Small Cell Carcinoma

Small cell carcinoma is a type of bronchogenic carcinoma which occurs at a younger age, and has a worse prognosis (these are the most aggressive and have more metastatic potential than any other type of bronchogenic carcinoma).

These cancers have a strong association with cigarette smoking, only 1% occur in nonsmokers. Most of these lesions are central, or arise in the hilar region, and are surgically unresectable. Note the obvious invasive character of the lesion shown, which has infiltrated through the cartilage, into the deeper tissue. The deep basophilic staining of the tumor is due to the active proliferation and close packing of the malignant cells.

This histopathologic specimen demonstrates the classic appearance of a small cell carcinoma with the "oat cell" morphology of the malignant cells. Note the relative lack of cytoplasm, and the close approximation of the nuclei in adjacent cells. Where cellular outlines can be appreciated, the cells have an attenuated, or spindle-shaped "oat cell" appearance. These tumors have the highest incidence of ectopic hormone production resulting in a paraneoplastic syndrome. Inappropriate ADH secretion was first demonstrated in a small cell carcinoma, but a wide variety of hormones can be secreted by these tumors, and the source of secretion is demonstrated using electron microscopy

Small cell carcinoma accounts for approximately 20% of all lung cancers. It is characterized by its origin in large central airways and histological composition of sheets of small cells with scanty cytoplasm. Small cell carcinoma is a tumor of neuroendocrine origin and is very aggressive, metastazing early and often. Smoking is a well demonstrated etiologic factor in the development of small cell tumors. This is also consistent with the predilection for the central airways and the mucosal irritation caused by smoking.

Without treatment, small cell carcinoma of the lung has the most aggressive clinical course of any type of pulmonary tumor, with median survival from diagnosis of only 2 to 4 months. Compared with other cell types of lung cancer, small cell carcinoma has a greater tendency to be widely disseminated by the time of diagnosis, but is much more responsive to chemotherapy and irradiation.

Because of its propensity for distant metastases, localized forms of treatment, such as surgical resection or radiation therapy, rarely produce long-term survival.[1] With incorporation of current chemotherapy regimens into the treatment program, however, survival is unequivocally prolonged, with at least a 4- to 5-fold improvement in median survival compared with patients who are given no therapy. Furthermore, about 10% of the total population of patients remain free of disease over two years from the start of therapy, the time period during which most relapses occur. However, even these patients are at risk of dying from lung cancer (both small and non-small cell types).[2] The overall survival at 5 years is 5% to 10%.[2-4]

At the time of diagnosis, approximately 40% of patients with small cell carcinoma will have tumor confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes. These patients are designated as having limited stage disease, and most 2-year disease-free survivors come from this group. In limited stage disease, median survival of 16 to 24 months with current forms of treatment can reasonably be expected.[5-7] A small proportion of patients with limited stage disease may benefit from surgery with or without adjuvant chemotherapy; these patients have an even better prognosis. Patients with tumor that has spread beyond the supraclavicular areas are said to have extensive stage disease and have a worse prognosis than patients with limited stage. Median survival of 6 to 12 months is reported with currently available therapy, but long-term disease-free survival is rare.

The pretreatment prognostic factors which consistently predict for prolonged survival include good performance status, female gender, and limited stage disease. Patients with involvement of the central nervous system or liver at the time of diagnosis have a significantly worse outcome In general, patients who are confined to bed tolerate aggressive forms of treatment poorly, have increased morbidity, and rarely attain 2-year disease-free survival. However, patients with poor performance status can often derive significant palliative benefit and prolongation of survival from treatment.

Regardless of stage, the current prognosis for patients with small cell lung cancer is unsatisfactory even though considerable improvements in diagnosis and therapy have been made over the past 10 to 15 years. Therefore, all patients with this type of cancer may appropriately be considered for inclusion in clinical trials at the time of diagnosis.

Many patients who are diagnosed with small cell lung cancer are symptomatic at presentation but have been symptomatic for less than three months.

Small cell carcinoma causes a number of paraneoplastic syndromes. Small cell carcinoma is the most common type of cancer to cause clinical hormone syndromes. The tumor cells may produce ectopic adrenocorticotropic hormone (ACTH), resulting in Cushing's syndrome. The symptoms of Cushing's syndrome are nonspecific and are often attributed to other factors. Another paraneoplastic hormone syndrome that commonly occurs is the syndrome of inappropriate anti-diuretic hormone (SIADH). This is caused by secretion of ADH from the tumor. Symptoms are related to the plasma hypotonicity that is secondary to water retention. Symptoms include weakness, lethargy, abnormal mentation, coma, and seizures. Laboratory evaluation shows inappropriately high urine osmolality.

Another paraneoplastic syndrome associated with small cell carcinomas is the Eaton-Lambert syndrome, also known as myasthenic syndrome. It is characterized by fatigability, proximal muscular weakness, dry mouth, muscle discomfort, and paresthesias. Unlike myasthenia, however, Eaton-Lambert is associated with improved strength with repeated muscle activity. Finally, small cell carcinoma is the most common cause of superior vena cava syndrome.

Unlike nonsmall cell carcinoma, small cell carcinoma is staged only as limited or extensive, depending on whether or not it has spread outside the chest. Limited stage carcinomas account for only 30% of all cases. Limited stage is confined to one hemithorax and regional lymph nodes (including mediastinal, contralateral hilar, and ipsilateral supraclavicular). 70% of small cell carcinomas are extensive. They are defined as diseases that extend beyond the anatomic boundaries of limited small cell carcinomas. Because extensive disease may not be clinically evident, patients should be evaluated with head CT scan, bone scan, liver scan and bone marrow biopsy. In addition, chest CT scan may demonstrate bilateral parenchymal involvement, pericardial disease or contralateral nodal involvement.

Gross Appearance

Over 90% of small cell tumors are found in a central location. They are typically white-gray, soft and bulky with areas hemorrhage and necrosis. Commonly they grow around major bronchi, and may result in a secondary stenosis. There may also be extensive spread within the lung parenchyma. The tumor typically extends along lymphatics and may invade vascular tissue.

Microscopic Features

Small cell tumors form sheets of uniform cells separated by thin strands of connective tissue. Peripheral palasading of the nuclei may also be present. Occasionally rosettes may be found. Zones of necrosis are typically present in the center, and vary in size. At low power magnification the cells are very hyperchromatic appearing owing to the tightly packed small cells with scanty cytoplasm. Individual cells vary in shape from ovoid to fusiform. The cells of small cell carcinoma bear a superficial similarity to normal lymphocytes. However, small cell carcinoma nuclei are about twice the size of normal lymphocyte nuclei. The nuclei are generally molded to the shape of the cell and show dense homogenous chromatin and nucleoli are difficult to identify. These cells tend to be fragile and often show "crush artifact."

Making the diagnosis of small cell lung cancer can be aided by the use of immunohistochemical stains for neuroendocrine features and cell products. Commonly used stains include: cytokeratins, neurofilaments, neuron-specific enolase, chromogranin, synaptophysin and markers for specific neuroendocrine peptides. Use of these stains aids in distinguishing this tumor from other small blue cell tumors, such as lymphoma.

CELLULAR CLASSIFICATION

Review of pathologic material by an experienced lung cancer pathologist is important prior to initiating treatment of any patient with small cell lung cancer. The intermediate subtype of small cell carcinoma and the more readily recognized lymphocyte-like or "oat cell" subtype are equally responsive to treatment.

The current classification of subtypes of small cell lung cancer are:[1]

small cell carcinoma

mixed small cell/large cell carcinoma

combined small cell carcinoma (small cell lung cancer combined with neoplastic squamous and/or glandular components)

There is increasing evidence that light microscopy has some limitations as a means of classifying bronchogenic carcinomas, particularly small cell carcinomas. Electron microscopy, which can detect neuroendocrine granules, may help to differentiate between small cell and non-small cell cancers.[2]

Neuroendocrine carcinomas of the lung represent a spectrum of disease. At one extreme is small cell lung cancer, which has a poor prognosis. At the other extreme are bronchial carcinoids, with an excellent prognosis after surgical excision.[3] Between these extremes is an unusual entity called well-differentiated neuroendocrine carcinoma of the lung.[4] It has been referred to as malignant carcinoid, metastasizing bronchial adenoma, pleomorphic carcinoid, nonbenign carcinoid tumor, and atypical carcinoid. Like small cell lung cancer, it occurs primarily in cigarette smokers, but it metastasizes less frequently. The 5-year survival rate is greater than 50% in some series, and surgical cure appears possible in most stage I patients. Careful diagnosis is important, however, since the differential pathologic diagnosis from small cell lung cancer may be difficult.

STAGE INFORMATION

Staging procedures are important in distinguishing patients who have disease limited to their thorax from those who have distant metastases. Determining the stage of cancer by nonsurgical means allows a better assessment of prognosis and identifies sites of tumor that can be evaluated for response. Also, the choice of treatment is usually influenced by stage, particularly when chest irradiation or surgical excision is added to chemotherapy for patients with limited stage disease. Staging procedures commonly used to document distant metastases include bone marrow examination, computed tomographic or magnetic resonance imaging scans of the brain, computerized tomographic scans of the chest and the abdomen, and radionuclide bone scans.

Because occult or overt metastatic disease is present at diagnosis in most patients, survival is usually not affected by small differences in the amount of locoregional tumor involvement. Therefore, the detailed TNM staging system developed for lung cancer by the American Joint Committee on Cancer (AJCC) is not commonly employed in patients with small cell carcinoma. This international staging system is outlined in detail in the PDQ summary on non- small cell lung cancer. A simple 2-stage system developed by the Veterans Administration Lung Cancer Study Group is more commonly used for staging small cell lung cancer patients.[1]

Limited stage

Limited stage small cell lung cancer means tumor confined to the hemithorax of origin, the mediastinum, and the supraclavicular nodes, which can be encompassed within a "tolerable" radiation therapy port. There is no universally accepted definition of this term, and patients with pleural effusion, massive pulmonary tumor, and contralateral supraclavicular nodes have been both included within and excluded from limited stage by various groups.

Extensive stage

Extensive stage small cell lung cancer means tumor that is too widespread to be included within the definition of limited stage disease above. Patients with distant metastases (M1) are always considered to have extensive stage disease.[1,2]

Neoplastic and Paraneoplastic Syndromes

Lung cancers can cause several well-defined neoplastic or paraneoplastic syndromes based on anatomic location or humoral factor production. Neoplastic syndromes in lung cancer are due to symptoms and signs arising from involvement of contiguous anatomic structures. Two examples of neoplastic syndromes are Pancoast's tumor and superior vena cava syndrome. Paraneoplastic syndromes are clinical syndromes resulting from a tumor-produced hormone and occur in about 10% of lung cancer patients.

Neoplastic Syndromes

Pancoast Syndrome

Superior Vena Cava (SVC) Syndrome

Paraneoplastic Syndromes

Hyponatremia and Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH)

Hypercalcemia

Clubbing and Hypertrophic Osteoarthropathy (HPO)

Treatment options:

Standard:

1. Combination chemotherapy with one of the following regimens and chest irradiation (with or without PCI given to patients with complete responses):

The following regimens produce similar survival outcomes:

EC: etoposide + cisplatin + 4000-4500 cGy chest radiation therapy

[3,7]

ECV: etoposide + cisplatin + vincristine + 4500 cGy chest radiation

therapy[5]

2. Combination chemotherapy (with or without PCI in patients with complete responses), especially in patients with impaired pulmonary function or poor performance status.

3. Surgical resection followed by chemotherapy or chemotherapy plus chest radiation therapy (with or without PCI in patients with complete responses) for patients in highly selected cases.[16-19]

Under clinical evaluation:

Areas of active clinical evaluation in limited stage small cell lung cancer

include new drug regimens, variation of drug doses in current regimens,

surgical resection of the primary tumor, new radiation therapy schedules and

techniques (e.g., 3-dimensional treatment planning), and timing of thoracic

radiation

Treatment options:

Standard:

1. Combination chemotherapy with one of the following regimens with or without PCI given to patients with complete responses:

The following regimens produce similar survival outcomes:

CAV: cyclophosphamide + doxorubicin + vincristine [24,25]

CAE: cyclophosphamide + doxorubicin + etoposide [26]

EP or EC: etoposide + cisplatin or carboplatin [27,28]

ICE: ifosfamide + carboplatin + etoposide [29]

Other regimens appear to produce similar survival outcomes but have

been studied less extensively or are in less common use, including:

cyclophosphamide + methotrexate + lomustine [30]

cyclophosphamide + methotrexate + lomustine + vincristine [31]

cyclophosphamide + doxorubicin + etoposide + vincristine [32]

CEV: cyclophosphamide + etoposide + vincristine [33]

single-agent etoposide [19]

2. Radiation therapy to sites of metastatic disease unlikely to be

immediately palliated by chemotherapy, especially brain, epidural, and

bone metastases.

3. Identification of effective new agents is difficult in patients who have

previously been treated with standard chemotherapy because response rates

to agents, even of known efficacy, are known to be lower than in

previously untreated patients. This situation led to the suggestion that

patients with extensive disease who are medically stable be treated with

new agents under evaluation, with provisions for early change to standard

combination therapy if there is no response.[34] Such a strategy has

been shown to be feasible, with survival comparable to survival with

initial standard therapy, as long as the patients with extensive disease

are carefully chosen.[35-37] A variety of other strategies have been

proposed, depending on the activity of the new agent in other tumors, in

preclinical small cell lung cancer models, or the activity of drug

analogs.[38] Active single agents undergoing further evaluation include

paclitaxel and topotecan.[39,40]

Under clinical evaluation:

Areas of active clinical evaluation in extensive stage small cell lung cancer

include evaluation of new drug regimens, dose intensity, alternative drug

schedules, and high-dose chemotherapy. A meta-analysis of long-term

outcomes in extensive stage disease did not show consistent evidence for

improved response rates or survival for more intense chemotherapy

regimens.[41][Level of evidence: 1iiA]