Typical and atypical carcinoid tumors of the lung: a clinicopathological correlation of 783 cases with emphasis on histological features.

We present 783 surgical resections of typical and atypical carcinoid tumors of the lung identified in the pathology files of 20 different pathology departments. All cases were critically reviewed for clinical and pathological features and further correlated with clinical outcomes. Long-term follow-up was obtained in all the patients and statistically analyzed to determine significance of the different parameters evaluated. Of the histopathological features analyzed, the presence of mitotic activity of 4 mitoses or more per 2 mm2, necrosis, lymphatic invasion, and lymph node metastasis were identified as statistically significant. Tumors measuring 3 cm or more were also identified as statistically significant and correlated with clinical outcomes. Based on our analysis, we consider that the separation of low- and intermediate-grade neuroendocrine neoplasms of the lung needs to be readjusted in terms of mitotic count as the risk of overgrading these neoplasms exceeds 10% under the current criteria. We also consider that tumor size is an important feature to be considered in the assessment of these neoplasms and together with the histological grade of the tumor offers important features that can be correlated with clinical outcomes.

Pulmonary Adenofibromas: A Clinicopathologic Correlation of 13 Cases.

Thirteen cases of primary pulmonary adenofibromas are presented. The patients are 8 women and 5 men between the ages of 41 and 73 years (average: 57 y). The patients presented with nonspecific symptomatology or their tumor was identified during routine chest films. A wedge resection was performed in all cases with lymph node sampling. Grossly, the tumors varied in size from 1 to 2.5 cm in greatest dimension. The entire tumor was histologically evaluated in all cases. All the tumors shared similar histologic features namely leaf-like/phyllodes-like growth patterns with varying areas of sclerosis, focal inflammation, and entrapped epithelium. A wide panel of immunohistochemical studies was performed including epithelial, neural, muscle, and vascular markers, all of which showed negative staining. The tumors were positive only for vimentin in the stroma and keratin in the entrapped epithelium. Further evaluation in 6 cases using in situ hybridization for the solitary fibrous tumor was performed and was negative. Clinical follow-up in all the patients showed no evidence of recurrence or metastatic disease, during a period of 12 to 36 months. The current cases highlight the unusual occurrence of pulmonary adenofibromas and the importance of separating these tumors from other tumors that may have the potential to recur or metastasize. The use of proper immunohistochemical stains/molecular analysis aids in the proper classification of these tumors.

Primary Mammary-Like Carcinoma of the Lung: A Case Report of a Distinct Type of Primary Lung Carcinoma.

A case of a primary lung carcinoma with histologic and immunohistochemical features of a mammary carcinoma is presented. The patient is a 72-year-old man who presented with symptoms of cough and dyspnea. Diagnostic imaging showed a bronchial tumor in the left lower lobe that was surgically resected by a left lower lobectomy. The tumor was characterized by a homogenous cellular proliferation composed of small to medium-sized cells with round nuclei and inconspicuous nucleoli. Multiple immunohistochemical stains were performed, and the tumor was notably positive for estrogen receptor, progesterone receptor, GATA3, and pan-keratin, while molecular analysis showed somatic mutation in ARID1A. Clinical follow-up showed that the patient is alive and well 18 months post-surgical resection without evidence of recurrence or metastatic disease. Based on the overall features of this neoplasm, we consider that the tumor herein presented represents an unusual type of lung carcinoma that we refer to as primary mammary-like carcinoma of the lung.

Hemangioblastoma-like Clear Cell Stromal Tumor of the Lung: A Clinicopathologic and Immunohistochemical Study of 5 Cases.

Five cases of an unusual primary benign stromal tumor designated as hemangioblastoma-like clear cell stromal tumor of the lung are presented. The patients are 4 women and 1 man between the ages of 39 and 52 years of age (average: 45.5 y). The patients presented with nonspecific symptoms of cough, chest pain, or dyspnea. None of the patients had any prior history of malignancy or tumor elsewhere. Diagnostic imaging showed the presence of an intrapulmonary tumor. Lobectomy was performed in all 5 patients. Grossly, the tumors were well-demarcated but not encapsulated with focal areas of hemorrhage without necrosis. Histologically, low power examination showed a cellular proliferation alternating with discrete dilated vessels reminiscent of a vascular neoplasm. Higher magnification showed medium-sized cells with clear cytoplasm arranged in sheets and cords. Mitotic activity and marked cellular atypia were not present. A wide panel of immunohistochemical studies was performed including epithelial, neural, muscle, vascular, and neuroendocrine markers, all of which showed negative staining. Tumor cells showed positive staining for vimentin. In 2 cases, fluorescence in situ hybridization for the solitary fibrous tumor was performed and was negative. Clinical follow-up in 3 patients showed no evidence of recurrence. The cases herein presented highlight an unusual benign stromal tumor of the lung, which needs to be considered in the differential diagnosis of tumors with a clear cell and vascular appearance.

Cystic and Encapsulated Atypical Thymoma (World Health Organization Type B3).

OBJECTIVES: Eight cases of encapsulated and cystic atypical thymomas (World Health Organization type B3) are presented. METHODS: Cases were identified after review of more than 500 thymomas. Histologic material from surgical resections was evaluated. RESULTS: The patients are seven men and one woman aged 43 to 71 years. Seven patients presented with nonspecific symptoms while one mass was found on autopsy. The tumors were 4 to 6 cm in greatest dimension and showed prominent cystic changes with an epithelial proliferation arranged in sheets and cords. Increased mitotic activity and nuclear pleomorphism were not identified. All tumors were encapsulated. Immunohistochemical studies showed the tumor cells positive for keratin cocktail, keratin 5/6, and p63. Clinical follow-up was available in five patients. All were alive without recurrence. CONCLUSIONS: These cases represent an unusual variant of atypical thymoma that can be misdiagnosed as thymic carcinoma or multilocular thymic cyst. Awareness of this histologic growth pattern is important for accurate diagnosis.

Xanthomatous Thymoma: A Clinicopathologic and Immunohistochemical Study of 10 Cases.

OBJECTIVES: Ten cases of thymomas with an extensive xanthomatous component are presented. METHODS: Cases were identified during a review of more than 500 cases of thymomas. Histologic material from surgical resections was evaluated. RESULTS: The patients included five men and five women aged 47 to 64 years who had nonspecific symptoms. Grossly, all tumors were solid, measuring 2.5 to 4.5 cm. Eight tumors were encapsulated; two were minimally invasive. Histologically, the tumors showed varying histologies, all with an extensive xanthomatous component comprising 50% to 80% of the tumor. Immunohistochemical stains showed tumor cells positive for keratin and keratin 5/6 while the xanthomatous component was positive for CD68. Follow-up information showed nine patients remain alive with no recurrence. No follow-up information was obtained in one patient. CONCLUSIONS: The presence of an extensive xanthomatous component may pose difficulties in the interpretation of these tumors. This study highlights the importance of proper sampling and awareness of this unusual feature.

Fibrosing/Sclerosing Lesions of the Mediastinum: A Review.

Fibrosing lesions of the mediastinum represent a small but challenging group of lesions that range in etiology from infectious to idiopathic to neoplastic. The diagnosis of such lesions becomes more challenging in the setting of mediastinoscopic biopsies. In addition, over the years, there has been further accumulation of knowledge of the clinical aspects of these lesions that needs to be incorporated into their evaluation. Therefore, it is essential that in the general evaluation of these fibrosing processes, one not only carefully examines the histopathologic features of the lesion, that of a fibroinflammatory process with the appropriate histochemical and immunohistochemical studies, but also carefully evaluates the clinical presentation and imaging findings. Needless to say, as will be illustrated in this review, determining a definitive unequivocal diagnosis on a small mediastinoscopic biopsy may be difficult, and often one needs to provide guidance on the perspective of the histologic features present. In some cases, mainly tumoral conditions with extensive fibrosis, a conclusive diagnosis can be made; however, it is those cases in which the extensive fibrosis is the only histopathologic feature where more appropriate guidance is required. While this review will focus more on the non-neoplastic fibroinflammatory lesions of the mediastinum, within the discussion of differential diagnoses, we will discuss some neoplastic conditions that commonly show extensive fibrosing features.

Osteoclast-like giant cell-rich carcinomas of the lung: a clinicopathological, immunohistochemical, and molecular study of 3 cases.

Three cases of primary carcinomas of the lung each with an extensive osteoclast-like giant cell component are presented. The patients are 3 men between the ages of 58 and 67 years (average, 62.5 years) who presented with nonspecific symptoms. A history of malignancy, infectious, or granulomatous disease was negative in all the patients. Diagnostic imaging disclosed the presence of a large intrapulmonary mass; in 1 case in the right upper lobe and in 2 cases in the right lower lobe. Surgical resection via lobectomy was performed in the 3 patients. Grossly, the tumors were described as soft, friable intrapulmonary masses, reddish in color, and measuring from 6 to 13 cm in largest diameter. Histologically, the tumors were each characterized by the extensive presence of a multinucleated osteoclast-like giant cell component, which represented approximately 80% of the tumor mass. The osteoclast-like giant cell component was admixed with a sarcomatoid carcinoma in 2 cases and an adenocarcinoma in 1 case. Immunohistochemistry showed that the osteoclast-like giant cells were positive for CD-68, cathepsin K, and histone H3, whereas the carcinoma component was positive for keratin, thyroid transcription factor-1, and histone H3 (patchy). Molecular studies were performed in 2 patients with negative results. Clinical follow-up was obtained in 2 patients; 1 died 14 months after initial diagnosis, whereas 1 remains alive 6 months after initial diagnosis. One patient was lost to follow-up. The current neoplasms represent an unusual type of lung carcinoma that needs highlighting as a separate type from conventional giant cell carcinoma.

Ketogenic diets enhance oxidative stress and radio-chemo-therapy responses in lung cancer xenografts.

PURPOSE: Ketogenic diets are high in fat and low in carbohydrates as well as protein which forces cells to rely on lipid oxidation and mitochondrial respiration rather than glycolysis for energy metabolism. Cancer cells (relative to normal cells) are believed to exist in a state of chronic oxidative stress mediated by mitochondrial metabolism. The current study tests the hypothesis that ketogenic diets enhance radio-chemo-therapy responses in lung cancer xenografts by enhancing oxidative stress. EXPERIMENTAL DESIGN: Mice bearing NCI-H292 and A549 lung cancer xenografts were fed a ketogenic diet (KetoCal 4:1 fats: proteins+carbohydrates) and treated with either conventionally fractionated (1.8-2 Gy) or hypofractionated (6 Gy) radiation as well as conventionally fractionated radiation combined with carboplatin. Mice weights and tumor size were monitored. Tumors were assessed for immunoreactive 4-hydroxy-2-nonenal-(4HNE)-modified proteins as a marker of oxidative stress as well as proliferating cell nuclear antigen (PCNA) and γH2AX as indices of proliferation and DNA damage, respectively. RESULTS: The ketogenic diets combined with radiation resulted in slower tumor growth in both NCI-H292 and A549 xenografts (P < 0.05), relative to radiation alone. The ketogenic diet also slowed tumor growth when combined with carboplatin and radiation, relative to control. Tumors from animals fed a ketogenic diet in combination with radiation showed increases in oxidative damage mediated by lipid peroxidation as determined by 4HNE-modified proteins as well as decreased proliferation as assessed by decreased immunoreactive PCNA. CONCLUSIONS: These results show that a ketogenic diet enhances radio-chemo-therapy responses in lung cancer xenografts by a mechanism that may involve increased oxidative stress.