1. Pathology of Mediastinal tumors (MT) Dr F.Hajmanoochehri 93/10/25

2. introduction
Appropriate therapy for various mediastinal tumors differs considerably according to the histological type and it may significantly impact on survival
minimally invasive sampling is usually to establish a
tumor as a thymic epithelial tumor and therefore a candidate for resection, as opposed to a lymphoma in which surgical resection is not indicated

3. MT : a Challenge in surgical pathology
many different types of lesions and overlapping histologic features
difficulty in obtaining good biopsies &may be non-diagnostic because: not adequate sample , crush artifact , extensive necrosis, fibrosis, or cystic change
overlapping histologic features E.g : Differentiation between thymoma, neuroblastoma, seminoma, metastatic small cell carcinoma and lymphoma
It needs significant experience with mediastinal pathology because specimens from this location are relatively uncommon.

4. Anatomic Distribution of Mediastinal Masses
C t,p: cysts, thymic and parathyroid; C p,b: cysts, pericardical and bronchogenic; C g: cysts, gastroenteric;
GV: germ cell and vasular tumors

6. Thymoma
defined as a low-grade epithelial neoplasm arising in the thymus
Most common primary anterior (anterosuperior )mediastinal tumor, also the mediastinum, the neck, pulmonary hilum, thyroid gland, lung, or pleura
most common cause of a thymic mass
M=F, most >40
Most patients are asymptomatic
Although they may seed the pleural space, pleural effusions are rare
Lymphatic and hematogenous metastases are rare
Up to 1/3 are invasive into mediastinal fat, pleura, pericardium, great vessels, heart and lung
from radio
1/3 have chest pain, cough or dyspnea on presentation
Myasthenia gravis occurs in 30-50% of pts with thymoma. All pts should have antiacetylcholine receptor antibodies measured prior to surgery and subsequently
Hypogammaglobulinemia occurs in 10% of pts with thymoma
Pure red cell aplasia occurs in 5%, but thymoma occurs in 50% of pts with red cell aplasia

7. Thymoma & parathymic syndromes
Half of patients suffer have associated parathymic syndromes
myasthenia gravis
hypogammaglobulinemia
pure red cell aplasia
30-45% of pts with thymoma have MG
10% of pts with MG have a thymoma
65% of pts with MG have thymic follicular hyperplasia
25% of pts with MG have normal thymuses

9. Gross features encapsulated, circumscribed, tan, firm lobulated masses
from microscopic to over 30 cm
cut surface:, bands of fibrous stroma
Cystic changes may be extensive, and in such cases, the cyst wall should be sampled carefully to search for tumor foci

10. Morphology a fibrous capsule (may be calcified)
typical low power : thick collagen bands connected to the capsule divide the tumor into multiple lobules of varying size
mixture of neoplastic epithelial cells and non-neoplastic T lymphocytes, admixed in varying proportions
epithelial component :
two type :the polygonal, round, or oval cell type, or the spindle cell type

12. Morphology
characteristic feature (in 70 %) :Prominent, dilated perivascular spaces filled by plasma fluid and may contain a few lymphocytes, plasma cells, or foamy macrophages
Small vessels with hyalinized walls are often present in the center of these spaces. Neoplastic cells surrounding these spaces may show a palisading arrangement.
Hassall's corpuscles (14 %), cystic change (19 %), a "starry-sky" pattern, and squamous differentiation (10 %)

13. Morphology storiform pattern (like in fibrous histiocytoma)
staghorn-shaped vessels (resembling solitary fibrous tumors)
rosettes (similar neuroendocrine tumors )
gland-like structures, or a papillary growth pattern
Prominent plasma cell infiltrates
microcystic patterns
prominent myoid cells (rhabdomyomatous thymoma)

16. benign (noninvasive) from malignant
(invasive) thymomas. Malignant thymomas were further subdivided
into category I (with no or minimal atypia) and category
II (showing moderate to marked atypia)

17. Prevalence &Prognostic Features of Subtypes
Type B2 and AB (each 20% to 35%).
Type B1 ,B3 and Type A rare (5% to 10%)
Type C 10% to 25%.
Prognosis :
(most relevant are :tumor stage, WHO-based histologic type, resection status)
Type A and AB thymomas in stages I and II almost always follow a benign clinical course
Type B1 :low malignant potential(local recurrences or metastases may occur >20 yrs
Type B2, B3, and C thymomas are clear-cut malignant
tumors

18. A: spindle epithelial cells (arrows) with lymphocytes (arrowheads)

19. AB: A (asterisk) and B (star) type lobules

20. B1: immature T cells (arrows), epithelial tumor cells with large nuclei (arrowheads)

21. B2: abundant epithelial cells with irregular nuclei (arrowheads) and fewer lymphocytes (arrows) than B1

22. B3: polygonal epithelial cells (arrows) with irregular nuclei

23. Prognostic factors
multifactorial but invasion is most important factor
the best determination of invasive is by the surgeon at the time of operation(better than CT imaging )
capsular invasion : Inking of the tumor capsule at the time of gross evaluation
adherent to adjacent structures without invasion: surgeon should designate the site of adhesion on the specimen, so the pathologist can take careful sections from that area. An inflammatory fibrous reaction can also lead to the false impression of tumor invasion.
completeness of resection

25. A, Spindle cell thymoma infiltrating skeletal muscle (H&E, ×10)
A, Spindle cell thymoma infiltrating skeletal muscle (H&E, ×10). B, Spindle cell thymoma infiltrating lung parenchyma (H&E, ×10).

26. staging purposes
thymomas can be divided into encapsulated, invasive, or metastatic tumors
Invasion :grossly or microscopically.
invasion needs to be transcapsular with microscopic invasion into adjacent mediastinal tissue before it impacts upon outcome

28. Differential Diagnosis of thymoma
1- malignant lymphomas : if thymoma was predominantly lymphocytic (>2/3) ( epithelial cells are inconspicuous )
Recommendation: use of keratin stains
2-thymic carcinomas , S.C.C , metastatic :when Predominantly epithelial thymomas

29. Thymic carcinoma & thymoma
may be found synchronously or carcinoma may develop within a preexisting thymoma after an interval of 10 to 14 years but mostly de novo
distinctive morphology and biology
TC :highly atypical cells with cytoarchitectural features of carcinoma similar to those seen in other organs ;lack encapsulation, presence of invasion and metastasis, frequent areas of cystic change and necrosis ,encapsulated ( 15 %), mucoid cut surface (MEC)
many lymphocytes can be seen in TC stroma (B cell type and mature T cell type but no immature T cell )
fail to recapitulate features of normal thymus, such as medullary differentiation
Carcinomas express CD5, unlike Type A, AB, and B thymomas

30. Thymic carcinomas subtypes
low-grade (W.D) and high-grade (P.D)
well-differentiated tumors :
squamous cell carcinomas(most), mucoepidermoid carcinomas (W.D) and basaloid carcinomas.
High-grade tumors :
lymphoepithelial-like carcinomas (non-keratinizing squamous cell carcinomas)(most), mucoepidermoid carcinoma(P.D), clear cell carcinoma, sarcomatoid carcinoma, and anaplastic/undifferentiated carcinoma

31. well-differentiated thymic carcinoma
controversial :Many of these =epithelial-predominant thymoma in traditional classification. According to WHO : is classified among thymomas rather than thymic carcinomas.
considerable overlap with epithelial-predominant thymoma because :
1- The high frequency of myasthenia gravis
2-excellent survival in patients

33. thymic carcinoma. A, Squamous cell carcinoma with B, High-grade undifferentiated carcinoma C, Lymphoepithelioma-like carcinoma D, Spindle cell (sarcomatoid) carcinoma showing fusiform cells arranged in intersecting fascicles

34. E, Mucinous adenocarcinoma F, papillary carcinoma
E, Mucinous adenocarcinoma F, papillary carcinoma. G, clear cell carcinoma. H, Rhabdoid carcinoma featuring cells with rhabdoid cytoplasmic inclusions. I, Anaplastic carcinoma with

35. Thymic carcinoma VS thymoma
Macroscopicaly : large, firm, infiltrating masses, with frequent areas of cystic change and necrosis ,encapsulated ( 15 %), mucoid cut surface (MEC), Multilocular thymic cysts
thymic carcinoma aganist thymoma :
no paraneoplastic syndromes.
no immature T lymphocytic ( but B lymphocytes, plasma cells, or mature T lymphocytes )
No lobulated pattern separated by thick fibrous bands (instead it has a desmoplastic stroma)
No characteristic histologic features : perivascular spaces, medullary differentiation, and Hassall's corpuscles

36. Thymic carcinoma VS metastatic carcinoma
no histologicaly pathognomonic features
exceptions :
obvious transition (eg, from preexisting thymic epithelium)
some special variant :basaloid carcinoma with cystic changes, carcinoma with rhabdomyomatous cells
Primary thymic carcinomas are rare,
clinical evaluation : search for a primary tumor, especially lung cancer
IHC study

37. immunohistochemical studies
CD5: 80% Positive in thymic carcinomas, Negative in : thymoma (B3) and Met.
C-kit (CD117) :
GluT-1 :
TTF-1 : Positive in Lung cancer , Negative in Thymic cancer
A high frequency of p53 protein expression has been reported in thymic carcinoma but not in thymoma,
Bcl2 and P53 are signs for more clinically agrassiveness

38. Prognostic implications of histology
low-grade vs high-grade tumors .
Squamous cell carcinoma also may have a better prognosis
Morphologic worse prognosis :
infiltrative tumor margin,
absence of a lobular growth pattern,
high grade nuclear atypia
Necrosis
>10 mitoses / 10 HPF

39. NEUROENDOCRINE TUMORS(NET)
1-well-differentiated NETs :
a-typical carcinoid b- atypical carcinoid (necrosis and the proliferative rate )
2-poorly-differentiated carcinomas (small cell ,and large cell variants).
The histological criteria similar to pulmonary neuroendocrine tumors.

40. Thymic carcinoid uncommon neoplasm (2 % mediastinal & 5 % thymic )
in adults, mean age =50 yrs , male preponderance.
Rarely associated with carcinoid syndrome
Associated endocrine abnormalities: Cushing’s syndrome due to ectopic ACTH or MEN(25 %)
vary in size from 1 to 18 cm
well-circumscribed or encapsulated tumors
solid, gray tan with frequent areas of hemorrhage and necrosis
Microscopy :organoid nests, trabeculae, rosettes, or palisading , homogeneous cytologic features with finely granular nuclear

42. Small cell neuroendocrine carcinoma
rarely occur as a primary thymic lesion.
similar morphologically to its counterpart in the lung.
Immunohistochemistry : keratin , neuroendocrine markers (chromogranin, CD56, or synaptophysin )
electron microscopy :dense core granules

43. GERM CELL TUMORS 
1-isolated metastases from occult primary gonadal neoplasms
2- true extragonadal origin has (most mediastinal GCT) :In primary form :Thymic origin? : PLAP positive cells in normal thymus support
20% of mediastinal tumor , mostly anterosuperior
Account for up to 10% of all germ cell tumors in men
Usually occur in young adults particularly in men
typically spread via lymphatics but can metastasize anywhere, especially choriocarcinoma
serum AFP (yolk sac tumour) and HCG (choriocarcinoma)
Associated with hematologic disorders, (M7,MDS)
presence of placental-like alkaline phosphatase (PLAP)-

44. Mediastinal Germ Cell Tumors
Teratoma :
Most common type,Occurs in children and young adults,Usually asymptomatic, but if large enough : symptoms of mediastinal compression
Mature: benign, well-differentiated
Immature: contains >50% immature components, may recur or metastasize
Malignant: a mature teratoma that contains a focus of carcinoma, sarcoma or malignant GCT
Seminoma;
Represents 40% of GCTs, alomstly in thymus,
Nonseminomatous Germ Cell
Embryonal cell carcinoma
Endodermal sinus tumor
Choriocarcinoma
Malignant teratoma
Mixed
radioHistologic subtypes: similar to those that occur in the testis and ovary
Occurs in children and young adults
Usually asymptomatic, but if large enough, may cause chest pain, dyspnea, cough or other symptoms of mediastinal compression
Contains derivatives of all three primitive germ layers including
Ectoderm: teeth, skin, hair
Mesoderm: cartilage and bone
Endoderm: bronchial, intestinal and pancreatic tissue
Expectoration of hair (trichoptysis) is rare but pathognomonic
Surgical excision is curative
Seminoma :AFP normal, -HCG may be elevated in 10%, Usually not invasive, but many have metastasized to regional lymph nodes, lung and/or bone by the time of diagnosis
20% of patients also have Klinefelter’s syndrome

45. Lymphadenopathy most common cause of mediastinal masses
Causes: depending on the patient (age, medical history etc) and the clinical setting :
metastatic carcinoma, especially lung cancer
lymphoma
infectious/inflammatory conditions, especially granulomatous process such as tuberculosis, histoplasmosis (or other fungal infections depending on the geographic location) and sarcoidosis

46. lymphoma Most types can involve the mediastinum
the commonest as a mediastinal mass are:
1. Nodular sclerosis Hodgkin's disease: classically in young women
2. Lymphoblastic lymphoma( Lymphoblastic leukemia/lymphoma) : occurs in children, can grow very rapidly
3. Diffuse large cell: can occur at any age
4-Low-grade B-cell lymphomas of the thymus are rare, most common type :MALT type

47. Primary Mediastinal Hodgkin’s Lymphoma
Presentation
Incidental mediastinal mass on chest xray is common presentation
Mass is usually large, (may be cystic)rarely causes retrosternal chest pain, cough, dyspnea, effusions or SVC syndrome
“B” symptoms,Generalized pruritus
prominent mixed inflammatory background, often rich in eosinophils and neutrophils
neoplastic cells in HL are CD30 and usually CD15 positive and are negative for CD45 and CD20
DDX; Large B cell lymphoma
Radio

48. Lymphoblastic Lymphoma
1st/2nd decade, M>F
Aggressive, high grade
Often present as a rapidly enlarging mediastinal mass which may cause compression of mediastinal contents
Morphologicaly Similar to ALL(may be the initial clinical presentation)
are usually, and in the thymus are nearly exclusively, of T-cell lineage
resemble cortical thymocytes morphologically and immunophenotypically (double CD4+ 8+,CD1a+, TdT+)
Unlike normal thymus or type B 1 thymomas: infiltrate the fat and form solid sheets rather than lobules
radio

49. Primary Mediastinal large cell Lymphoma
3rd decade, F>M,.
Presents as a rapidly expanding mediastinal mass which may invade the airway, chest wall and/or adjacent structures (superior venacava syn.)
Extrathoracic involvement is uncommon
Mostly B cell , positive for B-cell markers such as CD20, CD30, CD 45, and are negative for cytokeratin
DDx : perivascular position thymoma (B2), entrapment of normal thymus tissue (thymoma), artifactual cytoplasmic clearning (seminoma )
radio

50. Flow cytometry :
distinguishing low-grade B-cell lymphomas vs reactive lymphoid proliferations
gene rearrangement studies on frozen tissue
Distinguishing MLBCL from Hodgkin lymphoma in difficult cases
cytogenetics
unusual types of thymic carcinoma

51. mesenchymal tumours rare mediastinal neoplasms (< 2 %)
Lymphangioma, Hemangima, lipomas,…
anywhere ,but most common in anterior part
sarcomas are distinctly uncommon

52. Mediastinal Goiter
The inferior poles of the thyroid normally lie superior to the thoracic inlet
Growth through the thoracic inlet can produce symptoms related to compression of normal thoracic inlet contents
Pathology
Most are benign
Multinodular goiter and large follicular adenoma account for 95%
Large multinodular goiters have little functioning tissue. Usually have cystic degeneration, fibrosis, calcification, hemorrhage
Many are found to have areas of papillary thyroid cancer
radio

53. PARATHYROID MASSES
Ectopic parathyroid tissue is not uncommonly found adjacent to the thymus gland
mediastinum :most common location for ectopic parathyroid adenomas

54. Neurogenic tumours 19 to 39 %of all mediastinal tumors
most common cause of a posterior Med.mass, rarely arise elsewhere
Mostly benign, malignant ones generally occurring in younger patients
can cause neurologic symptoms by compression(Pancoast syndrome, and Horner's syndrome)
They are classified as
1-Tumours of sympathetic nervous system
i) neuroblastoma - rare, malignant, occur in those under age 10 usually
ii) ganglioneuroblastoma - more common, intermediate prognosis
iii) ganglioneuroma - most common, benign, can occur in young adults
2. Tumours of peripheral nerve and nerve sheath
i) schwannoma most common of all mediastinal neurogenic tumours, third and fourth decade
ii) neurofibroma - may be associated with Von Recklinghausen's disease
iii) malignant nerve sheath tumours / schwannomas - very rare

55. MEDIASTINAL CYSTS Mostly developmental
benign and incidental on imaging.
Note : variety of thymic tumors, such as Hodgkin lymphoma,germ cell tumors, and, rarely, thymomas and thymic carcinomas,may present as a thymic ‘cyst’.
The most common types :
Anterior: thymic, cystic thymoma, parathyroid, lymphangioma, cystic teratoma
Middle: pericardial, bronchogenic (the most common congenital mediastinal cyst)
Posterior: gastroenteric

56. SUMMARY
  Interpretation of pathologic specimens from the mediastinum requires familiarity with a wide range of neoplasms and careful clinical correlation. It is critical for surgeons, radiologists, and pathologists to communicate well.
If tumors originally treated by non surgical means do not respond as expected, additional biopsies, special studies, or consultations may be necessary to achieve the correct diagnosis