Anterior Mediastinal Masses November 30 2004 Neil J

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 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

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

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 5 year survival 10 year survival Encapsulated 75% 63% Invasive 50% 30% • 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%

Thymic Carcinoma Presentation • M>F, 40 s 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, 4 th/5 th 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 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 1020% 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 2 nd 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 • Et. OH-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

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 XRT 90% 3 Node regions on both sides of the diaphragm and/or splenic involvement or contiguous involvement of an extranodal site Diffuse or disseminated involvement of extranodal organs/tissues +/- node involvement Chemo XRT A: 80 -90% B: 60 -70% Chemo XRT 50 -60% 4

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 • 1 st/2 nd 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 • 3 rd 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 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 20 s-30 s • 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(12 p)

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(12 p) 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 -h. CG may have gynecomastia • Most have elevated AFP and/or -h. CG 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 -h. CG should be monitored to evaluate the effect of treatment and for recurrence

Anterosuperior Masses Thymus Germ Cell Tumor • • • Teratoma Thymic carcinoma Thymic carcinoid Thymolipoma Mediastinal Lymphoma • Hodgkin’s Lymphoma • Non-Hodgkin’s Lymphoma • Poorly differentiated lymphoblastic • Diffuse lymphocytic • Primary Mediastinal B-cell Lymphoma • 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 • 5 x 10 cm ovoid area • Anterior: Sternum • Posterior: T 1 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 • 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 pretreated 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 4 th pharyngeal pouch and lie posterior to the upper poles of the thyroid • Inferior parathyroids are derived from the 3 rd 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 99 m. Tc-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 • bilateral neck exploration • unilateral neck exploration • minimally invasive, image-guided parathyroidectomy • US-guided Et. OH ablation • Embolization

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

References Akerstrom G, Malmaeus J, Bergstrom R. Surgical anatomy of human parathyroid glands. Surgery 1984 January, 95(1): 14. Berghout, A, Wiersinga, WM, Drexhage, HA, et al. Comparison of placebo with L-thyroxine alone or with carbimazole for treatment of sporadic nontoxic goiter. Lancet 1990; 336: 193. Bokemeyer C, Nichols CR, Droz JP, et al. Extragonadal Germ Cell Tumors of the mediastinum and retroperitoneum. Journal of Clinical Oncology; 20: 1864. Hartmann JT, Nichols CR, Droz JP, et al. Hematologic disorders associated with primary mediastinal nonseminomatous germ cell tumors. Journal of the National Cancer Institute 2000, 92; 54. http: //rad. usuhs. mil http: //www. utdol. com Huysmans, DAKC, Hermus, RMM, Corstens, FHM, et al. Large, compressive goiters treated with radioiodine. Ann Intern Med 1994; 121: 757. Katlic MR, Grillo HC, Wang, CA. Substernal goiter: Analysis of 80 patients from Massachusetts General Hospital. American Journal of Surgery 1985, 149; 283. Moran CA, Suster S, Koss MN. Primary germ cell tumors of the mediastinum: yolk sac tumor, embryonal carcinoma, choriocarcinoma, and combined non-teratomatous germ cell tumors of the mediastinum - a clinicopathologic and immunohistochemical study of 64 cases. Cancer 1997, 80: 699. Nguyen BD. Parathyroid Imaging with Tc-99 m Sestamibi Planar and SPECT Scintigraphy. Radiographics 1999, 19: 61. Strollo DC, Rosado de Christenson, ML, Jett JR. Primary Mediastinal Tumors. Part 1. Tumors of the Anterior Mediastinum. Chest 1997; 112: 511. Strollo DC, Rosado de Christenson, ML, Jett JR. Primary Mediastinal Tumors. Part II. Tumors of the Middle and Posterior Mediastinum. Chest 1997; 112: 1344.