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Lymphology 49 (2016) 210-217

CHYLOTHORAX AS RARE MANIFESTATION OF PLEURAL INVOLVEMENT IN WALDENSTRÖM : MECHANISMS AND MANAGEMENT

G. Leoncini, C.C. Campisi, G. Fraternali Orcioni, F. Patrone, F. Ferrando, C. Campisi

Unit of Thoracic Surgery (GL), Unit of General & Lymphatic Surgery - Microsurgery and Department of Surgical Sciences and Integrated Diagnostics (DISC) (CCC,CC), Unit of Pathology (GFO), Unit of Internal Medicine and Medical Oncology and Department of Internal Medicine (DIMI) (FP,FF), IRCCS San Martino University Hospital - National Institute for Research, and University School of Medicine and Pharmaceutics, Genoa, Italy

ABSTRACT increase of IgM level. Pleuropulmonary involvement is reported to be rare (from 0 Here we report the clinical, pathological, to 5% of cases), and it usually occurs during and immunological features of a rare case of the late phase of the disease (3,4). In such a Waldenström macroglobulinemia (WM) with scenario, chylothorax is rarely observed in pleural infiltrations. An atypical chylothorax, WM patients; indeed only seven cases have successfully treated by videothoracoscopy, been reported in the literature (5-11). We represented the main clinical feature of this report the case of a 66-year old man with the case of low-grade lymphoplasmacytic main clinical presentation of pleural . Pleuropulmonary manifestations infiltrations with right chylothorax following are rare (from 0 to 5% of cases) in WM, with immunochemotherapy. An extra-bone chylothorax observed in just seven patients marrow involvement was suggested by both worldwide. In addition to describing this pleural fluid examination and multiple uncommon clinical presentation, we investi- pleural biopsies in parallel with a marked gate hypothetical pathogenetic mechanisms decrease of bone marrow (BM) participation causing chylothorax and through an up-to- (tumor cells in BM from 70% to 8%). The date review of available literature furnish resulting chylothorax was resistant to medical helpful suggestions for diagnosis and therapies, but it was successfully treated by management of chylothorax in WM patients. videothoracoscopy.

Keywords: Waldenström macroglobulinemia, CASE HISTORY chylothorax, thoracic duct, , talc , videothoracoscopy A 66-year old man with a history of and colon cancer (treated with Waldenström macroglobulinemia (WM) sigmoid resection plus chemotherapy) is a rare B-cell malignancy representing presented with an immunoglobulin M (IgM) about 2% of hematologic malignancies (1,2). λ (lambda) M-spike on serum protein It is characterized by proliferation of a cell electrophoresis and a diagnosis of monoclonal population consisting of lymphoplasmocytoid gammopathy of undetermined significance cells and associated with a monoclonal (MGUS) made in 2008. In 2010, during

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polymerase chain reaction for MYD88L265P confirmed the diagnosis of WM. Otherwise, abdominal ultrasound showed neither hepatosplenomegaly nor lymphadenopathy, and CT total body and PET/CT scans were not performed. Collectively these data supported the diagnosis of WM with renal involvement. Accordingly, from April to July 2013 the patient was treated with 6 doses of rituximab plus cyclophosphamide and prednisone. The therapy was well tolerated although fatigue and dyspnea occurred at the end of the first cycle and persisted during the entire course of treatment. Due to dyspnea worsening, a chest x-ray was carried out at the end of therapy displaying pleural effusion on the right side. As a result, two serial Fig. 1. CT scan shows the right pleural effusion thoracenteses were performed and approxi- which is still large despite numerous thoracenteses. mately 1900 mL of opaque milky fluid was Pleural thickening is evident posteriorly along the obtained. Based on and costovertebral space (asterisk) and in the prevertebral plane with contralateral extension concentration (1197 mg/dl and (arrowhead). 119 mg/dl, respectively), the diagnosis of chylothorax was made. In parallel, chest and abdomen CT scan showed persistence of follow-up examination, marrow biopsy pleural effusion on the right side together revealed a small lymphocytic infiltrate in with parietal pleura thickening (Fig. 1). No approximately 20-30% of the total popula- hepatosplenomegaly, or enlarged mediastinal tion. Renal function and calcium level were or abdominal lymphadenopathy were evident. normal apart from mild proteinuria During the subsequent two months, further attributed to the long-lasting hypertension thoracenteses were performed. history. Lytic lesions or hepatosplenomegaly In 2014, a remission of WM was observed. were absent. The patient denied any Indeed, blood tests were normal although a symptoms, his appetite was good, and no slight IgM level increase was observed in weight loss was documented during last serum proteins, and bone marrow biopsy months. Based on these findings, a diagnosis showed a lymphocytic infiltrate accounting of low-grade B lymphoma with an IgM for about 8% of the cellular population. A monoclonal component was made. pleural drainage was also performed obtaining During the following months, a about 2000 mL of . A subsequent progressive IgM serum level and free light lymphangiogram showed normal abdominal chains increase were observed in parallel lymphatic pattern, with cisterna chyli and with progressive impairment of renal thoracic duct normal during their entire function. A bone marrow biopsy repeated in course till termination at the left supracla- 2013 showed a replacement of the normal vicular space (Fig. 2). However, a slight cellular population by 60%-70% of the contrast leakage appeared to be present lymphoplasmacytic infiltrate. Likewise, a cephalad to the cisterna chyli at the emer- renal biopsy showed a lymphoid infiltrate gence of the thoracic duct into the chest. This indicating kidney involvement by lympho- finding was confirmed by CT scan (Fig. 2). plasmocytic lymphoma. An allele-specific PET/CT scan further corroborated presence

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Fig. 2. CT scan performed after lymphangiography. The thoracic duct arises in the with typical caliber and course. The cisterna chyli and thoracic duct origin are highlighted by circles and an arrow indicates the location of potential minimum leakage (* identifies ).

Fig. 3. Videothoracoscopic view of right costovertebral angle and diaphragmatic sinus (asterisk) (frontal view). of thickened pleura at the right paravertebral was started. Although fluid became clearer, space from D4 to D12 associated with its persistence of 400-500 mL daily leak was enhanced metabolic activity (SUV max of continually observed even after seven days. 3,8). Finally, flow cytometry analysis on Therefore, a videothoracoscopy was under- pleural fluid revealed pleural localization taken. A fatty meal was administered three of B-lymphoplasmocytic non-Hodgkin hours prior to surgery. The pleura was lymphoma with an IgMλ component. Based diffusely hyperemic, and a small amount of on these findings, conservative treatment of opalescent fluid was aspirated. A wide area the chylothorax, with fasting, total parenteral of opalescent and thickened pleura was nutrition, and subcutaneous evident posteriorly down to the diaphrag-

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Fig. 4. TachoSil® (Takeda UK Ltd) was used as a lymphostatic patch.

Fig. 5. Once insufflated using thoracoscopy, talc distributes uniformly on pleural surface allowing optimal pleuro- desis and inhibiting further pleural collections. The asterisk indicates the patch of TachoSil® (Takeda UK Ltd). matic sinus (Fig. 3). The diaphragm was prevent possible major lymphatic leakage retracted and the pulmonary ligament was from biopsy sites, a patch of TachoSil® exposed. No macroscopic chylous leak was (Takeda UK Ltd) was used (Fig. 4). Next, evident. Multiple biopsies were made. To pleurodesis was performed by using 6 grams

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Fig. 6. Histology revealed diffuse pleural involvement with neoplastic infiltrate composed predominantly of small (CD20+) mixed with variable numbers of plasmacytoid lymphocytes and plasma-cells. Often, mainly in extranodal sites, small-B cell and plasmacytic neoplasms are difficult to identify. In our case, clinical and laboratory findings supported the diagnosis of lymphoplasmocytic lymphoma. of talc, insufflated and uniformly distributed Waldenström macroglobulinemia is a on the pleural surface through a gas-propelled rare disease. An annual age-adjusted disposable atomizer (Steritalc®; Novatech, La incidence of 0.38 per 100,000 persons per Ciotat, France) (Fig. 5). Finally, a 28-French year was reported recently in the US (1). chest tube was imbedded and connected to It usually affects elderly people, and it is 20 cm H2O pressure for 72 hours. At the end characterized by high level of blood mono- of this period, a low- diet was started. In clonal IgM, bone marrow involvement by the following 72 hours, less than 100 mL of lymphoplasmacytic lymphoma cells, insidious clear fluid was drained daily and the chest onset, and relatively benign clinical course tube was removed. Histology was consistent with many patients diagnosed incidentally with pleural localization of lymphoplasmo- by routine blood examination. The most cytic lymphoma (Fig. 6). After 1 month, a CT common symptoms are weakness, anorexia, scan of chest and abdomen was performed, and weight loss (2). Peripheral lymphadeno- showing persistence of thickening in the right pathies and hepatosplenomegaly may be parietal pleura and absence of pleural present as well as ocular or central nervous effusion. Follow up visits were done at three, symptoms (12). Among clinical features, six, and 12 months and the patient continues pleural manifestations are uncommon to be asymptomatic and chest x-ray confirms (3,4,12,13). Indeed, Imhof et al summarized that the completely free of 114 cases of MW in 1959 with no mention effusion. Based on WM diagnosis, a “watch of lung or pleural involvement (12). In 1974 and wait” policy was chosen for the manage- Winterbauer et al reviewed 15 cases of ment of this patient. pleuropulmonary involvement in MW reported in the English literature with 7 cases DISCUSSION of pleural effusion (4). Rausch and Herion

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 215 reviewed 44 cases of pulmonary disease in The possible aggravating role played by the world literature from 1957 to 1979. chemotherapy in the occurrence of chylo- Pleural effusion was evident in 19 cases thorax is an issue of timely discussion with (isolated pleural effusion in 4) (13). In 1973, rituximab implicated. To date no published Yamaguchi reviewed 54 Japanese cases case of rituximab-related chylothorax has and only 5 patients were found to have been reported, but chylothorax has been cited clinical pulmonary disease with 1 case of by the FDA as an uncommon side effect of pleural effusion (14). In 1998 Fadil and such treatment. Taylor reviewed 34 cases of pleuropulmonary Timing of pleural involvement represents involvement in WM patients reported in the a further issue which makes our case report English literature with 14 cases of pleural unique. Since a chest CT scan was not effusion (3). Based on these studies, chylo- performed before any treatment, it is difficult thorax is a very uncommon presentation to know the exact time of pleural involve- with only seven cases reported to date in ment. Due to the patient reporting onset of literature (5-11). respiratory distress at the end of the first Chylothorax usually results from the cycle of therapy, we assume that pleural disruption and/or obstruction of the thoracic involvement and chylothorax were already duct with consequent leak of chyle from the present at the time of diagnosis. However, as duct itself or one of its tributaries (15). therapy resulted in decreased IgM levels and Malignant obstruction of the thoracic duct is lymphoplasmacytoid cell counts in the bone a major cause of non-traumatic chylothorax marrow, failure of therapy for the pleural with lymphoma accounting for 70% of cases infiltrations should be considered. A similar (16,17). Enlarged and/or confluent case has been previously reported: a 77-year nodes compress lymphatic channels as well old woman with a non-chylous pleural as block the centripetal drainage of lymphatic effusion and biopsy proven pleural involve- flow through the thoracic duct. Collectively ment of WMG was treated with Rituximab these events lead to to diffuse extravasation followed by fludarabine (19). Although the or oozing of chyle and lymph into the serum IgM dramatically decreased, her pleural space. pleural effusion persisted and progressed. To In our case, mechanisms causing explain this phenomenon, poor penetration of chylothorax remain unclear although the drugs into the pleural space or development presence of chyle within the pleural cavity of a resistant phenotype were hypothesized implies the involvement of the thoracic duct (19). By contrast, pleural involvement or one of its major tributaries. Remarkably, occurring after chemotherapy could be CT scan did not show thoraco-abdominal considered as an isolated pleural recurrence lymphadenopathy and the thoracic duct was of the disease as previously reported (4,18,19). not dilated (Fig. 2). Pleural biopsies showed a CT performed after lymphangiography subpleural tissue infiltration of lymphoplas- is reported to detect even small amounts of macytic lymphoma cells. This pattern, contrast material in the pleural space, con- previously described in WM patients without firming the chylous leak (20). Therefore, a chylous pleural effusions, could lead to chest CT scan was carried out in our patient, peripheral lymphatic channel compression which showed, along with thoracic duct and widespread leakage of lymph rather than integrity and preserved flow, the presence of chyle into the pleural space (18,19). Based pleural flocculation that prompted us to on minimal thoracic duct leak detected with speculate existence of minimal leak sites CT scan, involvement of the thoracic duct by responsible for the observed chylothorax. lymphoplasmacytoid cells may be hypothe- Whereas surgical therapy is often sized with duct permeability modification. recommended when post-surgical chylothorax

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 216 occurs, typically a conservative approach showed greater success at 30 days among represents the first choice option in case of a patients receiving talc insufflation (78 versus malignant etiology (15-17). Successful conser- 71 percent). In the subgroup of patients with vative treatment may be predicted according primary lung or breast cancer, talc to results from lymphangiography. Indeed, insufflation was significantly more successful duct patency, absence of leaks, or presence of at 30 days (82 versus 67 percent) (31). minimal leaks in minor tributaries are Three hours before surgery, a fatty meal positive prognostic markers for successful was administered to facilitate leak localiza- conservative treatment as well as drainage of tion (32,33). If this had been identified, the less than 300 mL/day (15). In line with these use of fibrin glue or a lymphostatic patch or data, a conservative approach based on even ligation of the thoracic duct would have fasting, , and octreotide been considered. The pleural sinus was fully was initially performed in our patient. exposed by retracting the diaphragm inferi- Noteworthy, randomized animal studies orly and the inferior pulmonary ligament was support use of octreotide also in treating displayed. Since no macroscopic chylous leak chylothorax caused by postoperative thoracic or collections was evident, talc pleurodesis duct injury (21). Thus, somatostatin or alone was considered to be adequate. octreotide have been previously used to reduce both intestinal chyle production and CONCLUSIONS chyle leak (22-25). Similarly, in our patient such an approach resulted in improved Chylothorax represents an uncommon nutritional status and clearer fluid; however, manifestation of WM with pleural involve- a steady leak rate of 500 mL daily was ment. It can be resistant to chemotherapy observed for a week. or can occur at the time of WM relapse. As a consequence, we thought that a Mechanisms causing chylothorax are minimally invasive surgical approach was frequently unclear but CT scan associated indicated in order to explore the pleural with lymphangiography may be useful to cavity, obtain a pleural biopsy, and finally investigate causes as well as to plan appro- to perform talc pleurodesis. The latter is a priate treatments. Thoracoscopic talc traditional option in malignant chylothoraces pleurodesis, in parallel with the use of glues (26). A 100% success rate was reported in 19 or lymphostatic material, is recommended in patients with 24 chylothoraces secondary to case of failure of a conservative approach. lymphoma and refractory to chemotherapy or (27). The reported REFERENCES morbidity is low (26-28). The main risk of chemical pleurodesis is 1. Wang, H, Y Chen, F Li, et al: Temporal and producing a multiloculated chylothorax that geographic variations of Waldenstrom macroglobulinemia incidence: A large can subsequently become organized. Talc population-based study. Cancer 118 (2012), slurry (administered via chest tube) distrib- 3793-3800. utes quite poorly over the pleural surfaces 2. Merlini, G, L Baldini, C Broglia, et al: and tends to collect at the caudal sinuses (29). Prognostic factors in symptomatic Waldenstrom’s macroglobulinemia. Semin Thoracoscopic talc “poudrage” (insufflation Oncol 30 (2003), 211-215. via thoracoscopy) is reported to be at least 3. Fadil, A, DE Taylor: The lung and equally effective, and in some studies Waldestrom’s macroglobulinemia. South significantly more effective than talc slurry Med. J. 91 (1998), 681-685. 4. Winterbauer, RH, RCK Riggins, FA Griesman, (29,30). Indeed, a randomized trial that et al: Pleuropulmonary manifestations of assigned 482 patients with malignant pleural Waldestrom’s macroglobulinemia. Chest 66 effusions to receive talc insufflation or slurry (1974), 368-375.

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 217

5. Perreau, A, F Joubaud, H Vernin: Chylothorax 22. Ulibari, J, Y Sanz, C Fuentes, et al: Reduction au cours de la maladie de Waldestrom. Press. of lymphorrhagia from ruptured thoracic duct Med. 73 (1965), 1641-1642. by somatostatin. Lancet 336 (1990), 258. 6. Rizzo, S, M Campagnoli: Chylothorax as a 23. Rimensberger, P, B Muller-Schenker, A of Waldeström’s disease. Eur. J. Kalangos, et al: Treatment of a persistent Respir. Dis. 65 (1984), 371-372. postoperative chylothorax with somatostatin. 7. Monteagudo, M, J Lima, F Garcia-Bragado, Ann. Thorac. Surg. 66 (1998), 253-254. et al: Chylous pleural effusion as the initial 24. Al-Zubairy, S, A Al-Jazairi: Octreotide as a manifestation of Waldeström’s macroglobu- therapeutic option for management of linemia. Eur. J. Respir. Dis. 70 (1987), 326-327. chylothorax. Ann. Pharmacother. 37 (2003), 8. Marti, JM, F Cervantes, P Lloberes, et al: 679-682. Chylothorax as the initial manifestation of 25. Rosti, L, R Bini, M Chessa, et al: The Waldeström’s macroglobulinemia. Med. Clin. effectiveness of octreotide in the treatment of (Barc.) 88 (1987), 591-593. postoperative chylothorax. Eur. J. Pediatr. 9. Antón Aranda, E: Quilotórax como complica- 161 (2002), 149-150. ción de la macroglobuline mia de Waldeström. 26. Weissberg, D, I Ben-Zeev: Talc pleurodesis. Arch. Bronconeumol. 37 (2001), 155-156. Experience with 360 patients. J. Thorac. 10. Misaki, S, H Sakoda, S Hakata, et al: Cardiovasc. Surg. 106 (1993), 689-695. Waldeström macroglobulinemia complicated 27. Mares, D, P Mathur: Medical thoracoscopic with chylothorax. Rinsho Ketsueki 53 (2012), talc pleurodesis for chylothorax due to 1916-1920. lymphoma: A case series. Chest 114 (1998), 11. Poisson, J, A Aregui, L Darnige, et al: 731-735. Association of chylothorax and direct pleural 28. Graham, D, E McGahren, C Tribble, et al: involvement in a case of Waldenström’s Use of videoassisted thoracic surgery in the macroglobulinaemia. Age Ageing 43 (2014), treatment of chylothorax. Ann. Thorac. Surg. 581-583. 57 (1994), 1507-1511. 12. Imhof, JW, H Baars, MC Verloop: Clinical 29. Stefani, A, P Natali, C Casali, et al: Talc and haematological aspects of macroglobu- poudrage versus talc slurry in the treatment linaemia Waldestrom. Acta Med. Scand. 163 of malignant pleural effusion. A prospective (1959), 349-366. comparative study. Eur. J. Cardiothorac. 13. Rausch, PG, JC Herion: Pulmonary manifes- Surg. 30 (2006), 827-832. tations of Waldestrom macroglobulinemia. 30. Colt, HG, V Russack, Y Chiu, et al: A Am. J. Hematol. 9 (1980), 201-209. comparison of thoracoscopic talc insufflations, 14. Yamaguchi, K: Pathology of macroglobu- slurry, and mechanical abrasion pleurodesis. linemia, a review of Japanese cases. Acta Chest 111 (1997), 442-448. Path. Jap. J. 23 (1973), 917-952. 31. Dresler, CM, J Olak, JE Herndon II, et al: 15. Platis, IE, CE Nwogu: Chylothorax. Thorac. Phase III intergroup study of talc poudrage Surg. Clin. 16 (2006), 209-214. vs talc slurry sclerosis for malignant pleural 16. Sukumaran, KN, M Petko, MP Hayward: effusion. Chest 127 (2005), 909-915. Aetiology and management of chylothorax in 32. Campisi, CC, S Spinaci, R Lavagno, et al: adults. Eur. J. Cardiothorac. Surg. 32 (2007), Immunodeficiency due to chylous dysplasia: 362-369. Diagnostic and therapeutic considerations. 17. McGrath, EE, Z Blades, PB Anderson: Lymphology 45 (2012), 58-62. Chylothorax: Etiology, diagnosis and thera- 33. Campisi, C, C Bellini, C Eretta, et al: Diag- peutic options. Respir. Med. 104 (2010), 1-8. nosis and management of primary chylous 18. Beumer, HM, WP Olislagers, RJ . J. Vasc. Surg. 43 (2006), 1244-1248. Djajadiningrat, et al: Pleuropulmonary involvement in Waldeström’s macroglobu- linemia. Respiration 45 (1984), 154-156. 19. Amin, CJ, I Rabinowitz: An unusual reoccurrence of Waldestrom’s macroglobu- Giacomo Leoncini, MD linemia as pleural effusions that had a U.O.C. Chirurgia Toracica discordant response with treatment. Clin. IRCCS AOU San Martino-IST Istituto Lab. Haem. 27 (2005), 200-202. Nazionale per la Ricerca sul Cancro 20. Kuhlman, JE, NK Singha: Complex disease L.go Giovanna Benzi, 10 Italy of the pleural space: Radiographic and CT evaluation. Radiographics 17 (1997), 63-79. 16132, Genova 21. Markham, K, J Glover, et al: Octreotide in the Tel+390105553599 treatment of thoracic duct injuries. Am. Surg. Fax: +390105556662 66 (2000), 1165-1167. Mail: [email protected]

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