Pleural epithelioid hemangioendothelioma harboring CAMTA1 rearrangement

Lung Cancer 83 (2014) 411–415

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Case report

Pleural epithelioid hemangioendothelioma harboring CAMTA1 rearrangement Sang Yun Ha a , In Ho Choi a , Joungho Han a,∗ , Yoon-la Choi a , Jong Ho Cho b , Kyung-Jong Lee c , Jong-Mu Sun d a

Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Republic of Korea Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Republic of Korea c Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Republic of Korea d Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Republic of Korea b

a r t i c l e

i n f o

Article history: Received 22 October 2013 Accepted 30 December 2013 Keywords: Pleura Lung Epithelioid hemangioendothelioma CAMTA1 FISH EHE

a b s t r a c t Pleural epithelioid hemangioendothelioma (EHE) is a very rare disease with adverse clinical outcomes. Recently, CAMTA1 rearrangement has been introduced as a consistent genetic abnormality in EHEs of different anatomical locations. We report a 71-year-old man with pleural EHE harboring CAMTA1 rearrangement confirmed by fluorescence in situ hybridization on paraffin embedded tissue. © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Pleural epithelioid hemangioendothelioma (EHE) is very rare, and only around 20 cases have been reported in English literature [1–10]. Based on these series of case reports, most patients with pleural EHE showed poor prognosis, less than 1 year of survival. Therefore, accurate diagnosis is very important, but often difficult in daily practice because of extremely low incidence and similar immunohistochemical profiling to other vascular tumor such as epithelioid hemangioma or epithelioid angiosarcoma [11]. Recently, CAMTA1 rearrangement has been introduced as a consistent genetic abnormality in EHEs of different anatomical locations [11,12]. Herein, we report a 71-year-old man with pleural EHE confirmed by CAMTA1 rearrangement. 2. Case report A 71-year-old man was referred to our hospital complaining of cough, dyspnea, fatigue and poor oral intake for 2 months. He also

∗ Corresponding author at: Department of Pathology, Samsung Medical Center, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Republic of Korea. Tel.: +82 2 3410 2765; fax: +82 2 3410 0025. E-mail address: [email protected] (J. Han). 0169-5002/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2013.12.015

had weight loss of 8 kg for last 6 months. He was an ex-smoker (10 pack-year) and had no past medical history. He was a retired teacher and no history of asbestos exposure. Laboratory findings were within normal limit, but mildly decreased total protein (5.1 g/dL), albumin (2.7 g/dL) and cholesterol (83 mg/dL) in serum. Conventional chest X-ray showed bilateral pleural effusion (Fig. 1A). Thoracocentesis showed >1000 leukocytes with normal distribution, glucose 93 mg/dL, protein 2826 mg/dL, LDH 285 UI/L, ADA 15.9 UI/L, CEA 0.2 ng/mL, and pH 7.3 in pleural fluid. Cytologic examination revealed no malignant cell. Chest CT scan reported subpleural interlobular septal thickening and consolidation of both lungs, especially in lower lung, with right pleural effusion and pericardial effusion (Fig. 1B-D). PET CT demonstrated increased FDG uptake along bilateral pleura and pericardium and hypermetabolic subpleural ground-glass opacities and consolidation in both basal lungs. There were another hypermetabolic foci of mesentery and bone marrow. The patient received video assisted thoracotomy’s biopsy for frozen diagnosis and subsequent wedge resection. The specimen from wedge resection showed diffuse irregular thickening of pleura and multifocal and variably sized subpleural and intraparenchymal nodules with infilitrative growth pattern (Fig. 2A and B). Focal sclerotic area with less cellularity was noted, especially in central zone (Fig. 2B). Histologically, proliferation of epithelioid cells with moderate nuclear plemorphism, abundant

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Fig. 1. (A) Conventional chest X-ray shows bilateral pleural effusion. (B–D) Chest CT scan shows subpleural interlobular septal thickening and consolidation of both lungs, especially in lower lung, right pleural effusion and pericardial effusion.

eosinophilic cytoplasm and intracytoplasmic vacuolization was characteristic (Fig. 2C and D). There were few mitotic figures and no necrosis. Immunohistochemically, tumor cells are positive for CD31 (1:40, JC/70A, DAKO, Carpenteria, CA, USA) (Fig. 2E) and negative for calretinin (1:40, 5A5, Novocastra, Newcastle, UK), WT-1 (1:50, 6FH2, DAKO), HBME-1 (1:50, HBME-1, DAKO), CK (AE1/AE3) (1:130, AE1/AE3, DAKO), CD34 (1:100, QBEND10, DAKO) and ALK (1:30, ALK1, DAKO). Based on these results, EHE was strongly suspicious. We performed fluorescence in situ (FISH) analysis using dual color break-apart probe (Macrogen, Seoul, Korea) on paraffinembedded tissue for detection of CAMTA1 rearrangement, which is known to be specific to EHE [11,12]. Detailed method is described in recently published report from our institution [13]. More than 30% of tumor nuclei revealed distinct break-apart signals with individual green and/or red signals, indicating the presence of CAMTA1 rearrangement (Fig. 2F), while the nuclei of adjacent normal pneumocytes did two yellow signals. Therefore, we confirmed the diagnosis of pleural EHE with CAMTA1 rearrangement. The patient is scheduled to have chemotherapy. 3. Discussion Pleura is a rare anatomical site of EHE, and only around 20 cases have been reported in English literature [1–10]. We summarized the cases of pleural EHE in Table 1, by modification from tables in previous reports by Lee et al. [6] and Marquez-Medina et al. [9]. While pulmonary EHE affects more commonly middle aged (mean age: about 40 years old) woman with no symptom, pleural EHE are more frequent in older adult males with clinical symptom associated with pleural effusion [4,6,14,15]. Most patients with pleural EHE showed poor prognosis of survival less than 1 year, although one patient with complete remission for 18 months after

chemotherapy was reported [1–4,6,7,9,10]. This clinical outcome of pleural EHE is distinguished from that of pulmonary counterpart, which shows 60% (range 47–71%) of 5-year survival rate [15]. The diagnosis of pleural EHE is made by histopathologic examination with ancillary immuohistochemical staining. Proliferation of epithelioid cells with abundant cytoplasm and cytoplasmic vacuole is characteristic and these tumor cells are positive for vascular endothelial markers, including CD31, CD34, factor VIII or Fli-1 [5]. However, the diagnosis of pleural EHE is often difficult in daily practice because of extremely low incidence and similar immunohistochemical profiling to other vascular tumor such as epithelioid hemangioma or epithelioid angiosarcoma, especially in limited tissue samples [11]. Recently, WWTR1/CAMTA1 gene fusion that corresponds with t(1;3)(p36;q25) was reported as a consistent genetic abnormality in EHEs of different anatomical locations [11,12]. We confirmed the diagnosis of rare pleural EHE by demonstrating CAMTA1 rearrangement by FISH on paraffin-embedded tissue samples. FISH is a simple and convenient method for detection of gene rearrangement in daily practice, and documentation of CAMTA1 rearrangement by FISH could be useful in the diagnosis of ambiguous case, especially in differentiating from other vascular tumors including epithelioid hemangioma or epithelioid angiosarcoma, in which tumor cells express vascular endothelial markers [11]. It is also useful to make a definite diagnosis of EHE in limited tissue samples. However, recent one study documented YAP1-TFE3 fusion gene in young EHE patient with no CAMTA1 rearrangement [16]. Further study is needed to define how much CAMTA1 rearrangement is sensitive and specific in the diagnosis of EHE. The treatment of pleural EHE has not been established, yet. Surgical resection is usually impossible due to diffuse involvement in pleural EHE patients, and it might explain the poorer prognosis of

Table 1 Reports of pleural epithelioid hemangioendothelioma in English literature. Year

No. of patients

Age/gender

Symptom

Radiology

Immunohistochemistry/fluorescence in situ hybridization

Treatment

Follow up

Yousem et al. [1]

1987

1

34/M

Dyspnea

Bilateral pleural effusion

NR

None

Died after 3 months

Lin et al. [2]

1996

6

36–58/M

NR

Pleural effusion (n = 6), pericardial effusion (n = 1)

NR

None

4 patients died of disease (duration NR); 1 patient survived after 6 months; NR in 1 patient

Pinet et al. [3]

1999

1

50/F

Asymptomatic

Pleural effusion, ascites

Factor VIII (+), BNH9 (−)

Chemotherapy

Complete remission for 18 months

Crotty et al. [4]

2000

4

55–71/M

Chest pain (n = 3), dyspnea (n = 3), cough and fever (n = 1), weight loss (n = 1)

Pleural effusion (n = 4), pleural nodules and thickness (n = 1)

CD31 (+), CD34 (+), Factor VIII (+)

None

3 patients died after mean 10 (range 1–19) months; NR in 1 patient

Al-Shraim et al. [5]

2005

1

51/M

Cough, dyspnea

Pleural effusion, pleural nodule

CD31 (+), CD34 (+), Factor VIII (+)

Interferon

NR

Lee et al. [6]

2008

1

31/F

Shoulder pain

Lung and pleural nodules

CD31 (+), CD34 (+), Factor VIII (+)

Radiotherapy + chemotherapy

Died after 10 months

Liu et al. [7]

2010

1

80/M

Dyspnea, pain

Pleural effusion, pleural thickness

CD31 (+), FLI1 (+), Pancytokeratin focal (+)

None

Died after 6 months

Kim et al. [8]

2011

1

46/F

Chest discomfort, cough

Pleural effusion

CD31 (+), CD34 (+)

Chemotherapy

Disease progression after 22 months

Marquez-Medina et al. [9]

2011

1

85/M

Shoulder pain, fatigue, anorexia, weight loss

Pleural effusion

CD31 (+), CD34 (−)

None

Died after 7 months

Bansal et al. [10]

2012

1

51/F

Nonpleuritic chest pain, weight loss

Pleural effusion, pleural thickening

CD31 (+), CD34 (+)

Chemotherapy

Died after 4 months

Present case

2013

1

71/M

Cough, dyspnea, fatigue and poor oral intake

Pleural effusion, pleural and lung nodule, pericardial effusion

CD31 (+), CD34 (−) CAMTA1 rearrangement (+)

NR

NR

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Authors

This table was made by modification from tables in previous reports by Lee et al. [6] and Marquez-Medina et al. [9]. M, male; F, female; NR, not recorded.

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Fig. 2. (A) The specimen from wedge resection shows diffuse irregular thickening of pleura and multifocal and variably sized subpleural and intraparenchymal nodules with infilitrative growth pattern. (B) Focal sclerotic area with less cellularity is noted, especially in central zone. (C and D) Proliferation of epithelioid cells with moderate nuclear plemorphism, abundant eosinophilic cytoplasm and intracytoplasmic vacuolization is characteristic. (E) Tumor cells are positive for CD31. (F) Representative figure of CAMTA1 rearrangement by fluorescence in situ hybridization. Tumor cell nuclei have distinct split signals with individual green and red signals (arrow). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

pleural EHE comparing to its pulmonary counterpart. Chemotherapy with diverse regimens, interferon treatment or radiotherapy has been tried, but did not alter adverse clinical course, except one patient with complete remission after chemotherapy of carboplatin and etoposide [3,5,6,8,10]. 4. Conclusion Pleural EHE is very rare disease entity with distinct clinical presentation and adverse outcome, comparing to its pulmonary counterpart. We report a 71-year-old man with pleural EHE confirmed by CAMTA1 rearrangement. Recently introduced CAMTA1 rearrangement by FISH may be useful ancillary test to confirm the diagnosis of pleural EHE, especially in small biopsy samples. Conflict of interest statement The authors declare no conflict of interest.

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