Pseudomesotheliomatous Adenocarcinoma of the Lung with Rhabdoid Features

PATHOLOGY

Teaching Case

RESEARCH AND PRACTICE © Urban & Fischer Verlag http://www.urbanfischer.de/journals/prp

Pseudomesotheliomatous Adenocarcinoma of the Lung with Rhabdoid Features Johannes H. Attems and Felix Lintner Department of Pathology, SMZ – Otto Wagner Hospital Vienna, Austria

Summary

Introduction

Pseudomesotheliomatous adenocarcinoma of the lung is a rare entity, clinically and pathologically mimicking diffuse malignant pleural mesothelioma. We report a case of pseudomesotheliomatous adenocarcinoma consisting of two distinct histopathologic components with marked differences in morphological appearance and immunohistochemical staining pattern: a small subpleural nodule consisting of adenocarcinoma and undifferentiated carcinoma with rhabdoid features, the latter extending to the visceral pleura in a diffuse mesothelioma-like growth pattern. The adenocarcinomatous component showed strong reactivity with various epithelial markers, but no reactivity with vimentin. The undifferentiated component showed strong reactivity for vimentin, but no reactivity for epithelial markers. Both components showed no reactivity with CEA, Ber Ep4, MOC-31, B72.3, cytokeratin 5/6, calretinin and thrombomodulin. Metastatic lesions in the duodenum and the periumbilical skin consisted entirely of undifferentiated carcinoma with rhabdoid features. Fluorescence in situ hybridisation (FISH) was performed for chromosomes 4, 7, 20, and 22. FISH results showed polysomy 7 in both components. The diagnosis of pseudomesotheliomatous adenocarcinoma in this case was based on the finding of the subpleural nodule. We conclude that in cases of undifferentiated malignant pleural tumors with cells of rhabdoid phenotype, the possibility of peripheral pulmonary adenocarcinoma dedifferentiating into a more aggressive phenotype should be considered.

Pseudomesotheliomatous adenocarcinoma (PMAC) of the lung was first described by Harwood et al. in 1976 [12]. Since then, 71 cases [4, 10, 16, 17, 22, 24, 28] have been reported in the literature. PMAC is a distinct variant of peripheral adenocarcinoma of the lung, resembling malignant pleural mesothelioma with respect to its clinical appearance, growth pattern, macroscopic, and microscopic morphologies [28]. We report a case of PMAC of the lung consisting of two different histologic components, i.e., a subpleural adenocarcinoma and a diffuse pleural mass of undifferentiated epithelial cells with rhabdoid features. Primary pulmonary tumors with rhabdoid features are rare, with 16 cases reported in the literature [6, 8, 19, 27]. To our knowledge this is the first reported case of pseudomesotheliomatous adenocarcinoma with rhabdoid features.

Key words: Pseudomesotheliomatous adenocarcinoma – Lung – Composite extrarenal rhabdoid tumor (CERT) Pathol. Res. Pract. 197: 841–846 (2001)

Case History A 69-year-old Caucasian woman presented with pain in the right hemithorax. She had a history of nicotine abuse (15–20 cigarettes per day), and no personal history of asbestos exposure. Lung X-ray and subsequent computer tomography of the lung showed right-sided pleural Address for correspondence: Johannes H. Attems, SMZ Baumgartner Höhe, Otto-Wagner-Spital mit Pflegezentrum, Pathologisch-Bakteriologisches Institut, Baumgartner Höhe 1, A - 1145 Vienna, Austria. Tel.: +43-1 910/60 21308, Fax: +43-1 910/60 49807. E-mail: [email protected] 0344-0338/01/197/12-841 $15.00/0

842 · J. H. Attems and F. Lintner

effusion and diffuse pleural thickening. Video-assistedthoracoscopy revealed pleural thickening of the right upper lobe, partially adherent to the thoracic wall. A pleural biopsy specimen was taken, suggesting malignant mesothelioma. Subsequently, a right upper lobectomy with resection of the complete parietal pleural was carried out. Due to persistent nausea the patient underwent duodenoscopy. Two polypous lesions in the bulbus duodeni were detected, and biopsy specimens were taken, showing undifferentiated carcinoma compatible with a metastatic lesion of the pulmonary primary tumor. A duodenogastrectomy was carried out together with the resection of a clinically suspicious subcutaneous tumor in the umbilical region. The periumbilical tumor’s histology also showed undifferentiated carcinoma compatible with a metastatic lesion of the pulmonary primary tumor. The patient died 3 months later. Autopsy revealed acute myocardial infarction and metastatic lesions in both adrenal glands.

Materials and Methods Tissue sections of the primary tumor, the duodenal metastases, and the subcutaneous metastasis were fixed in 10% buffered formalin and embedded in paraffin. Sections were stained for hematoxylin and eosin as well as period acid-Schiff with and without diastase pretreatment (D-PAS, PAS). Immunohistochemistry was done using the standard avidin-biotin complex / alkaline phosphatase technique. Antibodies used for immunohistochemistry are listed in Table 1. Fluorescence in situ hybridization (FISH) was carried out on sections of the primary tumor and the metastatic lesions, using commercially available reagents (Q-Biogene, Illkirch, France), according to the manufacturer’s directions. Four micrometer-thick specimens from the paraffin-embedded sections were prepared and mounted on silane-coated slides. After deparaffinization, tissue sections were placed in 30% pretreatment solution, digested in proteinase K, dehydrated, and denaturated. Single-color FISH was done using α-centromeric probes to chromosomes 4 (D4Z1), 7 (D7Z1), 20 (D20Z1), and 14/22. FISH probes were digoxigenin-labeled and detected using Rhodamine antidoxigenin. All slides were counterstained with DApi7antifade (0.1 mg/ml). To evaluate the fluorescence we used a Nikon E600 microscope with a Y-Fl EpiFluorescence Attachment (Nikon, Tokyo, Japan) and a blackand-white, charge-coupled device (CCD) camera (COHU 4912; Cohu, San Diego, CA) run by Lucia-Fish software (Laboratory-Imaging, Prague, Czech Republic).

Results Upon macroscopic evaluation, 99% of the pulmonary tumor mass presented as a 2 cm-thick, gray-whitish sheet replacing the entire visceral pleura of the right upper lobe and the adjacent middle lobe (Fig. 1). In the apical part of the right upper lobe, adherent to the pleu-

Fig. 1. Cut surface of the pleural tumor ensheathing the right upper lobe. Table 1. Immunohistochemical findings Antibody (clone)

Cytokeratin 20 (IT-Ks20.8) Cytokeratin (AE1/AE3) Pan Cytokeratin (lu-5) Cytokeratin 7 (OV-TL 12/30) Epithelial membrane antigen (E29) Vimentin (V9) Desmin (D33) Muscle actin (HHF35) Factor VIII (F8/86) Neuron specific enolase (BBS/NC/VI–H14) Leucocyte common antigenCa (2B11 and PD7/26) Human mesothelial cell (HBME-1) Cytokeratin 5/6 (D5/16B4) Calretinin (polclonal) Thrombomodulin (1009) Human epithelial related antigen (Moc-31) Carcinoembryonic antigen (SP-651) Human epithelial antigen (BerEp4) Tumor associated glycoprotein (B72.3) CD15 [Leu-M1] (MMA) Muc-1 glycoprotein (Ma695) Muc-2 glycoprotein (Ccp58) Human melanoma (HMB-45) S-100 protein (polyclonal) p53 (DO-7)

Source

Reactivity AC

RC

BG BM BG Dako Dako Dako Dako Enzo Dako Dako

+ + + + + – – – – +

– – – – – + – – – +

Dako

–

–

Dako Chemo Zymed Dako Dako

– – – – –

– – – – –

BG Dako BG

– – –

– – –

BD NC NC Dako Dako Dako

– + + – – –

– – – – – –

AC = adenocarcinomatous component; RC = rhabdoid component; + positive reaction; – negative reaction; BG = Biogenex, San Ramon, CA; BM = Boehringer Mannheim, Mannheim, Germany; Dako = Dako Corp, Santa Barbara, CA, Enzo = Enzo Diagnostics, Farmingdale, NY; Chem = Chemicon, Temecula, CA; Zymed = Zymed, San Francisco, CA; BD = Becton Dickinson, Mountain View, Ca; NC = Novocastra, Newcastle o.T., UK

Pseudomesotheliomatous Rhabdoid Pulmonary Adenocarcinoma · 843

ral rind, we detected a round graywhitish, centrally necrotic nodule measuring 1 cm in diameter. The first duodenal metastasis presented as a postpyloric, 1.4 cm-thick, graywhitish, centrally ulcerated, polypous lesion in the ventral wall. The second duodenal metastasis presented as a postpyloric, 0.8 cm in diameter, graywhitish, centrally ulcerated, polypous lesion in the dorsal wall. The periumbilical metastasis presented as a subcutaneous, gray-whitish nodule measuring 1.4 cm in diameter. Histologically, the subpleural nodule consisted of a moderately differentiated solid adenocarcinoma with an undifferentiated component. The undifferentiated component consisted of cells of rhabdoid phenotype with large eccentric nuclei, macronucleoli, abundant cytoplasm, globular eosinophilic cytoplasmatic inclusions frequently indenting the nucleus (Fig. 2), and multinucleated giant tumor cells. Cytoplasmatic inclusions did not stain for PAS or D-PAS. The undifferentiated component was the only histologic finding in the pleural rind, the duodenal metastases, and the subcutaneous metastasis. Immunohistochemical results are summarized in Table 1. Of note, epithelial markers were positive in the adenocarcinomatous component of the tumor (Fig. 3A). Vimentin-staining with intense staining of the cytoplasmatic inclusions was observed in the undifferentiated components of both the primary tumor and the metastases (Fig. 3B). FISH showed polysomy for chromosome 7 (Fig. 4) and disomy for chromosomes 4, 20, and 22 in both components of the primary tumor and the metastases.

Fig. 2. Rhabdoid cells with characteristic abundant eosinophilic cytoplasm, large eccentric nuclei with macronucleoli, in the pleural part of the tumor, HE ×200. Fig. 3. (A and B) Transision between adenocarcinomatous and rhabdoid component in the subpleural nodule; same area. A: Cytokeratin 7 shows strong reaction with the adenocarcinomatous component. ×400. B: Vimentin stains only the rhabdoid component, ×400.

844 · J. H. Attems and F. Lintner

Fig. 4. Indented nucleus of rhabdoid cell, fluorescence in situ hybridization (FISH) for chromosome 7 reveals five signals, indicating polysomy 7 (computer edited).

Discussion PMAC is a rare variant of peripheral adenocarcinoma of the lung characterized by clinical, radiologic, and pathologic features similar to malignant mesothelioma [28]. The diagnosis is usually based on histochemical [10, 12, 16, 22, 24], immunohistochemical [10, 17, 22, 24, 28], and ultrastructural findings [10]. Cytokeratin 5/6, calretinin and thrombomodulin are expressed in 42–100% of mesotheliomas, but only in 0–77% of pulmonary adenocarcinomas [5, 25]. Lack of expression of MOC 31, CEA, Ber-Ep4, B72.3, and LeuM1 has been described as a characteristic feature of mesotheliomas [5, 25]. Adenocarcinoma of the lung with extensive pleural growth and a variety of other adenocarcinomas metastatic to the pleura (e.g., ovary, endometrium, breast, thyroid, kidney, colon, and prostate) may mimic mesothelioma, therefore, immunohistochemistry is used as an ancillary method in the diagnosis thereof [25]. Immunoreactivity obtained from the pleural biopsy specimen was inconclusive in our case (Table 1). Thus, we initially diagnosed a malignant mesothelioma of epithelioid subtype. After identifying a subpleural nodule in the resected upper lobe of the lung presenting as adenocarcinoma, we modified the diagnosis to that of PMAC. There was in particular a striking difference in the histomorphologic appearance and the immunohistochemical staining pattern between the subpleural nodule and the tumor’s remaining part (Table 1). The remaining part of the tumor showed no histologic features suggestive of adenocarcinoma, but cells of a rhabdoid phenotype and strong immunoreactivity for vimentin and neuron-specific enolase (NSE) were noted. Immunoreactiv-

ity for vimentin and NSE is not an uncommon finding in pulmonary adenocarcinomas [9]. The subpleural nodule, however, did not show immunoreactivity for vimentin. According to Cavazza et al., the rhabdoid phenotype is characterized by large cells with abundant cytoplasm, rounded eosinophilic cytoplasmatic inclusions, and a large eccentric nucleus with a centrally-located macronucleolus [6]. Lung carcinomas may possess focal or extensive zones demonstrating a rhabdoid phenotype usually occurring in a poorly differentiated tumor component with the morphology of large cell carcinoma [30]. Large cell carcinoma is a diagnosis of exclusion after ruling out the presence of a squamous cell carcinoma component, adenocarcinoma component or small cell carcinoma component [30]. In our case, however, an adenocarcinoma component was present. Tumors composed entirely of rhabdoid cells are found in the kidney (Malignant Renal Rhabdoid Tumor [MRRT]) as well as in extrarenal organs (Malignant Extrarenal Rhabdoid Tumor [MERT], [35]). MRRT and MERT occur predominantly in the pediatric population [1, 23, 35]. These rhabdoid tumors are to be distinguished from composite neoplasms with rhabdoid features in a parent neoplasm (composite extrarenal rhabdoid tumor [CERT], [35]). There have been 16 cases of CERT reported. All of these cases showed evidence of aggressive growth [6, 8, 19, 27] with pleural infiltration mentioned in eight cases [6, 19]. Ten to 90% of the tumor cells were reported to be of a rhabdoid phenotype [6, 7, 19]. Gödken et al. investigated 480 adult renal cell carcinomas and found rhabdoid features in 23 cases [11]. Positive labeling for vimentin was the only common immunohistochemical finding in rhabdoid cells [6, 19, 27, 35]. The query whether rhabdoid tumors represent a phenotype or an entity is still controversial. Many authors, however, believe only pediatric MRRT [27, 32] and MERT [23] to be distinct pathologic entities, whereas rhabdoid cells in CERT can be interpreted as a sign of dedifferentiation. CERT’s exhibit aggressive biological behavior and occur in various tumors that are histogenetically unrelated [2, 11, 26, 27, 29, 31, 32, 34, 35]. To date, FISH results have only limited diagnostic value concerning the differentiation between pulmonary adenocarcinoma and malignant pleural mesothelioma. Polysomy 7, however, is well documented in non-small cell lung cancer (NSCLC; [14, 20, 21]) and monosomy for chromosome 22 has been described in MERT [35]. In our case, FISH showed polysomy 7 and disomy 4, 20, and 22. This finding supports the assumption that MERT should be distinguished from CERT, since the rhabdoid cell population in CERT supposedly represents the clonal expansion of dedifferentiated cells emerging from a well-defined malignancy [11, 23, 27, 33].

Pseudomesotheliomatous Rhabdoid Pulmonary Adenocarcinoma · 845

The differential diagnosis of pulmonary malignancies with rhabdoid phenotype includes primary and metastatic neoplasms [6]. In our case, mucinous adenocarcinoma with signet ring cells had to be considered, since cells of rhabdoid phenotype may be interpreted as signet ring cells [4, 15]. Absence of PAS, D-PAS, Muc1, and Muc2-positivity in the rhabdoid cells excluded this possibility [4, 13]. Malignant melanoma may also show a rhabdoid phenotype [3, 6, 7, 18]. Our case was negative for S-100 and HMB-45. We conclude that our case represents a high grade peripheral adenocarcinoma of the lung with dedifferentiation into a more aggressive phenotype. The change of immunohistochemical staining pattern towards vimentin positivity combined with the presence of cells of rhabdoid phenotype is a sign of dedifferentiation and highly aggressive biological behavior. This is also in accordance with the clinical findings in our case, e.g., extensive pleural growth and metastatic lesion seeding in the duodenal mucosa and periumbilical skin. Pseudomesotheliomatous adenocarcinoma is a diagnostic challenge, and pitfalls are likely to occur, especially when there are only pleural biopsy specimens available and immunoreactivity is inconclusive. We recommend careful examination of the adjacent lung parenchyma in cases of malignant pleural tumors with rhabdoid features. Acknowledgement. The authors thank Prof. Dr. Otto Dietze, Pathologisch-Anatomisches Institut, Landeskrankenanstalten Salzburg, Salzburg, Austria, for providing us with the original paraffin blocks from duodenal and periumbilical specimens.

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Received: June 28, 2001 Accepted in revised version: September 24, 2001