MAIN IMAGING FINDINGS IN LYMPHANGIOLEIOMYOMATOSIS

1. MAIN IMAGING FINDINGS IN LYMPHANGIOLEIOMYOMATOSIS ZAVARIZ JD, CARVALHO AP

2. INTRODUCTION Lymphangioleiomyomatosis (LAM), is a rare idiopathic disorder of unknown origin that affects almost exclusively premenopausal women. LAM is characterized by the proliferation of abnormal smooth-muscle cells (LAM cells) in the lungs (resulting in pulmonary cysts) and in the lymphatics of the thorax and retroperitoneum (resulting in lymphangioleiomyomas)(1-8). Abdominal abnormalities including angiomyolipomas, lymphangioleiomyomas and ascites.

3. PURPOUSE • The radiologist is often the first to suggest the diagnosis of LAM. However, misdiagnosis is common and may result in inappropriate therapeutic procedures that can further complicate treatment. • The purpose of this pictorial essay is to demonstrate the main findings of thoracic and abdominal image through ultrasound (US), chest radiography and computed tomography (CT) in reference to aid in the diagnosis of lymphangioleiomyomatosis.

4. CLINICAL PRESENTATION The most common presenting symptom in patients with LAM is dyspnea, that is usually progressive and may be exacerbated by exertion . Acute onset of dyspnea and chest pain may occur in association with spontaneous pneumothorax, leading to progressive loss of lung function. Cough is probably the third most common presenting complaint. Chyloptysis and chylothorax may occur during the course of the disease (2,3).

5. CHEST RADIOGRAPHY Posteroanterior chest radiograph demonstrates bilateral increased reticular opacities (ex: B), and bilateral pleural effusions (ex: A) The basic radiologic manifestations are a coarse reticulonodularpattern (B) predominantly in the lung bases, increased lung volume, recurrent pneumothorax, and pleural effusion. These conventional radiographic findings are nonspecific. B A DETAILED IMAGES A B

6. COMPUTED TOMOGRAPHY CHEST High-resolution CT scans (coronal view) show diffuse pulmonary involvement by thin-walled cysts. Computed tomography (CT) and high-resolution CT demonstrate bilateral diffuse thin-walled cysts surrounded by normal lung parenchyma.

7. COMPUTED TOMOGRAPHY CHEST High-resolution CT scan (sagitalview) reveals pulmonary involvement by thin-walled cysts of varying sizes and a right pneumothorax in apex (arrow). CT may also demonstrate associated pleural effusion and / or pneumothorax. Rupture of the thin-walled cysts results in pneumothorax in up to 55% of patients.

8. COMPUTED TOMOGRAPHY CHEST Chylothorax. CT scan (axial view) obtained at the level of the lung bases shows left pleural effusion (arrow), which turned out to be chylous. The CT attenuation of chylous pleural effusion is usually indistinguishable from that of other effusions because it is protein rich. Proliferation of lymphangioleiomyomatosis cells in the lymphatics disrupts their walls and allows chyle to leak into the pleural space and form chylous pleural effusions.

9. ABDOMINOPELVIC CT AND US FINDINGS The four major abdominopelvic abnormalities in patients with LAM include renal angiomyolipomas, lymphadenopathy, lymphangioleiomyoma, and chylous ascites.

10. ANGIOMYOLIPOMAS Benign tumors composed of varying proportions of mature adipose tissue, smooth muscle cells, and blood vessels. At US, renal angiomyolipomasdemonstrate marked increased echogenicity, which appears to be directly related to both the amount of adipose tissue within the tumor and the numerous tissue interfaces produced by blood vessels in this highly vascular lesion.

11. ANGIOMYOLIPOMAS US image of a well confined hyperechogenic nodule at the renal parenchyma using convex transducer (low frequency). detailed image shows the heterogeneity that results of multiple components using linear transducer (high frequency).

12. ANGIOMYOLIPOMAS Renal angiomyolipomas have been observed on abdominal CT scans of 20%– 54% of patients with LAM. Both CT and MR imaging rely on demonstrating deposits of fat within the angiomyolipoma; the fat appears either as low attenuation at CT or high T1 signal intensity that can be suppressed at MR imaging (2,5,9).

13. ANGIOMYOLIPOMAS Contrast-enhanced abdominal CT (axial view) demonstrates multiple fat-containing tumors in the kidneys (arrow).

14. LINFONODOMEGALY Enlarged lymph nodes are described in up to 40% of cases. Lymph nodes can measure up to 4 cm in diameter. Some lymph nodes contain low-attenuation areas, which indicate the presence of chylous lymph collections, or hamartomatoushyperattenuating areas that enhance after contrast material administration (3). DESCRICAO

15. LYMPHANGIOLEIOMYOMAS Lymphangioleiomyomasresult from the proliferation of smooth muscle cells in the lymph vessels, which causes dilatation and obstruction in the lymph vessels and results in cystic collections of chylous material (5). Lymphangioleiomyomais the third most common (16%–21% of these patients) abdominal manifestation of lymphangioleiomyomatosis.

16. LYMPHANGIOLEIOMYOMAS One distinctive feature of lymphangioleiomyomas is an increase in size during the day. Ultrasoundmay be considered the modality of choice to evaluate lymphangioleiomyomassize variation, given that it is readily available and has no associated radiation exposure. Awareness of the high prevalence of lymphangioleiomyomas in patients with lymphangioleiomyomatosis and the phenomenon of diurnal variation should help the radiologist establish the diagnosis of lymphangioleiomyomas and avoid unnecessary surgical intervention (1,4,5).

17. LYMPHANGIOLEIOMYOMAS US panoramic view shows lymphangioleiomyomas in the retroperitonium(inside oval shape). RD: right kidney / COL: lombarcolum / VCI: inferior vena cava / AO: aorta. Detail: US image in the abdomen demonstrates lymphangioleiomyomas: hypoechoic mass with multiple septations and central anechoic areas.

18. LYMPHANGIOLEIOMYOMAS At CT, the dilated retroperitoneal lymph vessels may have either thin or thick walls and may contain material low in attenuation (3–25 HU) Abdominal CT (axial view): shows low-attenuation retroperitoneal cystic masses (white arrows), which are consistent with dilatation of the abdominal lymph vessels.

19. CONCLUSIONS LAM is a serious progressive disease that predominantly affects premenopausal women and leads to chronic incapacitating respiratory insufficiency. The radiologist is often the first to suggest the diagnosis of LAM on the basis of the high-resolution CT thoracic findings that are very characteristic and can be considered diagnostic, particularly when typical abdominal lesions are also present. US and chest radiography are common tools of evaluation and its findings must be recognized in order to orientate the patient for further study.

20. REFERENCES • Avila NA, Dwyer AJ, Murphy-Johnson DV, et al. Sonography of lymphangioleiomyoma in lymphangioleiomyomatosis: demonstration of diurnal variation in lesion size. AJR2005;184:459–464. 2. Abbott GF, Rosado-de-Christenson ML, Frazier AA, Franks TJ, et al. Lymphangioleiomyomatosis: radiologic-pathologic correlation. RadioGraphics 2005;25:803–828. 3. Pallisa E, Sanz P, Roman A, et al. Lymphangioleiomyomatosis: pulmonary and abdominal findings with pathologic correlation. RadioGraphics 2002; 22:S185–S198. 4. Avila NA, Dwyer AJ, Moss J. Imaging features of lymphangioleiomyomatosis: diagnostic pitfalls. AJR 2011; 196:982–986. 5. Avila NA, Kelly JA, Chu SC, et al. Lymphangioleiomyomatosis: abdominopelvic CT and US findings. Radiology 2000; 216:147–153. 6. Wong YY, Yeung TK, Chu W. Atypical presentation of lymphangioleiomyomatosis as acute abdomen: CT diagnosis. AJR 2003;181:284-285. 7. Hui JP, Li A, Li HL. Lymphangioleiomyomatosis with florid endosalpingiosis. AJR2009; 192:826–827. 8. Avila NA, Bechtle J, Dwyer AJ, et al. Lymphangioleiomyomatosis: CT of diurnal variation of lymphangioleiomyomas. Radiology 2001; 221:415–421. 9. Craig HD, Fanburg-Smith JC, Henry LR, et al. Fat-containing lesions of the retroperitoneum: radiologic-pathologic correlation. RadioGraphics 2009; 29:261-290. 10. Carter TC, Angtuaco TL, Shah HR. US case of the day. RadioGraphics 1999; 19:555-558. 11. RajiahP, SinhaR, CuevasC, et al. Imaging of uncommon retroperitoneal masses. RadioGraphics 2011; 31:949–976.

21. MAIN IMAGING FINDINGS IN LYMPHANGIOLEIOMYOMATOSIS INTRODUCTION Lymphangioleiomyomatosis (LAM), is a rare idiopathic disorder of unknown origin that affects almost exclusively premenopausal women. LAM is characterized by the proliferation of abnormal smooth-muscle cells (LAM cells) in the lungs (resulting in pulmonary cysts) and in the lymphatics of the thorax and retroperitoneum (resulting in lymphangioleiomyomas)(1-8). Patients with LAM characteristically present with chronic dyspnea and cough and less commonly with spontaneous pneumothorax, leading to progressive loss of lung function (2,3). The radiologist is often the first to suggest the diagnosis of LAM. However, misdiagnosis is common and may result in inappropriate therapeutic procedures that can further complicate treatment. The basic radiologic manifestations are a coarse reticulonodular pattern predominantly in the lung bases, increased lung volume, recurrent pneumothorax, and pleural effusion. These conventional radiographic findings are nonspecific. Computed tomography (CT) and high-resolution CT demonstrate bilateral diffuse thin-walled cysts surrounded by normal lung parenchyma. CT may also demonstrate associated pleural effusion or pneumothorax; thoracic or abdominal lymphadenopathy; and other abdominal abnormalities including angiomyolipomas, lymphangioleiomyomas and ascites. Thus, high-resolution CT and abdominal CT reveal very characteristic abnormalities, which may so strongly suggest the diagnosis of LAM that lung biopsy could be obviated (2,3). As ultrasound (US) is a common tool in the beginning of the investigation of most diseases, the recognition of abdominal findings can lead to further evaluation of the patient. The purpose of this pictorial essay is to demonstrate the main findings of thoracic and abdominal image through US, chest radiography and CT in reference to aid in the diagnosis of lymphangioleiomyomatosis. ZAVARIZ JD, CARVALHO AP • Abdominopelvic CT and US Findings • The four major abdominopelvic abnormalities in patients with LAM include renal angiomyolipomas, lymphadenopathy, lymphangioleiomyoma, and chylous ascites. • Angiomyolipomas are benign tumors of the kidney composed of varying proportions of mature adipose tissue, smooth muscle cells, and blood vessels. Renal angiomyolipomas have been observed on abdominal CT scans of 20%– 54% of patients with LAM. Both CT and MR imaging rely on demonstrating deposits of fat within the angiomyolipoma; the fat appears either as low attenuation at CT or high T1 signal intensity that can be suppressed at MR imaging (2,5,9). At US, angiomyolipomas demonstrate marked increased echogenicity, which appears to be directly related to both the amount of adipose tissue within the tumor and the numerous tissue interfaces produced by blood vessels in this highly vascular lesion (Fig.2) (10). • Lymphangioleiomyomas result from the proliferation of smooth muscle cells in the lymph vessels, which causes dilatation and obstruction in the lymph vessels and results in cystic collections of chylous material (5). Lymphangioleiomyoma is the third most common (16%–21% of these patients) abdominal manifestation of lymphangioleiomyomatosis (11). At CT, the dilated retroperitoneal lymph vessels may have either thin or thick walls and may contain material low in attenuation (3–25 HU). The sonographic characteristics of lymphangioleiomyomas are not specific and are similar to those of malignant abdominal and pelvic masses such as lymphoma and ovarian (Fig. 3). One distinctive feature of lymphangioleiomyomas is an increase in size during the day. This variation in size can be detected on imaging and the diagnosis of lymphangioleiomyomas can be established with CT, ultrasound, or MRI. Ultrasound may be considered the modality of choice to evaluate lymphangioleiomyomas size variation, given that it is readily available and has no associated radiation exposure. Awareness of the high prevalence of lymphangioleiomyomas in patients with lymphangioleiomyomatosis and the phenomenon of diurnal variation should help the radiologist establish the diagnosis of lymphangioleiomyomas and avoid unnecessary surgical intervention (1,4,5). • Enlarged lymph nodes are described in up to 40% of cases. Lymph nodes can measure up to 4 cm in diameter. Some lymph nodes contain low-attenuation areas, which indicate the presence of chylous lymph collections, or hamartomatoushyperattenuating areas that enhance after contrast material administration (3). • Overdistention of lymphatic cysts may result in intraperitoneal rupture and chylous ascites. This is an unusual abdominal complication of LAM that can occur in the absence of pleural effusion (3). IMAGING FINDINGS AORTA COLUMN a. b. a. b. c. d. c. d. Figure 1. Pulmonary Findings. (a) Posteroanterior chest radiograph demonstrates bilateral increased reticular opacities, and bilateral pleural effusions. (b) High-resolution CT scans show diffuse pulmonary involvement by thin-walled cysts and bilateral pleural effusions. (c)Chylothorax. CT scan obtained at the level of the lung bases shows left pleural effusion, which turned out to be chylous. The CT attenuation of chylous pleural effusion is usually indistinguishable from that of other effusions because it is protein rich. (d) High-resolution CT scan reveals pulmonary involvement by thin-walled cysts of varying sizes and a right pneumothorax in apex (arrow). Methods Involved Retrospective evaluation of cases of the Hospital das Clinicas da Faculdade de Medicina da USP and selection of thoracic and abdominal ultrasound and CT images. DISCUSSION • In recent decades, great strides have been made in further understanding LAM, although its causes and pathogenesis are still unclear. Worldwide occurrence of LAM is estimated at more than 100 cases per year. LAM affects women exclusively, and most reported cases of the disease occur in white women of childbearing age with a mean age of 34 years. Hormonal factors may play a role in the pathogenesis and clinical course of LAM (2). • Clinical presentation • The most common presenting symptom in patients with LAM is dyspnea, that is usually progressive and may be exacerbated by exertion . Acute onset of dyspnea and chest pain may occur in association with spontaneous pneumothorax. Cough is probably the third most common presenting complaint. Chyloptysis and chylothorax may occur during the course of the disease (2). • Chest Radiography • The most commonly described radiographic manifestation of LAM is a pattern of generalized, symmetric, reticular, or reticulonodular opacities (Fig. 1a), seen in approximately 80%–90% of affected patients. It is postulated that these reticular and reticulonodular opacities may result from the visualization of numerous superimposed cyst walls (2). • Pulmonary CT Findings • The CT manifestations of LAM are distinctive, characterized by numerous thin-walled cysts surrounded by normal lung parenchyma and distributed diffusely and bilaterally (Fig 1b). Rupture of the thin-walled cysts results in pneumothorax in up to 55% of patients (Fig 1c). Proliferation of lymphangioleiomyomatosis cells in the lymphatics disrupts their walls and allows chyle to leak into the pleural space and form chylous pleural effusions (Fig 1c)(2,3, 4). CONCLUSIONS LAM is a serious progressive disease that predominantly affects premenopausal women and leads to chronic incapacitating respiratory insufficiency. The radiologist is often the first to suggest the diagnosis of LAM on the basis of the high-resolution CT thoracic findings that are very characteristic and can be considered diagnostic, particularly when typical abdominal lesions are also present. US and chest radiography are common tools of evaluation and its findings must be recognized in order to orientate the patient for further study. e. f. REFERENCES a. b. 1. Avila NA, Dwyer AJ, Murphy-Johnson DV, et al. Sonography of lymphangioleiomyoma in lymphangioleiomyomatosis: demonstration of diurnal variation in lesion size. AJR2005;184:459–464. 2. Abbott GF, Rosado-de-Christenson ML, Frazier AA, Franks TJ, et al. Lymphangioleiomyomatosis: radiologic-pathologic correlation. RadioGraphics 2005;25:803–828. 3. Pallisa E, Sanz P, Roman A, et al. Lymphangioleiomyomatosis: pulmonary and abdominal findings with pathologic correlation. RadioGraphics 2002; 22:S185–S198. 4. Avila NA, Dwyer AJ, Moss J. Imaging features of lymphangioleiomyomatosis: diagnostic pitfalls. AJR 2011; 196:982–986. 5. Avila NA, Kelly JA, Chu SC, et al. Lymphangioleiomyomatosis: abdominopelvic CT and US findings. Radiology 2000; 216:147–153. 6. Wong YY, Yeung TK, Chu W. Atypical presentation of lymphangioleiomyomatosis as acute abdomen: CT diagnosis. AJR 2003;181:284-285. 7. Hui JP, Li A, Li HL. Lymphangioleiomyomatosis with florid endosalpingiosis. AJR2009; 192:826–827. 8. Avila NA, Bechtle J, Dwyer AJ, et al. Lymphangioleiomyomatosis: CT of diurnal variation of lymphangioleiomyomas. Radiology 2001; 221:415–421. 9. Craig HD, Fanburg-Smith JC, Henry LR, et al. Fat-containing lesions of the retroperitoneum: radiologic-pathologic correlation. RadioGraphics 2009; 29:261-290. 10.Carter TC, Angtuaco TL, Shah HR. US case of the day. RadioGraphics 1999; 19:555-558. 11. RajiahP, SinhaR, Cuevas C, et al. Imaging of uncommon retroperitoneal masses. RadioGraphics 2011; 31:949–976. g. h. Figure 3. Lymphangioleiomyomas and Lymphadenopathy. (a), (b), (c), (d) and (e). US image in the abdomen demonstrates lymphangioleiomyomas (white arrows) and demonstrates multiple septations and central hypoechoic areas. (f) ,(g) and (h). Contrast-enhanced abdominopelvic CT scan shows low-attenuation retroperitoneal cystic masses (white arrows), which are consistent with dilatation of the abdominal lymph vessels. CT scan also shows a 1.3-cm para aortic lymph node (black arrow), with a central area of low-attenuating material. VCI = inferior vena cava; AO = aorta; COL = column; RD = right kidney. c. d. Figure 2. Renal Angiomyolipomas. (a): US image of a well confined hyperechogenic nodule at the renal parenquima(b): detailed image shows the heterogeneity that results of multiple components (arrows). (c) and (d): Contrast-enhanced abdominal CT demonstrates multiple fat-containing tumors in the kidneys.