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Mediastinal Pathology Compartment Approach
1. Armed Forces Institute of Pathology
Mediastinal Pathology:
Compartmental Approach
Teri J. Franks, MD
Chairman
Department of Pulmonary and Mediastinal Pathology
2. Faculty Disclosure Information
At the time of the VTC, Teri J. Franks, MD had no significant financial interests
or relationships to disclose.
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Medical Education, the Department of Medical Education of The
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3. Main Topics
• Clinical features
• Organization of lesions
– Mediastinal anatomy
– Compartment approach
• Selected lesions
– Thymoma and thymic carcinoma
4. Mediastinal Lesions
Clinical features
• Uncommon, 1% of all tumors
• Infant to 83 years, mean 35.4 years
• No gender bias
• 60% benign, 40% malignant
• 60% symptomatic
– Chest pain, cough, dyspnea, dysphagia, superior vena cava syndrome
• 97% can be detected on PA and lateral chest radiographs
• Surgical resection
– Low operative morbidity and mortality
24. Thymus
• Thymic lesions dominant mediastinal pathology
– 50% of mediastinal lesions occur in the anterior compartment
– Major organ of the anterior mediastinum
28. Thymus
Location
• Anterior mediastinum
– Base rests on pericardium and
great vessels
– Upper poles extend along
trachea, attach to
corresponding lobe of thyroid
via thyrothymic ligament
29. Thymus
Gross
• X- or H-shaped
• Fibrous capsule
• Wide variation in weight
– Mainly related to age
– Affected by state of
health
– Average
• 15 grams at birth
• 30-40 grams at puberty
• 10-15 grams at 60 years
39. Tumors of the Thymus and Mediastinum
WHO Classification
• Epithelial tumors
• Germ cell tumors
• Lymphomas and hematopoietic neoplasms
• Mesenchymal tumors
• Rare tumors
• Metastasis
40. Tumors of the Thymus and Mediastinum
WHO Classification
• Epithelial tumors
– Thymoma
– Thymic carcinoma
• Germ cell tumors
• Lymphomas and hematopoietic neoplasms
• Mesenchymal tumors
• Rare tumors
• Metastasis
41. Thymoma and Thymic Carcinoma
Clinical features
• Uncommon
– Incidence of 1-5/million population/year
– Incidence has not changed significantly over past three decades
• Wide age range, 7-89 years
– Peak 55-65 years
– Rare in children and adolescents
• No gender bias
• Increased incidence of second cancers
– Irrespective of histologic type of thymic epithelial tumor
• Autoimmune disease
– MG: variable in thymoma (10-80%), rare in thymic carcinoma
– Other: common in thymoma, rare in thymic carcinoma
42. Thymoma and Thymic Carcinoma
• Thymomas
– Arise from thymic epithelial cells
– Exhibit organotypic (thymus-like) architectural features
• Lobular pattern, perivascular spaces, immature TdT/CD1a/CD99+ T-cells
– No, mild, or moderate atypia of epithelial cells
– CD5, CD70, CD117 negative epithelial cells
– Not observed in organs other than thymus
• Arise from heterotopic tissue in head, neck, mediastinum, pleura, lung
– Absent/low to moderate biologic potential
• Often curable by surgery
• Variable invasion, metastases rare
• Typically long survival due to indolent clinical course
43. • 33 year old male
• Three month history
– Cough
– Intermittent chest pain
44.
45. Thymoma
Gross
• Well-circumscribed, firm
• Up to 34 cm
• Fibrous capsule
• Pink-tan lobulated cut surface
46. Thymoma
Gross
• Well-circumscribed, firm
• Up to 34 cm
• Fibrous capsule
• Pink-tan lobulated cut surface
• Cystic change common
• Adherence to adjacent
structures
53. Thymoma
• Biphasic population
• Organotypic features
– Lobular pattern
– Perivascular spaces
• Longitudinal spaces
• Hyalinized
54. Thymoma
• Biphasic population
• Organotypic features
– Lobular pattern
– Perivascular spaces
– Immature T-cells
• TdT+/CD1a+/CD99+
55. Thymoma and Thymic Carcinoma
• Thymic carcinoma
– Arise from thymic epithelial cells
– No or abortive organotypic architectural features
– Clear-cut cytologic atypia
– Frequent CD5, CD70, CD117 expression in epithelial cells, ~ 60%
– Resemble carcinomas in other organs
– Malignant
• Often unresectable
• Almost always invasive, metastases frequent
• Short survival due to progressive disease
56. • 56 year old male
• Two month history
– Chest pain
– Cough
59. Thymic Carcinoma
Gross
• Firm, gritty, gray-white mass
• Usually lacks well-defined
capsule and fibrous bands
• Foci of hemorrhage and
necrosis
60. Thymic Carcinoma
Histology
• Loss of organotypic features
• Cytologically malignant
– High N:C ratio
– Cellular pleomorphism
– Nucleoli
– Mitoses
– Necrosis
63. Thymoma and Thymic Carcinoma
Classification
Bernatz Suster & Moran WHO WHO
1961 1999 1999 2004
Spindle cell Well-diff thymoma Type A Type A
- “ “ Type AB Type AB
Lymphocyte rich “ “ Type B1 Type B1
Mixed “ “ Type B2 Type B2
Epithelial rich Atypical thymoma Type B3 Type B3
- Thymic carcinoma Type C Thymic carcinoma
64. Tumors of the Thymus and Mediastinum
Epithelial tumors
• Epithelial tumors
– Thymoma
• Type A (spindle cell; medullary)
• Type AB (mixed)
• Type B1 (lymphocyte-rich; lymphocytic; predominantly cortical; organoid
• Type B2 (cortical)
• Type B3 (epithelial; atypical; squamoid; well-differentiated thymic ca)
• Rare thymomas
– Micronodular thymoma with lymphoid stroma
– Metaplastic
– Microscopic
– Sclerosing
– Lipofibroadenoma
65. Tumors of the Thymus and Mediastinum
Epithelial tumors
• Epithelial tumors
– Thymic carcinoma
• Squamous cell carcinoma
• Basaloid carcinoma
• Mucoepidermoid carcinoma
• Lymphoepithelial-like carcinoma
• Sarcomatoid carcinoma (carcinosarcoma)
• Clear cell carcinoma
• Adenocarcinoma
• Papillary adenocarcinoma
• Carcinoma with t(15;19) translocation
• Neuroendocrine carcinoma
– Typical and atypical carcinoid
– Large cell neuroendocrine and small cell carcinoma
• Undifferentiated carcinoma
• Combined thymic epithelial tumors
66. Thymoma and Thymic Carcinoma
Terms
• Encapsulated
– Completely surrounded by a fibrous capsule
• Minimally or microscopically invasive
– Invasive through the capsule to involve pericapsular tissue
• Usually identified only after microscopic examination
• Generally appears encapsulated to surgeon
• Widely invasive
– Spread by direct extension into adjacent structures
• Implants
– Nodules separate from main mass on pericardium or pleura
• Lymph node metastases
– Nodes separate from main mass, excludes direct extension into node
• With distant metastases
– Most commonly to lung, liver, skeletal system
67. Capsular Invasion
• Evaluation of capsule is
essential
– Ink margins
• Adherence to adjacent
structures
– Common
– Doesn’t always indicate true
invasion
72. Thymoma and Thymic Carcinoma
Principles of classification
• Thymoma
– Two major types
• Uniformly bland spindle or oval epithelial cells – Type A
• Predominantly round or polygonal epithelial cells – Type B
– Type B subdivided by extent of lymphoid infiltrates and cellular
atypia
• B1 – lymphocyte rich
• B2 and B3 – epithelial cell rich
– Type A plus B1-like, and rarely B2-like, are designated AB
• Thymic carcinoma
– Thymic carcinomas are termed according to differentiation
– Combined thymomas are termed by WHO histology and %
– “Malignant thymoma” is discouraged
75. Thymoma
Type A
• Lymphocyte poor
• Solid sheets
– No pattern or storiform
– Cysts
– Lobules and bands less
conspicuous than other types
76. Thymoma
Type A
• Lymphocyte poor
• Solid sheets
– No pattern or storiform
– Cysts
– Lobules and bands less
conspicuous than other types
• Spindle or oval epithelial cells
– Reticulin fibers surround cells
77. Thymoma
Type A
• Lymphocyte poor
• Solid sheets
– No pattern or storiform
– Cysts
– Lobules and bands less
conspicuous than other types
• Spindle or oval epithelial cells
– Reticulin fibers surround cells
• Bland nuclei
– Dispersed chromatin
– Inconspicuous nucleoli
80. Thymoma
Type AB
• Mixture of Type A and Type B
– Discrete separate nodules or
– Intermixed A and B
• Type B epithelial cells
– Small polygonal
– Dispersed chromatin
– Inconspicuous nucleoli
81. Thymoma
Type AB
• Mixture of Type A and Type B
– Discrete separate nodules or
– Intermixed A and B
• Type B epithelial cells
– Small polygonal
– Dispersed chromatin
– Inconspicuous nucleoli
• B areas
– Medullary differentiation rare
– Hassall corpuscles absent
– Reticulin around B nodules
• Not around individual cells
84. Thymoma
Type B1
• Resembles cortex
• Scant small epithelial cells
– Pale nuclei
– Small nucleoli
• Dispersed epithelial cells
– Do not from groupings
85. Thymoma
Type B1
• Resembles cortex
• Scant small epithelial cells
– Pale nuclei
– Small nucleoli
• Dispersed epithelial cells
– Do not from groupings
• Medullary differentiation
always present
86. Thymoma
Type B1
• Resembles cortex
• Dispersed epithelial cells
– Do not from groupings
• Scant small epithelial cells
– Pale nuclei
– Small nucleoli
• Medullary differentiation
always present
• Hassall corpuscles may be
present
92. Thymoma
Type B3
• Lobules with thick septa
• Paucity of lymphoctyes
– Results in sheet-like growth
– Solid or epidermoid pattern
• No intercellular bridges
93. Thymoma
Type B3
• Lobules with thick septa
• Paucity of lymphoctyes
– Results in sheet-like growth
– Solid or epidermoid pattern
• No intercellular bridges
• Medium-size epithelial cells
– Small nucleoli
– Often grooved nuclei
94. Thymoma
Type B3
• Lobules with thick septa
• Paucity of lymphoctyes
– Results in sheet-like growth
– Solid or epidermoid pattern
• No intercellular bridges
• Medium-size epithelial cells
– Small nucleoli
– Often grooved nuclei
• Perivascular palisading
95. Thymoma
Type B3
• Lobules with thick septa
• Paucity of lymphoctyes
– Results in sheet-like growth
– Solid or epidermoid pattern
• No intercellular bridges
• Medium-size epithelial cells
– Small nucleoli
– Often grooved nuclei
• Perivascular palisading
• Foci of keratinization
– Mimicking Hassall corpuscles
• Medullary differentiation
usually absent
99. Thymoma and Thymic Carcinoma
Prevalence of subtypes
• AB – 20-35%
• B2 – 20-35%
• A – 5-10%
• B1 – 5-10%
• Thymic carcinoma 10-25%
100. Thymoma and Thymic Carcinoma
Spectrum of Malignancy
• Thymoma
– Type A
– Type AB
– Type B1
– Type B2
– Type B3
• Thymic carcinoids
• Thymic carcinoma
– Squamous cell, basaloid, mucoepidermoid
– Other subtypes
• Small cell and large cell neuroendocrine
101. Thymoma and Thymic Carcinoma
Prognosis
• Most important prognostic factors
– Tumor stage
• Masaoka stage is the most important and statistically most significant
independent prognostic indicator of survival in most studies
– WHO histologic type
– Completeness of resection
102. Thymoma and Thymic Carcinoma
Prognosis
Histology Stage Biologic Potential
A, AB, B1 l and ll None/very low
lll Low
B2, B3 l Low
ll and lll Moderate
Squam, basaloid, l and ll Moderate
mucoep, carcinoid lll High
Other histology Any High
103. Staging
TNM
• T1 – tumor completely encapsulated
• T2 – tumor invades pericapsular connective tissue
• T3 – tumor invades into neighboring structures, such as
pericardium, mediastinal pleura, thoracic wall, great vessels
and lung
• T4 – tumor with pleural or pericardial dissemination
• Currently no authorized TNM system for thymic epithelial or
neuroendocrine tumors
104. Staging
Modified Masaoka
• Stage 1: intact capsule or growth within capsule
• Stage 2a: microscopic invasion through capsule
2b: gross and microscopic invasion
• Stage 3: invasion into surrounding structures
• Stage 4a: pleural or pericardial dissemination
4b: lymphatic or hematogenous metastases
105. Thymoma and Thymic Carcinoma
Diagnosis
• Thymoma
– Encapsulated
– Invasive (term malignant thymoma is discourage)
• Surgical pathology report
– Correct diagnosis
• Up to 20% in some studies incorrectly diagnosed
– Assessment of surgical margins
• Requires inking
– Determination of invasiveness
• Multiple sections through capsule
106. Thymoma and Thymic Carcinoma
Diagnosis
• Thymic carcinoma
– Separation from metastatic carcinoma may be difficult
• Lung, thyroid, breast, prostate are most common
– May only be able to suggest or favor diagnosis
• Clinical history and radiologic studies are essential
107. Thymoma and Thymic Carcinoma
Diagnosis
Tumor Thymic primary Lung or head/neck
Squamous, basaloid,
Lobular growth 70% Lobular growth rare
lympho-epi ca
Perivascular spaces 50% Perivascular spaces rare
CD5 50% CD5 not expressed
CD70 50% CD70 not expressed
CD117 40-100% CD117 not expressed
NE carcinoma TTF-1 absent TTF-1 frequent (lung)
108. Tumors of the Thymus and Mediastinum
WHO Classification
• Epithelial tumors
• Germ cell tumors
– 2003 WHO Classification of Germ Cell Tumors
• Teratoma
• Seminoma
• Lymphomas and hematopoietic neoplasms
• Mesenchymal tumors
• Rare tumors
• Metastasis
109. Tumors of the Thymus and Mediastinum
WHO Classification
• Epithelial tumors
• Germ cell tumors
• Lymphomas and hematopoietic neoplasms
– 2001 WHO Classification of Hematopoietic and Lymphoid Tumors
• NS Classical HL
• PMLB-CL
• T-lymphoblastic leukemia/lymphoma
• MALT lymphoma
• Mesenchymal tumors
• Rare tumors
• Metastasis
110. Tumors of the Thymus and Mediastinum
WHO Classification
• Epithelial tumors
• Germ cell tumors
• Lymphomas and hematopoietic neoplasms
• Mesenchymal tumors
– 2000 WHO Classification of Nervous System
• Schwannoma
– 2002 WHO Classification of Soft Tissue and Bone
• Thymolipoma
• Rare tumors
• Metastasis
111. Tumors of the Thymus and Mediastinum
WHO Classification
• Epithelial tumors
• Germ cell tumors
• Lymphomas and hematopoietic neoplasms
• Mesenchymal tumors
• Rare tumors
– Ectopic tumors of the thymus
• Ectopic thyroid tumors
• Ectopic parathyroid tumors
• Metastasis
112. Rare Tumors
Ectopic tumors
• Uncommon, benign or
malignant
• Anterior or posterior
compartment
• Thyroid
– Extension from neck or
ectopic tissue
• Parathyroid
– Found adjacent to or within
thymus
113. Tumors of the Thymus and Mediastinum
WHO Classification
• Epithelial tumors
• Germ cell tumors
• Lymphomas and hematopoietic neoplasms
• Mesenchymal tumors
• Rare tumors
• Metastasis
– Thymus and anterior (middle) mediastinum
• Lung, thyroid, breast, prostate are most common
114. Mediastinal Pathology
Summary
• Three compartments
• Mediastinal lesions
– 50% of lesions
• Anterior compartment
– Thymic lesions dominate
– Organization by compartment