159 - Radionuclide Studies of the Mediastinum

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 188 - Poorly Differentiated Carcinoma of the Mediastinum

Chapter 188

Poorly Differentiated Carcinoma of the Mediastinum

John D. Hainsworth

F. Anthony Greco

The diagnosis of poorly differentiated carcinoma poses difficult problems for the clinician. Occasionally, a patient with a mediastinal tumor has such a diagnosis rendered at the time of biopsy. Five of 38 patients (13%) with primary mediastinal tumors described by Adkins and associates (1984) had undifferentiated carcinoma. This diagnosis indicates a tumor with no histopathologic features allowing precise identification of the site of origin. Patients with poorly differentiated carcinoma in the mediastinum are sometimes treated with palliative radiation therapy or symptomatic treatment alone, because they are assumed to have metastatic lung cancer with an undetected primary lesion that is unresectable and incurable. However, this approach is not recommended, because optimal clinical and pathologic evaluation can establish a more definitive diagnosis with specific therapeutic implications in some of these patients. In addition, some patients with poorly differentiated carcinoma involving the mediastinum are curable with intensive cisplatin-based chemotherapy.

The recommended pathologic evaluation, staging, and treatment of the patient with poorly differentiated carcinoma in the mediastinum is considered. This is an area in which treatment recommendations are still developing, and many unanswered questions remain.

PATHOLOGIC EVALUATION

Many types of cancer can involve the mediastinum, and some of these frequently have a poorly differentiated histology (Table 188-1). Because highly effective, specific treatments exist for some of these tumor types, it is essential to use all means possible to make a specific diagnosis before embarking on therapy. Optimal evaluation of these patients requires close communication between the clinician and pathologist. In some cases, the nonspecific diagnosis of poorly differentiated carcinoma or poorly differentiated neoplasm is given simply because the pathologist has a small, inadequate biopsy specimen to examine. Frequently, in such a situation, a larger, adequately handled biopsy specimen is all that is necessary to make a more specific diagnosis. In general, fine-needle aspiration (FNA) biopsies are inadequate to diagnose mediastinal tumors because they usually do not provide an adequate amount of tissue for histologic examination and special studies.

Immunoperoxidase Staining

When light microscopic examination of an adequate biopsy specimen fails to provide a specific diagnosis, specialized pathologic studies should be performed. Immunoperoxidase staining techniques are widely available and have become increasingly useful in the evaluation of poorly differentiated tumors. In evaluating such tumors in the mediastinum, immunoperoxidase staining can suggest the presence of: (a) unsuspected lymphoma (positive common leukocyte antigen, negative keratin stains), (b) malignant germ cell tumor (positive human chorionic gonadotropin, positive -fetoprotein stains), (c) poorly differentiated neuroendocrine carcinoma (positive neuron-specific enolase, chromogranin, synaptophysin stains), (d) poorly differentiated sarcoma (positive vimentin, positive desmin stains), and (e) melanoma (positive S-100 protein, positive HMB-45, negative keratin stains). In a large group of patients with poorly differentiated carcinoma (mediastinal and other metastatic sites), we (1991) performed immunoperoxidase staining that suggested specific diagnoses in 20% of patients. In the remaining 80% of patients, the diagnosis of poorly differentiated carcinoma was confirmed, or the test results were inconclusive.

Table 188-1. Mediastinal Tumors with Poorly Differentiated Histologic Features

Extragonadal germ cell tumor, seminoma or nonseminoma
Non-Hodgkin's lymphoma
Malignant thymoma
Thymic carcinoid tumor or other neuroendocrine carcinoma
Metastatic lung cancer, small cell or non small cell
Undifferentiated soft tissue sarcoma
Other metastatic tumors

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Electron Microscopy

Electron microscopy is also a valuable adjunct to light microscopy. The examination of ultrastructural features is particularly useful when the initial diagnosis is poorly differentiated neoplasm, a nonspecific diagnosis given when the tumor may be either a poorly differentiated carcinoma, lymphoma, sarcoma, or melanoma. Electron microscopy is reliable in distinguishing lymphoma from carcinoma and can often establish a definitive diagnosis of melanoma or poorly differentiated sarcoma. Table 188-2 shows the results of electron microscopy in a large series of patients with poorly differentiated carcinoma of unknown primary site reported by us and our associates (1987). Because electron microscopy is less readily available than immunoperoxidase staining and often requires another biopsy for special tissue preparation, this technique should be reserved for patients in whom the diagnosis is unclear after immunoperoxidase staining has been performed.

Chromosomal Abnormalities

Several tumor types are associated with specific chromosomal abnormalities, allowing definitive diagnosis (Table 188-3). All of these tumor types have poorly differentiated histology and can occur in the mediastinum. Motzer and associates (1995) performed molecular genetic analysis on a group of 40 young men with poorly differentiated tumors involving the mediastinum. In none of these patients had other pathologic methods yielded a specific diagnosis. On the basis of specific chromosomal abnormalities, precise diagnoses were made in 17 patients (42%), as follows: germ cell tumor, 12 patients; lymphoma, 1 patient; peripheral neuroepithelioma, 1 patient; desmoplastic small cell tumor, 1 patient; and melanoma, 2 patients. The patients with germ cell tumors identified in this manner had excellent responses to appropriate chemotherapy.

Table 188-2. Results of Electron Microscopy in 56 Patients with Poorly Differentiated Carcinoma of Unknown Primary Site

Diagnosis No. of Patients
Malignant neoplasm 6
Carcinoma 8
Adenocarcinoma 17
Melanoma 5
Neuroendocrine tumor 4
Lymphoma 2
Sarcoma 2
Hemangiopericytoma 2
Steroid-producing neoplasm 2
Bronchoalveolar carcinoma 2
Squamous cell carcinoma 1
Carcinosarcoma 1
Clear cell carcinoma 1
Ewing's tumor 1
Neuroblastic neoplasm 1
Seminoma 1
Total 56

Table 188-3. Specific Molecular Genetic Abnormalities Associated with Poorly Differentiated Tumors

Tumor Type Chromosomal Abnormality
Germ cell tumor i(12p)
Peripheral neuroepithelioma t(11:22)
Ewing's tumor t(11:22)
Melanoma t(12:22), i(6) (p10)
Non-Hodgkin's lymphoma Immunoglobulin gene rearrangements

DIAGNOSTIC EVALUATION AND STAGING WORKUP

After appropriate special pathologic evaluation, some patients with poorly differentiated carcinoma of the mediastinum are given a more specific diagnosis with specific therapeutic implications. For example, patients in whom the diagnosis of malignant lymphoma or malignant extragonadal germ cell tumor is established should be treated appropriately for these entities.

Patients with poorly differentiated carcinoma who have neuroendocrine features detected by either electron microscopy or immunoperoxidase staining are a distinct subset and require special evaluation and treatment (see Chapter 114). In patients with a smoking history, small cell lung cancer should be considered, and fiberoptic bronchoscopy should be performed. Patients who have no lung primary lesions detected, or who are nonsmokers, usually do not have another primary site detected and often exhibit rapid tumor growth and dissemination. Although these neuroendocrine tumors are not yet well defined, we and Johnson (1988) recognized that these tumors are usually highly responsive to combination chemotherapy.

Patients in whom optimal pathologic evaluation does not provide a diagnosis more specific than poorly differentiated carcinoma should be evaluated using standard guidelines for carcinoma of unknown primary site. The initial history and physical examination should be used to guide the search for a primary site. In addition to evaluating specific signs and symptoms, these patients should undergo computed

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tomography (CT) of the chest and abdomen. Extensive additional radiographic evaluation of asymptomatic areas is not recommended. Serum levels of human chorionic gonadotropin and -fetoprotein should be measured in all patients. High levels of these markers are diagnostic of a malignant extragonadal germ cell tumor. In middle-aged or elderly patients, particularly those with a smoking history, fiberoptic bronchoscopy should be performed to search for an unsuspected lung primary site. The finding of an endobronchial lesion provides strong evidence of a primary lung tumor.

TREATMENT

Results of the diagnostic evaluation define treatments for certain subsets of patients with poorly differentiated carcinoma in the mediastinum. Patients with high levels of either human chorionic gonadotropin or -fetoprotein should be treated for malignant nonseminomatous germ cell tumor, even if this diagnosis cannot be made definitively by histologic examination (see Chapter 187). Patients who are found to have an endobronchial lesion at bronchoscopy probably have lung cancer; those whose tumors have neuroendocrine features (under electron microscopy or immunoperoxidase staining) should receive therapy for small cell lung cancer, whereas those lacking these features should be treated for non small cell lung cancer (NSCLC).

A few patients with poorly differentiated carcinoma and no distinguishing pathologic or clinical features have tumors that seem limited to the mediastinum and that do not extensively invade local structures. In these patients, an attempt at total tumor resection should be considered, although this approach is curative in only a small percentage.

A large majority of patients in this group have obviously unresectable tumors and require treatment with other modalities. Our interest in such patients began in 1977, when we treated a young man with a huge, unresectable mediastinal tumor that was called a poorly differentiated carcinoma. Surprisingly, this patient had a complete and sustained response to cisplatin-based chemotherapy. Review of the pathologic data failed to indicate the presence of an unsuspected malignant germ cell tumor. Subsequent reports by Richardson and associates from Vanderbilt (1979, 1981) and Fox and colleagues (1979) in a small series of patients with poorly differentiated carcinoma of unknown primary site confirmed a high level of responsiveness to cisplatin-based chemotherapy. In these series, a total of 12 of 17 patients had tumors located in the mediastinum.

In a subsequent prospective series, we and Vaughn (1986) and we and Johnson (1992) treated a total of 252 patients with poorly differentiated carcinoma of unknown primary site with cisplatin-based chemotherapy effective for germ cell tumors. Thirty-seven of these patients (15%) had disease located predominantly in the mediastinum. Thirty patients were men; median age was 45 years (range 20 to 61 years). Most patients had metastases at one or more sites in addition to the mediastinum, and none was surgically resectable. Twenty-two of 32 evaluable patients responded to platinum-based chemotherapy; 14 patients (38%) had complete responses. Eight patients (22%) remain disease-free more than 5 years after completing therapy.

During the past several years, several new chemotherapeutic agents have improved the empiric therapy of patients with carcinoma of unknown primary site. Our group (1997, 2000a, 2000b, 2002) and Briasoulis and colleagues (2000) have investigated combinations containing a taxane (paclitaxel or docetaxel) and a platinum agent (carboplatin or cisplatin). With these regimens, 1- and 2-year survival rates are 40% to 50% and 20% to 25%, respectively, in an unselected group of patients with carcinoma of unknown primary site. Approximately 15% of these patients had tumor located predominantly in the mediastinum. In these patients, response rates were higher than 50%. Patients who had neuroendocrine features by immunoperoxidase staining were particularly sensitive to these regimens. In a group of 32 such patients reported by McKay and others at our center (2002), the actuarial 2-year survival rate was 38% following treatment with paclitaxel, carboplatin, and etoposide.

In summary, patients with mediastinal tumors who are initially given the diagnosis of poorly differentiated carcinoma are a heterogeneous group. Some of these patients actually have tumors of well-defined types, which can be identified precisely with either additional pathologic or clinical evaluation. Patients in whom a specific tumor type is identified should be treated according to standard guidelines for that tumor type. When no well-defined tumor type is recognized, patients should receive a trial of platinum-based or taxane/platinum-based chemotherapy. Some of these patients have highly responsive neoplasms, and a minority are cured with this treatment. Further improvement in the management of these patients awaits better means of identifying chemotherapy-responsive patients and optimization of the chemotherapy regimens used.

REFERENCES

Adkins RB Jr, Maples MD, Hainsworth JD: Primary malignant mediastinal tumors. Ann Thorac Surg 38:648, 1984.

Briasoulis E, et al: Carboplatin plus paclitaxel in unknown primary carcinoma: a phase II Hellenic Cooperative Oncology Group study. J Clin Oncol 18:3101, 2000.

Fox RM, et al: Undifferentiated carcinoma in young men. The atypical teratoma syndrome. Lancet 1:1316, 1979.

Greco FA, Vaughn WK, Hainsworth JD: Advanced poorly differentiated carcinoma of unknown primary site: recognition of a treatable syndrome. Ann Intern Med 104:547, 1986.

Greco FA, et al: Carcinoma of unknown primary site: phase II trials with docetaxel plus cisplatin or carboplatin. Ann Oncol 11:211, 2000a.

Greco FA, et al: Carcinoma of unknown primary site: long-term follow-up after treatment with paclitaxel, carboplatin, and etoposide. Cancer 89:2655, 2000b.

Greco FA, et al: Gemcitabine, carboplatin and paclitaxel for patients with carcinoma of unknown primary site: a Minnie Pearl Cancer Research Network study. J Clin Oncol 20:1651, 2002.

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Hainsworth JD, Johnson DH, Greco FA: Poorly differentiated neuroendocrine carcinoma of unknown primary site: a newly recognized clinicopathologic entity. Ann Intern Med 109:364, 1988.

Hainsworth JD, Johnson DH, Greco FA: Cisplatin-based combination chemotherapy in the treatment of poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown primary site: results of a 12-year experience. J Clin Oncol 10:912, 1992.

Hainsworth JD, et al: Poorly differentiated carcinoma of unknown primary site: correlation of light microscopic findings with response to cisplatin-based combination chemotherapy. J Clin Oncol 5:1275, 1987.

Hainsworth JD, et al: Poorly differentiated carcinoma of unknown primary site: clinical usefulness of immunoperoxidase staining. J Clin Oncol 9:1931, 1991.

Hainsworth JD, et al: Carcinoma of unknown primary site: treatment with 1-hour paclitaxel, carboplatin, and extended-schedule etoposide. J Clin Oncol 15:2385, 1997.

McKay CE, et al: Treatment of metastatic poorly differentiated neuroendocrine carcinoma with paclitaxel/carboplatin/etoposide: a Minnie Pearl Cancer Research Network phase II trial [Abstract 630]. Proc Am Soc Clin Oncol 21:158a, 2002.

Motzer RJ, et al: Molecular and cytogenetic studies in the diagnosis of patients with poorly differentiated carcinomas of unknown primary site. J Clin Oncol 13:274, 1995.

Richardson RL, et al: Extragonadal germ cell malignancy: value of tumor markers in metastatic carcinoma in young males [Abstract]. Proc Am Assoc Cancer Res 20:825, 1979.

Richardson RL, et al: The unrecognized extragonadal germ cell cancer syndrome. Ann Intern Med 94:181, 1981.



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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