Introduction

Malignant pleural mesothelioma (PM) is an uncommon but increasing highly aggressive disease with extremely poor prognosis; it is classified into three pathological types, viz., epithelioid, sarcomatoid, and biphasic [1]. Outcomes have remained dismal despite aggressive treatment strategies. In contrast to epithelioid PM, the histological diagnosis of sarcomatoid PM is often more difficult. In sarcomatoid mesothelioma, there are rare subtypes comprising heterologous elements. It is often difficult to discriminate between such heterologous osteosarcomatous mesothelioma and extra-skeletal osteosarcoma [2]. We report here a case of heterologous sarcomatoid PM accompanying osteosarcomatous differentiation.

Case

A 69-year-old man with a history of heavy asbestos exposure (demolition worker for 40 years) presented with left-sided chest pain. Computed tomography (CT) at the initial visit on April 13th, 2010 showed thickened pleura with plaques and a 5-cm coarsely calcified chest wall mass, accompanying a destructive change of the left 5th rib (Fig. 1a). A positron emission tomography-CT (PET/CT) showed low-grade fluorodeoxy glucose (FDG) uptake within the chest wall mass, and small nodules besides it (SUVmax 3.1). There was no FDG uptake in distant organs and hilar, mediastinal lymphnodes (Fig. 1b). A technetium bone scintigram showed a marked isotope uptake to the thickened, calcified tumour spreading along the pleura and chest wall mass, almost outlining the entire left thorax (Fig. 1c).

Fig. 1
figure 1

a Preoperative CT. Extensive spreading of thickened, calcified pleural tumor (arrowhead) and a 5-cm, coarsely calcified chest wall mass (arrow), accompanying a destructive change of the right 5th rib are demonstrated. b PET/CT. Low-grade FDG uptake within the chest wall mass with small nodules besides it (SUVmax 3.1, arrow) is demonstrated. c Technetium bone scintigram. Marked uptake of isotope is demonstrated along the thickened, calcified pleura and chest wall mass, outlining the entire left thorax. d CT after peritoneal recurrence. Massive ascites, numerous peritoneal nodular disseminations (arrowhead), and many calcified tumors (max 11 cm in diameter, arrow) located on the mesentery are demonstrated

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Laboratory findings at the first visit were unremarkable except for high serum alkaline phosphatase (ALP) 402 IU/mL (normal range, 115–359 IU/mL). Tumor markers [carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC), cytokeratin 19 fragment, type 1 collagen crosslinked C-terminal telopeptide (ICTP), pro-gastrin-releasing peptide (proGRP), and Krebs von den Lungen-6 (KL-6)] were all within normal range.

A thoracoscopic biopsy of the tumor on May 27th, 2010 revealed the proliferation of multi or mono-nuclear, round- or spindle-shaped atypical neoplastic cells accompanied with matrix formation with osteosarcomatous, or chondrosarcomatous differentiation, that was negative for both mesothelium- and epithelium-derived tissue-specific marker (Fig. 2a–c). The differential diagnosis included sarcomatoid PM, pulmonary sarcomatoid carcinoma (PSC), and osteosarcoma arising from ribs. The diagnosis of heterologous sarcomatoid PM was finally made based on clinical, pathological, and radiological findings, and the tumor spread pattern. High asbestos body count (35,523/g, dry lung) in the biopsied lung substantiated heavy asbestos exposure (Fig. 2d).

Fig. 2
figure 2

Pathological findings of the biopsied tumor. Matrix formation with chondrosarcomatous differentiation is seen adjacent to sarcomatoid atypical cells (hematoxylin–eosin staining, ×100). a Osteoid formation is also demonstrated (hematoxylin–eosin staining, ×200). b Multi or mono-nuclear, round- or spindle-shaped atypical neoplastic cells proliferates with osteoid or cartilages formation (Hematoxylin–eosin staining, ×400). c Asbestos body. High asbestos body count (35,523/g, dry lung) in the biopsied lung substantiates heavy asbestos exposure

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Preoperative assessment confirmed left extrapleural pneumonectomy (EPP) tolerability. Mediastinal lymph-node involvement was ruled out by mediastinoscopic biopsy. Although histological type of sarcomatoid of the case raised a doubt about the indication of surgery, EPP was eventually undertaken on July 13th, 2010, considering high probability of R1 resection and the patient’s tolerability to EPP, as well as patient’s strong will to have trimodality therapy. The pericardium, hemidiaphragm were combinedly resected and reconstructed utilizing Gore-Tex® ePTFE membrane (W. L. Gore & Associates, Inc. Flagstaff, AL, USA). The left pleural tumor partially invaded lateral aspect of the left chest wall, destroying the 5th rib, and combined resection of the 4th, 5th, and 6th costal segments was necessary. A macroscopic complete resection was achieved (Fig. 3). A preoperatively prepared autologous blood (800 cc) was administered, and allogeneic transfusion was avoided (estimated blood loss, 1730 cc).

Fig. 3
figure 3

Findings of resected specimen and autopsy. a Left entire lung with combinedly resected rib segments (arrow) is entirely covered by calcified pleural tumor. b Combinedly resected pericardium and hemidiaphragm (dotted line). Calcified tumor spreads over the entire pleural surface of left lung including interlobar fissures (arrow). PC pericardium, HD hemidiaphragm. c A 5-cm coarsely calcified chest wall mass (arrowhead) directly invades the 5th rib segment (arrow) that was combinedly resected with left lung. d Findings in autopsy. Several calcified tumors (max 11 cm in diameter, arrowhead) locates on the mesentery, and numerous peritoneal nodular disseminations extensively spread over the peritoneal cavity. e Specimen obtained by autopsy. A coarsely calcified tumors (arrowhead) on the peritoneum is demonstrated

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Immunohistochemical assessment of resected specimen using the antibody panels for mesothelioma re-confirmed the diagnosis of heterologous sarcomatoid PM with the osteosarcomatous differentiation with more precision through the identification of a small component of epithelioid mesothelioma with positivity for both mesothelium-derived and epithelium-derived markers (Fig. 4, Table 1).

Fig. 4
figure 4

Immunohistochemical assessment of resected specimen using the antibody panels for mesothelioma. a Hematoxylin–eosin staining ×50. A small component of epithelioid mesothelioma (area enclosed in dotted elliptic) was identified with positivity for both mesothelium-, and epithelium-derived markers. b Hematoxylin–eosin staining ×200. Magnified image of dotted elliptic area of a. is demonstrated. c Immunohistochemistry for Calretinin: +++. d Immunohistochemistry for CK5/6: +++. e Immunohistochemistry for Desmin: −. f Immunohistochemistry for MIB-1: 1%. g Immunohistochemistry for EMA: +++. h Immunohistochemistry for WT-1: ++. i Immunohistochemistry for GLUT-1: +++. j Immunohistochemistry for p16: −. CK cytokeratin, CD cluster of differentiation, CAM cytokeratin, CEA carcinoembryonic antigen, D2-40 podoplanin. EMA epithelial membrane antigen, p16 cyclin-dependent kinase inhibitor 2A, S-100P S100 calcium-binding protein P, SMA smooth muscle actin, TTF1 thyroid transcription factor-1, Glut-1 glucose transporter 1, WT-1 Wilms tumor protein

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Table 1 Immunohistochemical assessment using the antibody panels for mesothelioma
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After a 6-week uneventful post-operative course, 3 courses of chemotherapy using cisplatin (75 mg/m2) and pemetrexed (500 mg/m2) were administered, followed by intensity-modulated radiotherapy (IMRT) to the entire left hemithorax which was initiated 7 months after surgery. Due to respiratory insufficiency caused by radiation pneumonitis and possible cytomegalovirus pneumonia of the remnant lung, IMRT was abandoned at a total dose of 43.2 Gy. Steroid pulse therapy effectively treated respiratory insufficiency. After a 12-month disease-free period following the trimodality therapy, rapid intraperitoneal recurrence resulted in death within a month. Preoperative high serum ALP level, 402 IU/mL, normalized after surgery (Fig. 5a) and stayed within normal range (115–359 IU/mL), thereafter rising rapidly due to fulminant peritoneal recurrence, peaking at 4209 IU/mL at death (Fig. 5b).

Fig. 5
figure 5

Changes of serum alkaline phosphatase (ALP) level. a Preoperative high serum ALP level, 402 IU/mL, normalized after surgery. b Serum ALP level stayed within normal range (115–359 IU/mL) following TMT. Thereafter it rose rapidly along with fulminant peritoneal recurrence, peaking at 4209 IU/mL at death. Dotted rectangle represents a. ALP alkaline phosphatase

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Post-mortem autopsy revealed that the left thorax was tumor-free. However, several fingertip-sized pulmonary metastases in right middle and lower lobes and small right pleural dissemination were noted. In peritoneal cavity, several tumors (max 11 cm in diameter) showing coarse calcification were noted on the mesentery (Fig. 3d, e), accompanying numerous peritoneal nodular disseminations smaller than the tip of a thumb (Fig. 3d), as well as 3500 cc of malignant ascites.

Discussion

Malignant PM arises from mesothelial cells in the pleura, showing a diffuse pattern of growth over the pleural surface [3]. Accurate diagnosis at an early stage may improve treatment outcome, but can be challenging and requires specific immunohistochemical staining. The sarcomatoid type occasionally mimics malignant histiocytoma, true sarcoma, or pulmonary sarcomatoid carcinoma (PSC), making histopathological diagnosis difficult [4]. Sarcomatoid PM typically stains positively for cytokeratins, although staining may also be occasionally absent [3]. Histologically malignant sarcomatoid pleural tumors that stain strongly and diffusely positive for cytokeratin usually limit the differential diagnosis to sarcomatoid PM, PSC, and on occasion, true sarcoma, or other metastatic extrapulmonary sarcomatoid tumors, such as renal cell carcinoma [1].

Lucas et al. [5] reported that any of pancytokeratin, calretinin, and thrombomodulin was positive in more than 70% of sarcomatoid mesothelioma. As for true sarcoma, pancytokeratin was positive in 17%, calretinin in 17%, and thrombomodulin in 38%. Furthermore, regarding PSC, pancytokeratin was positive in 90%, calretinin in 60%, and thrombomodulin in 40% of cases. Thus, they concluded that pancytokeratin and calretinin have the most value in differentiating sarcomatoid mesothelioma from true sarcoma, but these antibodies are not useful in differentiating sarcomatoid mesothelioma from PSC. Takeshima et al. [6] reported that a mesothelium-derived marker D2-40 (Podoplanin) could be effective in this differentiation. Furthermore, Kushitani et al. [7] reported that CAM5.2 (cytokeratin) had the highest sensitivity and specificity for differentiating sarcomatoid mesothelioma from true sarcoma and PSC. In the present case, a small component of epithelioid mesothelioma was identified in the sarcomatoid PM, which comprised the major portion of resected specimen by EPP. Calretinin, WT-1, D2-40, and EMA (epithelial membrane antigen) were positive in both the sarcomatoid and epithelioid portions, and cytokeratin (CAM5.2 and AE1/AE3) was positive only in the epithelioid portion, supporting the diagnosis of sarcomatoid PM.

Meanwhile, tumour in the present case prominently accompanied the osteosarcomatous differentiation (Fig. 1a, c), compatible with heterologous mesothelioma (HM). HM is a very rare subtype of sarcomatoid mesothelioma characterized by the presence of malignant heterologous elements, i.e., osteosarcomatous, chondrosarcomatous, or rhabdomyoblastic elements. The incidence of HM is estimated at about 0.5% among all mesothelioma cases, reported mostly in individual case reports. HM shows similar clinical characteristics to sarcomatoid mesothelioma, and the median 6-month survival appears to be most akin to the prognosis for sarcomatoid mesothelioma [2].

Among 27 HM cases accompanying with histologically confirmed malignant heterologous elements, osteo- or chondrosarcomatous elements were the most common, being accompanied in 22 (82%) among 24 pleural cases [2]. It is often difficult to discriminate such HM from extra-skeletal osteosarcoma only by usual histological assessment [4]. Although approximately 10% of sarcomatoid mesothelioma lacks detectable expression of cytokeratins [5] and the areas with osteosarcomatous elements often stain negatively for cytokeratins [3], the identification of focal epithelioid components of mesothelioma with positive immunohistochemical labelling for cytokeratins in such tumors may greatly support the diagnosis of mesothelioma, as in the present case. A lack of labelling for cytokeratins in a sarcomatoid tumour, on the other hand, does not exclude the diagnosis of mesothelioma, regardless of the presence of heterologous elements. If the anatomical distribution of the tumor and history of asbestos exposure conform to that of mesothelioma, a diagnosis of HM should be made instead of that of primary osteochondrosarcoma, irrespective of cytokeratin positivity, as previously recommended for conventional non-heterologous sarcomatoid mesothelioma [5, 8].

We identified 54 pleural HM cases with osteo- or chondrosarcomatous elements, similar to the present case, including Klebe’s report [2], in the literature (Table 2). Among these cases, the median age at diagnosis was 68.0 years (range 27–85 years). Forty-five cases (83%) occurred in men and 9 (17%) in women. A history of asbestos exposure was confirmed in 34 cases (63%) and parietal pleural plaques were identified in 20 (37%). Median survival among 36 cases with available data was 6.0 months after diagnosis. Among 21 cases, mesothelioma was focally localized in the hemithorax in 8 (38%) and diffusely spread over the hemithorax in 13 cases (62%). Tumor calcification, identified in 19 cases, was distributed diffusely within the tumor in 14 (74%) and only focally in 5 (26%). Only 7 cases with a wider, diffuse spread of mesothelioma over the hemithorax, containing diffuse intra-tumoral calcification as in the present case, were identified. These 7 cases had a poorer median survival of 5.0 months after diagnosis. High serum ALP levels, seen in the present case, were referred to in only 4 of the 54 cases. High serum ALP levels reflect osteogenesis in growing osteogenic tumors such as osteosarcoma, as well as osteolytic bone resorption by bone metastasis or bone fracture. The precipitous increase of serum ALP levels leading towards death in the present case might have indicated the vigorous osteochondral metabolic turnover along with the massive increase in tumor burden. Among 54 cases, twelve cases (12%) underwent chemotherapy. Only 2 cases underwent EPP, and there were no cases those underwent both EPP and chemotherapy, nor trimodality therapy. Only 7 cases (13%) had autopsy, and there were no cases those underwent both EPP and autopsy. That is, the present case is the first reported case of heterologous sarcomatoid pleural mesothelioma that underwent trimodality therapy, and had its efficacy and outcome assessed by autopsy thereafter.

Table 2 Published cases of pleural mesothelioma with osteochondrosarcomatous differentiation
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In conclusion, our patient with extremely rare heterologous pleural mesothelioma had 12 months of disease control following trimodality therapy, followed by fulminant intraperitoneal recurrence that caused rapid death within a month. Although trimodality therapy achieved local control, it could not prevent abdominal recurrence. Immunohistochemistry panels were effective in histopathological diagnosis.