Ann Thorac Surg 2002;73:1957-1960
© 2002 The Society of Thoracic Surgeons
Case report
Large cell neuroendocrine carcinoma: an unusual presentation
Anthony L. Estrera, MDa,
Philip T. Cagle, MDc,
Ali Azizzadeh, MDc,
Michael J. Reardon, MDb*
a Department of Cardiovascular Surgery, University of Texas at Houston Medical School, Houston, Texas, USA
b Department of Pathology, Baylor College of Medicine, Houston, Texas, USA
c Department of Surgery, Baylor College of Medicine, Houston, Texas, USA
Accepted for publication March 2, 2001.
* Address reprint requests to Dr Reardon, Department of Surgery, Baylor College of Medicine, 6565 Fannin St, A853, Houston, TX 77030 USA
e-mail: reardonm{at}bcm.tmc.edu
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Abstract
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Primary lung cancer presenting as a pulmonary artery mass is unusual. We describe such a presentation in a patient with a large cell neuroendocrine carcinoma of the lung, its evaluation, and its treatment.
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Introduction
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Large cell neuroendocrine carcinomas (LCNECs) are rare malignancies of the lung with a similar prognosis as small cell cancer of the lung. These tumors typically present as a parenchymal lesion. Tumors appearing as a pulmonary artery (PA) mass have been reported with PA sarcomas but not with LCNECs. We report the case of a patient with an LCNEC that presented as a suspected PA mass and describe the evaluation and the treatment of this patient.
A 63-year-old woman with a medical history remarkable only for smoking was admitted to the medical service at The Methodist Hospital with a suspected pulmonary embolism. The patient had experienced acute onset of left shoulder pain on exertion and sought medical attention from her primary care physician when the discomfort persisted. Initial chest radiograph demonstrated a left lung mass. Subsequent chest computed tomographic scan revealed a normal left lung field, but a contralateral mass in the right main PA suggestive of pulmonary embolism was found (Fig 2).
The patient was admitted for further evaluation of a suspected pulmonary embolism. The correlation between the chest pain and the right PA mass remained uncertain because the symptoms resolved and subsequent cardiac evaluation was normal. Ventilation/perfusion lung scan and lower-extremity Doppler echocardiograms were normal. Pulmonary angiogram revealed a "thumbprint" defect in the distal right main PA suggestive of a mass instead of a thrombus (Fig 1).
The thoracic surgery department was consulted, and gadolinium-enhanced magnetic resonance imaging confirmed a mass suggestive of a malignancy. Further staging evaluation included bronchoscopy, which was nondiagnostic, and computed tomographic scan of the brain and abdomen, which demonstrated no evidence of metastasis.
Surgical exploration was performed by median sternotomy. Cardiopulmonary bypass was made available. Exploration revealed a tumor involving the right main PA just proximal to the origin of the truncus anterior. Without cardiopulmonary bypass, a right intrapericardial pneumonectomy was performed by isolating the right main PA with vascular clamps, dividing it from the main PA, and oversewing the remaining stump with polypropylene suture. The right PAs and the right mainstem bronchus were staple-divided. The diagnosis after intraoperative examination of frozen sections was intravascular malignant neoplasm compatible with PA sarcoma, pending additional study. Focal spindling of tumor cells on frozen sections was interpreted as suggestive of sarcoma. Surgical margins and mainstem bronchial lymph nodes were reported to be negative for tumor.
Gross examination of the pneumonectomy specimen disclosed a firm, yellow-tan mass 3 cm in diameter filling the lumen of the PA to within less than 5 mm of the surgical margin (Fig 2). The intravascular mass was connected to a similar-appearing mass in the adjacent lung parenchyma measuring 1.7 cm in diameter. Histopathologic examination of permanent sections disclosed an epithelioid neoplasm arising in the parenchyma and invading the PA causing distention of the lumen (Fig 3).
As a result, most of the neoplasm was intravascular.
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Fig 3. Large cell neuroendocrine carcinoma fills the lumen of the pulmonary artery. (Hematoxylin and Eosin; x60.)
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The neoplasm consisted of large polygonal cells with moderate eosinophilic cytoplasm and coarse to stippled nuclear chromatin arranged in an organoid pattern with scattered rosette formation (Fig 4).
Focal spindling of tumor cells, noted on frozen sections, was observed in the permanent sections. Tumor necrosis and apoptosis were extensive, and the mitotic rate was high. The malignant cells were immunopositive for keratin and synaptophysin and immunonegative for markers of muscle, neural, and vascular sarcomas (Fig 5).
On the basis of the histopathologic and immunohistochemical features, a diagnosis of LCNEC was made. Two of three lymph nodes not sampled for intraoperative frozen section proved positive for metastases.
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Fig 4. Large cell neuroendocrine carcinoma shows polygonal cells arranged in nests with focal tumor necrosis. (Hematoxylin and Eosin; x300.)
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Fig 5. Tumor cells stain immunopositive for synaptophysin, thus confirming their neuroendocrine nature. (Synaptophysin immunostain; x300.)
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The postoperative course was complicated by left lower lobe pneumonia, which was treated successfully with antibiotics. The patient was discharged on the tenth hospital day.
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Comment
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This is perhaps the first report of LCNEC mimicking PA sarcoma clinically, radiographically, and histopathologically at intraoperative study of frozen-sections. Although this is a rare presentation for an uncommon malignancy, surgeons, radiologists, and pathologists should be aware of this potential diagnostic dilemma and the impact on treatment and outcome.
Traditionally, neuroendocrine carcinomas (NECs) are those that share, to varying degrees, features of organoid histopathologic pattern, argyrophilia, dense-core neurosecretory granules on ultrastructural study, immunopositivity for one or more neuroendocrine markers such as chromogranin or synaptophysin, and production of hormones, neuropepetides, or both. In the lung, NECs are divided into tumor categories of increasingly malignant histologic appearance and behavior associated with generally decreasing degrees of neuroendocrine differentiation and increasing molecular genetic aberrations: typical carcinoids, atypical carcinoids, LCNECs and small cell carcinomas. At the least-malignant and best-differentiated end of the spectrum are typical carcinoids with low metastatic potential and a good prognosis (patient survival is excellent at 5 years). At the most malignant and least-differentiated end of the spectrum are small cell carcinomas that have usually metastasized by the time of diagnosis and have a very dismal prognosis. Atypical carcinoids have an intermediate behavior, differentiation, and prognosis, whereas LCNECs approach small cell carcinoma in terms of behavior, differentiation, and prognosis [1].
Classification of NEC into one of these four categories can be difficult because of overlapping or intermediate grades of features. This has led to the use of terms like well-differentiated or poorly differentiated NEC, terms that have also been given specific criteria in some classification schemes. Confusion over classification schemes can cause difficulties on occasion, although the World Health Organization classification scheme revised in 1999 is the most widely accepted. We [2, 3] have demonstrated the apparent reliability of Rb immunostaining in differentiating among categories of NECs, but this test is not available in many hospitals. Another category of tumor that should not be confused with LCNEC is non–small cell carcinoma with neuroendocrine differentiation. This group consists of tumors that are typical squamous cell carcinomas, adenocarcinomas, and large cell carcinomas by light microscopy but exhibit neuroendocrine markers by immunohistochemical examination or dense-core granules on ultrastructural study. At The Methodist Hospital over a 10-year period, the proportion of 536 NECs diagnosed on biopsy or surgical resection in each category was as follows: 84%, small cell carcinomas; 11%, typical carcinoids; 4%, LCNECs; and 1%, atypical carcinoids.
Travis and colleagues [4] first defined the criteria for LCNEC in 1991. Clinically, LCNECs are associated with tobacco smoking, occur in older individuals, and, as mentioned, are believed to have a prognosis nearly as poor as that of small cell carcinoma. The limited number of cases at any one institution has not yet permitted evaluation of therapy in a large series of patients, but surgical resection with or without adjuvant therapy is the usual therapeutic approach.
Grossly, LCNECs are tan, firm tumors with areas of necrosis and hemorrhage and are either central or peripheral. Histopathologically, LCNECs consist of polygonal to angular cells with moderate to abundant eosinophilic cytoplasm, coarse nuclear chromatin, frequent nucleoli, necrosis, and a high mitotic rate. Spindle cells occur but are not common. The cells are arranged in organoid, trabecular, pseudorosette, and palisading growth patterns. It is clear that tumors now categorized as LCNECs were once grouped as atypical carcinoids, small cell carcinomas, adenocarcinomas, and perhaps other cell types as well.
Though computed tomography–guided fine-needle aspiration biopsy, catheter suction biopsy, and angioscopic biopsy have been performed for PA masses, tissue diagnosis is not often possible prior to resection. This should not exclude an aggressive approach with possible resection of the PA mass once pulmonary embolism has been excluded from the differential diagnosis. Because the possibility of angiosarcoma exists, further investigation is necessary and often mandates resection.
Pathologically, LCNEC involving the main PA is advanced-staged disease with definitive treatment involving chemotherapy and irradiation. This treatment is suggested if the diagnosis of LCNEC can be established prior to resection. As the diagnosis of LCNEC is unlikely with small tissue biopsy specimen, resection is often required for definitive diagnosis. Moreover, resection is recommended to prevent the progression of possible complications including chronic thromboembolism, chronic pain, hemoptysis, right heart outflow tract obstruction, and right heart failure. Thus, if the diagnosis of a PA mass is undetermined, resection may be required for diagnosis, prevention of complications, and definitive treatment.
The techniques used in the resection of PA masses have been derived from the experience with PA sarcomas. Because tumors have been reported to invade the pulmonary trunk, pulmonary valve, and right ventricular outflow tract, cardiopulmonary bypass may be necessary. Median sternotomy with intrapericardial resection (pneumonectomy) can be used for resection of lesions involving the right PA, the left PA, and both PAs. Though more difficult, thoracotomy with pneumonectomy using cardiopulmonary bypass has been reported [5].
In summary, we report the case of a patient with LCNEC of the lung presenting as a PA mass. Large cell neuroendocrine carcinomas are rare and more often present as parenchymal lung lesions. Presentation as a PA mass, however, can warrant open exploration for diagnosis and possible definitive treatment.
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References
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Travis W.D., Linnoila R.I., Tsokos M.G., et al. Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol 1991;15:529-553.[Medline]
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Abstract
Introduction
