Blastoma

Inflammatory sarcomatoid carcinoma is an aggressive tumor with an unusually benign appearance. We report the case of a 65-year-old man with a history of inoperable poorly differentiated carcinoma of the right lung, for which he had received chemoradiotherapy. A new solitary mass was discovered 4 years later in the left lung on surveillance computed tomography. The patient underwent thoracotomy with a wedge biopsy on which frozen section was performed. The nodule was vaguely granulomatous and associated with a mixed inflammatory infiltrate and a deceptively bland spindle cell proliferation. Results of immunoperoxidase studies, however, showed that the nodule contained neoplastic cells with an epithelial phenotype that were invading the pulmonary vessels. These are features of the rare inflammatory sarcomatoid carcinoma. In contrast to sarcomatoid carcinomas, this case highlights the deceptively benign appearance of inflammatory sarcomatoid carcinoma. This leads us to concur with the recommendation to exercise caution when attempting the diagnosis of apparently benign lesions on intraoperative frozen section in patients with high clinical suspicion of malignancy.

(Arch Pathol Lab Med. 2005;129:1334-1337)

Identification of inflammatory sarcomatoid carcinoma (ISC) was initially made by Wick et al,1 who reported 3 cases of sarcomatoid bronchogenic carcinoma with a deceptively bland appearance and associated with marked reactive inflammation. In one of these cases, the tumor was initially misinterpreted at the time of intraoperative frozen section consultation as an inflammatory pseudotumor (IP) because it shared several clinical attributes and similar histologie features of IP. Subsequently, Rossi and colleagues2 described 2 cases of ISC simulating a reactive process similar to IP or bronchiolitis obliterans organizing pneumonia. In their opinion, helpful morphologic clues to the malignant nature of the lesion were the presence of focal moderate nuclear atypia and vascular invasion. Herein, a unique case of inflammatory sarcomatoid carcinoma is reported in a patient with a history of chemoradiotherapy.

REPORT OF A case

A 65-year-old man had a history of poorly differentiated carcinoma of the right upper lung that had proved to be inoperable because of a satellite nodule. After a needle core biopsy had been performed and the diagnosis of poorly differentiated carcinoma had been established, the patient received chemotherapy and radiation of the right upper lobe and mediastinum. Four years later, he underwent surveillance computed tomography, on which a new solitary mass of the left lower lung was discovered. The patient was a long-standing smoker with severe coronary artery disease and a history of myocardial infarction. His chest radiograph film showed radiating densities in the right lung but no other definite lesions.

He presented to our institution for resection of a new left lung mass. Because frozen section results were interpreted as granulomatous inflammation, the neoplasm was removed by limited wedge resection. On confirmation of malignancy, he was offered lobectomy or chemotherapy. He chose, however, to be followed up by computed tomography scan. The postoperative course was uneventful, and the patient was discharged after a brief hospital stay. He has remained well for 1 year after surgery, and the latest imaging studies were negative for the residual tumor.

PATHOLOGIC FINDINGS

Gross Findings

The left lower lobe wedge biopsy specimen was submitted with a single tumor nodule measuring 1.3 × 1.0 × 0.7 cm. The cut surface showed the tumor to be gray-white and well circumscribed. No areas of necrosis were appreciated.

Light Microscopy

The slides of a needle core biopsy specimen from the right lung were reviewed. The previous tumor showed a sheet of large uniform malignant cells without any sarcomatoid features, and it was diagnosed at an outside facility as poorly differentiated non-small cell carcinoma. Mucin staining results were negative. The second primary tumor in the left lower lung had an irregular interface with the surrounding lung tissue, demonstrated a vague granulomatous appearance, and consisted of bland, reactive-appearing spindle cells haphazardly arranged and intermixed with a dense inflammatory infiltrate (Figure 1). The tumor cells had slight to moderate nuclear atypia (Figure 2). Mitotic figures were rarely observed. Vascular invasion with disruption of the vascular elastica was evident on elastic van Gieson stain (Figure 3). The appearances of the tumors were completely different.

lmmunohistochemistry

The tumor cells (Figure 4), including part of the tumor that was invading vessels (Figure 5), snowed strong reactivity for pankeratin, which supports a diagnosis of tumor with epithelial differentiation. Expression of vimentin was focally positive. TTFl stained the alveolar epithelium and was negative in the tumor cells, whereas CK7 was positive. Immunoperoxidase studies using antibodies to vascular markers showed positive staining with CD31 and CD34 in normal endothelial cells and highlighted the presence of vascular invasion. CDS and CD20 showed reactivity for T and B lymphocytes, respectively, in the inflammatory infiltrate. Tumor cells were negative for ALKl and SlOO protein.

Electron Microscopy

Ultrastructurally, the tumor showed cells with cytoplasmic lumen, microvilli, and secretion, which are typical features of adenocarcinomas (Figure 6). This finding supports considerable electronic microscopic evidence that spindle cell carcinomas are poorly differentiated carcinomas rather than sarcomas.3

COMMENT

Inflammatory sarcomatoid carcinoma is not a separate entity in the World Health Organization classification, although it belongs to the category of carcinomas with pleomorphic, sarcomatoid, and sarcomatous elements, which includes carcinoma with spindle or giant cells, carcinosarcoma, and pulmonary blastoma.4 The World Health Organization classification states that there exists "a group of poorly differentiated non-small cell lung cancers that contain a component of sarcoma or sarcoma-like elements."4*42'

Sarcomatoid carcinomas are very rare and aggressive tumors. They comprise just 0.1% to 0.4% of all lung malignancies and usually occur in male smokers, with a mean age of 60 years at the time of diagnosis.2 Patients typically present with cough, hemoptysis, chest pain, and dyspnea. As in conventional non-small cell carcinomas of the lung, clinical stage seems to be the most important prognostic factor,2,5 although Fishback et al6 reported that a tumor size greater than 5 cm, a clinical stage higher than stage I, and lymph node involvement shortened patient survival significantly. Histologically, sarcomatoid carcinomas can appear as homologous biphasic tumors, with carcinoma intermingled with a nondescript spindle cell sarcomatoid component or with heterologous sarcomatous tissue, including malignant skeletal muscle, bone, or cartilage. A monophasic variant consists of a pure sarcomatoid component. Such a histologie classification has been favored by some authors,3,7 based on biologic tumor behavior and the fact that no difference exists in the clinical evolution of homologous and heterologous sarcomatoid carcinoma of the lung.7,8 The World Health Organization classification, in comparison, uses terms such as spindle cell carcinoma to describe monophasic sarcomatoid carcinoma, pleomorphic carcinoma for homologous biphasic sarcomatoid carcinoma, and carcinosarcoma for heterologous biphasic sarcomatoid carcinoma.8 The epithelial origin of the pleomorphic cells is accepted; however, some results have shown that they can acquire the expression of vimentin and other mesenchymal markers and that this phenotype can result in spindling of the cells and reduced cell-to-cell adhesion.5 TTFl and CK7 expression is positive in a significant percentage of sarcomatoid carcinomas. Rossi et al2 reported that TTFl and CK7 positivities were 55% and 70%, respectively, in tumors composed exclusively of spindle or giant cells and were 62.7% and 43.1%, respectively, in pleomorphic carcinomas. The sarcomatous parts of carcinosarcomas and blastomas, however, always express negative findings. Although our case demonstrated an adenocarcinoma component by electron microscopy, TTFl expression was negative, whereas CK7 staining was positive.

With only 5 cases described in the literature,1,2 to our knowledge, ISC is exceptionally rare, much more so than the very rare sarcomatoid carcinoma. The clinicopathologic features of the previously reported cases, including ours, are summarized in the Table. Inflammatory sarcomatoid carcinoma exhibits a bland cytologie appearance, limited mitotic activity, and an investment by inflammatory cells, unlike the other spindle cell carcinomas. Because at the time of frozen section it can be mistaken for a benign process, it is essential that immunohistochemical and ultrastructural analysis be performed. Although our electron microscopic analysis showed typical adenocarcinoma features, this does not exclude a diagnosis of ISC because these tumors can have a second component that is not recognizable under light microscopy. Whereas some authors believe that ISC exists in the continuum of sarcomatoid carcinoma,9 we think that by virtue of its benign appearance sufficient evidence is present to propose a subcategorization of this tumor. The inclusion of such a category would also help to ensure the most correct diagnosis.

The differential diagnosis of sarcomatoid carcinomas necessitates the exclusion of various entities that include reactive processes such as bronchiolitis obliterans organizing pneumonia, IP, different primary and metastatic sarcomas, and lymphoproliferative processes (ie, lymphomatoid granulomatosis). Therefore generous tumor sampling and ancillary studies are necessary.

Bronchiolitis obliterans organizing pneumonia is an inflammatory reaction to various injuries in the terminal bronchioles, alveolar ducts, and alveoli. Microscopically, it demonstrates an inflammatory exudate, chronic inflammation of the alveolar septa, and fibrous tissue proliferation forming plugs in the lumen of the terminal bronchioles and alveolar ducts. Vascular invasion, mitosis, and cell pleomorphism are not observed in cases of bronchiolitis obliterans organizing pneumonia.

Inflammatory pseudotumor and ISC have similar potential to develop in middle-aged and older individuals, although IP is found more often in patients younger than 40 years. Furthermore, IP is the most common primary lung tumor seen in young people, with both sexes being affected equally. Patients with ISC are usually men with a long history of cigarette use. Chest radiography is not always successful in distinguishing these 2 tumors because both can have blurred edges caused by consolidation or collapse of the surrounding lung in IP and by tumor infiltration in ISC.3,10 Both lesions are composed of a proliferation of bland spindle cells and marked inflammatory infiltrate. Although spindle cells are found in both neoplasms, they are more pleomorphic, atypical, and epithelioid-like in ISC compared with those in IP. Immunohistochemistry reveals staining of spindle cells with vimentin and smooth muscle actin in most IPT cases and with cytokeratin in one third of IPT cases.3,11 Smooth muscle actin expression is lacking in ISC. Ultrastructural studies reveal the myofibroblastic nature of the spindle cells in IP. Histologie features such as mitosis and vascular invasion cannot be used as distinguishing factors because they can be present in both tumors.3,10

The differential diagnosis of sarcomatoid carcinoma with primary or metastatic lung sarcomas, especially spindle cell carcinoma in which the carcinomatous component is absent, is particularly difficult. cases of leiomyosarcoma, fibrosarcoma, and malignant peripheral nerve sheath tumors have been reported.7 In addition, biphasic and monophasic synovial sarcomas can be challenging because they can be ultrastructurally and immunophenotypically identical to sarcomatoid carcinomas. Therefore, generous sampling of different areas of the tumor, immunohistochemical detection of cytokeratin, and electron microscopic and cytogenetic studies are essential in differentiating sarcomatoid carcinomas from primary and metastatic pulmonary sarcomas.

Lymphomatoid granulomatosis is also included in the differential diagnosis of ISC because it can present as a granulomatous process with marked lymphocytic infiltrate. The age at presentation varies widely, but most patients are middle-aged, immunocompromised men. Skin and peripheral and central nervous system involvement can precede lung disease by months and years. Radiographically, lymphomatoid granulomatosis usually presents as bilateral multiple nodules that may wax and wane. Lymphomatoid granulomatosis is an angiocentric, angioinvasive, and angiodestructive lesion now regarded as T-cell-rich B-cell lymphoma in which large B cells are monoclonal and positive for Epstein-Barr virus.12 A prominent inflammatory infiltrate with numerous reactive T cells admixed with plasma cells and histiocytes can sometimes obscure the malignant nature of lymphomatoid granulomatosis. The characteristic feature of this lesion is vascular infiltration, causing effacement of the vessel wall and central necrosis. Inflammatory sarcomatoid carcinoma, in comparison, has an inflammatory background and keratin-positive malignant epithelial cells invading the vessels.

Some reports indicate that radiation-induced second primary carcinoma usually develops during decades. Deutsch et al13 reported a statistically significant increase in the incidence of subsequent primary lung carcinomas, both ipsilateral and contralateral, in those patients who received comprehensive postmastectomy radiotherapy for breast tumors (mean follow-up, 21.4 years). There are also reports of sarcomatoid change caused by radiotherapy in adenocarcinomas in other organs. Nakajima et al14 reported a case of poorly differentiated adenocarcinoma in a lung biopsy specimen. After radiotherapy was performed, a subsequent pneumonectomy specimen showed sarcomatoid changes. Dundore et al15 observed 8 carcinosarcomas of the prostate that had been diagnosed 2 to 73 months (mean, 34 months) previously as adenocarcinomas. These had been treated with androgen deprivation or radiotherapy in the interim.15,16 Sarcomatoid change of a preexisting tumor caused by radiation takes place during several months to a few years. Therefore, we believe that in our case a new tumor was not induced by radiotherapy. However, there is a remote possibility that the lung tissue that had been exposed to chemotherapy or radiation spillover was more prone to undergoing sarcomatoid change. Our report herein presents a unique case of a second primary lung carcinoma with sarcomatoid elements.

We thank Henry D. Tazelaar, MD, for consultation and helpful critical comments. We thank Nafisa Burhani, MD, for providing clinical information. We thank Raoul Fresco, MD, for his support in electron microscopy.

References

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Tatjana Antic, MD; Umesh Kapur, MD; Wickii T. Vigneswaran, MD; Kiyoko Oshima, MD, DSc

Accepted for publication June 15, 2005.

From the Departments of Pathology (Drs Antic, Kapur, and Oshima) and Thoracic and Cardiovascular Surgery (Dr Vigneswaran), Loyola University Medical Center, Maywood, III.

The authors have no relevant financial interest in the products or companies described in this article.

Presented at Illinois Registry of Anatomic Pathology, Chicago, May 24, 2004.

Reprints: Kiyoko Oshima, MD, DSc, Department of Pathology, Loyola University Medical Center, Room 2241, 2160 S First Ave, Maywood, IL 60153 (e-mail: koshima@lumc.edu).

Copyright College of American Pathologists Oct 2005
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