Background: Primary pulmonary angiosarcoma is extremely rare and the prognosis is very poor. We report a combination therapy of pneumonectomy and intrapleural hypotonic hyperthermic chemotherapy (IPHHC). Case report: A 48-year-old male with exertional dyspnea was found to have a left massive pleural effusion. Bronchoscopic examination displayed endobronchial stenosis of the left lower bronchus B8,9,10 and diagnosed with pulmonary angiosarcoma. Chest computed-tomographic scanning revealed a 5-cm mass in the left inferior lobe, which invaded the left upperbronchus. Intrapleural dissemination and malignant pleural effusion were also suspected (cT3N1M1a, c-stage IV). As a palliative initial therapy, we performed a pneumonectomy. On the 7th postoperative day, under general anesthesia, we performed video-assisted IPHHC (43°C, 60 min, 200 mg/m2 of CDDP). After the IPHHC, there was no major adverse event (more than Grade 3) during the postoperative course. Histological examination of the resected specimen revealed a highly-cellular growth of atypical spindle cells with a storiform pattern. By immunohistochemical testing, the tumor cells stained positive for markers including CD31 and the factor VIII related antigen, and the diagnosis of pulmonary angiosarcoma was made. No adjuvant chemoradiotherapy was given, and the postoperative clinical course was uneventful. Although there had been a recurrence in the chest wall, the patient eventually died twenty-one months later. Conclusion: As a new therapeutic option, we performed IPHHC after the pneumonectomy for an advanced pulmonary angiosarcoma with malignant pleural effusion. Although the patient had a recurrence in the chest wall, he had a reasonable postoperative outcome, that is, he returned to a work, retained a good quality of life and had a longer survival in spite of the poor prognosis of the pulmonary angiosarcoma.
Primary pulmonary angiosarcoma is extremely rare and the prognosis is very poor. It can arise in any part of the body, such as the skin, heart, liver and breast [
As a traditional therapeutic option for patients with malignant pleuritis, we developed intrapleural hyperthermic perfusion with chemotherapy (IPHC) using hyperthermic perfusion [
The new IPHHC therapy had not been performed for lung cancer and malignant pleural mesothelioma by our department. For the first trial, we performed the new IPHHC treatment and we reported the results and the postoperative good outcome of the preserved quality of life and that a longer survival had been obtained.
In June 2010, a 48-year-old male with exertional dyspnea was admitted to a hospital and a left massive pleural effusion was indicated on X-ray film (
He was admitted to our hospital to receive a detailed examination and appropriate treatment. The results of the peripheral blood cells counts and biochemistry examinations were within normal limits. Tumor markers, in- cluding the carcinoembryonicantigen, cytokeratin 19 fragment and pro-gastrin-releasing peptide, were also within normal limits. Chest computed-tomographic scanning displayed a 5-cm mass in the left inferior lobe (
sion, consisted of athelectasis and lymph nodal metastasis (N1+) (
As a palliative therapy, surgical resection with pneumonectomy for the primary pulmonary angiosarcoma and intrapleural hypotonic hyperthermic chemotherapy (IPHHC) were scheduled. The patient signed an informed consent. In November 2010, under general anesthesia, one-lung ventilation, after the left open thoracotomy at the 5th intercostal space, the intraoperative cytology of pleural effusion resulted in a negative malignancy findings. Prompt intraoperative pathological examination showed a positive malignancy at the edge of the bronchial stump and disclosed tumor-cell-invasions of the pericardial fat tissue and pleura. The picking-up of mediastinal lymph nodes (station #8) showed a positive metastasis (N2+, pT3N2M1a, p-stage IV). Although the patient had suffered small daily discontinuous hemoptysis, we performed a left pneumonectomy to remove the pulmonary tumorous bleeding origin. We performed a blood transfusion of red cell concentrates of mannitol adenine phosphate (4 units) and fresh-frozen plasma (2 units). The specimen showed a pleural dissemination of the surface of the resected lung (
On the 7th postoperative day after the initial pneumonectomy operation, we performed IPHHC (43˚C, 60 min, 200 mg/m2 of CDDP), the therapy of which was based on the modified methods from the previous reports of Matzuzaki et al. [
Histological examination of the resected specimen revealed a highly-cellular growth of atypical spindle cells with a storiform pattern (
No adjuvant chemoradiation therapy was given and he returned to work as a self-employed person. The pa- tient had a good, preserved quality of life and longer postoperative lifetime, however, there had been a recur- rence in the chest wall. He eventually died twenty-one months later.
Primary pulmonary angiosarcoma is extremely rare. Angiosarcoma is a type of malignant vascular tumor characterized by the proliferation of neoplastic cells with vascular endothelial features, accounting for only 1% - 2% of all soft tissue sarcomas [
A definitive diagnosis of the pulmonary angiosarcoma was made on the basis of our histopathological and immunohistochemical findings [
For the treatment and prognosis, there have been few reports of an effective treatment for this pulmonary angiosarcoma. Surgical resection, radiation, chemotherapy and immunotherapy have all been attempted (
Case No. | Author (yr) | Gender | Age (yr) | Symptoms (time) | Therapy | Survival (months) | Reference |
---|---|---|---|---|---|---|---|
1 | Castleman, B., et al., 1954 | M | 48 | Hemoptysis | - | 1 | [ |
2 | Tralka, G.A., et al., 1963 | M | 64 | Chest pain, shortness of breath, malaise | Supportive care | 1 | [ |
3 | Spragg, R.G., et al., 1983 | M | 75 | Dyspnea, malaise | Steroid | <1 | [ |
4 | Ott, R.A., et al., 1987 | M | 60 | Shortness of breath (3 months) | Rt. pneumonectomy | 2 | [ |
5 | Palvio, D.H., et al., 1987 | M | 59 | Hemoptysis, chest pain | Surgery | <1 | [ |
6 | Segal, et al., 1988 | F | 72 | Malaise, dyspnea | Steroid | <1 | [ |
7 | Sheppard, M.N., et al., 1997 | M | 65 | Hemoptysis (3 months) | Steroid | <1 | [ |
8 | Junge, K., et al., 2001 | M | 41 | Shortness of breath (6 months) | Neoadjuvant CT*/RT** + Lt. lower lobectomy + Adjuvant CT*/RT** | Alive | [ |
9 | Atasoy, C., et al., 2001 | M | 50 | Chest pain, malaise, and hoarseness (2 months) | CT* | 9 | [ |
10 | Kojima, K., et al., 2003 | M | 25 | Chest pain, cough, shortness of breath, weight loss (1 month) | RT** + Interleukin-2 | Alive (1-year follow-up) | [ |
11 | Maglaras, G.C., et al., 2004 | M | 46 | Hemoptysis | CT* | 1 | [ |
12 | Pandit, S.A., et al., 2005 | F | 79 | Chest pain, shortness of breath | Supportive care | 18 | [ |
13 | Corpa-Rodriguez, et al., 2005 | M | 42 | Chest pain, cough | Rt. upper lobectomy with chest wall resection + Adjuvant CT*/RT** | 2 | [ |
14 | Bouhaouala, M.H., et al., 2005 | M | 46 | Hemoptysis (6 months) | Rt. lower lobectomy | 11 | [ |
15 | Ozcelik, C., et al., 2006 | M | 62 | Hemoptysis, chest pain, cough, shortness of breath, weight loss (5 months) | Rt. upper lobectomy + Adjuvant CT*/RT** | 5 | [ |
16 | Herrak, L., et al., 2007 | M | 48 | Chest pain, cough (3 months) | Refused treatment | - | [ |
17 | Wilson, R., et al., 2008 | M | 56 | Hemoptysis, chest pain, cough, shortness of breath, weight loss | Lt. upper lobectomy + Adjuvant CT*/RT** | 39 | [ |
18 | Kuroda, N., et al., 2009 | M | 43 | Cough | Lt. lower lobectomy | Alive (15-month follow-up) | [ |
19 | Chen, Y.B., et al., 2010 | M | 50 | Hemoptysis (2 months) | CT* | Alive | [ |
20 | Wan Musa, W.R., et al., 2010 | M | 23 | Shoulder pain, chest pain, shortness of breath, weight loss (6 months) | CT* | 4 | [ |
21 | Kakegawa, S., et al., 2011 | M | 45 | Hemoptysis | Lt. pneumonectomy | Alive (1-year follow-up) | [ |
22 | Ayabe, T., et al., 2015 | M | 48 | Shortness of breath, pleural effusion | Lt. pneumonectomy + Intrathoracic hypotonic hyperthermic chemotherapyy | 21 | Our case |
*Computed tomography; **Radiation therapy.
vious studies have demonstrated that angiosarcoma is radiosensitive [
The systemic administration of high doses of recombinant interleukin 2 (rIL-2) seems to have been effective [
Unfortunately, the prognosis of pulmonary angiosarcoma is very poor and the mortality is very high. After the diagnosis of the angiosarcoma, and any treatment, almost all patients are dead within one year [
As a palliative therapy, we performed IPHHC after a pneumonoectomy for the advanced pulmonary angiosarcoma with malignant effusion. In cases of advanced lung cancer with malignant effusion, to control the pleural effusion and to preserve the patient’s better quality of life, we sometimes performed a traditional intrapleural hyperthermic chemotherapy (IPHC) as a palliative therapy [
Generally, the aim of the traditional IPHC is the synergistic effectiveness of both the anti-tumor effect of cis- platin and hyperthermic damage to malignant tumor cells. On the other hand, the aim of the new IPHHC is the synergistic effectiveness of the triple concept of hypotonic, hyperthermic, and anti-tumor effects for malignant tumor cells. Based on this concept, a clinical trial of IPHC and/or IPHHC treatments should be considered in the future. However, clinically, in practice, the IPHC therapy has been performed for unresectable tumors with ma- lignant pleural effusion, even though which therapy should become one of the expected therapies for sarcoma- patients with no effective therapy has not been determined. There are no reports of IPHHC for pulmonary an- giosarcoma, however, this treatment strategy might be applicable for other forms of cancer except for lung cancer.
For the anti-cancer effectiveness of hyperthermia, generally, 1) tumor cells have a high hyperthermic sensitivity compared to those of normal cells, 2) tumor tissues have a high hyperthermic sensitivity selectively dependent on the specificity of the surrounding tissue-environment (low pH, hypoxic, fragility of tumor angiogenesis), 3) high hyperthermic sensitivity in the latter phase of synthesis in the cell cycle, and 4) enhancement of the sensitivity of anti-cancer drugs for cancer cells have been performed as a combination therapy with radiation and chemotherapy.
On the other hand, for the anti-cancer effectiveness of the hypotonic solution perfusion with cisplatin, the hypotonic cisplatin solution demonstrated a significantly greater anti-tumor activity than isotonic cisplatin [
The mechanism by which the hypotonic cisplatin treatment shows an anti-tumor effect is considered as follows: 1) distilled water itself has a direct cytotoxicity; 2) tumor cells exposed to the hypotonic cisplatin increase their cellular cisplatin level since the cells become swollen by the hypotonic solution; and 3) species such as chloro-aqua and diaqua, which are formed by the hydrolysis of cisplatin in the distilled water, are also believed to be active anti-tumor agents. Thus, the intrapleural hypotonic cisplatin treatment using cisplatin and distilled water is thought to have a synergistic anti-tumor effect which might result in a high local control rate and the dis- appearance of cancer cells in the drainage fluid after the operation in patients with carcinomatous pleuritis found during a thoracotomy.
We performed a palliative pneumonectomy of unresectable pulmonary angiosarcoma. The reason was to reduce the angiosarcoma volume and to prevent lethal pulmonary bleeding from the tumor. Because there were few effective therapies for pulmonary angiosarcoma, we selected a combination therapy of palliative surgical resection and IPHHC. For the residual disseminated intrathoracic sarcoma cells, as a local intrathoracic therapy, in addition to the effect of hyperthermic damage and sarcoma-cell cell injury, we used the perfusion solution of distilled water. During the postoperative hospitalization, there was no significant adverse event more than Grade 3. The patient’s survival after the treatment was 21 months, as a palliative and intrapleural local therapy for thoracic malignancies with pleural effusion, the IPHHC therapy should be one of the considered therapies.
For the treatment of primary pulmonary angiosarcoma, there are few therapies except for surgery, as there has been reported to be almost no effectiveness of chemotherapy and irradiation therapy. However, we performed a palliative pneumonectomy of advanced pulmonary angiosarcoma with malignant pleural effusion and IPHHC treatment. Although the patient had a postoperative recurrence in the chest wall, he had a reasonable postopera- tive outcome such as temporary preservation of his quality of life and a longer survival of 21 months in spite of the poor prognosis.
IPHC: Intrapleural Hyperthermic Chemotherapy
IPHHC: Intrapleural Hypotonic Hyperthermic Chemotherapy