficacy with a substantial benefit, strongly recommended
B	Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended
C	Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, etc.), optional
D	Moderate evidence against efficacy or for adverse outcome, generally not recommended
E	Strong evidence against efficacy or for adverse outcome, never recommended

RCT: Randomised controlled trial.

Table 2 Characteristic clinical manifestation of thymomas and differential diagnosis with other causes of mediastinal masses

	Speed of development	Associated clinical manifestations	Characteristic signs
Thymoma	Long course or indolent	Compressive symptoms: Chest pain, dyspnea, dysphagia, vena cava syndrome	Laboratory abnormalities: Anti-acetylcholine receptor antibodies (common if associated with MG), hypogammaglobulinemia, erythropenia, pancytopenia
		Neurological autoimmune disorders: MG, myotonic dystrophy, limbic encephalitis, peripheral neuropathy
		Hematologic autoimmune disorders: Red-cell aplasia, pernicious anemia, erythrocytosis, pancytopenia
Thymic carcinoma	Rapid growth	Collagen autoimmune disorders: Systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, scleroderma	PET-CT: Thymoma types A, AB, B1-2: Low uptake.
		Endocrine disorders: Multiple endocrine neoplasia, Cushing's syndrome, thyroiditis	PET-CT: Type B3 thymoma and thymic carcinoma: High uptake, with loss of bilobar structure of the thymus
		Autoimmune deficiencies: Hypogammaglobulinemia, T-cell deficiency
Lymphoma	Fulminant onset	Dermatological disorders: Pemphigus, Lichen planus	Elevated LDH
		“B” symptoms: Fever, weight loss, sweating
Teratoma	Slow development	Lymphadenopathy. Asymptomatic or compressive symptoms of long duration	CT: Heterogeneous mass, with cystic component and fat/calcifications
Germ cell tumors	Rapid development	Testicular mass	Seminoma: Elevated beta-HCG
			No seminoma: Elevated beta-HCG and AFP
Thymic hyperplasia	Indolent	Asymptomatic	PET-CT: Elevated uptake in mass that maintains the thymic bilobar structure

MG: Myasthenia gravis; PET-CT: Positron emission tomography-computed tomography; LDH: Lactate dehydrogenase; HCG: Human chorionic gonadotropin; AFP: Alpha fetoprotein.

Table 3 Diagnostic criteria of thymomas in the 2015 World Health Organization classification of thymic tumors

Thymoma subtype	Obligatory criteria	Optional criteria
Type A	Occurrence of bland, spindle-shaped epithelial cells (at least focally); paucity1 or absence of immature (TdT+) T cells throughout the tumor	Polygonal epithelial cells; CD20+ epithelial cells
Atypical type A variant	Criteria of type A thymoma; in addition, comedo-type tumor necrosis; increased mitotic count (> 4/2 mm2); nuclear crowding	Polygonal epithelial cells; CD20+ epithelial cells
Type AB	Occurrence of bland, spindle-shaped epithelial cells (at least focally); abundance of immature (TdT+) T cells focally or throughout tumor	Polygonal epithelial cells; CD20+ epithelial cells
Type B1	Thymus-like architecture and cytology: Abundance of immature T cells, areas of medullary differentiation (medullary islands); paucity of polygonal or dendritic epithelia cells without clustering (i.e., < 3 contiguous epithelial cells)	Hassall’s corpuscles; perivascular spaces
Type B2	Increased numbers of single or clustered polygonal or dendritic epithelial cells intermingled with abundant immature T cells	Medullary islands; Hassall’s corpuscles; perivascular spaces
Type B3	Sheets of polygonal slightly to moderately atypical epithelial cells; absent or rare intercellular bridges; paucity or absence of intermingled TdT+ T cells	Hassall’s corpuscles; perivascular spaces
MNT	Nodules of bland spindle or oval epithelial cells surrounded by an epithelial cell-free lymphoid stroma lymphoid stroma	Lymphoid follicles; monoclonal B cells and/or plasma cells (rare)
Metaplasticthymoma	Biphasic tumor composed of solid areas of epithelial cells in a background of bland-looking spindle cells; absence of immature T cells	Pleomorphism of epithelial cells; actin, keratin, or EMA-positive spindle cells
Rare others2

The atypical type A thymoma variant is the only new addition to the “historic” list of thymoma subtypes.

¹Paucity versus abundance: Any area of crowded immature T cells or moderate numbers of immature T cells in more than 10% of the investigated tumor are indicative of “abundance”.

²Microscopic thymoma, sclerosing thymoma, lipofibroadenoma.

MNT: Micronodular thymoma with lymphoid stroma.

Table 4 Clinical stage of thymic epithelial tumours according to Masaoka-Koga

Stage	Diagnostic criteria	10-yr survival
I	Tumours encapsulated macroscopically and microscopically (without capsular invasion)	84% (81%-86%)
II	A: Microscopic transcapsular invasion	83% (79%-87%)
	B: Macroscopic invasion of fatty tissue or pleural and/or pericardial adhesion
III	Macroscopic involvement of adjacent structures (pericardium, great vessels, or lung). A: With invasion of great vessels	70% (64%-75%)
	B: Without invasion of great vessels
IV	A: Pleural or pericardial spread	42% (26%-58%)
	B: Hematogenous or lymphogenic metastasis	53% (32%-73%)

Table 5 Clinical stage of thymic epithelial tumours: International Association for the Study of Lung Cancer/International Thymic Malignancy Interest Group tumor-node-metastasis

Stage		Description
Primary tumor (T)
T1	T1a	Encapsulated or unencapsulated, with or without extension into mediastinal fat
	T1b	Extension into mediastinal pleura
T2		Direct invasion of the pericardium (partial or full thickness)
T3		Direct invasion of the lung, brachiocephalic vein, superior vena cava, chest wall, phrenic nerveand/or hilar (extrapericardial) pulmonary vessels
T4		Direct invasion of the aorta, main pulmonary artery, myocardium, trachea, or esophagus
Lymph nodes (N)
N0		No nodal involvement
N1		Anterior (perithymic) lymph nodes (IASLC levels 1, 3a, 6 and/or supradiaphragmatic/inferior phrenic/pericardial)
N2		Deep cervical or intrathoracic nodes (IASLC levels 2, 4, 5, 7, 10 and/or internal mammary nodes)
Distant metastasis (M)
M0		No pleural, pericardial, or distant metastases
M1	M1a	Pleural or pericardial nodules
	M1b	Pulmonary intraparenchymal nodule or distant organ metastasis
TNM stage		MASOKA-KOGA stage
I	T1N0M0	I, IIA, IIB, III
II	T2N0M0	III
IIIA	T3N0M0	III
IIIB	T4N0M0	III
IVA	Any T, N0-1, M0-1a	IVA, IVB
IVB	Any T, N0-2, M0-1b	IVB

IASLC: International Association for the Study of Lung Cancer; TNM: Tumor-node-metastasis.

Table 6 Most commonly used chemotherapy regimens for thymic carcinoma

Scheme	Drugs
ADOC	Doxorubicin + Cisplatin + Vincristine + Cyclophosphamide
CAP	Cisplatin + Doxorubicin + Cyclophosphamide
PE	Cisplatin + Etoposide
VIP	Etoposide + Ifosfamide + Cisplatin
CODE	Cisplatin + Vincristine + Doxorubicin + Etoposide
Carbo-Px	Carboplatin + Paclitaxel
CAP-GEM	Capecitabine + Gemcitabine

ADOC: Anthropogenic dissolved organic carbon; CAP: Capecitabine; PE: Pulmonary embolism; VIP: Vasoactive intestinal peptide; GEM: Gemcitabine.

Table 7 Constraints to the main organs

Organ	Constraints
Spinal cord	Dmax < 45 Gy
	Dmax < 40 Gy if 3 Gy/fraction
Lung (total lung minus GTV; solely total lung for postoperative cases without GTV)	Mean dose < 20 Gy
	Mean dose < 8 Gy if post-pneumonectomy
	RT alone	RT with chemotherapy	Neoadjuvant treatment before surgery
	V20 ≤ 40%	V20 ≤ 35%	V20 ≤ 30%
		V10 ≤ 45%	V10 ≤ 40%
		V5 ≤ 65%	V5 ≤ 55%
	V20 < 10% and V5 < 60% if post-pneumonectomy
Heart	Mean dose < 26 Gy
	V30 ≤ 45%
Esophagus	Mean dose < 34 Gy
	Dmax ≤ 80 Gy
	V70 < 20%
	V50 < 50%
Kidney	20 Gy < 32% bilateral kidney
Liver	Mean dose < 30 Gy
	V30 ≤ 40%

GTV: Gross tumour volume; RT: Radiotherapy.