Advanced intravascular bronchioloalveolar tumour and review of reports in Japan

Respiratory Medicine (1989) 85, 127-132

Advanced intravascular bronchioloalveolar tumour and review of reports in Japan T. SHIRAKUSA*, M. YOSHIDAt, M. TSUTSUI*, A. IKEDA~, T. HAYASHI~, T. EIMOTO~, T, KUSANO~ AND H. IWASAKI~ *The Division of Thoracic Surgery, tDepartment of lnternal Medicine, ~Department of Pathology, School of Medicine, Fukuoka University, Fukuoka, Japan

Intravascular bronchioloalveolar tumour (IVBAT) is a rare pulmonary neoplasm. We report the clinical and pathologic findings of two patients who demonstrated unusual clinical features. Both of them were young males who showed a large mass or consolidated shadow and small nodules with pleurisy on chest X-rays due to the invasive growth of tumours. In the first case the presumptive diagnosis of lung carcinoma was made from the discovery of atypical cells in pleural fluid. In the second case pleural mesothelioma was suspected. However, the histological diagnoses of these cases, including the immuno-histological and ultrastructural data, were reported and clinical features of IVBAT described previously in Japan were summarized.

demonstrated an ill-defined mass in the left lower lung field and moderate pleurai effusion (Plate I). RadioloIn 1973, Farinacci et al. (1) reported a rare lung gically, the fight lung field appeared almost normal. tumour that they called pulmonary deciduosis. Two Cytology from the pleural fluid showed some atypical years later~ Dail and Liebow (2) described 20 histologicells suggestive of malignancy. A smear stained with cally similar cases and they termed this unusual Papanicolaou and Write-Giemsa showed scattered neoplasm intravascular bronchioloalveolar tumour clusters of atypical cells. These cells had a high N/C (IVBAT). Until the present, over 40 cases of IVBAT ratio, hyperchromatic nuclei and prominent nucleoli have been described in the world (I-21 ). Nine of these, (Plate 2), which was particularly evident against a including our two, occurred in Japan (3-8). Recently, background of many lymphoid cells and erythrocytes. we treated two patients with advanced IVBAT. This Lung carcinoma with pleuritis was suspected. There report presents ultrastructural and immunohistologiwere no abnormal findings suggestive of any maligcal findings and summarizes the clinico-pathological nant lesion in other organs. We planned left pleurofeatures of cases reported in Japan. pneumonectomy. A thoracotomy was performed, and about 500 ml ofplural fluid was removed. A hard mass with a size of 2.0 x 1-5 x 1-0 cm was preserit in the Case Reports lower lobe and multiple miliary nodules were found toCASE 1 be disseminated on the surface of the whole lung. The A 32-year-old man was admitted to our hospital lower lobe adhered partly to the chest wall and with complaints of severe chest pain and mild clyspnea. pericardium. A left pneumoneetomy with!ymph node Physical examination revealed a healthy man with dissection, and partial resection of the 9arietal pleura good nutrition. On auscultation, respiratory sounds of and pericardium were performed. 'Postoperative the left lower chest were diminished. The chest X-ray course was uneventful, however, after nine months of ordinary life, he abruptly complained of abdominal discomfort. He was admitted to a different hospital Received 8 April and in revisedform 2 August 1988 Correspondence to: T. Shirakusa, The Second Dept of Surgery, and died of intra-abdominal dissemination of neoplasm. Schoolof Medicine, Fukuoka Univ., 814-01,Fukuoka, Japan

Introduction

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Shirakusa et al.

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Plate 2 Atypical cells from the pleural fluid of Case 1. Papanicoloau stain ( x 400).

Plate 1 The chest lateral tomogram of Case 1, showing a

mass (thin arrow) and surrounding consolidated lesion (thick arrow).

CASE 2 A 31-year-old man had a cough and sputum in about January, 1987. His chest X-ray demonstrated left pleurisy, so he underwent pleurocentesis, however, no suggestive data were gained. Beginning in late February of the same year he complained of severe left chest pain located at the anterior chest wall. On May 23, he was admitted to our hospital for diagnosis and treatment. On auscultation, respiratory sounds were diminished in the left side. Routine laboratory data

Plate 3

were within normal limits. All of the tumour markers in peripheral blood were also normal. The chest X-ray taken at the time of admission, revealed a moderate retention of fluid i n the left pleural space. The computed tomogram showed a consolidated lesion in the lower lung field with pleural fluid (Plate 3). Although the cytology of the pleural fluid was normal, the hialuronic acid in the fluid was positive. We suspected diffuse pleural meosthelioma and performed left thoracotomy. During the thoracotomy thickening of the whole visceral pleura was prominent and a small mass with multiple nodules was found disseminated on the surface of the left lower lobe. The histology of a frozen section of the lesion showed that it was most likely pleural mesothelioma. Left pleuropneumonectomy was performed. After an eventful

The computed tomogram of Case 2, showing a consolidated lesion with pleural fluid.

A d v a n c e d intravascular b r o n c h i o l o a l v e o l a r t u m o u r

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Plate 4 Case I. Section showing the accumulated tumour cells occluding a blood vessel and surrounding marked hyalinization. (H & E x 200).

postoperative course he was discharged and is leading a normal life. HISTOLOGICAL FINDINGS

In Case 1, sections of the lung nodules showed sparse cellular sclerosing tumour with marked central hyalinization and accumulation of tumour cells in the peripheral area. The center of a large nodule from the lower lobe also exhibited massive hyalinization. Tumour cells in the lesion were very sparse. Some blood vessels were occluded by polypoid tumour protrusions (Plate 4). Tumour cells were positive for vimentin and factor VIII-related antigen. The large nodule in the lower lobe extended into the pleura and further to the pericardium. The perinodal soft tissues of the para-aortic and peribronchial nodes were infiltrated by a tumour. Immuno-histoiogical staining was used for the detection of a factor VIII-related antigen on atypical cells in the smear o f pleural fluid, and positive findings were observed. Using electron microscopy tumour cells were observed to be cubic or polygonal with an irregulary shaped cytoplasm. These cells attached to each other with normal intorcellular junctions. Occasionally, the nuclei were deeply indented and often contained prominent nucleoli. The distribution of chromatin was varied. There were many microfilaments in the cytoplasm and abundant rough endoplasmic reticulum. Tumour cells had many pinocytic vesicles near the cell membrane. A few vacuoles were present in some tumour cells. Elongated electron-dense 'rod-shaped tubular' bodies described

by Weibel and Palade were not seen in observed tumour cells. In Case 2, the lesions were nodular and diffuse in the periphery o f the lower lung field. They showed marked invasion into the visceral pleura. Using light microscopy, the nodules were observed to be composed of two elements; central hyalinization, and tumour cells in the margin which were oval or polygonal. The factor VIII-related antigen with PAP staining was positive. lntracytoplasmic vacuoles of tumor cells and pinocytic vesicles near the cell membrane were also characteristic. Epithelial membrane antigens in both of tumour were negative. CLINICAL FINDINGS OF REPORTED CASES IN JAPAN

Tables I and 2 summarize the clinical features of the nine IVBAT tumours reported in Japan, including the presented cases. Five of the nine were female. Three patients were 40-years-old (average; 43-year-old). Six were non-smokers. PPD reaction was examined in five, and three showed negative reactions. Cases 1, 8 and 9, as shown in the Table 1, had respiratory symptoms because of advanced disease. In every case, the chest X-ray film showed multiple nodular lesions in the peripheral zone of the bilateral lungs, however, this was accompanied by Neuritis in Cases 8 and 9. The most frequent clinical diagnosis was metastatic lung carcinoma. Two patients (Cases 1 and 3 in the tables), died ofcoronary insufficiency. The existence of IVBAT in the lung was confirmed at autopsy. Five of nine were diagnosed by open-lung biopsy• Factor

S h i r a k u s a et al.

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Table 1

Clinical features of Japanese cases with IVBAT

Case

Author (year reported)

1

Taguchi et al. (1980) Chihara et al. (1982) Nakaya et al. (1982) Genga et al. (1983) Miyake et al. (1986) Sugiyama et al. (1986) Watanabe et aL (1987) Presented Case 1 (1987) Presented Case 2 (1987)

2 3 4 5 6 7 8 9

Table 2

Age

Sex

Symptoms

Radiologieal findings

Original diagnosis

51

Female Female

68

Male

None

48

Female

None

18

Male

None

40

Female

None

53

Female

None

32

Male

31

Male

Chest pain, dyspnea Chest pain

Multiple nodules and infiltration (bilateral lung) Multiple small nodules (bilateral lung) Multiple small nodules (bilateral lung) Multiple small nodules (bilateral lung) Multiple small nodules (bilateral lung) Multiple small nodules (bilateral lung) Multiple small nodules (bilateral lung) Multiple nodules and pleurisy (unilateral lung) Multiple nodules and pleurisy (unilateral lung)

Metastatic lung carcinoma

48

Hemoptysis, chest pain None

Sarcoidosis Heart failure Metastatic lung carcinoma Metastatic lung carcinoma Not described Lung tuberculosis Lung carcinoma Diffusemesothelioma

Clinical features of Japanese cases with IVBAT Histologic findings

Case

Diagnostic method

Factor V-Ill related antigen

Weibel-Palade Liver bodies involvement

Therapy

I

Autopsy

Negative

Positive

N.D.

Chemotherapy

2 3

Open lung biopsy Autopsy

N.D. Positive

N.D. Positive

(-) (+)

N.D. None

4

Open lung biopsy

N.D.

N.D.

N.D.

None

5 6 7

Open lung biopsy Open lung biopsy Open lung biopsy

N.D. Positive Positive

N.D. Positive Negative

(-) (-) (-)

N.D. N.D. Chemotherapy

8

Left pneumonectomy Positive

Negative

(-)

None

9

Left pneumonectomy Positive

Obscure

(-)

Adjuvant chemotherapy

N.D., no data.

Outcome (period from discovery to report) Death due to respiratory insufficiency(2 yr) Alive (3 yr) Death due to coronary insufficiency(N.D.) Alive (5 yr) Alive (1 yr 3 m) Alive (2 yr) Death due to respiratory insufficiency(5 yr 3 m) Death due to neoplasm (I yr) Alive

A d v a n c e d intravascular bronchioloalveolar tumour

VIII-related antigen determined by immune-staining was positive in five of the nine cases and Weibel-Palade bodies were found, by electron microscopy, in three, though in some cases the results were not described. Immuno-ehemotherapy with antigens against the tumour was performed in 2 cases, however, no clear benefit was demonstrated. Cases 1, 7 and those presented were considered to have advanced IVBAT; the outcome in three of these cases was death due to respiratory insufficiency and abdominal involvement of neoplasm. Discussion

Almost all patients with IVBAT are asymptomatic and lung lesions are frequently discovered by chance. Usually the chest X-ray shows multiple small nodules in the peripheral zone of both lungs. In almost all cases, the diameter of the nodules is 2 cm or less. As for the histogenesis of IVBAT, Dail et al. (2) initially suggested an alveolar cell origin. However, on the basis of ultrastructural observations, Corrin et al. (1 O) considered that an angioblastic stem cell, such as the vasoformative reserve cell, is the most likely origin of this tumour. Moreover, this hypothesis was supported by the evidence of positive staining for factor VIIIrelated antigen, which is thought to be a marker for vascular endothelial cells (11-14). Corrin et al. (10) felt that the ultrastructural findings of IVBAT suggest an endothelial-differentiation in this tumour. They described the characteristic features, b-y electron microscopy, as abundant microfilaments, moderate amounts of rough endoplasmic reticulum and varying numbers of WeibeI-Palade bodies (15). In our cases, positive staining for factor VIII-related antigen was demonstrated in these tumour cells while alveolar pneumocytes showed no staining. Although Weibel-Palade bodies were obscure in the sections available from the tumour as in the case of Dail et al. (12), the other electron microscopic findings were otherwise in accord with those of Corrin et al. (10). The pathological features of IVBAT have been investigated world-wide. Grendhill et al. (11) reported a case of IVBAT with hepatic metastasis in 1984. In that case they stated that they could not rtlle out a multicentric origin. Only one of the 20 cases Dail et al. (12) had a liver lesion. They suggested that the unusual, slow growing, larger and calcified liver tumour is indistinguishable histologically from those of an IVBAT tumour throughout the lung fields. In 1982, Weiss et al. (17) reported specifi~ tumours which frequently originated in vessels and commonly involved the extremities. Although they termed these

131

tumours 'epithelioid hemangioendotbelioma', the clinical and histological features were extremely similar to those of IVBAT. In Japanese patients (3-8), the age tended to be older than that of patients in the USA and Europe. Almost all patients were non-smokers. Only one case, reported by Nakaya et aL (8), showed multiple nodules in both the lungs and liver. Our cases had unusual clinical features, namely unilateral lung lesions including a large mass, multiple small nodules, associated pleuritis and extra-pulmonary invasion by a tumour. In Case 1, the pericardium, chest wall, and perinodal soft tissues around hilar and mediastinal lymph nodes were also involved. We performed extended resections in both cases and they proved to be rare IVBAT cases as confirmed by our resections of the lung. In Case 1, it was considered that tumour cells might appear in the pleural fluid due to the invasive growth of IVBAT into the pericardium and parietal pleura. Case 2 also showed the involvement of visceral pleura. Corrin et al. (20) reported an additional case of IVBAT which showed the involvement of the parietal pleura as well as the lungs. Our Case 1 had massive pleural effusion and we could demonstrate the factor VIII-related antigen in the smear from the pleural fluid. In the literature there have not been any other reports on the immunocytological staining of pleural fluid caused by IVBAT. The prognosis of IVBAT is various (3-5). This disease usually progresses slowly at the onset and patients tend to live more than 5 or 10 years (5,12). Later, deterioration may be rapid and lead to respiratory insufficiency (9). Of the 20 patients, reported by Dail and Liebow (12), ten died. The Japanese cases (38), a case reported by Taguchi et al. (3) and presented Case I showed rapid progression of the disease in spite of the administration of anticancerous agents. At this time, we have no effective therapeutic regimens for IVBAT. However, if the patient meets the following conditions, the resection of the unilateral lung should be considered to protect against the advance of the disease--(1) the lesion is diffuse and unilateral; (2) there is no associated lesion in the liver; (3) symptomatically the patient's complaints are severe; and (4) the patient can tolerate pneumonectomy. In asymptomatic patients, no therapy can be recommended. References I. Fafinac~i CJ, Blauw AS, Jennings EM. Multifocal

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