A 45-year-old male with small cell lung cancer, superior vena cava syndrome

A 45-year-old male with about a 30 pack-year history of smoking presented to his primary care physician in March 2010 with a cough of few days duration.

He had no other significant past medical problems. He was a construction worker and his review of systems was unremarkable.

He was treated conservatively and his symptoms did not improve. Chest X-ray showed vague opacities in the right upper lobe. He was scheduled for a CT scan, but in the interim, he developed neck and facial swelling that got worse within a few days. He developed respiratory distress and was admitted to the hospital. Physical exam revealed multiple palpable bilateral supraclavicular and cervical lymph nodes with decreased air entry to the right lung and associated wheezing.

He also was noted to have dilated veins on the chest and some facial puffiness. He was diagnosed with superior vena cava (SVC) syndrome and was admitted to the ICU. A CT scan of the chest and PET CT showed extensive mediastinal adenopathy with compression of superior vena cava and compression of proximal airways with trachea narrowing (Figure 1).

Figure 1A. Axial and coronal images of the CT demonstrating extensive mediastinal mass with compression of the SVC. The mass also was compressing the trachea and proximal airways.

He underwent a left cervical lymph node biopsy, which revealed small cell carcinoma (Figure 2). He also had some enlarged lymph nodes in the upper abdomen around the gastrohepatic space and para celiac regions. Fine needle aspiration cytology of the abdominal node was inconclusive but suspicious for malignancy. Complete blood count and comprehensive metabolic panel were unremarkable.

Further metastatic workup with nuclear bone scan and MRI of the brain did not show any evidence of metastasis. He had a normal chromogranin A level but increased neuron-specific enolase at 16.4 mcg/mL (normal range: 3.7-8.9 mcg/mL). He was staged as having extensive-stage small cell lung cancer (SCLC). He was treated with six cycles of cisplatin and etoposide and whole-brain radiation therapy.

He had an excellent response to chemotherapy with improvement in his symptoms. Post-treatment CT scan showed significant decrease in size of mediastinal and abdominal lymph nodes. His post-treatment blood work showed decreased neuron-specific enolase, and he was placed on active surveillance. He died of recurrent disease about 1 year after presentation.

Small cell lung cancer

SCLC is associated with heavy tobacco use and accounts for about 13% of newly diagnosed lung cancers each year. About 28,500 cases of SCLC are diagnosed each year.

SCLC is a cancer of neuroendocrine origin, occurring in the central airways and characterized by rapid growth with significant mediastinal adenopathy. Common clinical symptoms include cough, chest discomfort, dyspnea, hemoptysis, weight loss, fatigue, malaise and anorexia. Severe cases can present as SVC syndrome.

SCLC is associated with paraneoplastic syndromes in about 50% of cases. The most common neuroendocrine features include ectopic adrenocorticotropic hormone secretion, causing Cushing’s syndrome in severe cases, and syndrome of inappropriate antidiuretic hormone hypersecretion, causing hyponatremia that could be life-threatening in extreme cases.

Other paraneoplastic syndromes with SCLC include Lambert-Eaton myasthenic syndrome, a syndrome of sensory neuronopathy/multifocal encephalomyelitis and cerebellar degeneration, limbic encephalitis and cancer-associated retinopathy. Pathological diagnosis is made by light microscopy, which shows round to fusiform small-sized cells with scant cytoplasm with finely granular nuclear chromatin and absent or inconspicuous nucleoli with extensive necrosis.

Immunohistochemistry can be helpful in difficult cases. Tumor markers such as lactate dehydrogenase, chromogranin A and neuron-specific enolase may be elevated. Radiological features include bulky mediastinal mass on chest CT with post-obstructive pneumonitis or collapse, bronchial encasement, compression or obstruction and, sometimes, associated pleural effusion and/or pulmonary nodule(s).

Figure 1B. A) Axial fusion image at the level of the mediastinum from PET/CT demonstrating enlarged and hypermetabolic mediastinal and bilateral hilar lymph nodes up to 1.9 cm in the short axis, with maximum standard uptake value (SUV) of 3.4. B) Fusion image from the same scan at the level of the upper lobes demonstrating hypermetabolic right upper lobe opacity with maximum SUV of 3.5.

The most commonly used classification is the Veterans Administration Lung Study Group (VALG) staging system, in which the disease is subdivided into limited stage (LS) and extensive stage (ES).

LS-SCLC is disease confined to one hemi-thorax with involvement of the ipsilateral and/or contralateral mediastinal and/or in the ipsilateral supraclavicular lymph nodes that can be encompassed within a reasonable radiation field. ES-SCLC is defined as disease that extends beyond the hemithorax. Ipsilateral malignant effusions are defined as having LS-SCLC according to the original VALG definition, but they are considered to have ES-SCLC by many cooperative groups.

LS-SCLC accounts for about 40% of the patients with SCLC and is a potentially curable disease. The treatment of choice is concurrent chemoradiotherapy, with a 5-year survival rate of about 25%. Workup for metastasis includes PET CT, nuclear medicine bone scan and MRI of the brain.

Tumor markers chromogranin A and neuron-specific enolase are helpful in monitoring the disease activity and response to treatment. The standard chemotherapeutic agents used are a combination of cisplatin and etoposide. However, carboplatin is used as an alternative agent to cisplatin in patients who cannot tolerate or have a contraindication.

ES-SCLC has very poor prognosis, with average survival of about 10 months, despite excellent response to chemotherapy. Common chemotherapeutic regimens include a platinum-based regimen with combination of cisplatin and etoposide or topotecan.

The incidence of central nervous system metastases in SCLC patients is about 50%. Prophylactic cranial irradiation is recommended in ES-SCLC and in patients who obtain a near complete or complete response to chemotherapy for patients with LS-SCLC, as it reduces the incidence of brain metastases and improves OS.

Radiation therapy also has a role in the symptomatic management of the brain metastasis and to relieve airway obstruction in cases of severe central airway compression. There is some data to suggest the use of continuing the chemotherapy after initial chemotherapy in patients with ES-SCLC with improvement of PFS but without improved OS.

Surveillance after the initial treatment includes history and physical exam every 3 to 4 months, along with chest imaging, during the first 2 years, every 6 months during the next 3 to 5 years, and then annually.

Docetaxel, irinotecan, gemcitabine, paclitaxel, ifosfamide and topotecan are some of the second-line chemotherapeutic agents used for the relapsed disease. The prognosis is more guarded in this setting, with about 20% to 30% response, and with median survival of weeks to months.

Figure 2. A) The tumor has totally replaced the lymph node and shows extracapsular extension. B and C) This high-grade neoplasm is composed predominantly of sheets of large, hyperchromatic cells, with high N/C ratio, salt and pepper type chromatin and inconspicuous nucleoli. The tumor shows a high mitotic rate and areas of necrosis and extensive apoptosis. Nuclear molding and crash effect (D) is also identified. Images courtesy of M. Ghesani, MD

SVC syndrome

SVC syndrome is caused by the invasion or extrinsic compression of the vena cava by adjacent pathologic processes, especially by the mass in the middle or anterior mediastinum, usually consisting of enlarged right paratracheal lymph nodes, lymphoma, thymoma, an inflammatory process or an aortic aneurysm, or by internal thrombus of SVC.

Lung cancer is the leading malignant cause of SVC syndrome, with non–small cell lung cancer accounting for about 50% of the cases and SCLC accounting for about 25% of cases occurring in malignancy.

The superior vena cava carries blood from the head, arms and upper body to the heart. Compression of the superior vena cava resulting in obstruction will cause blood flow through the collaterals to the lower body through the azygous vein or inferior vena cava.

Obstruction of the SVC causes increased venous pressure in the upper body, resulting in edema of the head, neck and arms, which is visually striking but without significant morbidity. Severe cases can present with laryngeal edema, causing dyspnea, stridor, cough, hoarseness and/or dysphagia. It also can cause cerebral edema, leading to cerebral ischemia, confusion, coma and, possibly, death.

It is considered a medical emergency, and the management of the SVC syndrome associated with malignant disease includes both treatment of the cancer and relief of the symptoms of obstruction. Major therapeutic modalities are supportive care and medical management, including chemotherapy, radiotherapy, placement of intravascular stent and surgery.

Conclusions

Very little progress has been made in the past 30 years with chemotherapy agents. Newer chemotherapeutic agents that showed some promise in early-phase clinical trials include amrubicin (a third-generation anthracycline), vinorelbine, vinflunine and pemetrexed.

Also, some targeted therapies have shown some activity with chemotherapy backbone. These include antiangiogenic agents such as bevacizumab (Avastin, Genentech), vandetanib (IPR Pharms), sorafenib (Nexavar, Bayer) and aflibercept (Eylea, Regeneron), growth factor receptor pathway inhibitors such as imatinib (Gleevec, Novartis) and temsirolimus (Torisel, Wyeth), and proteasome inhibitor bortezomib (Velcade, Millennium Pharmaceuticals).

It will be interesting to see how these newer agents affect the management of SCLC.

Munir Ghesani, MD, is an attending radiologist at St. Luke’s-Roosevelt Hospital Center and Beth Israel Medical Center, an associate clinical professor of radiology at Columbia University College of Physicians and Surgeons, and a HemOnc Today section editor. Rangaswamy Chintapatla, MD, is a fellow in hematology and oncology at St. Luke’s Roosevelt Hospital Center. Anupama Goel, MD, is an attending physician in the division of hematology and oncology at St. Luke’s Roosevelt Hospital Center. Sam Altman, MD, is a resident in radiology at St. Luke’s-Roosevelt Hospital Center. Zheng Ma, MD, is a resident at St. Luke’s-Roosevelt Hospital Center.

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