Intrathoracic rhabdoid carcinoma: a clinicopathological, immunohistochemical, and ultrastructural study of 6 cases

Annals of Diagnostic Pathology 9 (2005) 279 – 283

Intrathoracic rhabdoid carcinoma: a clinicopathological, immunohistochemical, and ultrastructural study of 6 cases Giovanni Falconieri, MDa,T, Cesar A. Moran, MDb, Stefano Pizzolitto, MDa, Andreja Zidar, MDc, Vito Angione, MDa, Paul E. Wakely Jr., MDd a

Department of Pathology, S. Maria della Misericordia General Hospital, Udine, Italy b Department of Pathology, M.D. Anderson Cancer Center, Houston, Tex, USA c Department of Pathology, Institute of Oncology, Ljubljana, Slovenia d Department of Pathology, Ohio State University, Columbus, Ohio, USA

Abstract

We evaluated the clinicopathological spectrum of intrathoracic rhabdoid carcinoma, including its immunophenotype and ultrastructural features. Our series included 6 cases arising from the lung (4 cases) and the anterior mediastinum (2 cases). The patients were 4 men and 1 woman aged between 40 and 63 years (median, 53 years). Microscopically, all of the lesions were composed of loosely cohesive, large, atypical polygonal cells, with glassy cytoplasms and eccentric nuclei. Chromatin texture was finely granular or open. On immunohistochemical stain, the neoplastic cells were positive for vimentin in all cases, positive for vimentin, keratins and/or epithelial membrane antigen in all cases, and negative for other antigens. In 1 case, neoplastic cells were also positive for CD34. Electron microscopic study showed prominent perinuclear whorls of densely packed intermediate filaments or mitochondria. All patients were treated with combined chemotherapy and radiotherapy. One patient died 8 months after the diagnosis was made. Of the remaining patients, 3 are alive with evidence of disease progression, including brain metastases. We concluded that rhabdoid neoplasms arising in the thoracic cavity are aggressive tumors of epithelial lineage and should be categorized as true brhabdoid carcinomasQ instead of being ambiguously designated as bintrathoracic rhabdoid tumorsQ or bcarcinomas with rhabdoid phenotype.Q D 2005 Elsevier Inc. All rights reserved.

Keywords:

Rhabdoid tumor; Lung; Mediastinum; Immunohistochemistry; Electron microscopy; Adult patients; Neoplasms

1. Introduction Rhabdoid cells similar to those seen in classic renal tumors of infancy have been described within virtually all solid malignancies, including carcinoma, lymphoma, melanoma, and sarcoma; their significance is still unclear, although this probably reflects phenotypic deviation during tumor progression or dedifferentiation [1]. In the thoracic cavity, carcinomas exhibiting a striking rhabdoid phenotype are rare and usually limited to the lung [2]. Although the topic of large cell carcinoma with rhabdoid features has been addressed previously, it is not clear whether this form T Corresponding author. Division of Anatomic Pathology, Department of Pathology and Laboratory Medicine, S. Maria della Misericordia General Hospital, I 33100 Udine UD, Italy. Tel.: +39 0432 552829; fax: +39 0432 552830. E-mail address: [email protected] (G. Falconieri). 1092-9134/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2005.07.003

of carcinoma segregates within a distinct entity and whether the proportion of rhabdoid elements has any influence on prognosis. In addition, rhabdoid carcinoma arising in the anterior mediastinum is an underreported subject that has not been specifically addressed in the literature. In this article, we report on 6 cases of intrathoracic rhabdoid carcinoma (IRC), 2 of which occurred in the anterior mediastinum. We emphasize specific sites, histological type, and tumor behavior, suggesting that pulmonary and mediastinal rhabdoid carcinoma may clinically and pathologically segregate within a broad category of IRC, entailing a poor prognosis. 2. Materials and methods Cases were departmental surgical pathology accessions. Routine histological sections were prepared from formalin-

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Table 1 Summary of clinical, instrumental, and pathological features of the 6 cases of IRC Age (y)/sex

Clinical history

Instrumental findings

Surgical procedure

Gross features

Treatment and follow-up

40/M

Cigarette smoking 1 pack/d, chest pain

Marked enlargement of upper mediastinum

Thoracotomy and mass biopsy

CT and RT; dead 8 mo after diagnosis

46/M

Mass of the anterior mediastinum, displacing the upper vena cava Right upper lobe mass

Thoracotomy and partial mass resection

50/M

Monoclonal gammopathy, fever, vomiting, joint pain, and prostration; increased lymphocyte count in the cerebrospinal fluid Chest pain

1.3-cm firm nodule with a gray-white lobulated surface 4-cm white-gray fragmented lobulated mass

Lobectomy

58/F 56/M 63/M

Cough, dyspnea, chest pain Chest pain, weight loss Weight loss, cough, chest pain

Left lower lobe mass Right lower lobe mass Right upper lobe mass

Lobectomy Lobectomy Lobectomy

8-cm peripheral, lobulated mass 3-cm firm mass 4-cm mass 4.8-cm tumor

Surgery and CT; alive; recent case Surgery and CT; alive Lost to follow-up CT; alive with disease progression (brain metastasis)

CT and RT; alive with evidence of local disease

M indicates male; F, female; CT, chemotherapy; RT, radiotherapy.

fixed, paraffin-embedded specimens. Tissue sections were stained with hematoxylin and eosin. Immunohistochemical analysis was performed by using the avidin-biotin complex technique with commercially available antibodies raised against broad-spectrum keratins, low–molecular-weight keratins (Cam 5.2), epithelial membrane antigen (EMA), TTF-1, S100 protein, neurofilaments, CD31, CD34, CD68, CD99, vimentin, smooth muscle actin, muscle-specific actin, myoglobin, and MyoD1. Antibody dilutions were assessed by means of a titration checkerboard as described elsewhere [3]. Diaminobenzidine was used as chromogen. Fresh tissue was available for ultrastructural studies in all the lung tumors; in one of the mediastinal cases, material was recovered from paraffin blocks. Clinical information was retrieved from hospital medical records and from the referring family physicians.

5 men and 1 woman ranging in age from 40 to 63 years (median, 53 years). Main clinical symptoms included chest pain, fever, and cough. Past medical history was usually unremarkable. Patients with either pulmonary or mediastinal lesions had an apparently localized disease at the time of diagnosis, although an abnormal mediastinal profile suggested possible tumor extension in the adjacent lung and displacement of upper vena cava in one case. In another case, the presence of monoclonal gammopathy along with the mediastinal tumor suggested a lymphoma. Lobectomy was successfully carried out in the 3 pulmonary lesions. The mediastinal lesions were sampled during mediastinoscopy. 3.2. Pathological outcomes

Clinical, pathological, and follow-up information for the 6 patients are summarized in Table 1. Tumors were from

Lung tumors ranged from 3 to 8 cm in diameter. They were grossly solid, grayish white, and firm. Histologically, the lung neoplasms were well circumscribed but not encapsulated (Fig. 1). The tumors obliterated the normal lung parenchyma in sheets of cells without any particular growth pattern. At higher magnification, the tumors were composed of relatively round to oval cells

Fig. 1. Rhabdoid carcinoma of the lung showing well circumscription and a diffuse growth pattern. (Low power, hematoxylin and eosin [H&E].)

Fig. 2. Higher magnification showing atypical polygonal cells with stainable, glassy cytoplasms and eccentric nuclei. (Intermediate power, H&E.)

3. Results 3.1. Clinical outcomes

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Fig. 3. Rhabdoid carcinoma of the mediastinum. Sheets of polygonal cells with abundant, intensely eosinophilic cytoplasms. There is a vague lobulation caused by delicate fibrous rims. (High power, H&E.)

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Fig. 5. A mediastinal rhabdoid carcinoma focally reacting for low– molecular-weight keratins. (Intermediate power, immunoperoxidase.)

with pale eosinophilic cytoplasms and the nuclei were displaced toward the periphery given the impression of rhabdomyoblasts (Fig. 2). No nucleolar prominence was present. Mitotic figures were present, but not in a high number. Fragments of mediastinal mass biopsy specimens were grayish tan and soft. Microscopically, they showed areas of necrosis with an irregular outline (Fig. 3) and a diffuse proliferation of atypical polygonal cells with an eccentric vesicular nucleus caused by glassy cytoplasmic inclusion (Fig. 4). Immunohistochemical studies demonstrated consistent positivity for vimentin. All pulmonary lesions were positive for keratins and EMA. Of the mediastinal tumors, both cases were positive for EMA and one case was focally positive for low–molecular-weight keratins (Fig. 5). Positivity for CD34 was also noted in this case. The remaining tested antigens were negative. Electron microscopic investigations showed that rhabdoid cells had abundant collections of intermediate filaments either as interlacing bundles or whorl-like arrays (Fig. 6). On followup, 1 patient with a partially resected mediastinal tumor died 8 months after the diagnosis was made. Of the 4 patients with a pulmonary lesion, 1 died of tumor, 1 is alive with

evidence of disease progression, 1 has been lost to follow-up, and 1 patient is a recent case.

Fig. 4. Sheets of polygonal cells with abundant, intensely eosinophilic cytoplasms. High power, H&E.

Fig. 6. Tumor cells showing packed intermediate filaments arranged in prominent perinuclear whorls (electron microscopy).

4. Discussion Although any malignant tumor may exhibit a rhabdoid phenotype, rhabdoid carcinomas are rare in the lung and even less common in the anterior mediastinum. Current review of the literature shows that less than 40 cases of rhabdoid pulmonary carcinoma have been compiled in the American and English literature [4-12]. This carcinoma is considered aggressive if compared with the more common non–small cell carcinoma. The rhabdoid component may be focal and associated with a conventional large cell carcinoma or adenocarcinoma. In the series by Tamboli et al [2], 11 cases of lung rhabdoid carcinoma were described: the patients were all adults and presented mostly in an advanced carcinoma stage (III or IV). History of cigarette smoking could be elicited in more than half of the patients. However, the rhabdoid cells were inconsistently

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observed. In addition, an epithelial differentiation could be recognized in all cases whereas features of glandular differentiation were seen in 4 cases. No specific immunohistochemical profile was detected, although most tumors reacted for keratins and vimentin. Interestingly, no immunostaining was reported for TTF-1, an antibody that frequently reacts with conventional adenocarcinoma of the lung. Metastatic deposits had a predominance of rhabdoid cells. On the contrary, our cases showed an exclusively rhabdoid component without any particular differentiation toward squamous or adenocarcinoma cells. The prognosis for pulmonary rhabdoid carcinoma is generally poor; however, long-term survivors are apparently not exceptional. In a case reported by Hiroshima et al [3], the patient was a 70-year-old woman with a stage I tumor. Recurrence was detected 6 years after thoracic surgery and was comparable with the primary lesion. The survival time noted in this case, which is even longer for the more common non–small cell carcinoma, suggests that localized diseases may have a greater chance of curability. Similarly, survival of longer than 5 years was observed in the case reported by Kaneko et al [5], who described a 59-year-old man presenting with a lung-confined tumor. The patient developed an adrenal metastasis 3 years after lobectomy. On the other hand, in their study of 14 patients, Shimazaki et al [7] found that rhabdoid cell–rich tumors entailed a poorer prognosis regardless of tumor stage; their observation was also validated by a statistical analysis suggesting that the number of rhabdoid cells may be a significant prognosticator. Interestingly, if the compiled cases of rhabdoid lung carcinoma were considered, then lymph node metastases have been documented in 13 of 33 cases; if our 4 cases were added, then the proportion of lung tumors without local metastases at presentation is roughly two thirds. Also, we are not aware of cases in which the metastases were found prior to the lung tumor. In our series, the patients were all adults and presented with a localized lung disease. Although no evidence of metastasis was seen at the time of diagnosis and staging, one patient died of tumor and another developed a brain metastasis despite proper antitumoral treatment. The tumors were exclusively composed of rhabdoid cells and there was no evidence of glandular and/or squamous differentiation. Immunohistochemistry and electron microscopy suggested an epithelial lineage, given the consistent immunoreactivity for keratins and ultrastructural features such as paranuclear intermediate filaments. Tumor size and stage did not appear to have any predictive means. On the other hand, mediastinal tumors with similar histology are exceedingly rare. None of our patients had concomitant or subsequent mass detected in the peripheral lung during follow-up, although one patient died of chemotherapy-related complications and another patient is alive with evidence of a mediastinal residual disease following antitumoral therapy. Given that the lesions are primary in the mediastinum, it is difficult to hypothesize a

potential parental cell. A possible relationship to a thymic precursor may be claimed; however, both tumors lack any morphological feature observed in thymic neoplasms, including lobulations, septa, and perivascular spaces. Keratin immunostaining was also only focal. Although rhabdoid cells may be present in thymic neoplasms, rhabdoid carcinomas have not been described in the thymus to the best of our knowledge. Another point of discussion may be raised by the recent observation of epithelioid sarcoma of proximal type in the chest wall [13], although no case has been described so far within the mediastinum. Such tumors display several features in commonality with IRC, including large polygonal cells with abundant eosinophilic cytoplasms, high mitotic activity, and necrosis. Keratin immunostaining is also often observed in epithelioid sarcoma of proximal type. Although a limited tumor sample was available in our mediastinal tumor cases, it is interesting to note that proximal-type epithelioid sarcomas recapitulate several features seen in extrarenal rhabdoid tumors to such an extent that their distinction may be impossible and probably impractical. The differential diagnosis of IRC includes a number of malignant conditions. The differentiation may be difficult on pure morphological grounds. However, the judicious use of a limited antibody panel may suffice for reliably segregating these lesions and singling out those that may benefit from specific treatments. Large cell lymphomas may occur as a primary pulmonary and/or mediastinal lesion. Tumor cells are often immunopositive for leukocyte common antigen, and lymphoid antigens such as CD3, CD20, and CD30 may be expressed. Specific pulmonary lymphoproliferative disorders such as lymphomatoid granulomatosis may be recognized by virtue of clinical and pathological features, although resorting to immunohistochemistry is useful to rule out other conditions. Melanoma can be virtually indistinguishable from rhabdoid tumors as well as from any other malignancy inasmuch as rhabdoid changes are often detected in recurrent or metastatic lesions; immunoreactivity for S100 protein, in the absence of staining for other antigens, is, however, expected in most cases of melanoma. Epithelioid angiosarcoma may rarely but not exceptionally occur in the lung as a primary tumor, either alone or in association with extensive pleural involvement: Poorly differentiated forms may lack evidence of diagnostic clues such as a freely anastomosing vascular channel pattern and intracellular lumina. In addition, tumor cells may have a rich stainable cytoplasm, recalling that seen in rhabdoid tumors, and epithelioid angiosarcoma cells may react to antibodies against low–molecular-weight keratins, thus suggesting a tumor of true epithelial lineage. However, clues such as abortive vessels and intracellular lumina may be often recognized; also, angiosarcoma is often positive for factor VIII–related antigen, CD31, and fli-1. In summary, we have described 6 cases of an intrathoracic neoplasm with exclusive rhabdoid features. Based on our findings, we consider that similar neoplasms should

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be categorized as brhabdoid carcinomasQ instead of being ambiguously designated as brhabdoid tumorsQ or bcarcinomas with rhabdoid phenotype.Q In addition, we have highlighted the importance of the ubiquitous nature of these tumors within the thoracic cavity (ie, lung and mediastinum).

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