A pleomorphic carcinoma of the lung producing multiple cytokines and forming a rapidly progressive mass-like opacity

Lung cancer cells have been reported to produce several cytokines and growth factors, especially granulocyte colony-stimulating factor (G-CSF), resulting in various systemic reactions [1‐12]. We encountered a lung cancer patient with a peritumoral permeation shadow, which increased rapidly due to recruitment of cells by interleukin (IL)-8/CXCR1.

A 52-year-old man complaining of a high-grade fever was referred to kitano hospital in August 2005. He previously had glucose intolerance, has a 26 pack-year history of smoking, and consumed 350 ml of beer per day. A chest X-ray showed a mass-like opacity in the apex of his right lung (Figure 1). A physical examination on admission showed reduced body weight (45.5 kg), sinus tachycardia (108/min), high respiratory rate (20/min) and high body temperature (38.0°C). Blood examination disclosed a marked leukocytosis (neutrophilia) and elevated serum concentrations of C-reactive protein (CRP) and liver enzymes (Table 1). A chest computed tomography (CT) scan showed a mass-like opacity in the apex of the right lung, with the inside of the mass being of low density (Figure 2).

His symptoms, blood examination and chest CT scan suggested a lung abscess. Despite the administration of antibiotics, however, the mass-like opacity rapidly grew (Figure 3). The transbronchial specimen and CT guided biopsy specimens were negative for bacteria, fungi and acid fast bacilli, but showed infiltration of lymphocytes. 18 F-fluoro-deoxy-glucose positron emission tomography (FDG-PET) showed the localized uptake of FDG to the center of the mass-like lesion and right hilar lymph node, in addition to diffuse uptake by the bone marrow and an enlarged liver and spleen (Figure 4). Before surgery, we considered that the lesion-like lung abscess was cancer and pneumonitis associated with cancer. The tumor was diagnosed as a cT3N1M0, stage IIIA lung cancer. Therefore, a right upper lobectomy was performed (Figures 5). The tumor was pathologically diagnosed as a pleomorphic carcinoma of the right upper lung (Figures 6). Following excision, it was shown to be of mixed subtype (predominantly large cell carcinoma with >10% giant cells and a few adenocarcinoma cells), measuring 40 × 34 × 28 mm, and graded pT3, pl0, G3, Ly0, V0, PLC0, R0, and pm0. The tumor was positive for lymph node metastases, and graded pN0, #2 (0/3), #3 (0/5), #4 (0/1), #10 (0/1), #11 (0/1), #12 (0/1) [pT3N0M0, pStage IIB]. The tumor was surrounded by intense infiltration of neutrophils and lymphocytes. The patient’s high grade fever, neutrophilia, and elevated CRP level rapidly subsided after the operation (Figure 3), as did his elevated serum concentrations of G-CSF and IL-6 (Table 2).

Since the rapid growth of the mass-like shadow likely resulted from the infiltration of neutrophils and lymphocytes, we assessed the mechanisms underlying the infiltration of these cells.

We encountered a rare patient with a pleomorphic carcinoma and rapidly growing tumor shadow in the apex of the right lung. This patient presented with a high-grade fever and marked inflammatory responses. The excised tumor consisted of a carcinomatous lesion in the center, surrounded by the intense infiltration of inflammatory cells. FDG-PET showed that FDG uptake was localized to the center of the mass-like lesion, along with diffuse uptake in the bone marrow, liver and spleen.

In addition to high grade fever, neutrophilia, and elevated serum CRP concentration, our patient presented with elevated serum concentrations of G-CSF and IL-6. Following right upper lobectomy, however, these elevated concentrations became normalized. In addition, immunohistochemical examination showed that the cancer cells were positive for G-CSF and IL-6. The elevated IL-6 levels in this patient may have contributed to his high-grade fever and increased CRP levels [15], whereas the increased serum G-CSF levels may have contributed to neutrophilia and hematopoietic activation, as indicated by diffuse bone marrow uptake of FDG [1, 16]. These cytokines have been reportedly produced by lung cancers, especially by large cell carcinomas [2‐11, 17]. Many lung cancers previously diagnosed as large cell carcinomas have been reclassified as pleomorphic carcinomas [18]. Additional studies are needed to determine the mechanism by which pleomorphic carcinomas produce cytokines.

The tumor shadow in this patient rapidly increased in size prior to surgery. Examination of the excised lung tissue showed that the area around the tumor consisted of non-cancerous tissue intensely infiltrated by lymphocytes and neutrophils. The formation of this inflammatory outer zone around the tumor was likely not due to the production by tumor cells of IL-6 or G-CSF. Rather, the tumor may have produced chemotactic factors, which in turn recruited the infiltration by inflammatory cells. To analyze this mechanism, we assessed the expression of several chemokines using RT-PCR and immunohistochemistry.

In investigating the expression of chemokine receptors, we observed the intense expression of CXCR1 mRNA in the outer inflammatory zone. We also found that mRNA encoding IL-8 mRNA, the ligand of CXCR1 [19], was expressed by the tumor cells, and that these cells were partly stained with antibody to IL-8. Lymphocytes infiltrating the tumor were weakly positive for IL-8. In contrast, inflammatory cells in the area surrounding the tumor were negative for IL-8, while lymphocytes in these areas were weakly positive for IL-8R/CXCR1. Taken together, these findings suggest that the tumor cells produced IL-8, which recruited CD8-positive lymphocytes and neutrophils from the bloodstream, resulting in the rapid organization of an inflammatory zone around the tumor (Figure 10).

Although both CD8+ lymphocytes and neutrophils express the same IL-8R [20], CD8+ lymphocytes predominated around the tumor. This surrounding area was also positive for CXCR3, while mRNAs encoding Mig and IP-10, the ligands of CXCR3 and T-cell chemoattractants [20], were strongly expressed in the tumor itself. Because CD8 lymphocytes were recruited not only by IL-8 but also by Mig and IP-10, whereas neutrophils were recruited only by IL-8, these findings suggested that the imbalance between CD8 positive lymphocytes and neutrophils surrounding the tumor may be due to differences in the concentrations of these chemokines [20].

FDG-PET examinations have occasionally shown a pattern, in which FDG accumulates on the periphery of a tumor shadow, but not in the center of the lung tumor, owing to central necrosis and lung abscesses. The preoperative pattern of FDG uptake was unique in this patient, being localized to the center, but not the periphery, of the mass in the right lung apex. These finding suggest that FDG accumulated strongly in the cancerous lesion, but not in the outer inflammatory zone. Similar images on FDG-PET examination should suggest a tumor together with a local immunological response induced by the tumor.

We encountered a patient with a pleomorphic carcinoma of the lung. This tumor produced several cytokines and chemokines, including G-CSF, IL-6, and IL-8, resulting in several systemic responses and a rapidly growing tumor surrounded by inflammatory cells. FDG-PET, in addition to a conventional radiological approach such as CT scanning, may distinguish between tumor-induced immunological responses and the tumor itself.