Anterior Mediastinal Masses November 30, 2004 Neil J. Fernandes, M.D.

Anatomy of the Mediastinum Boundaries Superior- Thoracic inlet Inferior- Diaphragm Anterior- Sternum Posterior- Vertebral bodies Lateral- Pleura

Anatomy of the Mediastinum Compartments Anterosuperior: anterior to the pericardium, extends superiorly to the thoracic inlet Middle: bounded by the pericardium and the diaphragm Posterior: pericardial reflection to the posterior border of the vertebral bodies, diaphragm to first rib

Anatomy of the Mediastinum

Anatomy of the Mediastinum Normal Contents Anterosuperior: thymus, extrapericardial aorta and branches, IVC, SVC, lymphatic tissue Middle: heart, intrapericardial great vessels, pulmonary hila, pericardium, trachea Posterior: esophagus, vagus nerves, thoracic duct, sympathetic chain, descending thoracic aorta, azygous venous system

Mediastinal Masses Compartment % Malignant Anterosuperior 59 Middle 29 Posterior 16

Anterosuperior Masses Thymus Mediastinal Lymphoma Germ Cell Tumor Thyroid/Parathyroid

Thymus Thymoma Thymic carcinoma Thymic carcinoid Thymolipoma

Thymoma Presentation Most common primary anterior mediastinal tumor M=F, most >40 Most patients are asymptomatic Half of patients suffer have associated parathymic syndromes myasthenia gravis hypogammaglobulinemia pure red cell aplasia 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 Pathology Histologically benign lymphoepithelial neoplasms Solid, surrounded by a fibrous capsule Up to 1/3 have necrosis, hemorrhage or cysts Up to 1/3 are invasive into mediastinal fat, pleura, pericardium, great vessels, heart and lung Although they may seed the pleural space, pleural effusions are rare Lymphatic and hematogenous metastases are rare

Thymoma Radiology Well-defined, rounded/lobular, mass arising from the thymus May give rise to pleural implants, rarely associated with effusions CT evaluation should evaluate the lung apices through the diaphragm to evaluate for vascular invasion and to rule out intrathoracic metastases The thymus is normally located at the level of the aortic root

Thymoma Treatment Complete surgical excision if possible Histologic evidence of tumor cells outside the capsule defines invasive thymoma XRT for incompletely resected or invasive tumor Chemotherapy has been attempted for metastatic or recurrent thymoma with cisplatin, doxorubicin and cyclophosphamide. In one study of 29 patients there were 3 CR, 12 PR and a median 5 year survival of 30% 5 year survival 10 year survival Encapsulated 75% 63% Invasive 50% 30%

Thymic Carcinoma Presentation M>F, 40s Pathology Cytologic features of malignancy Early local invasion, widespread lymphatic and hematogenous metastases Radiology Large, poorly defined, infiltrative, associated with pleural and pericardial effusions Pleural implants are uncommon Treatment Etoposide/cisplatin + XRT 5-year survival ranges from 15% to 90% depending on grade

Thymic Carcinoid Presentation Men, 4th/5th decade Rarely associated with carcinoid syndrome Associated endocrine abnormalities: Cushing’s syndrome due to ectopic ACTH or MEN 73% have regional lymph node and/or distant osteoblastic bone mets Pathology Histologically identical to carcinoid tumor at other sites Radiology Vascular, large, lobulated, invasive May have areas of hemorrhage and necrosis Punctate, dystrophic calcification Treatment Complete surgical excision Local invasion, mets to regional lymph nodes and distant mets have been treated with chemotherapy and XRT, but with poor results

Thymolipoma Presentation M=F, occurs over a wide age range, median age 27 Most are asymptomatic Pathology Mature adipose cells and thymic tissue Radiology Large, soft, encapsulated May fall into the anteroinferior mediastinum mimicking cardiomegaly or elevated hemidiaphragm CT demonstrates a combination of fat and soft tissue densities within an encapsulated mass Treatment Surgical excision curative

Anterosuperior Masses Thymus Thymoma Thymic carcinoma Thymic carcinoid Thymolipoma Mediastinal Lymphoma Germ Cell Tumor Thyroid/Parathyroid

Primary Mediastinal Lymphoma 5-10% of patients with lymphoma present with primary mediastinal lesions Primary mediastinal lymphoma represents 10-20% of primary mediastinal masses in adults and are usually in the anterosuperior compartment Usually present with fever, weight loss and night sweats Pain, dyspnea, stridor, SVC syndrome due to mass effects are uncommon

Primary Mediastinal Lymphoma Two Types Primary Mediastinal Hodgkin’s Lymphoma Primary Mediastinal Non-Hodgkin’s Lymphoma Poorly differentiated lymphoblastic Diffuse lymphocytic Primary Mediastinal B-cell Lymphoma

Primary Mediastinal Hodgkin’s Lymphoma Presentation Incidental mediastinal mass on chest xray is the 2nd most common presentation after asymptomatic lymphadenopathy Mass is usually large, rarely causes retrosternal chest pain, cough, dyspnea, effusions or SVC syndrome Bimodal age distribution maintained, however, first peak is larger in patients with mediastinal involvement “B” symptoms: fever, weight loss (>10% body wt in 6 months), night sweats Generalized pruritus may precede the diagnosis by up to a year and, if severe, is a negative prognostic indicator EtOH-induced pain, most common in nodular sclerosing subtype

Primary Mediastinal Hodgkin’s Lymphoma Radiology Multiple rounded masses (lymph nodes) Mediastinal nodal groups: prevascular, aortopulmonary, paratracheal, pretracheal, subcarinal, posterior mediastinal Hilar nodes are considered separately Dominant mass (nodal coalescence) Thymic mass May be associated with infiltration and displacement of mediastinal structures and/or extranodal extension into the sternum, chest wall, pleura, pericardium or lung Usually homogenous attenuation on CT, but large masses may have necrosis, hemorrhage or cysts

Loss of paratracheal stripe

Anterior mediastinal and parahilar masses

Single node region/lymphoid structure or extralymphatic site Modified Ann Arbor Staging for Hodgkin’s Lymphoma Definition Treatment Cure 1 Single node region/lymphoid structure or extralymphatic site XRT >90% 2 ≥2 node regions and/or extranodal organs on the same side of the diaphragm 90% 3 Node regions on both sides of the diaphragm and/or splenic involvement or contiguous involvement of an extranodal site Chemo A: 80-90% B: 60-70% 4 Diffuse or disseminated involvement of extranodal organs/tissues +/- node involvement 50-60%

Primary Mediastinal Non-Hodgkin’s Lymphoma Lymphocytic Lymphoma Median age at presentation is 55, slight male predominance Advanced disease at presentation with constitutional symptoms, generalized lymphadenopathy +/- extranodal disease

Primary Mediastinal Non-Hodgkin’s Lymphoma 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 Similar to ALL

Primary Mediastinal Non-Hodgkin’s Lymphoma Primary Mediastinal B-cell Lymphoma 3rd decade, F>M Presents as a rapidly expanding mediastinal mass which may invade the airway, chest wall and/or adjacent structures. Extrathoracic involvement is uncommon Originally classified as a separate category due to its poor prognosis

Anterosuperior Masses Thymus Thymoma Thymic carcinoma Thymic carcinoid Thymolipoma Mediastinal Lymphoma Hodgkin’s Lymphoma Non-Hodgkin’s Lymphoma Poorly differentiated lymphoblastic Diffuse lymphocytic Primary Mediastinal B-cell Lymphoma Germ Cell Tumor Thyroid/Parathyroid

Mediastinal Germ Cell Tumors Represent 10-15% of adult anterosuperior mediastinal tumors Account for up to 10% of all germ cell tumors in men Arise from primordial germ cells which are displaced during embryogenesis as they migrate along the dorsal mesentery to the genital ridges Usually occur in young adults, median age 27

Mediastinal Germ Cell Tumors Three types Teratoma Seminoma Nonseminomatous Germ Cell Tumor

Mediastinal Teratomas Most common mediastinal germ cell tumor Three types: 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

Mature Teratoma 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

Mature Teratoma Radiology Large Rounded to lobulated, well-defined Protrude to one side 26% include calcifications On CT, multilocular/cystic with fluid, soft tissue, calcium and fat densities

Immature Teratoma Rare Similar presentation to mature teratomas Composed of at least 2 out of 3 germinal layers and >50% immature elements Treated with radical resection The roles of neoadjuvant and/or adjuvant chemotherapy are undefined

Mediastinal Seminoma General Represents 40% of malignant mediastinal GCTs Afflicts Caucasian men in 20s-30s Only rarely represents a metastatic lesion from a testicular primary tumor, but testicular US is usually performed to rule this out If any other germ cell tumor histology is identified in the tumor, it is treated as a mixed NSGCT AFP normal, -HCG may be elevated in 10%

Mediastinal Seminoma Presentation Slow growing tumor, usually symptomatic at diagnosis Commonly presents with chest pain, dyspnea, cough, weight loss Presents infrequently with SVC syndrome Bulky, lobulated, homogeneous mass, no calcifications Usually not invasive, but many have metastasized to regional lymph nodes, lung and/or bone by the time of diagnosis

Mediastinal Seminoma Treatment Chemo and XRT sensitive tumors Small tumors are treated with primary resection followed by XRT Advanced tumors are treated with XRT and/or four cycles of bleomycin, etoposide and cisplatin Treatment followed by surveillance of residual tumor < 3 cm. or resection of residual tumor > 3 cm. Long-term survival is 60-80%

Mediastinal Nonseminomatous Germ Cell Tumors Five Types Embryonal cell carcinoma Endodermal sinus tumor: elevated AFP Choriocarcinoma: elevated -HCG Malignant Teratoma Mixed

Mediastinal Nonseminomatous Germ Cell Tumors NSGCTs of the mediastinum have a worse prognosis than mediastinal seminomas or teratomas Occur in men in the 20-40 age group 20% of patients also have Klinefelter’s syndrome Also associated with i(12p)

Mediastinal Nonseminomatous Germ Cell Tumors Associated with hematologic disorders, including, Megakaryoblastic leukemia Myelodysplasia Malignant mastocytosis Malignant histiocytosis Malignant hematologic cells often have the same i(12p) lesion identified in the mediastinal tumor Occasionally hematopoietic cells in the yolk sac portion of the tumor will have an immunohistochemical profile identical to malignant cells in the bone marrow

Mediastinal Nonseminomatous Germ Cell Tumors Presentation Common symptoms at presentation include fever, chills, weight loss, chest pain, dyspnea, SVC syndrome Patients with choriocarcinoma and high levels of -hCG may have gynecomastia Most have elevated AFP and/or -hCG and the combination of elevated tumor markers in a young male with a mediastinal mass may be used as an indication to begin treatment, even prior to a pathologic diagnosis

Mediastinal Nonseminomatous Germ Cell Tumors Radiology Large, irregular Extensive areas of heterogeneous low attenuation on CT due to necrosis, hemorrhage and/or cyst formation May invade the chest wall or adjacent structures Metastasizes to regional lymph nodes and distant sites Pleural and pericardial effusions are common

Mediastinal Nonseminomatous Germ Cell Tumors Treatment Four cycles BEP (bleomycin, etoposide, cisplatin) +/- XRT Residual masses are resected and two more cycles of chemotherapy given if malignant cells are found AFP and -hCG should be monitored to evaluate the effect of treatment and for recurrence

Anterosuperior Masses Thymus Thymoma Thymic carcinoma Thymic carcinoid Thymolipoma Mediastinal Lymphoma Hodgkin’s Lymphoma Non-Hodgkin’s Lymphoma Poorly differentiated lymphoblastic Diffuse lymphocytic Primary Mediastinal B-cell Lymphoma Germ Cell Tumor Teratoma Mature Immature Seminoma Nonseminomatous Germ Cell Embryonal cell carcinoma Endodermal sinus tumor Choriocarcinoma Malignant teratoma Mixed Thyroid/Parathyroid

Mediastinal Goiter A goiter is an enlargement of the thyroid gland The inferior poles of the thyroid normally lie superior to the thoracic inlet A minority of people may have thyroid glands that have descended to the level of the thoracic inlet Enlarging thyroid masses generally grow anteriorly as they are limited only by thin muscles, subcutaneous tissue and skin Growth through the thoracic inlet can produce symptoms related to compression of normal thoracic inlet contents

Mediastinal Goiter The Thoracic Inlet 5x10 cm ovoid area Anterior: Sternum Posterior: T1 vertebral body Lateral: First ribs Contains trachea, esophagus, carotid arteries, jugular veins, nerves

Mediastinal Goiter Presentation Visible cervical goiter Dyspnea - exertional, positional, nocturnal. May have stridor if tracheal compression is severe Cough/Choking sensation Dysphagia - especially if goiter is posterior Hoarseness Diaphragmatic paralysis Horner’s syndrome Venous compression Hyperthyroidism - occurs in about 20%, usually subclinical

Mediastinal Goiter Physical Exam Visible cervical goiter - present in 77-90% Inability to identify inferior pole of thyroid by palpation, even with neck hyperextension Tracheal deviation Pemberton’s maneuver Hold patient’s arms above head for 60 sec Positive test indicated by distended neck veins, facial plethora, cyanosis, inability to swallow, worsening of dyspnea or stridor May rarely result in impaction of goiter in thoracic inlet (“Thyroid cork” phenomenon)

Mediastinal Goiter Diagnostic Studies Plain films Nuclear Medicine May demonstrate tracheal narrowing and/or deviation with widening of the mediastinum superiorly Nuclear Medicine Radionuclide imaging with 123-I will help to define areas of autonomous functioning tissue May be misleading if mediastinal extension of the mass is hypofunctioning Pulmonary Function Tests Flow-volume loops demonstrate fixed upper airway obstruction Fine Needle Aspiration Indicated to evaluate for cancer if prominent discrete nodules are present or if there is a history of rapid growth, pain/tenderness, or firmness in one region

Mediastinal Goiter Diagnostic Studies, cont. CT Encapsulated, lobular heterogeneous mass Heterogeneity is due to cysts, hemorrhage and locally elevated concentrations of iodine Coarse punctate or ring-like calcifications are common Useful to show continuity between the cervical and mediastinal portions of the mass CT is usually performed with the neck neutral/flexed. If the goiter extends <1.5 cm below the sternal notch it may be completely cervical on extension and thus less likely to be the cause of the patient’s symptom If iodinated contrast is given, the patient should be pre-treated with methimazole or another anti-thyroid agent to reduce exacerbation of hyperthyroidism

Mediastinal Goiter 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

Mediastinal Goiter Treatment Medical management of hyperthyroidism with antithyroid medications and -blocker Early surgical resection Most goiters continue to enlarge As patient ages surgical complications become more common Difficult to rule out malignancy in mediastinal portion of tumor Risk of hemorrhage into mass causing acute airway compression Resection can usually be performed through a single cervical incision, but massive tumors may require sternotomy

Mediastinal Goiter Treatment, cont. Levothyroxine (suppressive dose) May reduce size of multinodular goiter over time Only helpful in patients who are euthyroid Patients with minimal mediastinal involvement, no compressive symptoms or patients who are poor surgical candidates may benefit Radioactive Iodine May be useful in patients who are poor surgical candidates, if mediastinal thyroid tissue is functional Radiation thyroiditis may worsen compressive symptoms

Parathyroid Adenoma Accounts for 85% of primary hyperparathyroidism Occurs in middle-aged adults, 2:1 F:M ratio Presents with Asymptomatic hypercalcemia Nephrolithiasis Bone pain Arthralgias/Myalgias Peptic ulcer disease Pancreatitis Fatigue/Anxiety/Depression

Parathyroid Adenoma Embryology/Anatomy Superior parathyroids are derived from the 4th pharyngeal pouch and lie posterior to the upper poles of the thyroid Inferior parathyroids are derived from the 3rd pharyngeal pouch and usually lie near the lateral surface of the lower poles of the thyroid Up to 20% of patients have ectopic parathyroid glands The inferior parathyroids may lie anywhere along the path of descent of the thymus

Parathyroid Adenoma Radiology Dual-phase 99mTc-sestamibi imaging The radiopharmaceutical is taken up within minutes of injection by both the thyroid and parathyroid glands. The rate of washout from normal thyroid tissue is much faster than the rate from parathyroid adenoma Early (10-15 min.) and Late (1.5-3 hr.) images of the neck and mediastinum are obtained and compared False-positives may occur with thyroid nodules or in parathyroid hyperplasia with one dominant gland False-negative studies can occur with very small lesions or abnormally rapid parathyroid washout

Parathyroid Adenoma Treatment Surgical removal US-guided EtOH ablation bilateral neck exploration unilateral neck exploration minimally invasive, image-guided parathyroidectomy US-guided EtOH ablation Embolization

Anterosuperior Masses Thymus Thymoma Thymic carcinoma Thymic carcinoid Thymolipoma Mediastinal Lymphoma Hodgkin’s Lymphoma Non-Hodgkin’s Lymphoma Poorly differentiated lymphoblastic Diffuse lymphocytic Primary Mediastinal B-cell Lymphoma Germ Cell Tumor Teratoma Mature Immature Seminoma Nonseminomatous Germ Cell Embryonal cell carcinoma Endodermal sinus tumor Choriocarcinoma Malignant teratoma Mixed Thyroid/Parathyroid Goiter Parathyroid adenoma

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