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Primary Mediastinal Tumors. Part 1*
reviews
Primary Mediastinal Tumors. Part 1*
Tumors of the Anterior Mediastinum
Diane C. Strollo, MD, FCCP; Lt Col Melissa L. Rosado de Christenson, MC, USAF; and fames R. Jett, MD, FCCP and account for 50% Primary anterior mediastinal neoplasms comprise a diverse group of tumors invasive and associated
of all mediastinal masses. Thymomas are most common and can be locally with parathymic syndromes. Thymic carcinomas and thymic carcinoids are rare malignancies with a propensity for local invasion and distant metastases. Thymolipomas are benign thymic tumors. The mediastinal germ cell tumors are a heterogeneous group of benign and malignant rare tumors and predominantly occur in young lymphangiomas are neoplasms.In Mediastinalmediastinal children. contrast, goiters are relatively common in adults. Mediastinal parathy¬a roid adenomas are an uncommon cause of persistent hyperparathyroidism and rarely cause discernible mass. The clinical, radiologic, and therapeutic aspects of the most common masses are reviewed. (CHEST 1997; 112:511-22)
Key words: germ cell tumors; goiter; lymphangioma; mediastinum; neoplasm; parathyroid adenoma; thymus Abbreviations: AFP=a-fetoprotein; p-HCG=beta-human chorionic gonadotropin HP he mediastinum is located in the central portion -*- of the thorax, between the two pleural cavities, the diaphragm and the thoracic inlet.1 It is usually divided into anterior, middle, and posterior "com¬ partments" to help categorize tumors and diseases according to their site of origin and location. How¬ ever, there are no fascial or anatomic planes that separate these compartments. Although various ra¬ diologic methods have been proposed for subdivid¬ ing the mediastinum, no single approach is univer¬ of sally applied. This reviewits uses the classification the It divides et al2 because of Fraser simplicity. mediastinum into anterior, middle, and posterior compartments based on the lateral chest radiograph (Fig 1). The anterior mediastinum is defined as the (Dr. Strollo), University of Department of Radiology Center; the Department of Radiologic Pa¬ Pittsburgh Medical Armed Forces Institute of thology (Dr. Rosado de Christenson), DC; and the University of Pittsburgh Pathology, Washington, Cancer Center (Dr. Jett). The and assertions contained herein are the
*From the
opinions
private
views of the authors and are not to be construed as official or as representing the views of the Department of the Air Force or
the Department of Defense. received November 4, 1996; revision accepted Jan¬ Manuscript 1997.
uary 16,
region posterior to the sternum and anterior to the
heart and brachiocephalic vessels. It extends from the thoracic inlet to the diaphragm and contains the thymus gland, fat, and lymph nodes. The middle mediastinum is defined as the space that contains the heart and pericardium to include the ascending and transverse aorta, the brachiocephalic vessels, the vena cavae, the main pulmonary arteries and veins, the trachea, bronchi, and lymph nodes. The poste¬ rior mediastinal compartment is bordered anteriorly by the heart and trachea and extends posteriorly to the thoracic vertebral margin to include the paraver¬ tebral gutters. The posterior mediastinum contains the descending thoracic aorta, esophagus, azygos veins, autonomic ganglia and nerves, thoracic duct, lymph nodes, and fat. Primary mediastinal tumors are a heterogeneous group of neoplastic, congenital, and inflammatory conditions.3 Neurogenic tumors, thymomas, and be¬ nign cysts account for approximately 60% of surgi¬ resected lesions while lymphoma, teratomas, cally and granulomatous diseases together comprise an additional 30%.l In nonsurgical series, vascular le¬ sions, typically aortic aneurysms, account for 10% of CHEST/112/2/AUGUST, 1997
511
equally affected and most patients are adults older than 40 years.5-7_9 Thymomas are rare in children and adolescents. Most patients are asymptomatic, al¬ though one third experience chest pain, cough, dyspnea, and/or other symptoms related to compres¬ sion or invasion of adjacent structures.10 Depending on the series, up to one half of patients suffer from
parathymic syndromes, most commonly and myasthenia gravis, hypogammaglobulinemia, 13 red cell in occurs pure aplasia.8 Myasthenia gravis 30 to 50% of with approximately patients thymoma. In comparison, only 15% of patients with myasthenia gravis have a thymoma.14 Because of this association, all patients with clinically suspected thymoma should have a serum antiacetylcholine receptor antibody level examined to exclude myasthenia gravis prior to surgery even if they are asymptomatic.1516 Falsepositive test results are rare. Approximately 25% of myasthenic patients with thymoma, particularly young women, have gradual improvement of symp¬ toms following thymectomy.61012 Uncommonly, my¬ asthenia gravis manifests in the postthymomectomy period5-617 and may be diagnosed by a rising titer of antiacetylcholine receptor antibody. Ten percent of patients with thymoma have hypogammaglobuline¬ mia.131718 While only 5% of patients with thymoma develop pure red cell aplasia, 50% of patients with red cell aplasia have a thymoma.513 Thymoma is also associated with various other autoimmune disorders and tumors.4'5-91113 While parathymic syndromes can cause significant morbidity and mortality,810 they can also prompt the early discovery of a thy¬ moma.511 are epithelial neoplasms Pathologically, thymomas characterized by an admixture of epithelial cells and mature lymphocytes.5 Most are solid neoplasms, but up to one third exhibit necrosis, hemorrhage, and cystic areas.510 Most thymomas are completely sur¬ rounded by a fibrous capsule. However, 34%, re¬ gardless of size, may invade through the capsule and extend directly into the mediastinal fat, pleura, peri¬ cardium, great vessels, right atrium, and/or the Because invasive thymomas lack his¬ lung.6-8-1119-21 features of malignancy and are microscopi¬ tologic to identical cally encapsulated thymomas,57 the term invasive thymoma is preferred over "malignant thy¬ moma."19 Transdiaphragmatic extension into the ab¬ domen and retroperitoneum and drop metastases to the ipsilateral pleura and pericardium may also occur.61119 Lymph node and hematogenous metas¬ tases are rare7810 and may occur both with invasive or encapsulated thymomas. Radiologically, thymoma is a well-defined, rounded, or lobulated anterior-superior mediastinal mass that typically arises from one of the thymic lobes and toward one side of the midline.22 one or more
Figure 1. Lateral chest radiograph. Using the classification of Fraser et al,2 the anterior mediastinal compartment is defined as the region anterior to a line (arrowheads) drawn along the anterior aspect of the heart and brachiocephalic vessels. The
middle and posterior mediastinal compartments are divided by a line (arrows) placed along the posterior tracheal wall and poste¬ rior heart border.
mediastinal mediastinal
masses.
tumors
two thirds of all ApproximatelyMore than 75% of benign.
are
asymptomatic patients with mediastinal tumors have benign lesions, while almost two thirds of symptom¬ atic patients with mediastinal masses have malignant lesions.4 This article will review primary anterior mediasti¬ nal tumors, which comprise approximately one half of all mediastinal masses. Anterior mediastinal neo¬ carcinoma, thymic plasms include thymoma, thymic carcinoid, thymolipoma, germ cell tumors, and para¬ thyroid adenoma; nonneoplastic conditions include thymic cyst, lymphangioma, and intrathoracic goiter.
occurs in the anterior mediasti¬ lymphoma will be discussed in part 2 of this series, which primarily addresses lesions of the middle and mediastinal
While
num, it
posterior
compartments.
Thymoma
Thymoma is the most common primary tumor of the anterior mediastinum.1'5-6 Men and women are 512
grows
Reviews
tumor extension occurs. commonly, bilateralresides usually just anterior to the thymoma aortic root,9 it can occur anywhere from the neck to the cardiophrenic angle.511 Most measure 5 to 10 cm with a reported size range from <1 cm to 34 cm5-8 (Fig 2). Radiographically detectable calcifications areor small, curvilinear, infrequent and are usually an On CT, encapsulated thymoma is a punctate.5-922 or well-defined, homogeneous, heterogeneous softtissue mass depending on the presence of hemor¬ rhage, necrosis, or cyst formation22 (Fig 3). Focalin areas of low attenuation can be a dominant feature large tumors.9 While subtle invasion may be difficult to detect on CT, an infiltrative appearance, obvious vascular compromise, and/or an irregular interface with the adjacent lung are highly suggestive findings of invasion22 (Fig 4). Thymoma can seed the pleural space, may progress to circumferentially encase the a diffuse lung, and can mimic the appearance ofEven with mesothelioma519'23 5). malignant (Fig extensive pleural involvement, pleural effusions are uncommon.11 Thoracic CT for the evaluation of thymoma should extend through the upper abdomen to exclude trans diaphragmatic extension.1924 On MRI, thymomas have intermediate signal intensity similar to or greater than that of skeletal muscle on ^-weighted images and increased signal intensity on T2-weighted images.9'22'25 Cystic areas with high fluid content characteristically have low signal inten¬ sity on Tx-weighted images and high signal intensity on T2-weighted images. Tumor lobules and fibrous
Less
While
septa are occasionally demonstrated.25 MRI excels in noninvasive evaluation of vascular structures to ex¬ clude invasion. Owing to the risk of recurrence,
long-term radiologic followup.6'8-9'12 To minimize the potential for invasion and to improve survival, complete surgical excision is at¬ tempted in most cases of thymoma.5612 Tumor invasiveness is determined by surgical findings of invasion supported by histologic evidence of tumor cells outside the confines of the tumor capsule.7-8 While patients with encapsulated thymoma have the best prognosis and are almost always cured by complete surgical resection, 2 to 12% of resected sometimes months or encapsulated thymomas recur, In years following excision.812 a series of 283 patients from Mayo Clinic,8 32% had locally invasive tumors, including 6% with metastases to the pleura or lung. The overall 5- and 10-year survivals were 67% and 53%, respectively. In those patients without invasive tumors, the 5- and 10-year survivals were 75% and 63%, respectively, vs 50% and 30%, respectively, in those with invasive thymomas. Forty-six percent had myasthenia but it was not associated with a worse survival (p=0.35). Radiation therapy is usually rec¬ ommended for invasive or incompletely excised tu¬ mors.26 Invasive is chemosensitive. Nuthymomas
merous
warrant
thymoma reports have documented responses
to
chemotherapeutic regimens, especially those In recent a utilizing cisplatin. report by Loehrer et 29 with or recurrent thymetastatic al,27 patients
various
Figure 2. Posteroanterior (left) and lateral (right) chest radiographs. A 10X7-cm sharply marginated thymoma (arrows) in the anterior mediastinum has been displaced inferiorly by its large weight.
CHEST/112/2/AUGUST, 1997
513
Figure 5. Enhanced chest CT. A recurrent, invasive thymoma has lobulated pleural implants that partially encase the right lung (arrowheads). Despite the extensive pleural tumor, note the absence of pleural effusion.
Figure 3. Enhanced chest CT. A well-circumscribed and lobulated thymoma (T) arises from the left thymic lobe and has curvilinear rim calcification in the tumor capsule (arrow); ao=aorta; t=trachea.
treated with cisplatin, doxorubicin, and The overall response rate was cyclophosphamide. 50% with three complete responses approximately and 12 partial responses. The median duration of moma were
response was 12 months with a median survival of 38 months and a 5-year survival of 30%. Thymic Carcinoma
The thymic carcinomas are a heterogeneous group aggressive epithelial malignancies that have a strong propensity for early local invasion and wide¬ spread metastases. Squamous cell carcinoma and carcinoma are the most lymphoepithelioma-like common cell types and usually occur in middle-aged men with a mean age of 46 years.28-29 Their malig¬ nant cytologic features distinguish them from both encapsulated and invasive thymomas as the latter are An occult primary lung malig¬ cytologically benign.30 to the metastatic nancy thymus must be excluded because the histologic types resemble those found more typically in the lung.2830 Thymic carcinoma is invasive and, unlike thymoma, frequently locally metastasizes to regional lymph nodes and distant of
sites.2931
Radiologically, thymic
carcinomas
com¬
monly manifest as large, poorly defined, infiltrative anterior mediastinal masses and are frequently asso¬ ciated with pleural and pericardial effusions,32 al¬
Figure 4. Enhanced chest CT at the level just below the aortic (ao) arch. An invasive thymoma (T) manifests as a midline, lobulated, homogeneous anterior mediastinal mass that slightly contains a punctate calcification. The thymoma invades the left brachiocephalic vein with tumor extension (asterisk) into the
superior vena cava (s).
514
though pleural implants are uncommon31 (Fig 6). Like thymoma, thymic carcinoma may exhibit cystic changes on cross-sectional imaging studies.32 and prognosis depend on tumor histo¬ Therapy condition and stage at presentation. Suster and logic Rosai28 reported a clinicopathologic series of 60 patients with thymic carcinoma. Although their se¬ ries was unable to document efficacy of the various treatment modalities, complete and partial response Reviews
Complete surgical exci¬to spread nodes, local tumor invasion, and distant regional metastases have been treated with radiotherapy and chemotherapy, but this tumor is highly resistant to
on
CT37 may also be
seen.
sion is the treatment of choice. Local
these modalities.34'36
Thymolipoma
Figure 6. Enhanced chest CT. Thymic carcinoma (a) originating
the anterior mediastinum infiltrates around the arch vessels and brachiocephalic veins. In the absence of lymphadenopathy and distant metastases, thymic carcinoma can be difficult to differentiate radiologically from invasive thymoma.
in
of thymic carcinoma to cisplatin-based chemother¬ apy has been reported.33 Combination chemother¬ apy with etoposide and cisplatin and concurrent is considered a reasonable treatment radiotherapyWhen approach. patients are unable to tolerate simultaneous chemoradiotherapy, sequential therapy is used.262733 The 3- and 5-year survival rates are 40% and 33%, respectively. The 5-year survival for high-grade tumors (defined as those with lobular severe cytologic atypia, extensive growth patterns, necrosis, and high mitotic activity) was 15 to 20% as opposed tothe90% for low-grade tumors,ofthus docu¬ menting prognostic importance histologic grade.
Thymic Carcinoid
is a rare malignancy that is Thymic carcinoid to carcinoid tumors at other histologically identical sites. It typically affects men in the fourth to fifth decades of life.3435 Approximately 50% of patients have endocrine abnormalities, most commonly adrenocorticoCushinghormone syndrome due to ectopic endocrine or multiple production tropin The classic carcinoid syn¬ neoplasia syndrome.5-34 drome is rarely associated with thymic carcinoid.36 or also be Patients
may
asymptomatic
experience
symptoms of compression and/or invasion.35
Re¬
metastases, including gional lymph node and distant are osteoblastic bone metastases, reported in up to 73% of cases and can occur late.34-36 Thymic carci¬ noid manifests as a large, lobulated, and usually invasive anterior mediastinal mass that may exhibit areas of hemorrhage and necrosis.534 Punctate and dystrophic calcification34 and contrast enhancement
benign slow-growing neo¬ Thymolipoma is a rare that affects male and female plasm of the thymus a wide age range. However, subjects equally over a mean adults (with age of 27 years) are most young afflicted.38 Approximately half of the pa¬ commonly tients are asymptomatic. is a large, soft, encapsulated mass Thymolipoma tissue.5 composed of mature adipose cells and thymic more than 2 Twenty-five percent of tumors weigh kg. Radiologically, thymolipoma is a large anterior mediastinal mass that frequently droops into the anterior inferior mediastinum and may occupy one or both hemithoraces. It is characterized by its ability to conform to adjacent structures simulating cardiomegaly and diaphragmatic elevation and by changes in shape that follow changes in patient position.38 CT the combination of fat and MRI demonstrate classic and soft-tissue elements and establish the tumor attachment to the anatomic region of the thymus (Fig 7). Some thymolipomas are of predominant fat attenuation and may resemble mediastinal lipomas.
Surgical excision is curative.
NONNEOPLASTIC THYMIC CYSTS
Thymic cysts are rare and represent approximately controversial. Thymic cysts may be congenital39 or is either due to inflammation or in associa¬ acquired, tion with an inflammatory neoplasm such as Hodgkin's lymphoma, seminoma, or thymic carcino¬ ma.40-41 Congenital thymic cysts are thought to be remnants of the thymopharyngeal duct and can be found anywhere along the embryologic course of the thymus as it migrates from theof neck into the anterior mediastinum.39 The origin inflammatory thymic cysts is less clear. They probably arise from inflamed cystic dilata¬ thymic parenchyma through secondary tion of epithelial-derived structures and contain ar¬ eas of inflammation and fibrosis. Approximately 50% of congenital thymic cysts are incidentally discovered in the first two decades of life,39 while inflammatory in asymptomatic adult thymic cysts usually occur men.40 Thymic cysts associated with neoplasia are more likely to cause symptoms. Most congenital cysts 3% of all anterior mediastinal masses.4 Their etiology
CHEST/112/2/AUGUST, 1997
515
Figure 7. Posteroanterior (top left) and lateral (top right) chest radiographs. A large thymolipoma (arrows) droops into the right inferior portion of the anterior mediastinum and conforms to the heart and right hemidiaphragm. Bottom, enhanced CT scans through the lower thorax. The thymolipoma arises from the anterior mediastinum, extends into the right hemithorax, and contains characteristic whorls of fat and thymic soft tissue. measure <6 cm, are usually rounded and uniloculated or multiloculated, and have thin walls without inflammatory change.40 Acquired thymic cysts range in size from 3 to 17 cm, are usually multiloculated,40 and have a variable wall thickness. Because inflam¬ matory thymic cysts may have microscopic and gross features identical to those of cystic thymic neo¬
516
plasms, thorough specimen sampling and examina¬ tion of the cyst wall are mandatory to exclude neoplasia.40 Radiologically, thymic cysts typically manifest as well-circumscribed anterior superior me¬ diastinal masses. They may be uniloculated or mul¬ tiloculated and have low usually
attenuation
con¬
tents, with occasional visualization of septa and linear Reviews
wall calcification. Surgical excision is the therapy of choice.41 Acquired lesions may recur after excision.40 Mediastinal Germ Cell Tumors
Mediastinal germ cell tumors (teratomas, seminoand nonseminomatous malignant germ cell tumors) are a heterogeneous group of benign and malignant neoplasms thought into originate from primitive germ cells "misplaced" the mediastinum The anterior medi¬ during early embryogenesis.42-43 astinum, especially the anterosuperior portion, is the most common extragonadal primary site.4244 Medi¬ astinal germ cell tumors represent approximately 10 to 15% of adult anterior mediastinal tumors142 and are histologically identical to their gonadal counter¬ parts.44-45 Patients are usually young adults with a mean age of 27 years.42-46 While mature teratomas occur with approximately equal frequency in male and female subjects, >90% of malignant germ cell tumors occur in male subjects.42 When a malignant mediastinal germ cell tumor is diagnosed, a primary mas,
gonadal malignancy (although rarely metastatic solely to the anterior mediastinum) must be exclud¬ ed.45-4748 Serologic evaluation for a-fetoprotein (AFP) and (3-human chorionic gonadotropin (pHCG) is helpful in the evaluation of patients with clinically suspected malignant mediastinal germ cell
tumor.
Mediastinal Teratomas Teratomas are die most common mediastinal germ cell tumors.4244 They are composed of tissues that arise from more than one of the three primitive germ cell layers42-45 and are "foreign" to the anatomic site in which they occur.45 The vast majority are mature teratomas that are histologically well differentiated and 42 A teratoma benign rarely contains fetal tissue and is then classified as an immature teratoma, which has a good prognosis in children but may recur or metastasize.45 Rarely, a mature teratoma can contain a focus of carcinoma, sarcoma, or malignant germ cell tumor; when it does, it is then termed a "malignant teratoma"45
sign of ruptured mediastinal teratoma.46-50 an encapsulated mass character¬ ized by the presence of cystic and solid areas.46 The tumor may attempt organ formation45 and can con¬ tain teeth, skin, and hair (ectodermal derivatives); derivatives); and/or cartilage and bone (mesodermal and bronchial, intestinal, pancreatic tissue (endodermal derivatives).45'46-49 Radiologically, these are rounded to lobulated, well-defined anterior medias¬ monic
Mature teratoma is
tinal masses that usually protrude to one side of midline and can reach large sizes.46 On chest radio¬ graphs, up to 26% exhibit calcification and may rarely display recognizable bone or teeth.46 On CT, these are typically multilocular cystic tumors with walls of variable thickness.51 The combination of fluid, soft tissue, calcium, and/or fat attenuation in an anterior mediastinal mass is a highly specific finding that allows the prospective diagnosis of mature ter¬ atoma (Fig 8). Fat-fluid levels produced by high lipid content in the cyst fluid are diagnostic but rare
findings. Surgical excision is curative.
Mediastinal Seminoma
Seminoma represents 40% of malignant germ cell single histology.47 White men in their third and fourth decades of life are most commonly
tumors of
afflicted and are usually symptomatic. Approximately 10% of patients with pure seminoma may have an elevated P-HCG level, but never an elevated AFP level. Radiologically, seminoma manifests as a bulky lobulated homogeneous anterior mediastinal mass,47 which uncommonly invades adjacent structures,4252 but can metastasize to regional lymph nodes and bone.47-53 Calcification is rare.54 Mediastinal semino-
"teratocarcinoma." Mature teratoma represents approximately 60 to 70% of mediastinal germ cell tumors.42 It occurs most frequently in children and young adults, with male and female subjects equally affected. Patients or
usually asymptomatic, but large tumors may chest pain, dyspnea, cough, or other symptoms of compression.46 Digestive enzymes secreted by intestinal mucosa or pancreatic tissue in the tumor can precipitate rupture into the bronchi, pleura, pericardium, or lung.42-45-46'49-50 Expectoration of hair (trichoptysis) or sebum is a rare but pathognoare
cause
Figure 8. Enhanced chest CT. A large mature teratoma was discovered in an asymptomatic patient. This multiincidentally cystic tumor has moderate septal enhancement (arrowhead) and contains fat and calcification char¬ acteristic
(white arrow)
of mature teratoma;
ao=aorta.
(black arrow),
CHEST/112/2/AUGUST, 1997
517
highly sensitive to both radiation and sys¬ chemotherapy.55 Treatment is somewhat con¬ troversial. Small localized tumors may be treated with primary resection followed by radiotherapy. In patients with locally advanced disease, the preferred treatment is systemic chemotherapy (see nonseminomatous germ cell tumors) followed by surgical resection of any residual disease. Therapy should be survival is 60 to in mas are
temic
curative
80%.42-55
most patients.
Long-term
Mediastinal Nonseminomatous Malignant Germ Cell Tumors The nonseminomatous malignant germ cell tu¬ mors include embryonal cell carcinoma, endodermal sinus tumor, choriocarcinoma, or mixed germ cell tumors composed of multiple histologic features. These are malignant and typically cause symptoms in young adult men.42 Lactate dehydrogenase and se¬ as AFP and p-HCG are fre¬ rologic markers such In of patients with extragoa series quently positive. nadal germ cell tumors, 20 of 28 (71%) patients with nonseminomatous tumors had an elevated AFP level and 15 of 28 (54%) had an elevated P-HCG level.55 In comparison, none of the 11 patients with semi¬ noma had an elevated AFP level and 2 of 11 had an elevated p-HCG level. Nonseminomatous malignant germ cell tumors are uniquely associated with hemaand approximately 20% of tologic malignancies4356 Klinefelter's have Radiologi¬ syndrome.43-57 patients mediastinal anterior are these large, irregular, cally, often with extensive, central, irregular, and masses, of low attenuation due to ne¬ areas heterogeneous and/or crosis, hemorrhage, cyst formation.52 Invasion of adjacent structures, including the chest wall, may occur as well as metastases to regional lymph nodes and distant sites58-59 (Fig 9). Pleural and pericardial effusions are common.4252 Bukowski and associates55 of the Southwest On¬ Group treated 41 patients with extragonadal cology seminoma or nonseminomatous malignant germ cell tumors with four cycles of chemotherapy containing and various other agents bleomycin and cisplatin followed by surgical resection. Twenty-four of 41 patients had mediastinal tumors while 15 had retro¬ tumors and 2 had unknown primary sites. peritoneal The 2- and 5-year survivals for the patients in this series were 67% and 60%, respectively.55 Currently, the standard treatment for a primary mediastinal malignant germ cell tumor is four cycles of bleomy¬ cin, etoposide, and cisplatin. Surgical resection of a residual mass is indicated, especially if the tumor markers are negative.55 While surgical excision should not be the initial treatment, a tissue diagnosis is necessary before starting chemotherapy. 518
Figure 9. Unenhanced chest CT. At the level of the carina, a mixed malignant germ cell tumor has multiple cystic areas (black arrows) and heterogeneous enhancement. It is associated with a small effusion (white arrow) and subsegmental atelectasis (a).
Mediastinal Lymphangioma
Mediastinal lymphangioma (cystic hygroma) is a histologically benign60 proliferation of interconnect¬ ing lymphatic vessels and sacs that may grow in an infiltrative fashion.61 Its etiology is controversial; some authors suggest it is a developmental lesion61 while others postulate it has a hamartomatous or origin.6061 Lymphangioma is typically a neoplastic tumor of very young children. Fifty percent are present at birth and 90% are discovered by 2 years of age.6062 Ninety-five percent involve the neck or axilla and 10% extend into the superior aspect of the anterior mediastinum63 or, less commonly, other mediastinal compartments.64 Rarely, lymphangiomas occur as primary mediastinal tumors in adults or as a generalized lymphangiomatosis with extensive multifocal involvement of multiple organ systems.6162 Pathologically, the dilated lymph spaces can range in caliber from capillary size to several centimeters in dimension.61 Mediastinal lymphangioma typically occurs in the superior aspect of the anterior medi¬ astinum and is usually contiguous with a cervical or these are axillary component.62 Radiologically, tumors that can rounded, lobulated, multicystic reach massive sizes and may infiltrate across tissue (Fig 10). They may surround or displace planes63 mediastinal structures.63-64 On CT, "cysts" (repre¬ senting the large vascular spaces) vary in diameter from 1 to 2 mm to several centimeters, are usually Reviews
commonly in asymptomatic women with cervical palpable goiter. Occasionally patients have of or symptoms compression pain. Radiologically, mediastinal goiter is an encapsu¬ lated, lobulated, heterogeneous tumor.6667 The di¬ agnostic radiologic feature is the continuity between the cervical and mediastinal components that is usually evident on cross-sectional imaging (Fig 11). Well-defined areas of low attenuation on an unen¬ hanced chest CT can reflect hemorrhage and cyst formation while areas of increased attenuation rela¬ tive to adjacent soft-tissue structures represent in¬ trinsic iodine within the gland.6667 Coarse, punctate, or ring-like calcifications are common65 (Fig 12). After IV contrast administration, the goiter fre¬ quently demonstrates intense and sustained en¬ hancement.67 Radioactive iodine 131 and 123 scin¬ can be diagnostic when functioning thyroid tigraphy tissue is present.65 The treatment of choice for symptomatic or potentially symptomatic lesions is surgical resection. Most can be excised through a cervical incision but occasionally a sternotomy is occur a
most
required.
Mediastinal Parathyroid Adenoma Figure 10.
of the neck. A large multicystic Top: enhanced CT has
neck lymphangioma (L) slight septal enhancement (arrow) and infiltrates throughout the tissue planes. Bottom: enhanced chest CT at the top of the aortic arch (ao). The is a sharply marginated water attenuation mass lymphangioma that insinuates between the aorta and superior vena cava (s).
right
adenoma is a benign functioning parathyroid that occurs most commonly in the neck. neoplasm A
display thin or thick after contrast minimally administration.63 Because of its insinuating nature, complete surgical resection of lymphangiomas may be difficult and surveillance is needed to exclude near
water
attenuation, and
septa that may enhance
recurrence.60-62
Mediastinal Goiter
While mediastinal goiter represents only 10% of mediastinal masses in surgical series,1 it is one of the most commonly seen in clinical practice. Twenty percent of cervical goiters descend into the thorax, usually into the left anterior superior mediastinum.65 Infrequently, they can extend behind the trachea and involve the middle and posterior mediastinal compartments. Primary intrathoracic goiters without a cervical component are very rare.66 These tumors rarely contain foci of malignancy. Mediastinal goiters
Figure 11. Posteroanterior chest
radiograph. A large intratho¬
goiter (arrows) extends from the left thyroid lobe into the bilateral anterior mediastinum and displaces the trachea (aster¬ isk) to the right. racic
CHEST/112/2/AUGUST, 1997
519
with vague chest complaints or with signs and symp¬ toms related to compression or invasion of medias¬ tinal structures. The most common primary anterior mediastinal tumors are thymoma, teratoma, substernal goiter, and lymphoma. All other lesions are extremely rare. Patients with anterior mediastinal masses should be evaluated preoperatively for myasthenia gravis that could result in respiratory failure in the postopera¬ tive period if untreated. Neck palpation should be performed to exclude the mediastinal extension of a cervical goiter and to detect occult generalized
Figure 12. Unenhanced chest CT at the thoracic inlet. A left cervical goiter (G) extends into the anterior superior mediasti¬ num, with moderate mass effect on the trachea (t). The goiter has attenuation equal to and slightly greater than skeletal muscle and contains curvilinear dystrophic calcifications (arrow).
tumors are ectopic68 and almost the anterior mediastinum, usually within the thymus due to a common embryfrom the third and fourth brachial origin ologic Older women are most commonly af¬ pouches.70 fected and present with signs and symptoms of hyperparathyroidism that persist following cervical
Ten
percent of
half39
occur near or
in
parathyroidectomy.mediastinal parathyroid adenomas Pathologically, are identical to cervical parathyroid adenomas. They are encapsulated and rounded and usually measure <3 cm.69 Because of their small size, they are rarely detected on chest radiographs. On unenhanced CT, can resemble a lymph node and only 25% they demonstrate perceptible enhancement after IV con¬ trast administration.68-69 Parathyroid adenomas can avidly take up radioactive 99mTc and 201Tl. For localizing parathyroid adenomas,of 99mTc-sestamibi 88 to 100% is with a sensitivity scintigraphy to dual isotope imaging using
superior
99mTc-per-
technetate and 201Tl which has a sensitivity of 55 to 100%.68'7172 On MRI, parathyroid adenomas have increased signal intensity on T2-weighted images and
gadolinium-enhanced ^-weighted images.68-71in parathyroid glands Fifty to 75% of abnormal patients with persistent or recurrent hyperparathy¬ with MRI.73 on
roidism
can
be detected
Conclusion
Many mediastinal masses are serendipitously dis¬ on chest radiographs obtained for other reasons. Some patients will come to clinical attention covered 520
lymphadenopathy. The radiologic evaluation of these patients begins with the chest radiograph and is followed by crosssectional imaging with CT. CT is useful in excluding vascular causes and some benign causes of medias¬ tinal widening such as lipomatosis. In addition, con¬ fident diagnosis of some lesions such as mature teratoma and mediastinal goiter can be accomplished as well as evaluation of adjacent structures to exclude evidence of mass effect or invasion. In addition to basic laboratory tests, serologic evaluation for detection of antiacetylcholine receptor antibodies, AFP and (3-HCG should be performed to exclude myasthenia gravis and nonseminomatous malignant germ cell tumors, respectively. Patients with primary mediastinal masses and cysts will usually undergo surgical resection. The presence of lymphadenopathy (in the case of lymphoma and metastatic disease) or positive AFP or P-HCG sero¬ logic test results should prompt limited biopsy spec¬ imens of the lesion followed by oncologic consulta¬ tion and chemotherapy or radiotherapy when Resection of residual tumor will follow appropriate.
m some cases.
Special thanks to Vivian L. McBride for her expertise in preparing the manuscript.
ACKNOWLEDGMENT:
1
Wychulis ment
References AR, Payne WS, Clagett OT,
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cysts and neoplasms of the mediastinum:
recent
Primary
changes in
clinical presentation, methods of diagnosis, management and results. Ann Thorac Surg 1987; 44:229-37 5 Rosai J, Levine GD. Tumors of the thymus. In: Firminger HI, ed. Atlas of tumor pathology, fasc 13, ser 2. Washington, DC: Armed Forces Institute of Pathology, 1976; 34-212 6 Lattes R. Thymoma and other tumors of the thymus: an Reviews
analysis of 107 cases. Cancer 1962; 15:1224-60 7 O'Gara RW, Horn RC Jr, Enterline HT. Tumors of the anterior mediastinum. Cancer 1958; 11:562-90 8 Lewis JE, Wick MR, Scheithauer BW, et al. Thymoma: a clinicopathologic review. Cancer 1987; 60:2727-43 9
Morgenthaler TI,
Brown
LR,
Colby TV,
et
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Thymoma.
Mayo Clin Proc 1993; 68:1110-23 10 Wilkins EW Jr, Edmunds LH Jr, Castleman B. Cases of thymoma at the Massachusetts General Hospital. J Thorac Cardiovasc Surg 1966; 52:322-30 11 Verstandig AG, Epstein DM, Miller WT, et al. Thymoma. report of 71 cases and a review. Crit Rev Diagn Imaging 1992; 33:201-30 12 Maggi G, Giaccone G, Donadio M, et al. Thymomas: a review of 169
cases
with
treatment. Cancer
particular reference to results of surgical 1986; 58:765-76
30 Snover DC, Levine GD, Rosai
distinctive 6:451-70
tumors
33
Cancer 1993; 71:1219-23 MR, Bernatz PE, Carney JA, et al. Primary mediastinal carcinoid tumors. Am J Surg Pathol 1982; 6:195-205 35 Wick MR, Scott RE, Li CY, et al. Carcinoid tumor of the thymus. Mayo Clin Proc 1980; 55:246-54 36 Economopoulos GC, Lewis JW Jr, Lee MW, et al. Carcinoid tumors of the thymus. Ann Thorac Surg 1990; 50:58-61 37 Brown LR, Aughenbaugh GL, Wick MR, et al. Roentgenonoma.
39
acetylcholine receptors 1983; 308:402-03
in
myasthenia gravis. N
Engl J
Med
Jr, Finley J, al. Clinical correla¬ tion of antibodies that bind, block or modulate human acetylcholine receptors in myasthenia gravis. Ann NY Acad
16 Howard FM
Lennon VA,
et
Sci i987; 505:526-38 17 Kimura J. Post-thymectomy 18 19
myasthenia gravis: report of a case of ocular myasthenia gravis after total removal of a thymoma and review of the literature. Neurology 1967; 17:413-20 Walderman TA. Thymoma, hypogammaglobulinemia, and absence of eosinophils. J Clin Invest 1967; 46:1127-28 Zerhouni EA, Scott WW, Baker RR, et al. Invasive thymomas: diagnosis and evaluation by CT. J Comput Assist Tomogr
1982; 6:92-100 20 Korobkin M, Casano VA. Case report: intracaval and intracardiac extension of malignant thymoma: CT diagnosis. J Comput Assist Tomogr 1989; 13:348-50 21 Yokoi K, Miyazawa N, Mori K, et al. Invasive thymoma with intracaval growth into right atrium. Ann Thorac Surg 1992;
53:507-09 22 Rosado de Christenson ML, Galobardes moma:
J, Moran CA. Thy¬ radiologic-pathologic correlation. Radiographics 1992;
12:151-68 23 Moran CA, Travis
WD, Rosado de Christenson ML,
Thymomas presenting as pleural tumors. Am J Surg 1992; 16:138-44
al. Pathol et
Scatarige JC, Fishman EK, Zerhouni EA, et al. Transdiaphragmatic extension of invasive thymoma. AJR Am J Roent¬ genol 1985; 144:31-35 25 Sakai F, Sone S, Kiyono K, et al. MR imaging of thymoma: radiologic-pathologic correlation. AJR Am J Roentgenol 1992; 24
158:751-56 26 Currans WJ, Kornstein MJ, Brooks JT, et al. Invasive thy¬ moma: the role of mediastinal irradiation following complete or incomplete surgical resection. J Clin Oncol 1988; 6:1722-27 27 Loehrer PJ, Kim KM, Aisner SC, et al. Cisplatin plus
plus cyclophosphamide in metastatic or recur¬ thymoma. J Clin Oncol 1994; 12:1164-68 Suster S, Rosai J. Thymic carcinoma: a clinicopathologic study
doxorubicin
28
rent
of 60 cases. Cancer 1991; 67:1025-32 29 Wick MR, Weiland LH, Scheithauer BW, et al. Primary thymic carcinomas. Am J Surg Pathol 1982; 6:613-30
SJ, et al. CT findings in primary thymic carcinoma. J Comput Assist Tomogr 1991; 15:429-33 W7eide LG, Ulbright TM, Loehrer PJ, et al. Thymic carci¬
34 Wick
J Med 1971; 38:497-537 15 Lennon VA, Jones G, Howard F, et al. Auto antibodies to
review of a 20-year experience in over 1200 patients. Mt Sinai
JG, Lee BH, et al. CT findings in malignant of thymic epithelium. J Comput Assist Tomogr 1995;
19:192-97 32 Lee JD, Choe KO, Kim
38
14
J. Thymic carcinoma: five J Surg Pathol 1982;
variants. Am
31 Do YS, Im
Souadjian JV, Enriquez P, Silverstein MN, et al. The spec¬ trum of diseases associated with thymoma. Arch Intern Med 1974; 134:374-79 Osserman KE, Genkins G. Studies in myasthenia gravis:
13
histological
40 41
42 43
logic diagnosis of primary7 corticotropin-producing carcinoid of the mediastinum. Radiology 1982; 142:143-48 Rosado de Christenson ML, Pugatch RD, Moran CA. Thymolipoma: analysis of 27 cases. Radiology 1994; 193: 121-26 Indeglia RA, Shea MA, Grage TB. Congenital cysts of the thymus gland. Arch Surg 1967; 94:149-52 Suster S, Rosai J. Multilocular thymic cyst: an acquired reactive process. Am J Surg Pathol 1991; 15:388-98 Graeber GM, Thompson LD, Cohen DJ, et al. Cystic lesions of the thymus. J Thorac Cardiovasc Surg 1984; 87:295-300 Nichols CR. Mediastinal germ cell tumors: clinical features and biologic correlates. Chest 1991; 99:472-79 Dexeus FH, Logothetis CJ, Chong C, et al. Genetic abnor¬ tumors
malities in men with germ cell tumors. J Urol 1988; 140:80-84 MA, Valenzuela-Tamariz J. Germ-cell tumors of the mediastinum, postmortem findings. Am J Clin Pathol 1976; 65:450-54 Crussi-Gonzalez F. Extragonadal teratomas. In: Hartmann WH, ed. Atlas of tumor pathology, fasc 18, ser 2. Washington, DC: Armed Forces Institute of Pathology, 1982; 77-94 Lewis BD, Hurt RD, Payne WS, et al. Benign teratoma of the mediastinum. J Thorac Cardiovasc Surg 1983; 86:727-31 Aygun C, Slawson RG, Bajaj K, et al. Primary mediastinal seminoma. Urology 1984; 23:109-17 Johnson DE, Appelt G, Samuels ML, et al. Metastases from testicular carcinoma. Urology 1976; 8:234-39 Sommerlad BC, Cleland WP, Yong NK. Physiological activity in mediastinal teratoma. Thorax 1975; 30:510-15 Thompson DP, Moore TC. Acute thoracic distress in child¬ hood due to spontaneous rupture of a large mediastinal teratoma. J Pediatr Surg 1969; 4:416-23 Brown LR, Muhm JR, Aughenbaugh GL, et al. Computed tomography of benign mature teratomas of the mediastinum. J Thorac Imaging 1987; 2:66-71 Lee KS, Im JG, Han CH, et al. Malignant primary germ cell tumors of the mediastinum: CT features. AJR Am J Roent¬ genol 1989; 153:947-51 Polansky SM, Barwick KW, Ravin CE. Primary mediastinal seminoma. AJR Am J Roentgenol 1979; 132:17-21 Shin MS, Ho KJ. Computed tomography of primary medias¬ tinal seminomas. J Comput Assist Tomogr 1983; 7:990-94 Bukowski RM, Wolf M, Kulander BG, et al. Alternating combination chemotherapy in patients with extragonadal germ cell tumors. Cancer 1993; 71:2631-38 Nichols CR, Roth BJ, Heerema N, et al. Hematologic neoplasia associated with primary mediastinal germ-cell tu¬ mors. N Engl J Med 1990; 322:1425-29 Nichols CR, Hoffman R, Einhorn LH, et al. Hematologic malignancies associated with primary mediastinal germ cell
44 Luna
45 46
47 48 49
50
51 52
53 54
55 56 57
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521
tumors. Ann Intern Med 1985; 102:603-09 58 Levitt RG, Husband JE, Glazer HS. CT of primary germ-cell tumors of the mediastinum. AJR Am J Roentgenol 1984; 142:73-78 59 Knapp RH, Hurt RD, Payne WS, et al. Malignant germ cell tumors of the mediastinum. J Thorac Cardiovasc Surg 1985; 89:82-89 60 Bill AH Jr, Sumner DS. A unified concept of lymphangioma and cystic hygroma. Surg Gynecol Obstet 1965; 120:79-86 61 Scalzetti EM, Heitzman ER, Groskin SA, et al. Development lymphatic disorders of the thorax. Radiographics 1991; 11: 1069-85 62 Brown LR, Reiman HM, Rosenow EC, et al. Intrathoracic lymphangioma. Mayo Clin Proc 1986; 61:882-92 63 Shaffer K, Rosado de Christenson ML, Patz EF, et al. Thoracic lymphangioma in adults: CT and MR imaging features. AJR Am J Roentgenol 1994; 162:283-89 64 Pilla TJ, Wolverson MK, Sundaram M, et al. CT evaluation of
Radiology Bashist B, Ellis K, Gold RP. Computed tomography of intrathoracic goiters. AJR Am J Roentgenol 1983; 140:455-60 cystic lymphangiomas
65
522
144:841-42
of the mediastinum.
1982;
Carcangiu ML, DeLellis RA. Tumor-like conditions: of the thyroid gland. In: Rosai J, ed. Atlas of tumor pathology, fasc 5, ser 3. Washington, DC: Armed Forces Institute of Pathology, 1992; 297-316 67 Glazer GM, Axel L, Moss AA. CT diagnosis of mediastinal 66 Rosai J, tumors
thyroid. AJR Am J Roentgenol 1982; 138:495-98 68 Yousem DM, Scheff AM. Thyroid and parathyroid gland pathology. Otolaryngol Clin North Am 1995; 28:621-49 69 Stark DD, Gooding GAW, Moss AA, et al. Parathyroid imaging: comparison of high-resolution CT and high-resolu¬ tion sonography. AJR Am J Roentgenol 1983; 141:633-38 70 Nathaniels EK, Nathaniels AM, Wang C. Mediastinal para¬ thyroid tumors: a clinical and pathological study of 84 cases. Ann Surg 1970; 171:165-70 71 Hopkins CR, Reading CC. Thyroid and parathyroid imaging. Semin Ultrasound CT MR 1995; 16:279-95 72 Oates E. Improved parathyroid scintigraphy with Tc99m MIBI, a superior radiotracer. Appl Radiol 1994; 23:37-40 73 Seelos KC, DeMarco R, Clark OH, et al. Persistent and recurrent
hyperparathyroidism:
pentetate dimeglumine-enhanced 1990; 177:373-78
assessment
MR
with
gado-
imaging. Radiology
Reviews
Primary Mediastinal Tumors. Part 1*
Tumors of the Anterior Mediastinum
Diane C. Strollo, MD, FCCP; Lt Col Melissa L. Rosado de Christenson, MC, USAF; and fames R. Jett, MD, FCCP and account for 50% Primary anterior mediastinal neoplasms comprise a diverse group of tumors invasive and associated
of all mediastinal masses. Thymomas are most common and can be locally with parathymic syndromes. Thymic carcinomas and thymic carcinoids are rare malignancies with a propensity for local invasion and distant metastases. Thymolipomas are benign thymic tumors. The mediastinal germ cell tumors are a heterogeneous group of benign and malignant rare tumors and predominantly occur in young lymphangiomas are neoplasms.In Mediastinalmediastinal children. contrast, goiters are relatively common in adults. Mediastinal parathy¬a roid adenomas are an uncommon cause of persistent hyperparathyroidism and rarely cause discernible mass. The clinical, radiologic, and therapeutic aspects of the most common masses are reviewed. (CHEST 1997; 112:511-22)
Key words: germ cell tumors; goiter; lymphangioma; mediastinum; neoplasm; parathyroid adenoma; thymus Abbreviations: AFP=a-fetoprotein; p-HCG=beta-human chorionic gonadotropin HP he mediastinum is located in the central portion -*- of the thorax, between the two pleural cavities, the diaphragm and the thoracic inlet.1 It is usually divided into anterior, middle, and posterior "com¬ partments" to help categorize tumors and diseases according to their site of origin and location. How¬ ever, there are no fascial or anatomic planes that separate these compartments. Although various ra¬ diologic methods have been proposed for subdivid¬ ing the mediastinum, no single approach is univer¬ of sally applied. This reviewits uses the classification the It divides et al2 because of Fraser simplicity. mediastinum into anterior, middle, and posterior compartments based on the lateral chest radiograph (Fig 1). The anterior mediastinum is defined as the (Dr. Strollo), University of Department of Radiology Center; the Department of Radiologic Pa¬ Pittsburgh Medical Armed Forces Institute of thology (Dr. Rosado de Christenson), DC; and the University of Pittsburgh Pathology, Washington, Cancer Center (Dr. Jett). The and assertions contained herein are the
*From the
opinions
private
views of the authors and are not to be construed as official or as representing the views of the Department of the Air Force or
the Department of Defense. received November 4, 1996; revision accepted Jan¬ Manuscript 1997.
uary 16,
region posterior to the sternum and anterior to the
heart and brachiocephalic vessels. It extends from the thoracic inlet to the diaphragm and contains the thymus gland, fat, and lymph nodes. The middle mediastinum is defined as the space that contains the heart and pericardium to include the ascending and transverse aorta, the brachiocephalic vessels, the vena cavae, the main pulmonary arteries and veins, the trachea, bronchi, and lymph nodes. The poste¬ rior mediastinal compartment is bordered anteriorly by the heart and trachea and extends posteriorly to the thoracic vertebral margin to include the paraver¬ tebral gutters. The posterior mediastinum contains the descending thoracic aorta, esophagus, azygos veins, autonomic ganglia and nerves, thoracic duct, lymph nodes, and fat. Primary mediastinal tumors are a heterogeneous group of neoplastic, congenital, and inflammatory conditions.3 Neurogenic tumors, thymomas, and be¬ nign cysts account for approximately 60% of surgi¬ resected lesions while lymphoma, teratomas, cally and granulomatous diseases together comprise an additional 30%.l In nonsurgical series, vascular le¬ sions, typically aortic aneurysms, account for 10% of CHEST/112/2/AUGUST, 1997
511
equally affected and most patients are adults older than 40 years.5-7_9 Thymomas are rare in children and adolescents. Most patients are asymptomatic, al¬ though one third experience chest pain, cough, dyspnea, and/or other symptoms related to compres¬ sion or invasion of adjacent structures.10 Depending on the series, up to one half of patients suffer from
parathymic syndromes, most commonly and myasthenia gravis, hypogammaglobulinemia, 13 red cell in occurs pure aplasia.8 Myasthenia gravis 30 to 50% of with approximately patients thymoma. In comparison, only 15% of patients with myasthenia gravis have a thymoma.14 Because of this association, all patients with clinically suspected thymoma should have a serum antiacetylcholine receptor antibody level examined to exclude myasthenia gravis prior to surgery even if they are asymptomatic.1516 Falsepositive test results are rare. Approximately 25% of myasthenic patients with thymoma, particularly young women, have gradual improvement of symp¬ toms following thymectomy.61012 Uncommonly, my¬ asthenia gravis manifests in the postthymomectomy period5-617 and may be diagnosed by a rising titer of antiacetylcholine receptor antibody. Ten percent of patients with thymoma have hypogammaglobuline¬ mia.131718 While only 5% of patients with thymoma develop pure red cell aplasia, 50% of patients with red cell aplasia have a thymoma.513 Thymoma is also associated with various other autoimmune disorders and tumors.4'5-91113 While parathymic syndromes can cause significant morbidity and mortality,810 they can also prompt the early discovery of a thy¬ moma.511 are epithelial neoplasms Pathologically, thymomas characterized by an admixture of epithelial cells and mature lymphocytes.5 Most are solid neoplasms, but up to one third exhibit necrosis, hemorrhage, and cystic areas.510 Most thymomas are completely sur¬ rounded by a fibrous capsule. However, 34%, re¬ gardless of size, may invade through the capsule and extend directly into the mediastinal fat, pleura, peri¬ cardium, great vessels, right atrium, and/or the Because invasive thymomas lack his¬ lung.6-8-1119-21 features of malignancy and are microscopi¬ tologic to identical cally encapsulated thymomas,57 the term invasive thymoma is preferred over "malignant thy¬ moma."19 Transdiaphragmatic extension into the ab¬ domen and retroperitoneum and drop metastases to the ipsilateral pleura and pericardium may also occur.61119 Lymph node and hematogenous metas¬ tases are rare7810 and may occur both with invasive or encapsulated thymomas. Radiologically, thymoma is a well-defined, rounded, or lobulated anterior-superior mediastinal mass that typically arises from one of the thymic lobes and toward one side of the midline.22 one or more
Figure 1. Lateral chest radiograph. Using the classification of Fraser et al,2 the anterior mediastinal compartment is defined as the region anterior to a line (arrowheads) drawn along the anterior aspect of the heart and brachiocephalic vessels. The
middle and posterior mediastinal compartments are divided by a line (arrows) placed along the posterior tracheal wall and poste¬ rior heart border.
mediastinal mediastinal
masses.
tumors
two thirds of all ApproximatelyMore than 75% of benign.
are
asymptomatic patients with mediastinal tumors have benign lesions, while almost two thirds of symptom¬ atic patients with mediastinal masses have malignant lesions.4 This article will review primary anterior mediasti¬ nal tumors, which comprise approximately one half of all mediastinal masses. Anterior mediastinal neo¬ carcinoma, thymic plasms include thymoma, thymic carcinoid, thymolipoma, germ cell tumors, and para¬ thyroid adenoma; nonneoplastic conditions include thymic cyst, lymphangioma, and intrathoracic goiter.
occurs in the anterior mediasti¬ lymphoma will be discussed in part 2 of this series, which primarily addresses lesions of the middle and mediastinal
While
num, it
posterior
compartments.
Thymoma
Thymoma is the most common primary tumor of the anterior mediastinum.1'5-6 Men and women are 512
grows
Reviews
tumor extension occurs. commonly, bilateralresides usually just anterior to the thymoma aortic root,9 it can occur anywhere from the neck to the cardiophrenic angle.511 Most measure 5 to 10 cm with a reported size range from <1 cm to 34 cm5-8 (Fig 2). Radiographically detectable calcifications areor small, curvilinear, infrequent and are usually an On CT, encapsulated thymoma is a punctate.5-922 or well-defined, homogeneous, heterogeneous softtissue mass depending on the presence of hemor¬ rhage, necrosis, or cyst formation22 (Fig 3). Focalin areas of low attenuation can be a dominant feature large tumors.9 While subtle invasion may be difficult to detect on CT, an infiltrative appearance, obvious vascular compromise, and/or an irregular interface with the adjacent lung are highly suggestive findings of invasion22 (Fig 4). Thymoma can seed the pleural space, may progress to circumferentially encase the a diffuse lung, and can mimic the appearance ofEven with mesothelioma519'23 5). malignant (Fig extensive pleural involvement, pleural effusions are uncommon.11 Thoracic CT for the evaluation of thymoma should extend through the upper abdomen to exclude trans diaphragmatic extension.1924 On MRI, thymomas have intermediate signal intensity similar to or greater than that of skeletal muscle on ^-weighted images and increased signal intensity on T2-weighted images.9'22'25 Cystic areas with high fluid content characteristically have low signal inten¬ sity on Tx-weighted images and high signal intensity on T2-weighted images. Tumor lobules and fibrous
Less
While
septa are occasionally demonstrated.25 MRI excels in noninvasive evaluation of vascular structures to ex¬ clude invasion. Owing to the risk of recurrence,
long-term radiologic followup.6'8-9'12 To minimize the potential for invasion and to improve survival, complete surgical excision is at¬ tempted in most cases of thymoma.5612 Tumor invasiveness is determined by surgical findings of invasion supported by histologic evidence of tumor cells outside the confines of the tumor capsule.7-8 While patients with encapsulated thymoma have the best prognosis and are almost always cured by complete surgical resection, 2 to 12% of resected sometimes months or encapsulated thymomas recur, In years following excision.812 a series of 283 patients from Mayo Clinic,8 32% had locally invasive tumors, including 6% with metastases to the pleura or lung. The overall 5- and 10-year survivals were 67% and 53%, respectively. In those patients without invasive tumors, the 5- and 10-year survivals were 75% and 63%, respectively, vs 50% and 30%, respectively, in those with invasive thymomas. Forty-six percent had myasthenia but it was not associated with a worse survival (p=0.35). Radiation therapy is usually rec¬ ommended for invasive or incompletely excised tu¬ mors.26 Invasive is chemosensitive. Nuthymomas
merous
warrant
thymoma reports have documented responses
to
chemotherapeutic regimens, especially those In recent a utilizing cisplatin. report by Loehrer et 29 with or recurrent thymetastatic al,27 patients
various
Figure 2. Posteroanterior (left) and lateral (right) chest radiographs. A 10X7-cm sharply marginated thymoma (arrows) in the anterior mediastinum has been displaced inferiorly by its large weight.
CHEST/112/2/AUGUST, 1997
513
Figure 5. Enhanced chest CT. A recurrent, invasive thymoma has lobulated pleural implants that partially encase the right lung (arrowheads). Despite the extensive pleural tumor, note the absence of pleural effusion.
Figure 3. Enhanced chest CT. A well-circumscribed and lobulated thymoma (T) arises from the left thymic lobe and has curvilinear rim calcification in the tumor capsule (arrow); ao=aorta; t=trachea.
treated with cisplatin, doxorubicin, and The overall response rate was cyclophosphamide. 50% with three complete responses approximately and 12 partial responses. The median duration of moma were
response was 12 months with a median survival of 38 months and a 5-year survival of 30%. Thymic Carcinoma
The thymic carcinomas are a heterogeneous group aggressive epithelial malignancies that have a strong propensity for early local invasion and wide¬ spread metastases. Squamous cell carcinoma and carcinoma are the most lymphoepithelioma-like common cell types and usually occur in middle-aged men with a mean age of 46 years.28-29 Their malig¬ nant cytologic features distinguish them from both encapsulated and invasive thymomas as the latter are An occult primary lung malig¬ cytologically benign.30 to the metastatic nancy thymus must be excluded because the histologic types resemble those found more typically in the lung.2830 Thymic carcinoma is invasive and, unlike thymoma, frequently locally metastasizes to regional lymph nodes and distant of
sites.2931
Radiologically, thymic
carcinomas
com¬
monly manifest as large, poorly defined, infiltrative anterior mediastinal masses and are frequently asso¬ ciated with pleural and pericardial effusions,32 al¬
Figure 4. Enhanced chest CT at the level just below the aortic (ao) arch. An invasive thymoma (T) manifests as a midline, lobulated, homogeneous anterior mediastinal mass that slightly contains a punctate calcification. The thymoma invades the left brachiocephalic vein with tumor extension (asterisk) into the
superior vena cava (s).
514
though pleural implants are uncommon31 (Fig 6). Like thymoma, thymic carcinoma may exhibit cystic changes on cross-sectional imaging studies.32 and prognosis depend on tumor histo¬ Therapy condition and stage at presentation. Suster and logic Rosai28 reported a clinicopathologic series of 60 patients with thymic carcinoma. Although their se¬ ries was unable to document efficacy of the various treatment modalities, complete and partial response Reviews
Complete surgical exci¬to spread nodes, local tumor invasion, and distant regional metastases have been treated with radiotherapy and chemotherapy, but this tumor is highly resistant to
on
CT37 may also be
seen.
sion is the treatment of choice. Local
these modalities.34'36
Thymolipoma
Figure 6. Enhanced chest CT. Thymic carcinoma (a) originating
the anterior mediastinum infiltrates around the arch vessels and brachiocephalic veins. In the absence of lymphadenopathy and distant metastases, thymic carcinoma can be difficult to differentiate radiologically from invasive thymoma.
in
of thymic carcinoma to cisplatin-based chemother¬ apy has been reported.33 Combination chemother¬ apy with etoposide and cisplatin and concurrent is considered a reasonable treatment radiotherapyWhen approach. patients are unable to tolerate simultaneous chemoradiotherapy, sequential therapy is used.262733 The 3- and 5-year survival rates are 40% and 33%, respectively. The 5-year survival for high-grade tumors (defined as those with lobular severe cytologic atypia, extensive growth patterns, necrosis, and high mitotic activity) was 15 to 20% as opposed tothe90% for low-grade tumors,ofthus docu¬ menting prognostic importance histologic grade.
Thymic Carcinoid
is a rare malignancy that is Thymic carcinoid to carcinoid tumors at other histologically identical sites. It typically affects men in the fourth to fifth decades of life.3435 Approximately 50% of patients have endocrine abnormalities, most commonly adrenocorticoCushinghormone syndrome due to ectopic endocrine or multiple production tropin The classic carcinoid syn¬ neoplasia syndrome.5-34 drome is rarely associated with thymic carcinoid.36 or also be Patients
may
asymptomatic
experience
symptoms of compression and/or invasion.35
Re¬
metastases, including gional lymph node and distant are osteoblastic bone metastases, reported in up to 73% of cases and can occur late.34-36 Thymic carci¬ noid manifests as a large, lobulated, and usually invasive anterior mediastinal mass that may exhibit areas of hemorrhage and necrosis.534 Punctate and dystrophic calcification34 and contrast enhancement
benign slow-growing neo¬ Thymolipoma is a rare that affects male and female plasm of the thymus a wide age range. However, subjects equally over a mean adults (with age of 27 years) are most young afflicted.38 Approximately half of the pa¬ commonly tients are asymptomatic. is a large, soft, encapsulated mass Thymolipoma tissue.5 composed of mature adipose cells and thymic more than 2 Twenty-five percent of tumors weigh kg. Radiologically, thymolipoma is a large anterior mediastinal mass that frequently droops into the anterior inferior mediastinum and may occupy one or both hemithoraces. It is characterized by its ability to conform to adjacent structures simulating cardiomegaly and diaphragmatic elevation and by changes in shape that follow changes in patient position.38 CT the combination of fat and MRI demonstrate classic and soft-tissue elements and establish the tumor attachment to the anatomic region of the thymus (Fig 7). Some thymolipomas are of predominant fat attenuation and may resemble mediastinal lipomas.
Surgical excision is curative.
NONNEOPLASTIC THYMIC CYSTS
Thymic cysts are rare and represent approximately controversial. Thymic cysts may be congenital39 or is either due to inflammation or in associa¬ acquired, tion with an inflammatory neoplasm such as Hodgkin's lymphoma, seminoma, or thymic carcino¬ ma.40-41 Congenital thymic cysts are thought to be remnants of the thymopharyngeal duct and can be found anywhere along the embryologic course of the thymus as it migrates from theof neck into the anterior mediastinum.39 The origin inflammatory thymic cysts is less clear. They probably arise from inflamed cystic dilata¬ thymic parenchyma through secondary tion of epithelial-derived structures and contain ar¬ eas of inflammation and fibrosis. Approximately 50% of congenital thymic cysts are incidentally discovered in the first two decades of life,39 while inflammatory in asymptomatic adult thymic cysts usually occur men.40 Thymic cysts associated with neoplasia are more likely to cause symptoms. Most congenital cysts 3% of all anterior mediastinal masses.4 Their etiology
CHEST/112/2/AUGUST, 1997
515
Figure 7. Posteroanterior (top left) and lateral (top right) chest radiographs. A large thymolipoma (arrows) droops into the right inferior portion of the anterior mediastinum and conforms to the heart and right hemidiaphragm. Bottom, enhanced CT scans through the lower thorax. The thymolipoma arises from the anterior mediastinum, extends into the right hemithorax, and contains characteristic whorls of fat and thymic soft tissue. measure <6 cm, are usually rounded and uniloculated or multiloculated, and have thin walls without inflammatory change.40 Acquired thymic cysts range in size from 3 to 17 cm, are usually multiloculated,40 and have a variable wall thickness. Because inflam¬ matory thymic cysts may have microscopic and gross features identical to those of cystic thymic neo¬
516
plasms, thorough specimen sampling and examina¬ tion of the cyst wall are mandatory to exclude neoplasia.40 Radiologically, thymic cysts typically manifest as well-circumscribed anterior superior me¬ diastinal masses. They may be uniloculated or mul¬ tiloculated and have low usually
attenuation
con¬
tents, with occasional visualization of septa and linear Reviews
wall calcification. Surgical excision is the therapy of choice.41 Acquired lesions may recur after excision.40 Mediastinal Germ Cell Tumors
Mediastinal germ cell tumors (teratomas, seminoand nonseminomatous malignant germ cell tumors) are a heterogeneous group of benign and malignant neoplasms thought into originate from primitive germ cells "misplaced" the mediastinum The anterior medi¬ during early embryogenesis.42-43 astinum, especially the anterosuperior portion, is the most common extragonadal primary site.4244 Medi¬ astinal germ cell tumors represent approximately 10 to 15% of adult anterior mediastinal tumors142 and are histologically identical to their gonadal counter¬ parts.44-45 Patients are usually young adults with a mean age of 27 years.42-46 While mature teratomas occur with approximately equal frequency in male and female subjects, >90% of malignant germ cell tumors occur in male subjects.42 When a malignant mediastinal germ cell tumor is diagnosed, a primary mas,
gonadal malignancy (although rarely metastatic solely to the anterior mediastinum) must be exclud¬ ed.45-4748 Serologic evaluation for a-fetoprotein (AFP) and (3-human chorionic gonadotropin (pHCG) is helpful in the evaluation of patients with clinically suspected malignant mediastinal germ cell
tumor.
Mediastinal Teratomas Teratomas are die most common mediastinal germ cell tumors.4244 They are composed of tissues that arise from more than one of the three primitive germ cell layers42-45 and are "foreign" to the anatomic site in which they occur.45 The vast majority are mature teratomas that are histologically well differentiated and 42 A teratoma benign rarely contains fetal tissue and is then classified as an immature teratoma, which has a good prognosis in children but may recur or metastasize.45 Rarely, a mature teratoma can contain a focus of carcinoma, sarcoma, or malignant germ cell tumor; when it does, it is then termed a "malignant teratoma"45
sign of ruptured mediastinal teratoma.46-50 an encapsulated mass character¬ ized by the presence of cystic and solid areas.46 The tumor may attempt organ formation45 and can con¬ tain teeth, skin, and hair (ectodermal derivatives); derivatives); and/or cartilage and bone (mesodermal and bronchial, intestinal, pancreatic tissue (endodermal derivatives).45'46-49 Radiologically, these are rounded to lobulated, well-defined anterior medias¬ monic
Mature teratoma is
tinal masses that usually protrude to one side of midline and can reach large sizes.46 On chest radio¬ graphs, up to 26% exhibit calcification and may rarely display recognizable bone or teeth.46 On CT, these are typically multilocular cystic tumors with walls of variable thickness.51 The combination of fluid, soft tissue, calcium, and/or fat attenuation in an anterior mediastinal mass is a highly specific finding that allows the prospective diagnosis of mature ter¬ atoma (Fig 8). Fat-fluid levels produced by high lipid content in the cyst fluid are diagnostic but rare
findings. Surgical excision is curative.
Mediastinal Seminoma
Seminoma represents 40% of malignant germ cell single histology.47 White men in their third and fourth decades of life are most commonly
tumors of
afflicted and are usually symptomatic. Approximately 10% of patients with pure seminoma may have an elevated P-HCG level, but never an elevated AFP level. Radiologically, seminoma manifests as a bulky lobulated homogeneous anterior mediastinal mass,47 which uncommonly invades adjacent structures,4252 but can metastasize to regional lymph nodes and bone.47-53 Calcification is rare.54 Mediastinal semino-
"teratocarcinoma." Mature teratoma represents approximately 60 to 70% of mediastinal germ cell tumors.42 It occurs most frequently in children and young adults, with male and female subjects equally affected. Patients or
usually asymptomatic, but large tumors may chest pain, dyspnea, cough, or other symptoms of compression.46 Digestive enzymes secreted by intestinal mucosa or pancreatic tissue in the tumor can precipitate rupture into the bronchi, pleura, pericardium, or lung.42-45-46'49-50 Expectoration of hair (trichoptysis) or sebum is a rare but pathognoare
cause
Figure 8. Enhanced chest CT. A large mature teratoma was discovered in an asymptomatic patient. This multiincidentally cystic tumor has moderate septal enhancement (arrowhead) and contains fat and calcification char¬ acteristic
(white arrow)
of mature teratoma;
ao=aorta.
(black arrow),
CHEST/112/2/AUGUST, 1997
517
highly sensitive to both radiation and sys¬ chemotherapy.55 Treatment is somewhat con¬ troversial. Small localized tumors may be treated with primary resection followed by radiotherapy. In patients with locally advanced disease, the preferred treatment is systemic chemotherapy (see nonseminomatous germ cell tumors) followed by surgical resection of any residual disease. Therapy should be survival is 60 to in mas are
temic
curative
80%.42-55
most patients.
Long-term
Mediastinal Nonseminomatous Malignant Germ Cell Tumors The nonseminomatous malignant germ cell tu¬ mors include embryonal cell carcinoma, endodermal sinus tumor, choriocarcinoma, or mixed germ cell tumors composed of multiple histologic features. These are malignant and typically cause symptoms in young adult men.42 Lactate dehydrogenase and se¬ as AFP and p-HCG are fre¬ rologic markers such In of patients with extragoa series quently positive. nadal germ cell tumors, 20 of 28 (71%) patients with nonseminomatous tumors had an elevated AFP level and 15 of 28 (54%) had an elevated P-HCG level.55 In comparison, none of the 11 patients with semi¬ noma had an elevated AFP level and 2 of 11 had an elevated p-HCG level. Nonseminomatous malignant germ cell tumors are uniquely associated with hemaand approximately 20% of tologic malignancies4356 Klinefelter's have Radiologi¬ syndrome.43-57 patients mediastinal anterior are these large, irregular, cally, often with extensive, central, irregular, and masses, of low attenuation due to ne¬ areas heterogeneous and/or crosis, hemorrhage, cyst formation.52 Invasion of adjacent structures, including the chest wall, may occur as well as metastases to regional lymph nodes and distant sites58-59 (Fig 9). Pleural and pericardial effusions are common.4252 Bukowski and associates55 of the Southwest On¬ Group treated 41 patients with extragonadal cology seminoma or nonseminomatous malignant germ cell tumors with four cycles of chemotherapy containing and various other agents bleomycin and cisplatin followed by surgical resection. Twenty-four of 41 patients had mediastinal tumors while 15 had retro¬ tumors and 2 had unknown primary sites. peritoneal The 2- and 5-year survivals for the patients in this series were 67% and 60%, respectively.55 Currently, the standard treatment for a primary mediastinal malignant germ cell tumor is four cycles of bleomy¬ cin, etoposide, and cisplatin. Surgical resection of a residual mass is indicated, especially if the tumor markers are negative.55 While surgical excision should not be the initial treatment, a tissue diagnosis is necessary before starting chemotherapy. 518
Figure 9. Unenhanced chest CT. At the level of the carina, a mixed malignant germ cell tumor has multiple cystic areas (black arrows) and heterogeneous enhancement. It is associated with a small effusion (white arrow) and subsegmental atelectasis (a).
Mediastinal Lymphangioma
Mediastinal lymphangioma (cystic hygroma) is a histologically benign60 proliferation of interconnect¬ ing lymphatic vessels and sacs that may grow in an infiltrative fashion.61 Its etiology is controversial; some authors suggest it is a developmental lesion61 while others postulate it has a hamartomatous or origin.6061 Lymphangioma is typically a neoplastic tumor of very young children. Fifty percent are present at birth and 90% are discovered by 2 years of age.6062 Ninety-five percent involve the neck or axilla and 10% extend into the superior aspect of the anterior mediastinum63 or, less commonly, other mediastinal compartments.64 Rarely, lymphangiomas occur as primary mediastinal tumors in adults or as a generalized lymphangiomatosis with extensive multifocal involvement of multiple organ systems.6162 Pathologically, the dilated lymph spaces can range in caliber from capillary size to several centimeters in dimension.61 Mediastinal lymphangioma typically occurs in the superior aspect of the anterior medi¬ astinum and is usually contiguous with a cervical or these are axillary component.62 Radiologically, tumors that can rounded, lobulated, multicystic reach massive sizes and may infiltrate across tissue (Fig 10). They may surround or displace planes63 mediastinal structures.63-64 On CT, "cysts" (repre¬ senting the large vascular spaces) vary in diameter from 1 to 2 mm to several centimeters, are usually Reviews
commonly in asymptomatic women with cervical palpable goiter. Occasionally patients have of or symptoms compression pain. Radiologically, mediastinal goiter is an encapsu¬ lated, lobulated, heterogeneous tumor.6667 The di¬ agnostic radiologic feature is the continuity between the cervical and mediastinal components that is usually evident on cross-sectional imaging (Fig 11). Well-defined areas of low attenuation on an unen¬ hanced chest CT can reflect hemorrhage and cyst formation while areas of increased attenuation rela¬ tive to adjacent soft-tissue structures represent in¬ trinsic iodine within the gland.6667 Coarse, punctate, or ring-like calcifications are common65 (Fig 12). After IV contrast administration, the goiter fre¬ quently demonstrates intense and sustained en¬ hancement.67 Radioactive iodine 131 and 123 scin¬ can be diagnostic when functioning thyroid tigraphy tissue is present.65 The treatment of choice for symptomatic or potentially symptomatic lesions is surgical resection. Most can be excised through a cervical incision but occasionally a sternotomy is occur a
most
required.
Mediastinal Parathyroid Adenoma Figure 10.
of the neck. A large multicystic Top: enhanced CT has
neck lymphangioma (L) slight septal enhancement (arrow) and infiltrates throughout the tissue planes. Bottom: enhanced chest CT at the top of the aortic arch (ao). The is a sharply marginated water attenuation mass lymphangioma that insinuates between the aorta and superior vena cava (s).
right
adenoma is a benign functioning parathyroid that occurs most commonly in the neck. neoplasm A
display thin or thick after contrast minimally administration.63 Because of its insinuating nature, complete surgical resection of lymphangiomas may be difficult and surveillance is needed to exclude near
water
attenuation, and
septa that may enhance
recurrence.60-62
Mediastinal Goiter
While mediastinal goiter represents only 10% of mediastinal masses in surgical series,1 it is one of the most commonly seen in clinical practice. Twenty percent of cervical goiters descend into the thorax, usually into the left anterior superior mediastinum.65 Infrequently, they can extend behind the trachea and involve the middle and posterior mediastinal compartments. Primary intrathoracic goiters without a cervical component are very rare.66 These tumors rarely contain foci of malignancy. Mediastinal goiters
Figure 11. Posteroanterior chest
radiograph. A large intratho¬
goiter (arrows) extends from the left thyroid lobe into the bilateral anterior mediastinum and displaces the trachea (aster¬ isk) to the right. racic
CHEST/112/2/AUGUST, 1997
519
with vague chest complaints or with signs and symp¬ toms related to compression or invasion of medias¬ tinal structures. The most common primary anterior mediastinal tumors are thymoma, teratoma, substernal goiter, and lymphoma. All other lesions are extremely rare. Patients with anterior mediastinal masses should be evaluated preoperatively for myasthenia gravis that could result in respiratory failure in the postopera¬ tive period if untreated. Neck palpation should be performed to exclude the mediastinal extension of a cervical goiter and to detect occult generalized
Figure 12. Unenhanced chest CT at the thoracic inlet. A left cervical goiter (G) extends into the anterior superior mediasti¬ num, with moderate mass effect on the trachea (t). The goiter has attenuation equal to and slightly greater than skeletal muscle and contains curvilinear dystrophic calcifications (arrow).
tumors are ectopic68 and almost the anterior mediastinum, usually within the thymus due to a common embryfrom the third and fourth brachial origin ologic Older women are most commonly af¬ pouches.70 fected and present with signs and symptoms of hyperparathyroidism that persist following cervical
Ten
percent of
half39
occur near or
in
parathyroidectomy.mediastinal parathyroid adenomas Pathologically, are identical to cervical parathyroid adenomas. They are encapsulated and rounded and usually measure <3 cm.69 Because of their small size, they are rarely detected on chest radiographs. On unenhanced CT, can resemble a lymph node and only 25% they demonstrate perceptible enhancement after IV con¬ trast administration.68-69 Parathyroid adenomas can avidly take up radioactive 99mTc and 201Tl. For localizing parathyroid adenomas,of 99mTc-sestamibi 88 to 100% is with a sensitivity scintigraphy to dual isotope imaging using
superior
99mTc-per-
technetate and 201Tl which has a sensitivity of 55 to 100%.68'7172 On MRI, parathyroid adenomas have increased signal intensity on T2-weighted images and
gadolinium-enhanced ^-weighted images.68-71in parathyroid glands Fifty to 75% of abnormal patients with persistent or recurrent hyperparathy¬ with MRI.73 on
roidism
can
be detected
Conclusion
Many mediastinal masses are serendipitously dis¬ on chest radiographs obtained for other reasons. Some patients will come to clinical attention covered 520
lymphadenopathy. The radiologic evaluation of these patients begins with the chest radiograph and is followed by crosssectional imaging with CT. CT is useful in excluding vascular causes and some benign causes of medias¬ tinal widening such as lipomatosis. In addition, con¬ fident diagnosis of some lesions such as mature teratoma and mediastinal goiter can be accomplished as well as evaluation of adjacent structures to exclude evidence of mass effect or invasion. In addition to basic laboratory tests, serologic evaluation for detection of antiacetylcholine receptor antibodies, AFP and (3-HCG should be performed to exclude myasthenia gravis and nonseminomatous malignant germ cell tumors, respectively. Patients with primary mediastinal masses and cysts will usually undergo surgical resection. The presence of lymphadenopathy (in the case of lymphoma and metastatic disease) or positive AFP or P-HCG sero¬ logic test results should prompt limited biopsy spec¬ imens of the lesion followed by oncologic consulta¬ tion and chemotherapy or radiotherapy when Resection of residual tumor will follow appropriate.
m some cases.
Special thanks to Vivian L. McBride for her expertise in preparing the manuscript.
ACKNOWLEDGMENT:
1
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