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

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

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.

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

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

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

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

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

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 %)

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)

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)

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

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

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

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

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

B3: polygonal epithelial cells (arrows) with irregular nuclei

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

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).

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

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

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

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

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

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

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

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

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

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

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

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.

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

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

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)-

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

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

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

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

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

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

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

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

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

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

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

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

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