Thymic epithelial tumours and recent updates

1. DR. ARGHA BARUAH

3. –At birth: 15g , At puberty: 35g , At 25y: 25g , At 75y: 6g
Maturation and selection of immature T-cell precursors (prothymocytes) to mature,
naïve T-cells

10. The blood–thymus barrier regulates exchange of substances between the circulatory
system and thymus, providing a sequestered environment for immature T cells to develop.
The barrier also prevents the immature T cells from contacting foreign antigens (since contact
with antigens at this stage will cause the T cells to die by apoptosis).
The barrier is formed by the continuous blood capillaries in the thymic cortex, reinforced
by epithelial reticular cells (sometimes called thymic epithelial cells) and macrophages.

13. EPITHELIAL TUMORS OF THYMUS

15. OTHER TUMORS OF THYMUS

18. THYMOMA:
5th to 6th decade
More common among females
CLINICAL FEATURES
 Obstructive symptoms(cough,dyspnoea,dysphagia)
 Paraneoplastic syndromes(1/3rd cases)

19. Paraneoplastic syndromes
NEUROMUSCULAR DISEASES
 Myasthenia gravis
 Neuromyotonia*, rippling muscle
disease
 Polymyositis/Dermatomyositis
 Encephalitis
 Intestinal pseudoobstruction
HAEMATOLOGIC AUTOIMMUNE DISEASES
 Anaemia: pure red cell aplasia
(in all thymoma subtypes)
pernicious anaemia, haemolytic anaemia, aplastic
anaemia
 Other isolated cytopenias, eg eosinophils,
basophils, neutrophils
 Immunodeficiencies:
Hypogammaglobulinaemia +/-, T-cell
deficiencies (Good syndrome)
DERMATOLOGIC DISEASES
 Pemphigus (foliaceus, paraneoplastic)
 Lichen planus
 Alopecia areata
ENDOCRINE DISORDERS
 Addison disease, Cushing disease
 Graves disease
RENAL AND HEPATIC DISEASES
 Glomerulonephritis, autoimmune
hepatitis
 Systemic Autoimmune Diseases*
 SLE, Sjögren disease, systemic
sclerosis
 Graft-versus-Host-Disease

20. Location
 95% in anterior mediastinum.
 Neck.
 Left hilar region.
 Within lung parenchyma.
 Anterior cardiophrenic angle.

21. GROSS APPEARANCE

22. Microscopic types:
A = atrophic, represents thymic cells of
adult life
B = bioactive, represents the biologically
active organ of the foetus and infant
C = carcinoma
Most common-AB,B2 followed by B3,B1 and A

23. Type A Thymoma :
Spindle cell, mimics adult thymus; homogenous population
of neoplastic epithelial cells with spindle / oval shape, no
nuclear atypia and accompanied by few or no
nonneoplastic lymphocytes
ORIGIN : normal thymic medullary epithelial cells

24. Types of Type A:
Short spindled: 57%, often in hemangiopericytic or
microcystic pattern.Epithelial cells often CD20+
Long spindled:31%, fibroblast-like epithelial cells
resembling fibrohistiocytic neoplasms.Epithelial cells often
CD20+

26. Atypical type A thymoma
A new addition in the 4th edition is the delineation of an
“atypical type A thymoma variant” from conventional type
A thymomas .
The new term reflects the experience that rare type A
thymomas can show hypercellularity, increased mitotic
activity(>4/10hpf) and necrosis . Necrosis in particular
appears to correlate with advanced stage, including
metastasis.

29. THYMOMA Type AB
 DEFINITION: Is an thymic epithelial neoplasm composed of a
mixture of a lymphocyte-poor type A thymoma component & a more
lymphocyte-rich type B-like component
 SYNONYM : mixed type
 INCIDENCE : most common, mean age – 55 yrs, M>F
usually associated with MG/ pure red cell aplasia

30. Type AB thymoma

31. New criteria differentiating Type A versus
AB thymoma:
 The distinction between type A and AB thymoma has been
notoriously difficult.
 It is now stressed that both thymoma types share the occurrence
of bland-looking spindle epithelial cells and are distinguished
from each other by a low and high content of immature T cells,
respectively. Any lymphocyte-dense areas (with crowded TdT+
cells) or >10% tumor areas with a moderate infiltrate of
immature T cells should prompt classification as type AB
thymoma

33. THYMOMA Type B1
DEFINITION: Is a organotypic tumour which is histologically
indistinguishable from normal thymus, composed predominantly of
areas resembling cortex with epithelial cells scattered in a prominent
population of immature lymphocytes & areas of medullary
differentiation, with or without Hassall’s corpuscles
ORIGIN: from thymic epithelial cells capable of differentiating towards
both cortical & medullary types
SYNONYM: Lymphocyte-rich thymoma; lymphocytic thymoma;
organoid thymoma; predominantly cortical thymoma

34. GROSS: well circumscribed/ encapsulated, gray-white, thick fibrous capsule &
septae. C/S- areas of haemorrhage, necrosis & cystic spaces

37. THYMOMA Type B2
DEFINITION: Is a tumor made of large, polygonal tumour cells arranged in a loose network with
large vesicular nuclei & prominent large nucleoli closely resembling the normal thymic
cortex. A background population of immature T cells is always present and usually
outnumbers/ equals the neoplastic epithelial cells.
ORIGIN: from thymic epithelial cell capable of differentiation towards cortical type epithelial-
cell
SYNONYMS: Cortical thymoma
INCIDENCE: most cases are associated with MG
Medullary islands are missing/ inconspicuous
Typical Hassall´s corpuscles are exceptional findings

39. Type B1 and B2
 Type B1 and B2 thymomas are, by definition, both lymphocyte-rich tumors.
 The thymus-like architecture and cytology of B1 thymomas are highlighted as
obligatory criteria, including presence of medullary islands as a ‘must’, and
absence of epithelial cell clusters.
 Type B2 thymomas must show a higher than normal number of polygonal
(non-spindle) neoplastic epithelial cells that commonly occur in clusters
(defined as 3 or more contiguous epithelial cells).
 Medullary islands optionally occur in type B2 thymomas, while Hassall’s
corpuscles occur as optional feature commonly in type B1 and rarely in B2
thymomas

41. THYMOMA Type B3
DEFINITION: Is a thymic tumour predominantly composed of
medium–sized round or polygonal cells with slight atypia.
Epithelial cells are mixed with a minor component of
intraepithelial lymphocytes, resulting in a sheet-like growth of
epithelial cells
SYNONYMS: Well-differentiated thymic carcinoma, epithelial
thymoma; squamoid thymoma
INCIDENCE: 45-50 yrs, usually associated with MG

42. Type B3 thymoma

44. ORIGIN: from thymic epithelial cells capable of
differentiation towards a less differentiated cortical
type epithelial cells
COURSE : intermediate malignant, always invasive.
Mets + in 20% at presentation

45. Type B2 and B3 differentiation
 Because of the lack of distinguishing markers, the differential
diagnosis rests on the visual impression that type B2 thymomas
look blue on H&E staining (due to the presence of many
admixed lymphocytes), while type B3 thymomas look pink (due
to sheets of confluent tumor cells).

46. MICRONODULAR THYMOMA with LYMPHOID STROMA
DEFINITION: Is an organotypic thymic epithelial tumour
characterized by multiple, discrete epithelial nodules separated
by an abundant lymphocytic stroma that usually has prominent
germinal centres.
INCIDENCE: rare.

49. Metaplastic thymoma is composed of nests and strands of bland-appearing tumor
epithelial cells, some of which can contain nuclear
pseudoinclusions (D, right-hand side) and are surrounded by metaplastic spindle cells

50. Microscopic Thymoma
It defines an epithelial proliferation, with <1 mm in diameter, usually multifocal, that
preferentially occurs in patients suffering from myasthenia gravis without a
macroscopically evident tumour.

51. Sclerosing Thymoma Lipofibroadenoma

54. THYMIC CARCINOMA
Unique features are:
1. Rarely associated with MG/ other immune-
mediated diseases
2. Lack the ancillary/ organoid features of thymoma:
perivascular spaces , foci of medullary differenciation ,
abortive hassal’s corpuscle.
3. Lack immature T- lymphocytes
4. Usually metastasizes to lymphnode,bone,lung ,liver

55. Thymic carcinoma
Foci of necrosis

59.  IHC CD5 + thymic carcinoma. -ve in thymoma and non-
thymic origin carcinomas. Also positive for CD117,GLUT1
and MUC1

60. 1. SCC
Hallmarks for diagnosis:
 Clear-cut cytological atypia in the
large epithelial cells arranged in
nests and cords
 broad zone of fibrohyaline-stroma
separating the tumour cell nests
 FoxN1 and CD205 are novel
markers that complement CD5 and
CD117 as markers that are expressed
in most TSQCC

63.  Thymic carcinomas that were called “adenoid-cystic
carcinomas (ACC)” in the 3rd edition are now labelled
as ‘thymic carcinomas with adenoid cystic carcinoma-
like features’ in the 4th edition since they lack the
immunohistochemical features of true ACC in other
organs

64. Type B3 thymoma and Thymic squamous
cell carcinoma (TSQCC)
 Type B3 thymoma from TSQCC can be a challenge when rare tumors
with a type B3 thymoma morphology show focal expression of
“TSQCC-markers” (such as CD5 and CD117) and/or lack of “type B3
thymoma markers” (such as TdT+ T cells).
 In the 4th edition it is now stated that tumors that look like type B3
thymoma on H&E staining should be diagnosed as type B3 thymoma,
and tumors with TSQCC morphology should be labelled as TSQCC,
irrespective of immunohistochemistry.

65. Combined thymic carcinomas
 Combined thymic carcinomas was introduced for tumors that are either
composed of different types of thymic carcinomas (extremely rare), or of a
thymic carcinoma and any type of thymoma or carcinoid (rare).
 Heterogeneous thymic epithelial tumors with a small cell carcinoma
component or a large cell neuroendocrine carcinoma component are not
counted among the combined thymic carcinomas but among the
neuroendocrine carcinomas
 The reporting of a combined thymic carcinoma must start with the carcinoma
component irrespective of its proportion, followed by the thymoma
component. In case of two or more carcinoma components, the dominant
component is reported first.

66. THYMIC NEUROENDOCRINE TUMOURS
 The descriptive terms “well differentiated neuroendocrine carcinoma”
(referring to carcinoids) and “poorly differentiated neuroendocrine carcinoma”
(referrring to LCNEC and small cell carcinoma) of the 3rd edition were
abandoned, since LCNECs and even Small Cell Carcinoma may be highly
differentiated in terms of neuroendocrine features.
 Following the strategy in the lung, the 4th edition instead separates typical and
atypical carcinoids as low and intermediate grade neuroendocrine tumors,
respectively, from high grade neuroendocrine carcinomas that comprise
LCNEC and small cell carcinoma.

69. Fleshy appearance with vast areas of haemorrhage

70. Typical carcinoid

71. Atypical carcinoid

72. LCNEC

73. Small cell carcinoma

74. Conceptual continuity
 The definition of ‘neuroendocrine differentiation’ in the
carcinoids and large cell neuroendocrine carcinomas, i.e. strong
and diffuse expression of usually more than one of four
neuroendocrine marker (chromogranin A, synaptophysin, CD56
and NSE) in >50% of tumor cells has been maintained.
 As before, small cell carcinoma remains a histological diagnosis;
expression of neuroendocrine markers is often present but not
required.

75. TNM staging

77. Modified Masaoka Koga System

78. Thymic Adenocarcinomas
 Papillary adenocarcinomas of the thymus commonly
co-occur with type A and type AB thymomas and are
now defined as low-grade carcinomas, while high-
grade adenocarcinomas with (usually focal) papillary
growth are counted among the “adenocarcinomas,
NOS”

80. Enteric differentiation occurs in a subset of
mucinous carcinomas and
adenocarcinomas, NOS, and is currently of
unknown clinical significance. Such cases
require clinical staging to exclude metastasis
from a colorectal primary

81. NUT carcinoma:
 These highly aggressive cancers that were first observed as midline thoracic
tumors in children and young adults and harboured a unique t(15;19)-
translocation with generation of a BRD4-NUT fusion oncogene were called
‘carcinoma with t(15;19) translocation’ in the 3rd edition.
 These tumors are now known to occur at all ages, outside the thorax (and rarely
outside the midline) .Therefore, these tumors are now labelled NUT
carcinomas irrespective of anatomic location.
 IHC-NUT 1(speckled nuclear positivity),Pan CK ,EMA ,p63/p40 positive

84. Undifferentiated carcinoma:
 This tumor shows epithelial differentiation but is otherwise a diagnosis
of exclusion. Poorly differentiated squamous cell carcinoma,
lymphoepithelioma-like carcinoma, sarcomatoid carcinoma, NUT
carcinoma, small and large cell neuroendocrine carcinoma, and
adenocarcinoma of the thymus, germ cell tumor, extension from the
lung and metastasis must be excluded.
 By definition, immunohistochemical markers (e.g. CK5/6; p63, CD5)
of any of the aforementioned tumors are absent, but CD117 and PAX8
may be expressed.

87. Conclusion
 Refined diagnostic criteria for type A, AB, B1–B3 thymomas and
thymic squamous cell carcinoma are included in WHO 4th
edition and will hopefully improve the reproducibility of the
classification and its clinical relevance.
 In WHO 4th edition there is introduction of
immunohistochemical features and new genetic markers as
criteria for diagnosis of thymomas with ambiguous histology

88. References:
1. Travis, WD.; Brambilla, E.; Burke, AP., et al. WHO classification of tumours
of the lung, pleura, thymus and heart. IARC Press; 2015.
2. Marx A, Chan JK,Coindre JM, Detterbeck F,Girard N, Harris NL, Jaffe
E,Kurrer, Moreira AL, Mukai K, Orazi A, Ströbel P. The 2015 WHO
Classification of Tumors of the Thymus: Continuity and Changes. J Thorac
Oncol. 2015 October ; 10(10): 1383–1395.
3. Fletcher, CDM.; Bridge, JA.; Hogendorn, PCW., et al. WHO Classification of
tumours of soft tissue and bone. IARC Press; 2014.