Malignant Mesothelioma with Heterologous Elements: Clinicopathological Correlation of 27 Cases and Literature Review

Home , Leiomyosarcoma, Liposarcoma, Rhabdomyosarcoma

Malignant mesothelioma with heterologous elements: clinicopathological correlation of 27 cases and literature review

Sonja Klebe1, Annabelle Mahar2, Douglas W Henderson1 and Victor L Roggli2

1Department of Anatomical Pathology, Flinders University of South Australia, Adelaide, SA, Australia and 2Department of Pathology, Duke University Medical Center, Durham, NC, USA

Only a small number of malignant mesotheliomas with heterologous elements have been described. There are currently no criteria for diagnosis and little data regarding prognosis. We suggest that the term heterologous mesothelioma should be reserved for tumours that show malignant heterologous elements, notably osteosarcomatous, chondrosarcomatous, or rhabdomyoblastic elements but have immunohistochemical and clinical characteristics of mesothelioma. We identified 27 such cases and characterized the clinical and pathological characteristics of these tumours. In our series, 89% originated in the pleura, and 11% from the peritoneal cavity. The median age at diagnosis was 68 years, ranging from 27 to 85 years. Of these cases, 93% occurred in males and 7% in women. Of the 27 mesothelioma cases 16 (59%) were sarcomatoid, 10 (37%) were biphasic, and one was reported as epithelioid; 40% (11 cases) showed osteosarcomatous elements only, 19% showed areas of rhabdomyosarcoma only, 19% contained areas of chondrosarcoma only, and 22% exhibited osteochondromatous elements. Immunohistochemical labelling for cytokeratins was present in the majority of cases. Exposure to asbestos was identified in all the 17 cases for which an exposure history was available (63%). Median survival was 6 months after diagnosis, similar to the survival seen in sarcomatoid mesotheliomas. The differential diagnosis includes primary and secondary pleural sarcomas, including osteosarcomas and chondrosarcomas. Immunohistochemical labelling for cytokeratins is helpful in the distinction, but lack of labelling for cytokeratins in a spindle cell/sarcomatoid tumour does not exclude the diagnosis of mesothelioma, irrespective of the presence of heterologous elements. We suggest that if the anatomical distribution conforms to that of mesothelioma, a diagnosis of heterologous mesothelioma should be made in preference to a diagnosis of primary pleural osteosarcoma or chondrosarcoma, regardless of cytokeratin positivity, as for conventional non-heterologous sarcomatoid mesothelioma. Modern Pathology (2008) 21, 1084–1094; doi:10.1038/modpathol.2008.125; published online 27 June 2008

Keywords: malignant mesothelioma; pleura; peritoneum; heterologous differentiation; asbestos

According to the 2004 WHO classification, malig- ized by even shorter survival compared with nant mesotheliomas can be broadly classified as epithelial and sarcomatoid mesothelioma without epithelial, biphasic, and sarcomatoid.1 These groups desmoplastic features.5 For most of these subgroups, show significant differences in histological and criteria for diagnosis are well defined; for example, clinical features. In addition, there are several to qualify for a diagnosis of biphasic mesothelioma, further subtypes, including desmoplastic2 and lym- the International Mesothelioma Panel specifies that phohistiocytoid mesothelioma,3 with some of these each component must occupy at least 10% of the subtypes carrying a particularly adverse prognosis; tumour in an adequate tissue sample.6 To qualify for for example, sarcomatoid mesotheliomas are typi- a diagnosis of desmoplastic sarcomatoid mesothe- cally more rapidly lethal than epithelial meso- lioma, the paucicellular collagen-rich tissue must theliomas,4 and desmoplastic mesotheliomas, as occupy at least 50% of a tissue specimen, and other subtype of sarcomatoid mesothelioma, is character- diagnostic features include invasion, foci of overtly malignant (sarcomatoid) tissue, and areas of ‘bland’ necrosis. In contrast, the criteria for diagnosis of Correspondence: Dr S Klebe, MD, PhD, FRCPD, Department of heterologous mesothelioma are less well defined. Anatomical Pathology, Flinders Medical Centre, Bedford Drive, Only a handful of cases of mesothelioma contain- Bedford Park, Adelaide, SA 5042, Australia. 7–20 E-mail: [email protected] ing heterologous elements have been described. Received 06 May 2008; revised and accepted 05 June 2008; Amongst the heterologous elements that have been published online 27 June 2008 recorded, osseous and chondroid elements are most Heterologous mesothelioma S Klebe et al 1085 commonly seen, with liposarcomatous differentia- with two earlier cases from the files of one of the tion representing an extremely rare finding.20,21 No authors (DWH). We did not specify any particular case showing leiomyosarcomatous elements in iso- proportion of the heterologous elements for inclu- lation has been described in the literature, and sion into this series (specifically, we did not require smooth muscle elements in this location are thought the heterologous elements to account for 10% or to arise from submesothelial cells rather than the more of the tumour), but to be classified as a mesothelium itself.22 Endothelial differentiation is heterologous mesothelioma we required the hetero- regarded as inconsistent with a diagnosis of me- logous elements to show sarcomatoid features sothelioma.23 It is worth noting that because cur- (osteosarcomatous, chondrosarcomatous, or rhabdo- rently no clear definition of the term ‘mesothelioma myosarcomatous). In particular, small foci of benign with heterologous elements’ or ‘heterologous me- osseous metaplasia were considered insufficient for sothelioma’ exists in the literature, some of the the diagnosis, because these may be seen in benign reported cases or case series do not distinguish calcified pleural plaques and may simply represent between benign mesenchymal metaplasia and ‘true’ involvement of plaque by tumour. We also excluded histologically malignant heterologous elements.17 In mesothelioma with stromal osteoclast-like giant addition, there are no criteria as to the types of cells unless more definite evidence of osteoid/bone ‘heterologous’ elements that should be included in production was evident. Taking into account the this diagnostic subgroup, for example, whether clinical information regarding the anatomical dis- smooth muscle differentiation and liposarcomatous tribution, a diagnosis of heterologous mesothelioma elements are acceptable. Mesotheliomas with ‘rhab- was made regardless of cytokeratin positivity, as for doid’ features have been reported separately in a sarcomatoid mesothelioma. single large series,12 with only two additional cases that have been reported.10,13 The true incidence of mesothelioma with heterologous differentiation is Immunohistochemical Studies therefore difficult to ascertain. Also, some cases are reported in radiology or surgery literature,7,18,24–26 As many of the cases were received in consultation, sometimes without histopathologic correlation. only limited immunohistochemical studies were Little data has been collected with regards to available for much of the material. In addition, epidemiologic features and with relationship to some of the immunohistochemical assessment was previous asbestos exposure. To the best of our based on immunohistochemical stains that had been knowledge, only two cases of peritoneal mesothe- performed in other laboratories. All tissues had been lioma with malignant heterologous elements have fixed in 10% buffered formalin and had undergone been reported to date.9 standard processing and embedding in paraffin wax. Finally, there are currently conflicting data on Sections were cut 4 mm thick, deparaffinized, and survival for these tumours. Some authors describe rehydrated, if blocks had been received. For all of unusually long survival of up to 3 years for what is the cases received at Duke University and the most often a subtype of sarcomatoid mesothelio- majority of cases reviewed at Flinders Medical ma—highly unusual when one keeps in mind that Center, the streptavidin-biotin-peroxidase complex the mean survival for patients with mesothelioma method was used (Ultra Strepatavidin Detection overall is in the order of 9 months.4 System, Signet Laboratories) as a detection system, This paper represents the largest series of such whereas for one of the cases the DakoCytomation tumours of which we are aware, consisting of 27 EnVision þ Dual Link System (Dako) was used. cases of mesothelioma with heterologous elements, including three arising within the peritoneal cavity. The aims of the series were to propose a definition Results that provides clear criteria for the recognition of The salient case information for the tumours heterologous mesothelioma, based on clinical, radio- included in this study are summarized in Tables 1 logical, histologic, and immunohistochemical and 2. characteristics; to discuss the differential diagnosis; and to ascertain whether the prognosis for heterologous mesothelioma differs significantly from Incidence conventional mesothelioma. Among 2694 mesothelioma cases at Duke University Medical Center between 1982 and 2008, 19 (0.6%) Materials and methods cases were identified, and 6 cases were identified Selection of Cases among 594 consecutive malignant mesotheliomas accessioned at the Flinders Medical Centre (1%) Cases were obtained from the departmental over a 10-year period. These consecutive Flinders archives, consultation cases, and some medicolegal Medical Centre accessions do not include medico- referral files for two of authors spanning the period legal referrals to one of the authors (DWH) over the of 1982–2008 (VLR) and 1998–2008 (DWH) and same time for which no additional investigations

Modern Pathology (2008) 21, 1084–1094 Heterologous mesothelioma S Klebe et al 1086 Table 1 Clinical and patient data

Age Sex PPP Type/site Asbestos exposure Asbestosis Fibre analysis Survival Differentiation

1 53 M Y SPl Shipyard ND ND ND O 2 53 M N SPe ND ND ND ND R 3 77 M Y BPl ND ND ND ND C 4 71 M Y SPl Nylon plant N AB, AC, TAA 8 mo O, R 5 60 M ND SPl Construction Y ND 6 we OC 6 69 M ND SPl ND ND ND ND OC 7 85 M ND EPl Carpenter ND ND 6 mo Chondrosarcoma myxoid 8 68 M ND BPl Electrician ND ND 1 we C 9 71 M ND BPl Maintenance N ND ND O 10 73 M Y BPl Shipyard electrician ND ND 8 mo C 11 49 F N SPe HH (spouse, power plant) N Normal range 6 mo OC 12 64 M Y SPl Navy electrician ND ND 11 mo OC 13 61 M ND SPl Navy ND ND 46mo O 14 59 M N SPl Truck driver N AB, AC 2 mo R 15 81 M Y SPl ND ND ND 2 days R 16 40 M ND SPl Bus mechanic ND ND 24 mo R 17 81 M Y SPl Maintenance ND ND 4 mo O 18 44 M ND BPe Irrigation Tech ND ND ND O 19 81 M Y BPl ND ND ND 46mo O 20 72 M Y SPl Y; no details ND ND ND O 21 73 M ND BPl Y; no details ND ND ND C 22 68 M ND BPl ND ND ND ND OC 23 73 M ND SPl ND ND ND ND OC 24 65 M ND SPl ND ND ND ND O 25 64 M ND SPl ND ND ND ND O 26 27 F ND BPl Environmental ND ND 6 mo O 27 ND M ND BPl ND ND ND ND R

AB, asbestos bodies; AC, amosite and crocidolite; BPe, biphasic peritoneal mesothelioma; BPl, biphasic pleural mesothelioma; C, chondrosarcoma; EPl, epithelial pleural mesothelioma; HH, house hold; mo, months; N, no; ND, no data; O, osteosarcoma; OC, osteochondrosarcoma; PPP, parietal pleural plaques; R, rhabdomyosarcoma; Spe, sarcomatoid peritoneal mesothelioma; SPl, sarcomatoid pleural mesothelioma; TAA, tremolite, antophyllite, actinolite; we, weeks; Y, yes.

were carried out and therefore were not included in women. A history of exposure to asbestos was the department accessions. There were no cases of confirmed in all 17 cases for which an exposure ‘heterologous MM’ among those medicolegal refer- history had been obtained (63% of all cases). rals (estimated at approximately 1000 cases for Parietal pleural plaques were identified in nine of which confirmation of diagnosis was sought), and those patients, with no data available for the had those cases been included, the percentage remaining patients. frequency for heterologous differentiation is estimated at about 0.5%. Two additional cases (Cases 26 and 27) were identified in the files of one of the Prognosis authors (DWH) and predated the specified 10-year Information regarding the clinical outcome was period. For these cases only limited clinical infor- available for 12 of our 27 cases, with a median mation was available. One of these cases (Case 26 in survival of 6 months after diagnosis and only one of Table 1) had previously been included in the series the patients confirmed to be alive after 1 year. by Yousem and Hochholzer.17 This case—a biphasic pleural mesothelioma with osseous differentiation— had also been described earlier by Langlois et al Histological Features in 1978.26 Only 1 of the 27 cases was reported as epithelioid mesothelioma, and in this case the diagnosis was Clinical Characteristics based on a needle biopsy, which may not have adequately represented the tumour. No follow-up Of the total of 27 cases of mesotheliomas with biopsy was available for that case. Of the remaining heterologous elements, 24 (89%) originated from the tumours, 16 mesotheliomas (59%) were sarcomatoid pleural cavity and 3 (11%) from the peritoneal and 10 (37%) were biphasic. Of the cases, 11 cavity, one of which occurred in a woman. The showed osteosarcomatous elements only, 5 showed median age at the time of diagnosis was 68 years, areas of rhabdomyosarcoma only, 5 contained areas with an age range of 27–85 years. Twenty-five (93%) of chondrosarcoma only, and 6 exhibited a mixture of the cases occurred in males and two (7%) in of heterologous elements. The osteosarcomatous

Modern Pathology (2008) 21, 1084–1094 Heterologous mesothelioma S Klebe et al 1087 Table 2 Immunohistochemical labelling of heterologous mesotheliomas

No. Heterologous AE1/3 Cam MNF Cal WT1 CK5/6 Vim Des CEA EMA CD15 Ber B72 TTF S1 Other

1 Osteosarcoma ND 2 Rhabdomyosarcoma + – ++ Myogenin + Myoglobin + MyoD1+ 3 Chondrosarcoma ++ ÀÀ 4 Osteosarcoma ++ 5 Osteochondrosarcoma À 6 Osteochondrosarcoma ++ 7 Chondrosarcoma ++ ÀÀ 8 Chondrosarcoma ++ + ÀÀ À 9 Osteosarcoma + ÀÀÀÀ 10 Chondrosarcoma ++ ÀÀÀÀ 11 Osteochondrosarcoma ++++ À 12 Osteochondrosarcoma +++ À 13 Osteosarcoma ÀÀÀÀ + 14 Rhabdomyosarcoma +++ À 15 Rhabdomyosarcoma +++À + ÀÀÀ 16 Rhabdomyosarcoma +++ ++ÀÀ ÀMyoD1+ Myogenin+ HMB45À 17 Osteosarcoma +++À ++ À CD31À HMB45À CD45À SMA+ 18 Osteosarcoma +++À + À 19 Osteosarcoma ++ ÀÀSMA+ 20 Osteosarcoma ++ À + SMA+ 21 Chondrosarcoma ++ 22 Osteochondrosarcoma ++ + 23 Osteochondrosarcoma ÀÀÀ 24 Osteosarcoma ++ CK7+ 25 Osteosarcoma ++ ÀÀ+ 26 Osteosarcoma À 27 Rhabdomyosarcoma ÀÀ Myoglobin +

Cam, Cam5.2; MNF, MNF116; Cal, calretinin; Vim, vimentin; Des, desmin; Ber, BerEP4; TTF, TTF-1; S1, S100; SMA, smooth muscle actin; ND, no data; +, Positive; À, negative.

areas varied from partly calcified osteoid in direct had been performed on 23 tumours, and there was at continuity with malignant spindle cells to large least focal labelling in 20 of those cases, which areas indistinguishable from osteosarcoma on H&E- included 12 sarcomatoid mesotheliomas, 7 biphasic stained sections (Figure 1). Similarly, areas of mesotheliomas, and 1 epithelial mesothelioma. chondrosarcoma were indistinguishable from chon- Immunohistochemical labelling for calretinin had drosarcomas elsewhere, and generally were located been performed on 11 cases, and 4 demonstrated directly adjacent to malignant spindle cell compo- positive nuclear staining, 3 of which were biphasic. nents (Figure 2). Rhabdomyoblastic areas were seen The staining was predominantly located in the in close proximity to both spindle cell and epithelial epithelial areas of the tumours. One of the sarcoma- components (Figure 3) and showed typical features toid mesotheliomas labelled for calretinin, and there of rhabdomyoblastic differentiation, including strap was equivocal labelling in one further sarcomatoid cells, large eccentric pleomorphic nuclei and abun- mesothelioma that was located in the peritoneal dant eosinophilic cytoplasm (Figure 3), with cross cavity. Eight of the nine tumours tested showed striations occasionally visible. labelling for vimentin. Labelling for desmin was present in three of the four tumours where this Immunnohistochemical Characteristics marker had been studied. Only one of the three mesotheliomas tested showed strong membranous The results of immunohistochemical studies were and circumferential staining for EMA typical of available for 26 of the 27 mesotheliomas included in epithelial mesothelioma in the epithelial compo- the study and are summarized in Table 2. nent of a biphasic tumour. None of the mesothelio- No such data was available on case no. 1, where mas for which immunohistochemical studies for the the diagnosis was based on typical clinical and carcinoma-related markers (CEA, CD15, B72.3, Ber- histological appearances. For the remaining 26 cases, EP4, and TTF-1) had been performed, labelled with immunohistochemical studies for various cytokeratins any of these antibodies.

Modern Pathology (2008) 21, 1084–1094 Heterologous mesothelioma S Klebe et al 1088 these tumours there was also labelling with myogenin. Another case showed positive labelling of rhabdomyoblasts for myoglobin.

Discussion Mesothelial cells are of mesodermal origin but retain the ability to differentiate towards an epithelial growth pattern during adult life. This multipotent behaviour of the mesothelium with its ability to differentiate into stromal phenotypes has been emphasized in the concept of the ‘mesodermoma’.19,27–29 Due to this plasticity of differentiation, which is also evident in the spectrum of recognized histologic types of mesothelioma, mesothelial cells have been invoked as a source of adult stem cells.30 Differential patterns of gene expression have been associated with growth patterns and cellular phenotypes in vitro.31 Heterologous differentiation in mesothelioma is well recognized, mostly as individual case reports, the largest series consisting of the 12 cases being reported by Yousem and Hochholzer in 1987.17 If only the cases containing histologically confirmed malignant heterologous elements are considered, 23 cases of heterologous mesothelioma were identified in a search of the literature (Table 3).7–20 It seems likely that at least some of the cases that have in the past been reported as primary pleural sarcomas may in fact represent heterologous mesothelioma—those where no cytokeratin labelling was performed, the anatomical distribution was indistinguishable from mesothelioma, and where asbestos bodies were found in the lung parenchyma.32 We do not consider ‘rhabdoid’ change (as distinct from rhabdomyosar- comatous) as true heterologous differentiation, and the morphological appearances suggest an overlap with deciduoid13 and pleomorphic mesothelioma. The incidence of these tumours in our series corresponds to approximately 0.5% of all mesothelioma cases. However, both Duke University and Flinders Medical Centre serve as major referral centres for mesothelioma, so this figure may overestimate the true prevalence.

Epidemiological Data Of our cases, 11% were located in the peritoneal cavity, compared to 10% of cases in the published literature17 and 6% of all mesotheliomas. The M:F Figure 1 (a) Malignant mesothelioma showing an area of ratio of 13:1 in this series is relatively high, osteosarcoma adjacent to a spindle cell area. (b) Nuclear labelling of some of the spindle cells for the mesothelial-related marker compared to 2:1 in the published cases of mesothe- calretinin. Not all sarcomatoid mesotheliomas show labelling for lioma with heterologous elements, and approxi- calretinin. (c) More extensive labelling of the spindle cells with mately 5:1 to 7:1 for all mesotheliomas in HSE33 the pancytokeratin marker AE1/AE3. The majority of sarcomatoid and Leigh and Driscoll.34 A definite exposure mesotheliomas labels for pancytokeratins. history to asbestos could be elicited in 63% of our cases, compared to 55% of the published cases In addition, three mesotheliomas with areas of (Tables 1 and 2). National mesothelioma registries rhabdomyosarcoma showed labelling of rhabdomyo- report exposure to asbestos in approximately 90% of blasts with antibodies against MyoD1, and for two of male34,35 and 70% of female patients.36 Our data are

Modern Pathology (2008) 21, 1084–1094 Heterologous mesothelioma S Klebe et al 1089

Figure 2 (a) Area of chondrosarcoma (on the right) adjacent to a spindle cell area of predominantly sarcomatoid mesothelioma with minor epithelial tubular elements (arrow). (b) Higher power view of the transition of spindle cell sarcomatoid area to area of chondrosarcoma. (c) Labelling of the sarcomatoid spindle cell component and some of the chondrosarcoma component with the pancytokeratin marker AE1/AE3. likely to underestimate the true exposure to asbes- history. The presence of asbestosis was specifically tos, because information regarding exposure was noted in only one of our cases, with four specifically unavailable in 35% of our cases. Fibre analysis was commenting on the lack of asbestosis and no data performed in three cases and revealed a mixture of available for the remaining cases. Our series con- fibre types in two cases. The third was within the firms chondroid and osteoblastic differentiation as background range, despite a positive exposure the most common patterns. A relatively large

Modern Pathology (2008) 21, 1084–1094 Heterologous mesothelioma S Klebe et al 1090

Figure 3 (a) Area of rhabdomyosarcoma intimately associated with sarcomatoid mesothelioma. (b) Desmin labelling of the rhabdomyoblastic cells. (c) Medium-power view showing typical strap cells (thin arrow) and rhabdomyoblast (short arrow) indicative of rhabdomyoblastic differentiation (d) Low-power view showing the same area (to the left) adjacent to a sarcomatoid area (middle of picture) and a minor epithelial component (right bottom corner of picture). (e) Positive labelling of rhabdomyoblasts for myoglobin. (f) Positive labelling of one of the same cells in an adjacent level for pancytokeratin AE1/AE3.

proportion of our cases (5/27) showed rhabdomyo- We suggest that the term heterologous mesothe- blastic features (19% compared to 5% in the lioma should be reserved for those tumours that literature). show malignant heterologous elements, namely

Modern Pathology (2008) 21, 1084–1094 Table 3 Published cases of heterologous mesothelioma

Source Age Sex PPP Site/type Asbestos Survival Heterologous elements Comments

Goldstein8 35 F Yes BiPl ND Days Osseous, cartilaginous 38 F Yes BiPl Yes 6 mo Osseous, cartilaginous Donna and Betta28 52 F ND BPl Yes ND Osteochondromatous Exposure to asbestos environmental Yousem and Hochholzer17 83 F SPl No 3 mo Osteochondromatous 60 M SPl No 2 mo Osteochondromatous 65 M BiPl Yes 10 mo Osteochondromatous 68 M SPl Yes 5 mo Osteochondromatous 62 F Yes SPl No 4 mo Osteochondromatous 65 M Yes SPl Yes 9 mo Osseous metaplasia Heterologous elements were benign 60 M BPl Yes 9 mo Osteochondromatous 27 F BPl Yes 6 mo Osseous Same case as our case 26 68 M SPl No 2 mo Osteochondromatous 64 M SPl Yes 2 mo Osteochondromatous Andrion et ala 51 F No SPl Yes 4 mo Osteochondromatous Yoshii C et al16 85 M BPl ND ND Osteochondromatous Krishna and Haqqani20 F 8 hours Liposarcomatous Raizon et al18 69 M Yes BPl Yes—brake ND Osteosarcoma like mechanic

68 M Yes SPl Yes—shipyard ND Osteochondromatous Klebe S mesothelioma Heterologous Donna et al21 80 M SPe ND Liposarcomatous Okamoto et al11 63 M SPl Yes ND Osseous, chondroid, rhabdomyoblastic al et Kiyozuka et al9 72 M Yes BPe Yes—plumber 41 mo Osteochondromatous No asbestos bodies in lung described as ‘immature’ Chave et al7 59 M ? BPl Yes 36 mo Osseous ‘malignant Two biopsies 3 years apart, osteoid tissue’ interferon treatment. Suen et al15 80 M Yes ?Pl Yes 4 mo Osseous Unsure if osseous elements were malignant Quoix et al25 76 M SPl Yes ND Osteosarcoma Salgado et al24 ? M ? ? No ? Osseous heterologous Focused on radiology findings elements no detailed histology Demirag et al61 65 M Yes BPl Yes—asbestos 39 mo Osseous Osteoclasts described as benign bodies found oenPtooy(08 1 1084–1094 21, (2008) Pathology Modern 54 M BPl Yes 69 mo Osseous Benign-appearing osteoclasts in direct contact with malignant spindle cell component

BPl, biphasic pleural mesothelioma; BPe, biphasic peritoneal mesothelioma; mo, months; ND, no data; SPe, sarcomatoid peritoneal mesothelioma; SPl, sarcomatoid pleural mesothelioma. aAndrion A, Mazzucco G, Bernardi P, et al. Sarcomatous tumour of the chest wall with osteochondroid differentiation. Evidence of mesothelial origin. Am J Surg Pathol 1989;13:707–12. Cases that may not fulfill our strict definition requiring malignant heterologous elements are in italics (refer to text). 1091 Heterologous mesothelioma S Klebe et al 1092 osteosarcomatous, chondrosarcomatous, or rhabdo- another of a 76-year-old Navy engineer (with myoblastic elements. Care must be taken to exclude no data regarding asbestos exposure available), tumours showing benign metaplastic changes.37 Our make no mention of immunohistochemical series did not include any cases showing liposarco- studies that might have suggested a diagnosis of matous differentiation, making it difficult to com- mesothelioma.48,49 ment on. However, only few primary pleural Heterologous elements have rarely been described liposarcomas38–42 and even fewer liposarcomas with in other primary pleural sarcomas, such as malig- pleural metastases have been described.43 Lack of nant fibrous histiocytoma and malignant nerve labelling for keratin, knowledge of the clinical and sheath tumour.50 We are not aware of pleural radiological characteristics, and absence of a clinical synovial sarcoma showing heterologous differentia- history of soft tissue sarcoma are required for the tion, but knowledge of the anatomical distribution diagnosis of primary liposarcoma at this site.40,44 and molecular studies demonstrating the SYT-SSX fusion gene would be helpful in that instance.51 A pleural localized mass lesion with an anatomical Definition of Heterologous Mesothelioma distribution distinct from mesothelioma and lack of labelling for cytokeratins has been reported as We suggest that the criteria for recognition of malignant pleural mesenchymoma with areas of osteosarcomatous differentiation should mirror liposarcoma, leiomyosarcoma, and osteocartilagi- those applied for primary osteosarcoma of bone nous differentiation,52 but it seems possible that and soft tissue. Recognition of osteoid can be this case might represent an example of a localized difficult, but the presence of hyaline collagen with mesothelioma with heterologous differentiation. a trabecular and lacework pattern, isolating indivi- Metastases of sarcomas including osteosarcoma dual neoplastic cells or small groups, and the and liposarcoma to the pleura have been des- ‘normalization’ of cell pattern within osteoid trabe- cribed,53–55 but mimic mesothelioma only rarely, culae, whereby those cells are smaller and less and can usually be recognized from the clinical pleomorphic than those at periphery, should be history of an antecedent sarcoma. Furthermore, the required for the diagnosis. If osteoid formation is clinical demographics are likely to be different.55,56 considered equivocal, consultation with a soft tissue A recent study by Knuuttila et al suggests that and bone specialist pathologist is recommended. comparative genomic hybridization may help to The extent of heterologous differentiation may vary distinguish mesothelioma from other chest wall from minor and focal to extensive. We do not suggest sarcomas.6,57 a minimal percentage of heterologous elements In summary, immunohistochemical findings con- necessary to make the diagnosis. firm the usefulness of cytokeratin labelling for the purpose of diagnosing malignant mesothelioma, Differential Diagnosis and Role of including sarcomatoid mesotheliomas. However, a Immunohistochemical Studies proportion of these tumours (approximately 10% of sarcomatoid mesotheliomas) lack detectable expres- The presence of heterologous elements within a sion of cytokeratins.6 Consequently, lack of labelling pleural- or peritoneal-based tumour raises a differ- for cytokeratins in a spindle cell/sarcomatoid tu- ential diagnosis that includes pulmonary blastoma, mour does not exclude the diagnosis of mesothelio- primary sarcomas including synovial sarcomas, and ma, regardless of the presence of heterologous metastases. In biopsy tissue, the distinction from elements.6,58,59 primary chest wall osteosarcoma and chondrosarcoma (in contrast to pleura/peritoneum-based mesothelioma) requires correlation with the Clinical Characteristics and Prognosis clinical-radiologic findings—in particular the exact location of the tumour, localized mass lesion as The median survival of 6 months in our series is opposed to a confluent pleura-based tumour, and comparable to the published median survival of 5.5 the age of the patient.45 Identification of epithelial months for mesothelioma with heterologous ele- components may greatly aid in the diagnosis, ments (data from Table 3) and similar to the 6.2 particularly if positivity with mesothelial-related months survival seen for desmoplastic sarcomatoid markers can be demonstrated. mesothelioma.5 The slightly longer survival in our Primary osteosarcomas and chondrosarcomas of cases may in part reflect the presence of epithelial pleura have been described,32,46 but pleural sarco- elements in the biphasic cases, a factor that has been mas other than mesothelioma, malignant solitary associated with a better prognosis.60 Three cases of fibrous tumour, and pleural synovial sarcoma are mesothelioma with heterologous elements with extremely rare.43,45 Some of the reported cases prolonged survival, including one with a reported antedate immunohistochemical labelling for cyto- survival of 69 months, have been reported.9,61 Some keratins.32,46,47 However, even recent reports of authors attribute this prolonged survival to the extraskeletal oesteosarcoma, one in a 73-year-old expression of bone morphogenetic protein 2.61 For patient with known exposure to asbestos and two of these cases the heterologous elements were

Modern Pathology (2008) 21, 1084–1094 Heterologous mesothelioma S Klebe et al 1093 described as ‘bland’, and these cases would not 8 Goldstein B. Two malignant pleural mesotheliomas fulfill our strict criteria for diagnosis. with unusual histological features. Thorax 1979;34: 375–379. 9 Kiyozuka Y, Miyazaki H, Yoshizawa K, et al. An autopsy case of malignant mesothelioma with osseous Summary and cartilaginous differentiation: bone morphogenetic protein-2 in mesothelial cells and its tumor. Dig Dis Sci Heterologous mesothelioma is a rare subtype of 1999;44:1626–1631. mesothelioma characterized by the presence of any 10 Matsukuma S, Aida S, Hata Y, et al. Localized amount of malignant heterologous elements. These malignant peritoneal mesothelioma containing rhab- tumours show similar clinical characteristics to doid cells. Pathol Int 1996;46:389–391. other types of mesothelioma, including a relation- 11 Okamoto T, Yokota S, Shinkawa K, et al. Pleural malignant mesothelioma with osseous cartilaginous ship to exposure to asbestos. The median survival of and rhabdomyogenic differentiation. Nihon Kokyuki 6 months appears to be most akin to the prognosis Gakkai Zasshi 1998;36:696–701. for sarcomatoid mesothelioma. The differential 12 Ordonez NG. Mesothelioma with rhabdoid features: an diagnosis includes rare primary and metastatic ultrastructural and immunohistochemical study of 10 pleural sarcomas, and the demonstration of positive cases. Mod Pathol 2006;19:373–383. labelling for cytokeratins by immunohistochemical 13 Puttagunta L, Vriend RA, Nguyen GK. Deciduoid studies may aid in that distinction. However, if the epithelial mesothelioma of the pleura with focal anatomical distribution conforms to that of mesothe- rhabdoid change. Am J Surg Pathol 2000;24: lioma, a diagnosis of heterologous mesothelioma 1440–1443. should be made in preference to a diagnosis of 14 Rittinghausen S, Ernst H, Muhle H, et al. Atypical malignant mesotheliomas with osseous and cartilagi- primary pleural osteosarcoma or chondrosarcoma, nous differentiation after intraperitoneal injection of irrespective of cytokeratin positivity, as has various types of mineral fibres in rats. Exp Toxicol previously been recommended for conventional Pathol 1992;44:55–58. non-heterologous sarcomatoid mesothelioma.6 15 Suen HC, Sudholt B, Anderson WM, et al. Malignant mesothelioma with osseous differentiation. Ann Thor- ac Surg 2002;73:665. 16 Yoshii C, Imai S, Hoshino H, et al. A case of malignant Acknowledgement pleural mesothelioma with osseous and cartilaginous Commercial relationships policy: none. formation. Nihon Kyobu Shikkan Gakkai Zasshi 1992;30:338–342. 17 Yousem SA, Hochholzer L. Malignant mesotheliomas with osseous and cartilaginous differentiation. Arch References Pathol Lab Med 1987;111:62–66. 18 Raizon A, Schwartz A, Hix W, et al. Calcification as a 1 Churg A, Roggli V, Galateau-Salle F, et al. Mesothelio- sign of sarcomatous degeneration of malignant pleural ma. In: Travis WD, Brambilla E, Mu¨ ller-Hermelink HK, mesotheliomas: a new CT finding. J Comput Assist Harris C, (eds). Pathology and Genetics of Tumours of Tomogr 1996;20:42–44. the Lung, Pleura, Thymus and Heart. IARC: Lyon, 19 Donna A, Betta PG, Bianchi V, et al. A new insight into 2004, pp 128–136. the histogenesis of ‘mesodermomas’—malignant me- 2 Kannerstein M, Churg J. Desmoplastic diffuse malig- sotheliomas. Histopathology 1991;19:239–244. nant mesothelioma. In: Fenoglio CM, Wolff M, (eds). 20 Krishna J, Haqqani MT. Liposarcomatous differentia- Progress in Surgical Pathology. Masson: New York, tion in diffuse pleural mesothelioma. Thorax 1993;48: 1980, pp 19–29. 409–410. 3 Henderson DW, Attwood HD, Constance TJ, et al. 21 Donna A, Betta PG, Ribotta M. Lipoblastic differentia- Lymphohistiocytoid mesothelioma: a rare lymphoma- tion in a primary localized fibrous mesothelioma of the toid variant of predominantly sarcomatoid mesothe- peritoneum. Pathol Res Pract 1996;192:1252–1256; lioma. Ultrastruct Pathol 1988;12:367–384. discussion 7–8. 4 Henderson DW, Shilkin KB, Langlois SL, et al. (eds). 22 Kuo T, London SN, Dinh TV. Endometriosis occurring Malignant Mesothelioma. Hemisphere: New York, in leiomyomatosis peritonealis disseminata: ultra- 1992, pp 412. structural study and histogenetic consideration. Am J 5 Cantin R, Al-Jabi M, McCaughey WT. Desmoplastic Surg Pathol 1980;4:197–204. diffuse mesothelioma. Am J Surg Pathol 1982;6: 23 Attanoos RL, Suvarna SK, Rhead E, et al. Malignant 215–222. vascular tumours of the pleura in ‘asbestos’ workers 6 Galateau-Salle´ F, (ed). International Mesothelioma and endothelial differentiation in malignant mesothe- Panel: Brambilla E, Cagle PT, Churg AM, Colby, TV, lioma. Thorax 2000;55:860–863. Gibbs AR, Hammar SP, Hasleton PS, Henderson DW, 24 Salgado RA, Corthouts R, Parizel PM, et al. Malignant Inai K, Praet M, Roggli VL, Travis WD, Vignaud JM. pleural mesothelioma with heterologous osteoblastic Pathology of Malignant Mesothelioma. Springer: elements: computed tomography, magnetic resonance, London, 2006. and positron emission tomography imaging character- 7 Chave G, Chalabreysse L, Picaud G, et al. Malignant istics of a rare tumor. J Comput Assist Tomogr pleural mesothelioma with osteoblastic heterologous 2005;29:653–656. elements: CT and MR imaging findings. AJR Am J 25 Quoix E, Chenard MP, Orion B, et al. A left pleural Roentgenol 2002;178:949–951. effusion with a calcified tumoral mass and left

Modern Pathology (2008) 21, 1084–1094 Heterologous mesothelioma S Klebe et al 1094 hemithoracic uptake on bone scan. Lung Cancer 44 Fujinami K, Kondoh K, Kondoh I, et al. A case of 2001;32:203–205. advanced retroperitoneal dedifferentiated liposarcoma 26 Langlois SL, Glancy JJ, Henderson DW. The radiology treated effectively with high-dose ifosfamide. of malignant pleural mesothelioma in Western Hinyokika Kiyo 1999;45:463–466. Australia. Australas Radiol 1978;22:305–314. 45 Gladish GW, Sabloff BM, Munden RF, et al. Primary 27 Donna A, Betta PG. Mesodermomas: a new thoracic sarcomas. Radiographics 2002;22:621–637. embryological approach to primary tumours of 46 Cohn L, Hall AD. Extraosseous osteogenic sarcoma of coelomic surfaces. Histopathology 1981;5:31–44. the pleura. Ann Thorac Surg 1968;5:545–549. 28 Donna A, Betta PG. Differentiation towards cartilage 47 Pearson KD, Rubin D, Szemes GC, et al. Extraosseous and bone in a primary tumour of pleura. Further osteogenic sarcoma of the chest. Br J Dis Chest evidence in support of the concept of mesodermoma. 1969;63:231–234. Histopathology 1986;10:101–108. 48 Sabloff B, Munden RF, Melhem AI, et al. Radiologic- 29 Krismann M, Muller KM, Jaworska M, et al. Severe pathologic conferences of the University of Texas M. D. chromosomal aberrations in pleural mesotheliomas Anderson Cancer Center: extraskeletal osteosarcoma of with unusual mesodermal features. Comparative the pleura. AJR Am J Roentgenol 2003;180:972. genomic hybridization evidence for a mesothelioma 49 Chandak P, Hunt I, Rawlins R, et al. Bone or pleura? subgroup. J Mol Diagn 2000;2:209–216. Primary pleural osteosarcoma. J Thorac Cardiovasc 30 Gotloib L, Gotloib LC, Khrizman V. The use of Surg 2007;133:587–588. peritoneal mesothelium as a potential source of adult 50 Ordonez NG, Tornos C. Malignant peripheral nerve stem cells. Int J Artif Organs 2007;30:501–512. sheath tumor of the pleura with epithelial and 31 Sun X, Gulyas M, Hjerpe A. Mesothelial differentiation rhabdomyoblastic differentiation: report of a case as reflected by differential gene expression. Am J clinically simulating mesothelioma. Am J Surg Pathol Respir Cell Mol Biol 2004;30:510–518. 1997;21:1515–1521. 32 Goetz SP, Robinson RA, Landas SK. Extraskeletal 51 Ten Heuvel SE, Hoekstra HJ, Suurmeijer AJ. Diagnostic myxoid chondrosarcoma of the pleura. Report of a Accuracy of FISH and RT-PCR in 50 routinely case clinically simulating mesothelioma. Am J Clin processed synovial sarcomas. Appl Immunohistochem Pathol 1992;97:498–502. Mol Morphol 2008;16:246–250. 33 HSE. Mesothelioma Mortality in Great Britain: Esti- 52 Deslee G, Guillou PJ, Baehrel B, et al. Malignant mating the Future Burden. HSE: London, 2003. mesenchymoma of the pleura. Interact Cardiovasc 34 Leigh J, Driscoll T. Malignant mesothelioma in Aus- Thorac Surg 2003;2:376–378. tralia 1945–2002. Int J Occup Environ Health 2003;9: 53 Shanley DJ, Mulligan ME. Osteosarcoma with 206–217. isolated metastases to the pleura. Pediatr Radiol 1991; 35 Spirtas R, Heineman EF, Bernstein L, et al. Malignant 21:226. mesothelioma: attributable risk of asbestos exposure. 54 Eskenasy A. Histopathology of tumorous ribs: a review Occup Environ Med 1994;51:804–811. of 130 cases. Morphol Embryol (Bucur) 1985;31:35–50. 36 Spirtas R, Connelly RR, Tucker MA. Survival patterns 55 Mori T, Yoshioka M, Iwatani K, et al. Kissing pleural for malignant mesothelioma: the SEER experience. Int metastases from metastatic osteosarcoma of the lung. J Cancer 1988;41:525–530. Ann Thorac Cardiovasc Surg 2006;12:129–132. 37 Fadare O, Bifulco C, Carter D, et al. Cartilaginous 56 Bai H, Aswad BI, Gaissert H, et al. Malignant solitary differentiation in peritoneal tissues: a report of two fibrous tumor of the pleura with liposarcomatous cases and a review of the literature. Mod Pathol differentiation. Arch Pathol Lab Med 2001;125: 2002;15:777–780. 406–409. 38 Benchetritt M, Hofman V, Venissac N, et al. Dediffer- 57 Knuuttila A, Jee KJ, Taskinen E, et al. Spindle cell entiated liposarcoma of the pleura mimicking a tumours of the pleura: a clinical, histological and malignant solitary fibrous tumor and associated with comparative genomic hybridization analysis of 14 dedifferentiated liposarcoma of the mediastinum: cases. Virchows Arch 2006;448:135–141. usefulness of cytogenetic and molecular genetic 58 Attanoos RL, Dojcinov SD, Webb R, et al. Anti- analyses. Cancer Genet Cytogenet 2007;179:150–155. mesothelial markers in sarcomatoid mesothelioma 39 Minniti A, Montaundon M, Jougon J, et al. Liposarco- and other spindle cell neoplasms. Histopathology ma of the pleural cavity. An exceptional tumour. 2000;37:224–231. Monaldi Arch Chest Dis 2005;63:170–172. 59 Lucas DR, Pass HI, Madan SK, et al. Sarcomatoid 40 Okby NT, Travis WD. Liposarcoma of the pleural mesothelioma and its histological mimics: a com- cavity: clinical and pathologic features of 4 cases with parative immunohistochemical study. Histopathology a review of the literature. Arch Pathol Lab Med 2003;42:270–279. 2000;124:699–703. 60 Antman K, Shemin R, Ryan L, et al. Malignant 41 Wong WW, Pluth JR, Grado GL, et al. Liposarcoma of mesothelioma: prognostic variables in a registry of the pleura. Mayo Clin Proc 1994;69:882–885. 180 patients, the Dana-Farber Cancer Institute and 42 Wouters EF, Greve LH, Visser R, et al. Liposarcoma of Brigham and Women’s Hospital experience over the pleura. Neth J Surg 1983;35:192–193. two decades, 1965–1985. J Clin Oncol 1988;6: 43 Toro JR, Travis LB, Wu HJ, et al. Incidence patterns of 147–153. soft tissue sarcomas, regardless of primary site, in the 61 Demirag F, Unsal E, Tastepe I. Biphasic malignant surveillance, epidemiology and end results program, mesothelioma cases with osseous differentiation and 1978–2001: an analysis of 26 758 cases. Int J Cancer long survival: a review of the literature. Lung Cancer 2006;119:2922–2930. 2007;57:233–236.

Modern Pathology (2008) 21, 1084–1094