Primary pulmonary epithelioid hemangioendothelioma

Abstract

Pulmonary epithelioid hemangioendothelioma (PEH) is a rare tumour of vascular origin with low to intermediate malignancy. Typical radiological finding on CT is multiple small nodules in bilateral lungs, and some will have punctate calcifications and pleural thickening. The diagnosis of PEH is confirmed by histopathological findings and positive immunohistochemistry staining. We report a case of a woman in her 50s with a medical history of lung adenocarcinoma. Later, regular chest CT during a routine cancer follow-up revealed multiple small pulmonary nodules and increased sizes of these nodules on serial images, initially misdiagnosed as multiple lung metastases. The histopathological diagnosis was made on a pulmonary wedge resection. Finally, PEH was diagnosed on the basis of positive immunohistochemical staining for CD31, ERF and TFE3. In the current study, the clinicopathological features and review of the literature were investigated. Our case highlights the importance of a histological diagnosis to avoid misdiagnosis.

Background

Pulmonary epithelioid hemangioendothelioma (PEH) is a rare tumour of vascular origin because the neoplastic cells have characteristics in common with normal, non-neoplastic endothelial cells. The term of epithelioid hemangioendothelioma (EHE) was first described by Weiss and Ezinger in 1982,¹ which previously named as intravascular bronchioloalveolar tumour since 1975. The 2015 WHO classification described PEH as a low to intermediate grade malignant vascular tumour.² The International Hemangioendothelioma, Epithelioid Hemangioendothelioma and Vascular Disorders Registry has the largest collection of data on this rare disease and its natural history.³ The treatment is still not standardised due to the rarity.⁴ In this study, we present a woman with lung adenocarcinoma history who had multiple nodules in bilateral lungs during routine regular follow-up. She was initially misdiagnosed with metastatic lung cancer and finally diagnosed with PEH by single incision thoracoscopic wedge resection. The literatures of PEH are also reviewed in this article.

Case presentation

A non-smoking woman in her 50s with a medical history of lung adenocarcinoma in the left lower lobe who had undergone thoracoscopic segmentectomy and mediastinal lymph node dissection 7 years ago. The pathological diagnosis was adenocarcinoma, mixed subtype, 1.9 cm, pT1aN0M0, p-stage IA2. She was regularly followed-up since then. She also had underlying history of type 2 diabetes mellitus, hypertension and hyperlipidaemia, all under medication control. She is a housekeeper by occupation and has no family history of cancer.

Investigations

During the follow-up period, small ground-glass nodules in bilateral lungs were first noted on chest CT 3 years ago (figure 1A–C). Over the 2 years, serial images revealed increased sizes of these nodules (figure 1D–F), the largest size measured about 1.1 cm in the right upper lobe, which were initially diagnosed as multiple lung metastases. The patient was asymptomatic, and the results of physical examination had been unremarkable. The pulmonary function test revealed a moderate obstructive pattern, while the lung capacity diffusion showed no signs of impairment.

Figure 1.

Imaging of the pulmonary epithelioid hemangioendothelioma. (A–C) CT scan revealed multiple bilateral lung nodules. The nodule diameter ranged from 2 to 4 mm. (D-F) The followed-up CT scans showed increased the sizes of some of the pulmonary nodules ranged from 2 mm to 1.2 cm.

Treatment

The patient underwent right upper lobe wedge resection by video-assisted thoracoscope (figure 2). The immunohistochemical stains were performed and showed positive in CD31, ERF, TFE3 (figure 3). Finally, the patient was diagnosed with PEH.

Figure 2.

The resected specimen of the right upper lobe measured approximately 6×1x1 cm, weighted 5 g in weight and the right lower lobe approximately 6×4.5x1 cm, weighted 4 g in weight.

Figure 3.

(A) The tumour had higher cellularity and the cells consisted of nests of epithelioid cells (H&E, x40). (B–D) Immunohistochemical stains showed the tumour cells to be endothelial in origin and were positive for CD31, TFE 3 and ERG (x100).

Outcome and follow-up

After surgery, the patient has been in regular follow-up at our hospital. During this long-term follow-up, we observed stable pulmonary condition. After 1 year CT scan follow-up, no increased the sizes of the residual pulmonary nodules or distant metastases after then.

Discussion

EHE is a rare tumour with prevalence less than one in million cases and female predominance at a rate of twofold. The median age of diagnosis is 36 years old.⁵ EHE mainly affects the liver and the incidence of PEH was much less than liver EHE. Most patients with PEH are asymptomatic or with non-specific respiratory symptom such as cough, short of breath, chest pain, haemoptysis. Patients with PEH are often incidentally detected by imaging modalities since physical examination is non-specific.⁶

Prior studies have proposed three typical CT imaging patterns in patients with PEH: multiple pulmonary nodules, multiple pulmonary reticulonodular opacities and diffuse infiltrative pleural thickening. Some would also accompany with punctate calcification and other unusual findings included ground-glass opacities and interstitial thickening.^7–10 Single solitary nodule or mass were very rare but indicated well prognosis.¹¹ Our patient had multiple bilateral ground-glass nodules of different sizes with clear and well-defined borders. These features are typical in lung metastases, especially in the patient with medical history of lung adenocarcinoma. However, the immunohistochemical analysis confirmed the diagnosis of PEH.

The diagnosis of PEH is confirmed by histopathological findings and positive immunohistochemistry staining for vascular-endothelial markers.⁴ Typical microscopic appearance includes hyalinisation, cytologic atypia, necrosis and varying calcification. Relatively specific and sensitive vascular-endothelial markers of PEH include CD31, CD34 and factor VIII. Other cell markers such as Fli-1, Fli-20, Ulex-1 are also present in some PEH tumours.^12–16

To our knowledge, current treatment is based on case reports and series. No standard treatment or guidelines are available due to the low incidence.⁴ Observation with serial CT scan may be appropriate for asymptomatic PEHs since spontaneous partial regression had been observed in asymptomatic patients.¹⁷ Tumour resection can be performed if feasible because of the unpredictable nature.^{18 19} Chemotherapy is preferred in disseminated or unresectable cases.²⁰ Radiotherapy had been proven ineffective.²¹ Other options include antiangiogenetic drugs, immunostimulants, lung transplantation, recombinant human endostatin and mammalian target of rapamycin inhibitors.^22–27

In conclusion, we have described a rare case of PEH with a medical history of lung adenocarcinoma who was misdiagnosed as lung metastases. For patients with PEH, the histopathological analysis is necessary. As best as we known, this is the first case who both diagnosed with lung adenocarcinoma and PEH.

We conducted a literature search on PubMed using the MeSH term ‘pulmonary Epithelioid Hemangioendothelioma’ to gather relevant studies published in English within a 20-year timeframe. The obtained information regarding patient characteristics and CT image findings is summarised in table 1.

Table 1.

Literature review of the pulmonary hemangioendothelioma

Author	Age	Gender	Site	Pattern	Size	Attenuation	Calcification	Border
Mukundan et al28	53	Female	Bilateral peripheral	Linear and nodular	–	Partly solid	No	Irregular
Machida et al29	45	Male	Bilateral	Multiple nodules	Up to 1 cm	Solid	No	Well-defined
Kumazawa et al30	15	Female	Bilateral	Multiple nodules	Up to 0.3 cm	Solid	No	Well-defined
Hristova et al31	65	Female	RML Bilateral	One mass Multiple nodules	2.5 cm 0.2–0.4 cm	– Ground-glass	– –	Ill-defined Ill-defined
Jang et al32	33	Male	RUL	One cavitary mass	2 cm	Solid	–	Well-defined
Takahashi et al33	54	Female	Bilateral	Six nodules	–	Partly solid	–	Ill-defined
Theurillat et al34	59	Female	Bilateral Bilateral	Multiple nodules Diffuse ground-glass	– –	– –	– –	– –
Volmar et al35	54	Male	Bilateral peripheral lower	Multiple nodules	–	–	–	–
Rossi et al36	14	Male	Bilateral	Multiple nodules	–	Partly solid	No	Ill-defined
Cronin et al37	35	Female	Bilateral Bilateral	Multiple nodules Diffuse ground-glass	About 0.5 cm –	Solid –	No –	Well-defined –
Fagen et al38	66	Male	RUL	One mass	2×1 cm2	Solid	No	Irregular
Mhoyan et al39	25	Female	Left Bilateral	One mass Multiple nodules	3.5 cm –	– –	– –	– –
Ghekiere et al40	55	Female	Bilateral peripheral	Multiple nodules	–	Ground-glass	No	Ill-defined
Diaz et al41	55	Male	Bilateral	Multiple nodules	–	Solid	Yes	Well-defined
Al-Shraim et al42	51	Male	LLL	One mass	6.2 cm	Solid	No	Irregular
Sakamoto et al7	54	Female	Bilateral	Multiple nodules	–	Partly solid	No	Ill-defined
	18	Female	Bilateral	Multiple nodules	–	Solid	No	Well-defined
Marsh et al43	57	Female	Bilateral	Multiple nodules	–	–	–	–
Aalaei and Jakate44	41	Male	–	Four nodules	0.2–0.3 cm	–	–	–
Amin et al45	70	Female	LUL	One heterogenous mass	5×4.2 cm2	Solid	No	Lobulated
Ergun and Lim46	40	Female	Bilateral	Multiple nodules	–	Solid	No	Spiculated
Chen et al47	78	Female	RUL	One mass	–	Solid	No	Well-defined
Celikel et al48	48	Male	Bilateral	Multiple nodules	0.5–0.9 cm	Solid	No	Well-defined
Anagnostou et al49	36	Female	Bilateral	Multiple nodules	Up to 1 cm	Solid	No	Ill-defined
Scattenberg et al50	25	Male	RLL LLL	One mass One mass	3 cm 0.8 cm	Solid Solid	No No	Lobulated Smooth
Scattenberg et al5	44	Female	Bilateral	Multiple nodules	–	Solid	No	Well-defined
	68	Male	Bilateral	Multiple nodules	–	–	–	–
	30	Female	RUL, RML, LLL	Five nodules	–	–	–	–
Bahrami et al51	37	Male	LUL	One mass	4 cm	Solid	No	Well-defined
Lee et al52	31	Female	RUL RML, RLL	One mass Multiple nodules	1.5 cm –	Solid –	No –	Smooth –
Saleiro et al53	39	Female	Bilateral	Linear and nodular	Up to 1 cm	Partly solid	No	Ill-defined
Watanabe et al54	60	Male	Bilateral	Multiple nodules	Up to 2.5 cm	Solid	Yes	Lobulated
Belmont et al55	41	Male	Bilateral	Multiple nodules	–	Partly solid	Yes	Ill-defined
Radzikowska et al56	62	Female	Bilateral	Multiple nodules	Up to 1 cm	Solid	Yes	Well-defined
Ouadnouni et al57	45	Male	Right	Three masses	–	Solid	Yes	Well-defined
Shang and Wang58	40	Female	LLL	One mass	2 cm	Partly solid	No	Ill-defined
Ye et al59	56	Female	Bilateral	Multiple nodules	–	Partly solid	No	Ill-defined
Chen et al60	19	Female	Right	Multiple nodules	1–2.5 cm	Partly solid	No	Spiculated
Madhusudhan et al61	11	Male	RML	Two masses	–	Solid	Yes	Irregular
Reich et al62	15	Female	Bilateral	Multiple nodules	–	Partly solid	–	–
Darbari et al63	33	Female	LLL	One heterogeneous mass	6×6 cm2	Solid	No	Well-defined
Kawachi et al64	62	Female	RLL	One mass	3 cm	Solid	No	Well-defined
Tochigi et al65	50	Female	RUL RUL	One mass Multiple nodules	2 cm 0.3–0.5 cm	Solid –	– –	– –
Baba et al18	51	Female	Bilateral	Multiple nodules	Up to 1 cm	Solid	No	Smooth
Ryu et al66	41	Male	RLL RLL	One mass Multiple nodules	4×3 cm2 –	– –	– –	Ill-defined –
Raphael et al67	53	Female	Bilateral	Multiple nodules	–	Partly solid	No	Well-defined
Mizuno et al68	30	Female	Bilateral	Multiple nodules	Up to 1 cm	Solid	No	Well-defined
	67	Female	Bilateral	Multiple nodules	Up to 1 cm	–	–	–
Haruki et al69	28	Female	Bilateral	Multiple nodules	Up to 1 cm	Solid	No	Well-defined
Jinghong and Lirong70	42	Female	RML Bilateral	One mass Multiple nodules	6 cm Up to 1 cm	Solid Solid	No Yes	Well-defined Well-defined
Cazzuffi et al71	67	Male	Bilateral	Multiple nodules	0.3–3 cm	Solid	No	Spiculated
Mizota et al72	59	Female	RUL	One mass	2.5×3.5 cm2	Partly solid	No	Ill-defined
Dahabreh et al73	12	Female	Bilateral	Multiple nodules	–	–	Yes	Ill-defined
Mehta et al74	65	Male	Bilateral	Multiple nodules	Up to 2 cm	–	–	Irregular
Wu et al75	58	Female	Right	One heterogenous mass	–	Solid	No	Well-defined
Sangro et al76	22	Male	Bilateral	Multiple nodules	–	Partly solid	No	Ill-defined
Ye et al20	40	Male	Bilateral	Multiple nodules	–	Partly solid	No	Ill-defined
	54	Female	Bilateral upper	Multiple nodules	–	–	–	–
	44	Female	Bilateral	Multiple nodules	Up to 1.5 cm	–	–	–
Palfoldi et al14	49	Female	RUL Bilateral	One mass Multiple nodules	3.6 cm 0.5–1 cm	Solid –	– –	Ill-defined Well-defined
Yu et al77	39	Female	Left	One mass	–	Solid	Yes	Ill-defined
Liu et al9	54	Female	Bilateral	Multiple nodules	Up to 1.5 cm	Solid	Yes	Irregular
	63	Female	bilateral	Multiple nodules	Up to 5.2 cm	Solid	Yes	Irregular
	57	Female	Bilateral	Multiple nodules	Up to 3 cm	Solid	Yes	Irregular
	55	Female	Bilateral	Multiple nodules	Up to 1.9 cm	Solid	Yes	Irregular
	35	Female	Bilateral	Multiple nodules	Up to 3.5 cm	Partly solid	No	Irregular
	54	Male	Bilateral	Multiple nodules	Up to 1.1 cm	Solid	No	Irregular
Shao and Zhang15	54	Male	Bilateral	Multiple nodules	0.5–1 cm	–	–	–
	30	Female	Bilateral	Multiple nodules	1.5–3 cm	Solid	No	Well-defined
Yi et al78	38	Female	Bilateral	Multiple nodules	0.1–2.5 cm	Solid	No	Well-defined
Nizami et al79	13	Female	Bilateral	Multiple nodules	–	Partly solid	No	Ill-defined
Eguchi and Sawafuji19	54	Female	Bilateral	Multiple nodules	Up to 1 cm	Partly solid	No	Well-defined
Geramizadeh et al80	60	Female	LLL	Multiple nodules	–	Solid	No	Well-defined
Mucientes et al81	19	Male	Bilateral	Multiple nodules	–	Partly solid	No	Ill-defined
Tan et al82	58	Female	Bilateral	Multiple nodules	Over 0.5 cm	Solid	No	Irregular
Ramchandar Wojtczak83	14	Male	Bilateral	Multiple nodules	2–3 cm	Ground-glass	No	Irregular
Semenisty et al22	62	Female	Bilateral	Multiple nodules	Up to 0.6 cm	–	–	–
Kim et al84	50	Male	Bilateral	Multiple nodules	–	Solid	No	Well-defined
Lee et al85	61	Female	Bilateral	Multiple nodules	Up to 1.4 cm	Solid	Yes	Lobulated
Haro et al86	42	Female	Bilateral	Multiple nodules	–	Solid	No	Well-defined
Sayah et al87	20	Female	Bilateral lung base	Multiple nodules	About 0.8 cm	–	–	–
Kundu et al88	16	Female	RUL RML	One mass One mass	– –	Partly solid Solid	No Yes	Ill-defined Ill-defined
Bally et al23	38	Female	Bilateral	Multiple nodules	–	Solid	No	Well-defined
Tsuchiya et al89	24	Female	Bilateral	Multiple nodules	–	Partly solid	No	Ill-defined
Soo et al90	59	Male	RUL	One heterogenous mass	–	–	–	–
	67	Male	RUL	One mass	–	Solid	No	Spiculated
Ro et al91	76	Male	RLL	One mass	0.9 cm	Solid	No	Lobulated
Calabrese et al92	20	Female	Bilateral	Multiple nodules	Up to 1 cm	Solid	No	Well-defined
Adamane et al93	20	Male	Right	Multiple nodules	–	–	–	–
Lochowski et al94	62	Male	RUL	One mass	–	Solid	No	Halo
Mao et al16	43	Male	Bilateral	Multiple nodules	–	Solid	No	Well-defined
Zheng et al24	44	Male	RML	Multiple nodules	Up to 5 cm	–	–	–
Mesquita et al95	35	Male	Bilateral	Multiple nodules	Up to 1 cm	Solid	No	Well-defined
	67	Female	LLL Bilateral	One mass Multiple nodules	– –	Solid Solid	No No	Irregular Well-defined
Sasaki et al96	69	Male	Bilateral	Multiple nodules	0.2–1 cm	Solid	No	Well-defined
Zhou et al97	60	Male	Bilateral	Multiple nodules	0.1–2 cm	Partly solid	No	Halo
Lytle et al98	46	Female	RUL RML Diffuse reticulonodular	One mass One mass –	2.4×2.2 cm2 – –	Solid – –	Yes – –	Irregular Well-defined –
Xiong et al99	54	Female	Bilateral	Multiple nodules	–	Ground-glass	No	Smooth
Aung et al6	58	Female	Bilateral LLL	Multiple nodules One mass	– 0.8 cm	Ground-glass Solid	No No	Ill-defined Well-defined
Zhang et al100	64	Female	Bilateral	Multiple nodules	Up to 1.3 cm	Solid	No	Well-defined
Moale et al101	48	Female	Bilateral RLL	Multiple nodules One mass	– –	– Solid	Yes No	– Ill-defined
Thevenot et al102	35	Female	Bilateral	Multiple nodules	–	Solid	Yes	Well-defined
Abramian et al103	49	Male	RLL	One mass	3.9×4.4×3.5 cm3	Solid	No	Irregular
Oda et al104	63	Female	RUL RLL	One mass Two masses	4 cm –	Solid Solid	No No	Ill-defined Spiculated
Kimura et al105	83	Female	Bilateral	Multiple nodules	–	–	–	–
Ido et al106	38	Female	Bilateral	Multiple nodules	Up to 0.7 cm	Partly solid	No	Ill-defined
Kolokotronis et al107	37	Female	Bilateral	Multiple nodules	–	Solid	Yes	Well-defined
Somers et al108	32	Female	Bilateral	Multiple nodules	–	Solid	No	Well-defined
Chang et al (current)	50 s	Female	Bilateral	Multiple nodules	Up to 1.1 cm	Solid	No	Well-defined

Patient’s perspective.

I first found multiple nodules in bilateral lungs. That was a massive shock because I’m going to die within a couple of months, especially I had a past history of lung adenocarcinoma. Thanks god. After the multidisciplinary meeting, the thoracic surgeon, the chest physician, and the radiologist recommended me to have the wedge resection for the histopathological diagnosis. And no further chemotherapy is given.

Learning points.

• Pulmonary epithelioid hemangioendothelioma is a rare neoplasm of vascular origin with low to intermediate malignant potential.

• Typical radiologic finding on CT is multiple small nodules in bilateral lungs, which mimicks lung metastases.

• This histopathological diagnosis is essential in patients with suspicious lung metastases, especially in the atypical presentation, in order to achieve safe and accurate patient care.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s)