XXVI - Noninvasive Investigations

Editors: Shields, Thomas W.; LoCicero, Joseph; Ponn, Ronald B.; Rusch, Valerie W.

Title: General Thoracic Surgery, 6th Edition

Copyright 2005 Lippincott Williams & Wilkins

> Table of Contents > Volume II > The Mediastinum > Section XXIX - Primary Mediastinal Tumors and Syndromes Associated with Mediastinal Lesions > Chapter 186 - Primary Seminomas of the Mediastinum

Chapter 186

Primary Seminomas of the Mediastinum

Robert J. Dabal

Douglas E. Wood

Initially described by Woolner and associates in 1955, primary mediastinal seminomas are the second most common of the mediastinal germ cell tumors. Whereas mediastinal germ cell tumors account for only 3% to 5% of all germ cell tumors, primary seminomas are the most common of the malignant mediastinal germ cell tumors, accounting for 40% to 50% of these tumors.

ETIOLOGY

Although the exact origin of mediastinal seminomas is unknown, there have been several commonly espoused theories. Frideman (1951) was the first to propose that all germ cell tumors originated from extragonadal, potentially biphasic germ cell tumors left within the embryonic thymus. This theory was further endorsed by Lattes in 1962. A second, more recent theory espoused by Frideman (1987) holds that germ cells are present in ectopic sites other than the thymus in all healthy persons as part of a wide distribution during normal embryogenesis or as part of misplacement during migration along the midline from the yolk sac to the embryonal gonadal ridge. A third but largely discounted theory holds that mediastinal sites of germ cell tumor merely represent metastatic lesions from a gonadal primary site that is occult and are not primary lesions. Autopsy series such as that published by Johnson and colleagues (1973) have basically disproved this theory. In addition, clinical reports by Polansky (1979) and El-Domeiri (1968) and their associates of primary mediastinal seminomas occurring in women dispute this theory.

PATHOLOGY

Seminomas are typically slow-growing tumors that present as large mediastinal masses with a lobulated appearance, including areas of necrosis, hemorrhage, or both. The average size of these tumors at presentation is 5 cm, although many have been as large as 14 cm, as noted by Martini (1974) and Schantz (1972) and their associates. Encapsulation is present about half of the time, and the tumors are frequently lobulated. Calcification is infrequently seen. Rarely, the tumor may present as a cystic structure, as reported by Kataoka and Seno (1997). Some authors have suggested an association with the thymus. However, the large size of these tumors at the time of diagnosis makes it difficult to distinguish a thymic origin from thymic displacement by tumor growth.

Histologically, they are nearly identical to testicular seminomas in appearance, characterized by sheets of cells that may adopt a discrete nesting pattern. According to Moran and co-workers (1997), the malignant cells are round or polygonal cells that are medium to large (15 to 30 m) with indistinct cell borders, lightly eosinophilic cytoplasm, and round or oval nuclei with prominent nucleoli (Fig. 186-1). Delicate connective tissue septa typically separate the sheets or lobules of cells. It is uncommon to find mitoses, and an inflammatory cellular infiltrate composed predominantly of lymphocytes can accompany the neoplastic proliferation. Remnants of thymic tissue, foci of necrosis, epithelioid granulomas, occasional nonneoplastic, multinucleated giant cells, and trophoblastic cells are other histologic features that may be present, as noted by Frideman (1951). Because mixed tumors frequently occur, histologic analysis is important to exclude nonseminomatous elements that might change treatment or prognosis of a given tumor; however, the latter is more importantly ruled in or out by the presence or absence of -fetoprotein (AFP) in the blood serum (discussed later).

Immunohistochemical staining of mediastinal seminomas reveals results that correspond to known serum expression of tumor markers. These tumors typically express high levels of placental alkaline phosphatase (PLAP), rarely express -human chorionic gonadotropin ( -HCG), and do not express AFP. Of note, Moran and associates (1997)

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reported that focal dotlike positive results for CAM 5.2 low-molecular-weight keratins occur in 75% of these tumors. Of interest, only 20% of testicular seminomas were positive for CAM 5.2 low-molecular-weight keratin, according to Suster and associates (1998). Focal cytoplasmic staining for wide-spectrum keratin is present 70% of the time, and positive staining for vimentin occurs in 70% of cases.

Fig. 186-1. Photomicrograph of an anterior mediastinal seminoma from a young man. Typical features include round and polygonal cells with abundant clear cytoplasm and central nuclei. Courtesy of Patricia Camuto, M.D.

DIAGNOSIS

Primary seminomas of the mediastinum typically present as large anterior mediastinal masses, although they have also been rarely described in the middle and posterior mediastinum by Kitami and colleagues (1998) and Makiyama and Senga (2001). An overwhelming majority of these tumors occur in men, typically in their twenties to forties. It is predominantly a disease of white men, rarely occurring in African-American men. Symptoms are variable and can be vague, such as chest pain, cough, dyspnea, fever, and weight loss. Symptoms due to compression of adjacent structures, including hoarseness from recurrent laryngeal nerve invasion, dysphagia from esophageal compression, or superior vena cava syndrome from vascular compression, are uncommon but may occur in up to 10% of patients. More than 80% of patients are symptomatic at the time of presentation, and 60% to 70% have metastatic disease, with metastases to bone, lung, liver, spleen, spinal cord, or brain.

Radiographic Studies

Chest radiographs are the first diagnostic test that should be obtained in patients suspected of having an anterior mediastinal tumor. Standard posteroanterior and lateral chest radiographs demonstrate most of these tumors (Fig. 186-2). Small tumors may, however, be missed. Chest computed tomography (CT) is the most useful subsequent imaging procedure and is important in diagnosing small tumors. CT scanning provides clear localization of the tumor relative to other mediastinal structures, may help determine tissue composition (Fig. 186-3), and may detect mediastinal lymphadenopathy or intrathoracic metastases, particularly those in the lung hidden by the tumor on plain radiographs. Additional radiologic studies, such as a bone scan, head CT, or magnetic resonance (MR) imaging, are indicated only if there are signs or symptoms of metastatic disease in these locations.

Serum Tumor Markers

Serum tumor markers are a critical component of the diagnosis, treatment, and follow-up of patients with mediastinal seminomas. All young men with an anterior mediastinal mass should be suspected of having a mediastinal germ cell tumor and should have AFP and -HCG levels obtained. Primary mediastinal seminomas may have a minimal elevation of -HCG but will not have AFP. Nichols (1991) noted that up to 10% of patients with pure seminoma have a mild elevation (<100 mIU/mL) in -HCG level. Higher levels of -HCG should raise suspicion of a mixed tumor. Any presence of AFP in the serum, regardless of the inability to identify nonseminomatous elements, renders the tumor a nonseminomatous or germ cell mixed tumor and must be treated as such. Finally, most patients with a seminoma have elevated lactate dehydrogenase levels, the significance or absence thereof is of no importance as to the diagnosis or treatment of the tumor.

Given the identical histologic appearance of primary mediastinal and testicular seminomas, all patients with mediastinal disease must undergo testicular evaluation, including a careful bimanual exam and an ultrasound of the testicles. In addition, a thorough staging workup should include a CT scan of the abdomen to evaluate for systemic disease. The importance of this may be questioned if chemotherapy is elected as the therapy of choice.

Although classic tumor marker elevation may be adequate for initiation therapy in nonseminomatous germ cell tumors, in suspected seminomas, surgical biopsy is indicated for diagnosis. Tissue can be obtained from the anterior mediastinum either by anterior mediastinotomy or anterior mediastinoscopy. Cervical mediastinoscopy and thoracoscopy can also be considered. Video-assisted thoracic surgery (VATS) is preferred by many over the use of anterior mediastinotomy. There is no indication for surgery beyond obtaining a tissue diagnosis (discussed later).

Fig. 186-2. Posteroanterior (A) and lateral (B) chest radiographs of an adult man with a large anterior mediastinal mass. C. CT scan revealed posterior displacement of the trachea and esophagus. Pure seminoma was seen on the biopsy. No elevation of human chorionic gonadotropin- level was noted, and -fetoprotein level was normal. Complete remission was seen for more than 10 years after combination chemotherapy.

Fig. 186-3. CT scan of mediastinal seminoma. Fat planes surrounding adjacent mediastinal structures are obliterated, and the mass itself is homogeneous throughout.

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STAGING

In terms of staging, there is no standard staging system that is universally accepted for primary extragonadal seminoma. Two separate staging systems are available, that of Cefaro and colleagues (1988) and that of Moran and associates (1997). However, the rarity of these tumors makes establishment of a reliable staging system that is able to stratify patients for treatment purposes and is able to predict prognosis difficult. Poor prognostic indicators are well established, as published by Heitmiller and Marasco (1995). These include age greater than 35 years, bulky mediastinal disease, superior vena caval obstruction, and lymphadenopathy.

TREATMENT

Radiation Therapy

The treatment of primary mediastinal seminomas has evolved greatly over the past 10 to 20 years as experience with the tumor has increased. Initially treated by surgical biopsy or debulking followed by radiation therapy for localized disease, it is now clear that the first line of treatment should be chemotherapy in all cases. Although irradiation is effective in treating this disease, it results in a long-term complete remission in only about 65% of patients, as noted by Fizazi and co-workers (1998).

Chemotherapy

The use of platinum-based chemotherapy has resulted in a complete remission rate of 88% to 100%, as recorded by Jain (1984) and Bokemeyer (2002) and their associates. Mencel and collaborators (1994), in a review of 142 patients reported in the literature, reported a 5-year survival rate of 70% to 85% with various cisplatin-based regimens. The most common combination regimen used is cisplatin, bleomycin, etoposide, and vinblastine.

Failure of induction chemotherapy to eradicate bulky mediastinal disease necessitates further treatment. Adjuvant radiation therapy is recommended in cases of local recurrence or if there is persistent disease after chemotherapy.

Surgical Resection

The role of surgical resection in the treatment of primary mediastinal seminoma is controversial. Some authors have suggested primary resection in good-risk surgical candidates with small, localized mediastinal tumors. In addition, surgical resection may be performed for an undiagnosed anterior mediastinal mass that is postoperatively found to be a seminoma. In both of these cases, surgical resection is inadequate as the sole treatment modality. These patients should have adjuvant irradiation at a minimum. Given the high percentage of patients with systemic disease, chemotherapy should also be considered as adjuvant therapy.

Surgical resection has also been proposed by Kolodziejski and associates (1999) in patients with residual mediastinal masses larger than 3 cm following chemotherapy and radiation therapy to detect any persistent, viable tumor. The role of resection with residual tumor is twofold in this situation. First, it is to document if there is residual disease as opposed to necrotic debris following treatment. Second, it is to rule out the presence of a nonseminomatous component to the tumor that was previously unrecognized. Motzer and colleagues (1987) opine that the residual tumor would then be treated either with additional chemotherapy or thoracic irradiation. However, there are no data to suggest that surgical excision enhances either local control or survival when compared with radiation therapy, chemotherapy, or combined chemoradiotherapy. Given the excellent results achievable with irradiation and chemotherapy, the role of surgery for primary mediastinal seminoma is negligible.

REFERENCES

Bokemeyer C, et al: Extragonadal germ cell tumors of the mediastinum and retroperitoneum: results from an international analysis. J Clin Oncol 20:1864, 2002.

Cefaro GA, et al: Primary mediastinal seminoma. Br J Urol 62:461, 1988.

El-Domeiri AA, et al: Primary seminoma of the anterior mediastinum. Ann Thorac Surg 6:513, 1968.

Fizazi K, et al: Initial management of primary mediastinal seminoma: radiotherapy or cisplatin-based chemotherapy? Eur J Cancer 34:347, 1998.

Frideman NB: The comparative morphogenesis of extragenital and gonadal teratoid tumors. Cancer 4:265, 1951.

Frideman N: The function of the primordial germ cell in extragonadal tissues. Int J Androl 10:43, 1987.

Heitmiller RF, Marasco WJ: Primary mediastinal seminoma. In Wood DE, Thomas CR Jr (eds): Mediastinal Tumors. Berlin: Springer-Verlag, 1995, pp. 49 54.

Jain KK, et al: The treatment of extragonadal seminoma. J Clin Oncol 2:820, 1984.

Johnson DE, et al: Extragonadal germ cell tumors. Surgery 73:85, 1973.

Kataoka K, Seno N: A case of mediastinal seminoma undergoing extremely cystic degeneration. Nihon Kyobu Shikkan Gakkai Zasshi 35: 1108, 1997.

Kitami A, et al: Primary seminoma in the middle mediastinum: case report in a 69 year old male. Jpn J Clin Oncol 28:142, 1998.

Kolodziejski L, et al: Occurrence of malignant non-germ cell components in primary mediastinal germ cell tumours. Eur J Surg Oncol 25:54, 1999.

Lattes R: Thymoma and other tumors of the thymus. Cancer 15:1224, 1962.

Makiyama K, Senga Y: Primary seminoma in the posterior mediastinum. J Urol 165:908, 2001.

Martini N, et al: Primary mediastinal germ cell tumors. Cancer 33:763, 1974.

Mencel PJ, et al: Advanced seminoma: treatment results, survival, and prognostic factors in 142 patients. J Clin Oncol 12:120, 1994.

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Moran CA, et al: Primary germ cell tumors of the mediastinum: II. Mediastinal seminomas a clinicopathologic and immunohistochemical study of 120 cases. Cancer 80:691, 1997.

Motzer R, et al: Residual mass: an indication for further therapy in patients with advanced seminoma following systemic chemotherapy. J Clin Oncol 5:1065, 1987.

Nichols CR: Mediastinal germ cell tumors: clinical features and biologic correlates. Chest 99:472, 1991.

Polansky SM, Barwick KW, Ravin CE: Primary mediastinal seminoma. AJR Am J Roentgenol 132:17, 1979.

Schantz A, Sewall W, Castleman B: Mediastinal germinoma: a study of 21 cases with an excellent prognosis. Cancer 30:1189, 1972.

Suster S, et al: Germ cell tumors of the mediastinum and testis: a comparative immunohistochemical study of 120 cases. Hum Pathol 29:737, 1998.

Woolner LB, Jamplis RW, Kirklin JW: Seminoma (germinoma) apparently primary in anterior mediastinum. N Engl J Med 252:653, 1955.

Reading References

Aygun C, et al: Primary mediastinal seminoma. Urology 23:109, 1984.

Dulmet EM, et al: Germ cell tumors of the mediastinum: a 30-year experience. Cancer 72:1894, 1993.

Gerl A, et al: Cisplatin-based chemotherapy of primary extragonadal germ cell tumors: a single institution experience. Cancer 77:526, 1996.

Goss PE, et al: Extragonadal germ cell tumors: a 14-year Toronto experience. Cancer 73:1971, 1994.

Jyothirmayi R, et al: Primary malignant germ cell tumors of the mediastinum results of multimodality treatment. Acta Oncol 36:317, 1997.

Nagi DK, Jones WG, Belchetz PE: Gynaecomastia caused by a primary mediastinal seminoma. Clin Endocrinol (Oxf) 40:545, 1994.

Uematsu M, et al: The role of radiotherapy in the treatment of primary mediastinal seminoma. Radiother Oncol 24:226, 1992.



General Thoracic Surgery. Two Volume Set. 6th Edition
General Thoracic Surgery (General Thoracic Surgery (Shields)) [2 VOLUME SET]
ISBN: 0781779820
EAN: 2147483647
Year: 2004
Pages: 203

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