A Localized Pleural Based Mass With Intense Uptake on Positron Emission Tomography Scan

CHEST

Postgraduate Education Corner CHEST IMAGING AND PATHOLOGY FOR CLINICIANS

A Localized Pleural Based Mass With Intense Uptake on Positron Emission Tomography Scan* Amir M. Khan, MD, MSc; Kaoutar Tlemcani, MD; Nataraj Shanmugam, MD; Dingming Y, MD; Steven Keller, MD; and Andrew R. Berman, MD

(CHEST 2007; 131:294 –299)

man was referred for evaluation of a left A 77-year-old chest mass found on a routine radiograph during

hospitalization for a myocardial infraction. The patient underwent successful coronary stenting for occluded right coronary and left circumflex coronary vessels and remained asymptomatic. His medical history was significant for hypertension, hyperlipidemia, benign prostatic hypertrophy, and peripheral vascular disease. He had undergone a carotid endarterectomy 2 years prior to this hospital admission. His medications included atenolol, aspirin, clopidogrel, pantoprazole, simvastatin, tamsulosin, and amlodipine. His social history was remarkable for cigarette smoking (1 pack a day for ⬎ 50 years) until he quit 4 years ago. He was retired from the merchant marine, and his work involved ship repair for several weeks at a time. No clear asbestos exposure could be established. His purified protein derivative status was negative. His vital signs, the findings of physical and cardiopulmonary examinations, and results of basic laboratory investigations were unremarkable on presentation. Radiologic Findings A plain chest radiograph showed a solitary opacification on the left side of the chest. A CT scan of the chest revealed a 2 ⫻ 1 cm soft homogenous lesion in the *From the Departments of Pulmonary Medicine (Drs. Khan and Berman), Oncology (Dr. Tlemcani), Nuclear Medicine (Dr. Shanmugam), Pathology (Dr. Y), and Surgery (Dr. Keller), Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY. The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Manuscript received March 14, 2006; revision accepted September 8, 2006. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Amir M. Khan, MD, MSc, 3600 Fieldston Rd, No. 7C, Bronx, NY 10463; e-mail: [email protected] DOI: 10.1378/chest.06-0655 294

Figure 1. Top, A: chest radiograph (anteroposterior view), showing a solitary pulmonary left nodule. Bottom, B: CT scan of the chest-lung window showing the left anterior nodule, which is pleura-based. Postgraduate Education Corner

Figure 2. PET scan image showing the uptake of the anterior left nodule.

anterior left hemithorax forming oblique angles with adjacent lung parenchyma consistent with either pleural or extrapleural origin, without evidence of apparent chest wall or rib involvement. No adjacent bony destruction or invasion was noted. A corresponding intense focal fluorodeoxyglucose uptake was noted on positron emission tomography (PET) scans of the chest (Fig 1, 2). The patient underwent a left thoracoscopic resection of this parietal pleura-based mass. At the time of surgery, no other lesions were noted in the lung, pleura, or chest surface. The mass was removed en bloc and sent for pathologic examination. Pathologic Findings On gross inspection, a tan white homogenous 1.7 ⫻ 1.2 ⫻ 0.6 cm mass was noted. On cut section,

small foci of yellow nodules (maximum dimension, 0.1 ⫻ 0.2 cm) were also noted. Histology confirmed tumor cells of epithelioid proliferation, which formed diffuse sheets and showed focal infiltration into an associated dense fibrotic stroma but without infiltration of any of the margins of the specimen. The immunophenotype of the cells confirmed the diagnosis of mesothelioma as they stained strongly positive for CK 5/6, and calretinin (cytoplasmic staining with nuclear sparing), and were negative for other immunomarkers (eg, TTF1, WT1, BerEP4, B72.3, CD34, Bcl2, and CEA polyclonal) [Fig 3, 4]. The patient had made an uneventful recovery postoperatively. No recurrence was been detected at his 1-year follow-up visit. What is the diagnosis?

Figure 3. Histology at low power (hematoxylin-eosin, original ⫻40). At lower power, the pleural surface is smooth and fibrotic. The lesion shows sheets of epithelioid cells with centrally located nuclear cytoplasm and an ample amount of eosinophilic cytoplasm. The immunostains are negative for TTF-1, but positive for CK5/6. www.chestjournal.org

Figure 4. Histology at high power (hematoxylin-eosin, original ⫻40). High-power epithelioid cells. CHEST / 131 / 1 / JANUARY, 2007

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Table 1—Localized Mesotheliomas* Study/Year

Location of Study

Localized pericardial mesotheliomas Sane and United States Roggli4/1995 Bierhoff and Pfeifer5/1996 Shimazaki et al6/2000 Val-Bernal et al7/2002 Localized peritoneal mesotheliomas Matsukuma et al8/1996 Imura et al9/ 2002 Allen et al10/ 2005

LMMs Obers et al11/ 1988 Crotty et al12/ 1994

Age, yr/Sex

27/F

2⫻4

Germany

50/M

Japan

44/F

Spain

76/F

NA

Japan

68/M

CT imaging

Japan

64/M

CT scan/MRI of segment 7 of liver NA

United States/ 56/M United Kingdom/Canada United States/ 83/F United Kingdom/Canada South Africa

United States/ Canada

10

Surgery

Follow-up

Curative resection Epithelial

Alive at 28-yr F/U

Autopsy

Biphasic cystic

DOD

Epithelial

DOD at 3 d

Sarcomatous

DOD†

11

Inadequate resection 3.6 ⫻ 2.4 ⫻ 2.5 Autopsy

5.5 ⫻ 1.7 ⫻ 5

Histology

Resection

3.2 ⫻ 2.5 ⫻ 2.2 Laparotomy adherent diaphragm 15 Resection

Biphasic rhabdoid DOD at 10 mo Epithelial

Alive at 3.5-yr F/U

Epithelial

Alive at 2-yr F/U

NA

NA

Hemicolectomy

Epithelial

DOD at 1 yr

72/F

CXR ⫹ FNA

NA

Thoracotomy

Epithelial

DOD at 7 mo

40/F 76/F

CXR ⫹ FNA CXR

7 6

Thoracotomy Resection

Sarcomatous Epithelial

DOD at 4 mo Alive at 8-yr F/U

63/F 69/F 74/F 42/F

CXR CXR CXR CXR

7 2 10 10

Biphasic Biphasic Epithelial Epithelial

Alive at 8-mo F/U Alive at 2-yr F/U DOD at 2 yr DOD at 1 yr

CXR ⫹ biopsy CT scan of left posterior pleural mass CT scan/MRI of right apical posterior ⫹ rib involvement CT scan/MRI left upper CT scan cystic left apical pleura CT scan/MRI of right pleura ⫹ 7th/ 8th rib involvement NA

5 7

Resection Resection Thoracotomy Exploratory thoracotomy ⫹ resection Resection En bloc resection after biospy

Biphasic Epithelial

DOD at 8 mo Reoccurrence at 1 mo

5 ⫻ 5 ⫻ 54

Right lateral thoracotomy

Epithelial

Alive ⫹ disease at 1-yr F/U

7 ⫻ 4 ⫻ 3.5

Sarcomatous

United States

61/F 66/M

Erklic et al14/ 2001

Turkey

61/F

Okamura et al15/2001 Umezu et al16/ 2002 Gomez-Roman et al17/2002

Japan

56/F

Japan

70/F

Spain

47/F

296

Size, cm

CO2 involvement into pleural space CT scan of mediastinal mass CT imaging

Ojeda et al13/ 1998

Allen et al10/ 2005

Imaging Study

United States/ 52/M United Kingdom/Canada 67/F 76/F 76/M

NA NA NA

3.8 ⫻ 1.8 ⫻ 2

DOD at 1 5 yr

Resection after CT scan biopsy Exploratory thoracotomy ⫹ resection

Epithelial

DOD at 8 mo

Sarcomatous

DOD at 2.8 yr†

2.2

Resection

Epithelial

Alive at 4.5-yr F/U

4 3 6

Resection Resection Resection

Epithelial Epithelial Epithelial

Alive at 2-yr F/U Alive at 3-yr F/U Alive at 8-yr F/U

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Postgraduate Education Corner

Table 1—continued Study/Year

Khan et al 2006 (current study)

Location of Study

United States

Age, yr/Sex

Imaging Study

72/M 48/F

NA NA

11 3.5

Resection Resection

Epithelial Epithelial

60/M 37/F

NA NA

3.2 NA

Resection Resection

Epithelial Biphasic

70/M

NA

5

Resection

Biphasic

66/M 78/F 43/M 65/F 64/M 54/M 53/M 67/M 72/M 52/M 61/M 60/M 77/M

NA NA NA NA NA NA NA NA NA NA NA NA CT scan/PET scan

Resection Resection Resection Resection Resection Resection Resection Resection Resection Resection Resection Resection Thorascopic resection

Epithelial Epithelial Epithelial Epithelial Epithelial Epithelial Biphasic Biphasic Biphasic Sarcomatous Epithelial Biphasic Epithelial

Size, cm

5 3 2.5 7 7 8 7 8.5 1.7 ⫻ 2 ⫻ 0.6

Surgery

Histology

Follow-up Alive at 8-yr F/U Alive at 6.5-yr F/U Alive at 11-yr F/U Alive at 1.5-yr F/U Alive at 1.5-yr F/U DOD at 6 mo DOD at 1.5 yr DOD at 3 yr DOD at 9 mo DOD at 1.53 yr DOD at 1.58 yr DOD at 1.5 yr DOD at 7 mo DOD at 1 mo DOD at 6 yr NA NA Alive at 1-yr F/U

*F ⫽ female; M ⫽ male; CXR ⫽ chest x-ray; FNA ⫽ fine-needle aspiration; F/U ⫽ follow-up; DOD ⫽ dead of disease; NA ⫽ not available. †Update received via correspondence as of 2006.

Diagnosis: Localized malignant mesothelioma

The 2004 World Health Organization classification of tumors of the pleura recognized LMM as a separate entity.22

Discussion Mesothelioma is a primary tumor of the serosal membranes that can involve the pleura, peritoneum, and pericardium.1 Diffuse malignant mesothelioma (DMM) is an aggressive variant that grows widely over the serosal membrane surfaces; patients have very poor outcomes, with death occurring within 24 months of its diagnosis in most cases. DMM presents with its characteristic extensive studding of the serosal surface by tumor nodules, which progresses to the encasement of organs in the later stages.2,3 A small number of cases of so-called localized malignant mesothelioma (LMM) have been described in the literature with immunohistochemical and ultrastructural features that are identical to those of DMM, but with improved clinical outcomes (Table 1).4 –17 The term localized malignant mesothelioma of the pleura was described by Wagner as early as 1870.18 Distinction between the local and diffuse forms was provided in 1931 by Klemperer and Rabin.19 Up to 1950,20 and then from 1950 to 1978,21 only a handful of cases were reported. In 1994, Crotty et al12 described a series of six patients and redefined LMM based on modern immunohistochemical features. www.chestjournal.org

Clinical and Radiologic Discussion LMMs are rare, solitary, circumscribed, nodular tumors, which are attached to the surface of the pleura, peritoneum, or pericardium. Malignant mesotheliomas are predominately of three types (Table 1). Most LMMs are incidental findings or present with nonspecific symptoms. Unlike the situation with DMMs, in which most cases occur in men, the sex ratio of patients with LMMs is approximately equal in our review (Table 1). While DMM is associated with asbestos exposure, in our review of 35 cases of LMM, only 5 cases had a definite history of exposure and another 3 cases had a history that was suspicious for exposure. Since information about asbestos exposure was not available in many of the cases, we were unable to ascertain the role of asbestos exposure nor were we able to establish any other common etiology in the causation of LMM (Table 1). Patients in reported cases of LMM have had tumor varying in size from as small as 1.8 cm to as large as 10 cm. The pattern shown by CT scans in this case, consisting of a small localized subpleural nodule, is much more likely to be a solitary fibrous CHEST / 131 / 1 / JANUARY, 2007

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tumor (SFT) than a malignant mesothelioma. The diagnosis of localized mesothelioma can only be distinguished pathologically. The initial imaging of choice to define the nodule is a CT scan that has been followed by an MRI for better description in a few cases.14,15,17 The role of PET scans in differentiating LMM from other entities (eg, fibroma) is still unclear. In the patient our case, an increased uptake was noted that might help differentiating an LMM from other entities; however, it must be emphasized that the role of PET scanning in diagnosing LMMs is yet to be defined. Similarly, only a handful of patients have been biopsied with imaging techniques, probably because of the small size of the tumor and occasionally because of their location. Again, the role of biopsy with improved imaging modalities is also yet to be determined. LMM has better overall outcome than DMM. However, in LMM, according to our review of the literature, neither the histologic subtype nor tumor size was found to correlate with survival (Table 1). One of the important features of LMM is that many cases can apparently be cured with early surgical intervention. In contrast to other studies in our review, half of the patients in the study by Allen et al10 were alive, many after a significant period of follow-up. The authors of this study were unsure whether this was due to a slightly different case definition or to other factors such as better imaging modalities, improved staining procedures, earlier intervention, or advanced surgical techniques. Those cases in the literature that were reported to recur tend to metastasize in the fashion of sarcomas, emphasizing their differences from DMM. While chemotherapy has a definitive role in DMM, very little if any information is available on the role of chemotherapy in patients with LMM and also in those patients where it reoccurs (Table 1). Pathologic Discussion Mesotheliomas are classified into localized and diffuse types, of mesothelial and submesothelial origin, respectively. Localized mesotheliomas of submesothelial origin are now called solitary fibrous tumors. Until the 1980s, the term fibrous mesothelioma was often used for what is now called SFT. Some of these older articles may have been referring to SFT when they discussed LMM. SFT and malignant mesothelioma are now recognized to be completely different neoplasms with important clinical, radiologic, and pathologic differences, and the term fibrous mesothelioma is no longer used for SFT, as SFTs are considered to be of mesenchymal stem cell 298

origin. Mesothelioma cell origin is rare and may be of epithelioid, sarcomatoid (spindle), or biphasic subtypes.4 –17 Immunohistochemisty is useful in differentiating mesothelioma from adenocarcinoma, which can present similarly.1,23–29 Although not pathognomonic, an immunohistochemical profile that is positive for calretinin, keratin, thrombomodulin, and vimentin, and is negative for CEA, SP-A, and CD15, the markers for adenocarcinoma, is highly suggestive of the mesothelial origin of the cells.1,24,26 Some authors have suggested that the proliferation index of 67 Ki should be part of the pathology report, as it was found to have an important prognostic value.30 –33 The characteristic appearance of mesothelial cells on electron microscopy (ie, numerous long, slender, and smooth microvilli) point to the diagnosis of mesothelioma.1,3,29 By definition, LMMs are immunohistochemically, and ultrastructurally identical to DMMs. Epithelium-type LMMs predominate, and very few tumors are purely sarcomatous. DMMs show macroscopic and/or microscopic evidence of widespread tumors on the serosal surface, whereas LMMs are well circumscribed. Reported cases34 –37 of LMM that recur as DMM should be carefully reviewed to ensure that a DMM was not present at the time of the original diagnosis. In conclusion, we would suggest that, although LMMs share similar microscopic and immunohistochemical features with DMMs, LMM should probably be considered a separate entity, distinct by its occult clinical presentation, its sharp morphologic demarcation, and its higher curability with surgical resection. References 1 Churg A, Cagle PT, Roggli VL. Tumors of the serosal membranes. In: Atlas of tumor pathology. 4th series, fascicle 10. Washington, DC: Armed Forces Institute of Pathology, 2006 2 Hammer DP. Pleural diseases. In: Dial DH, Hammer SP, eds. Pulmonary pathology. 2nd ed. New York, NY: Springer, 1994; 1463–1579 3 Suzuki Y. Diagnostic criteria for human diffuse malignant mesothelioma. Acta Pathol Jpn 1992; 42:767–786 4 Sane AC, Roggli VL. Curative resection of a well-differentiated papillary mesothelioma of the pericardium. Arch Pathol Lab Med 1995; 119:266 –267 5 Bierhoff E, Pfeifer U. Malignant mesothelioma arising from a benign mediastinal mesothelial cyst. Gen Diagn Pathol 1996; 142:59 – 62 6 Shimazaki H, Shinsuke A, Yasuhiro I, et al. Vacuolated cell mesothelioma of the pericardium resembling liposarcoma: a case report. Hum Pathol 2000; 31:767–770 7 Val-Bernal JF, Figols J, Gomez-Romain JJ. Incidental (solitary) epithelial mesothelioma of the pericardium: case report and literature review. Cardiovasc Pathol 2002; 11:181–185 8 Matsukuma S, Aida S, Hata Y, et al. Localized malignant peritoneal mesothelioma containing rhabdoid cells. Pathol Int 1996; 46:389 –391 Postgraduate Education Corner

9 Imura J, Ichikawa K, Takeda J, et al. Localized malignant mesothelioma of the epithelial type occurring as a primary hepatic neoplasm: a case report with review of the literature. APMIS 2002; 110:789 –794 10 Allen TC, Cagle PT, Churg AM, et al. Localized malignant mesothelioma. Am J Surg Pathol 2005; 29:866 – 873 11 Obers VJ, Leiman G, Girdwood RW, et al. Primary malignant pleural tumors (mesotheliomas) presenting as localized masses: fine needle aspiration cytologic findings, clinical and radiologic features and review of the literature. Acta Cytol 1988; 32:567–575 12 Crotty BT, Myers JL, Katzenstein AA, et al. Localized malignant mesothelioma. Am J Surg Pathol 1994; 18:357–363 13 Ojeda HF, Mech K, Hicken W. Localized malignant mesothelioma: a case report. Am Surg 1998; 64:881– 885 14 Erkilic S, Sari I, Tuncozgur B. Localized pleural malignant mesothelioma. Pathol Int 2001; 51:812– 815 15 Okamura H, Kamei T, Mitsuno A, et al. Localized malignant mesothelioma of the pleura. Pathol Int 2001; 51:654 – 660 16 Umezu H, Kuwata K, Ebe Y, et al. Microcystic variant of localized malignant mesothelioma accompanying an adenomatoid tumor-like lesion. Pathol Int 2002; 52:416 – 422 17 Gomez-Roman JJ, Mons-Lera R, Olmedo IS, et al. Flow cytometric analysis of a localized malignant mesothelioma. Ann Thorac Surg 2002; 73:1292–1294 18 Wagner E: Das tuberkelahnliche lymphadenom (Der cytogene oder reticulirte Tuberkel). Arch Heilk (Leipzig) 1870; 11:497 19 Klemperer P, Rabin CB. Primary neoplasms of the pleura: a report of five cases. Arch Pathol 1931; 11:385– 412 20 Clagett OT, Mcdonald JR, Schmidt HW. Localized fibrous mesothelioma of the pleura. J Thorac Surg 1952 Sep; 24:213– 230 21 Okike N, Bernatz PE, Woolner LB. Localized mesothelioma of the pleura; benign and malignant variants. J Thorac Cardiovasc Surg 1987; 75:363–372 22 Churg A, Roggli V, Galateau-Salle F, et al. Tumours of the pleura: mesothelial tumours. In: Travis WD, Brambilla E, Mu¨ller-Hermelink HK, et al, eds. World Health Organization classification of tumours (vol 10): pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon, France: IARC Press, 2004 23 Brown RW, Clark GM, Tandon AK, et al. Multiple-marker immunohistochemical phenotypes distinguishing malignant pleural mesothelioma from pulmonary adenocarcinoma. Hum Pathol 1993; 24:347–354 24 Doglioni C, Tos AP, Laurino L, et al. Calretinin: a novel

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