- Email: [email protected]
Intravascular lymphomatosis of the lung and liver following eyelid lymphoma in a Chinese man and review of primary pulmonary intravascular lymphomatosis
Pathology (2002 ) 34, pp. 82– 85
CASE
REPORT
INTRAVASCULAR LYMPHOMATOSIS OF THE LUNG AND LIVER FOLLOWING EYELID LYMPHOMA IN A CHINESE MAN AND REVIEW OF PRIMARY PULMONARY INTRAVASCULAR LYMPHOMATOSIS SENG GEOK NICHOLAS GOH , KHOON LEONG CHUAH
AND
PUAY HOON TAN
Department of Pathology, Singapore General Hospital, Singapore
Summary Intravascular lymphomatosis (IVL) is characterised by an almost exclusive intravascular proliferation of malignant lymphoid cells, with the diagnosis often made only when the illness is in its terminal phase or at autopsy. We detail a case of IVL affecting the lung and liver of a 49-year-old Chinese man presenting primarily with lung symptoms and incidental findings of abnormal serum transaminase levels, the antemortem diagnosis being established on transbronchial lung biopsy and percutaneous liver biopsy specimens, respectively. Histology disclosed CD20 + CD5 CD10 malignant large mononuclear B cells within the lumina of the blood vessels of the affected organs as well as sinusoids of the liver. Significantly, the patient had a history of large B cell lymphoma affecting the eyelid 18 months prior to the angiotropic disease, suggesting a possible link between the more common types of non-Hodgkin’s lymphoma and IVL. A brief review of all cases of primary pulmonary intravascular lymphomatosis is also presented. Key words: Intravascular lymphomatosis, eyelid, lung, liver. Received 5 February, revised 23 May, accepted 4 June 2001
INTRODUCTION In 1959, Pfleger and Tappeiner coined the term ‘angioendotheliomatosis proliferans systemisata’ for what was thought to represent a malignant endothelial cell disorder.1 This term is now replaced by ‘angiotropic lymphoma or intravascular lymphomatosis’ ( IVL), since malignant lymphoid cells play a central role in the pathogenesis of this disease, featuring proliferation of neoplastic lymphoid cells confined within the lumina of small arteries, veins and capillaries with no or minimal involvement of the adjacent parenchymal tissue.2 – 4 The most common immunophenotype of this rare variant of large cell lymphoma5,6 is B cell with occasional reports of T cell as well as anaplastic large cell.5 Interestingly, a subset of intravascular B cell lymphoma expresses CD5.5 While the diagnosis of IVL can be confidently clinched on histology, the clinical presentation of IVL is often variable, with the diagnosis often made when the disease is at its advanced stage or at postmortem examination.2 Often, IVL exhibits cutaneous or neurological manifestations. This case report details the antemortem histological findings of IVL affecting the lung and liver of a 49-year-old Chinese
man presenting mainly with pulmonary symptoms and with a previous history of large B cell lymphoma of the left eyelid.
CASE REPORT A 49-year-old Chinese cobbler, a non-smoker, presented with pyrexia of 3 weeks duration associated with cough, chills and rigors. There were no specific complaints referable to nervous and hepatobiliary systems or skin. Significantly, there was a history of a locally confined large B cell nonHodgkin’s lymphoma of the left eyelid 18 months prior to the current admission, for which he was treated with chemotherapy and radiotherapy. Apart from a temperature of 39°C, physical examination of all systems was normal. Besides increased monocyte levels, the patient had normal blood counts and serum electrolyte levels. Liver function tests revealed normal bilirubin and total serum protein levels with slight hypoalbuminaemia. Significantly, there was a 2– 4-fold increase in the serum alkaline phosphatase, alanine transaminase and aspartate transaminase levels, suggesting a mixed hepatocellular and cholestatic injury. The serum lactate dehydrogenase and g-glutamyl transferase levels were markedly raised, being 5938 U/l ( normal range 180–380) and 363 U/l ( normal range 9– 41), respectively. Microbiology investigations for bacterial and fungal organisms as well as viruses on blood, urine and sputum samples were negative. Chest X-ray and CT scan of the lung disclosed an ill-defined pulmonary infiltrate in the left upper zone. No mediastinal or hilar lymphadenopath y was noted. Except for a small 1-cm cyst in the left hepatic lobe, CT scans of the abdomen and pelvis were essentially normal, showing no obvious lymphadenopathy. CT scan of the head was unremarkable . Bone marrow trephine aspirate and biopsy revealed no malignancy. No obvious abnormalities were noted on subsequent bronchoscop y. Bronchoalveolar lavage specimens submitted for microbiological investigation were negative for fungi and mycobacteria. Transbronchial lung biopsy was carried out in the same setting. In view of the raised transaminase levels, a percutaneous liver biopsy was also performed. Following the histological diagnosis of the liver and lung specimens, the patient was given a course of chemotherapy consisting of cisplatin, Ara-C and dexamethasone. This resulted in diminution but not resolution of the pulmonary interstitial infiltrates on repeat chest X-ray a week later. Serum liver transaminase levels also dropped to slightly above normal about 2 weeks later. Two months after the diagnosis of IVL, the patient is alive but still has persistent pyrexia associated with elevated hepatic transaminase levels and without any respiratory symptoms.
MATERIALS AND METHODS The block and slides of the initial left eyelid biopsy were retrieved for study. Tissues obtained from the percutaneous liver and transbronchial lung
ISSN 0031–3025 printed/ISSN 1465– 3931 online/02/010082 – 04 © 2002 Royal College of Pathologists of Australasia DOI:10.1080/00313020120105705
INTRAVASCULAR LYMPHOMATOSIS
( A)
83
( B)
Fig. 1 ( A) Excision specimen from left eyelid showing diffuse proliferation of large lymphoid cells with enlarged irregular nuclei and discernible nucleoli ( arrow ) admixed with smaller lymphoid cells ( H&E, original magnification, ´400 ). ( B) Antibodies against CD20 decorating the tumour cells which are infiltrating fat. Note the mitotic figure ( ABC, original magnification, ´400 ).
biopsies were received, fixed in formalin and processed for routine haematoxylin and eosin sections. From formalin-fixed paraffin-embedded tissues, 4-mm sections were stained with antibodies against CD2 ( 1:40; Neomarkers, USA) , CD3 ( 1:100; Dako, Denmark), CD5 ( 1:20; Novocastra, UK), CD10 ( 1: 60; Novocastra ), CD20 ( 1:80; Dako ), CD34 ( 1:30; Novocastra) and CD45 ( 1:15; LCA, Dako) using the avidin–biotin complex ( ABC) method with the microwave antigen retrieval technique, except for CD20 where the pressure cook method was employed. Appropriate positive and negative controls were used throughout .
RESULTS Sections from the previous left eyelid nodule which measured 2.5 cm in diameter showed a diffuse infiltrate of large lymphoid cells with scanty basophilic cytoplasm, vesicular nuclei and discernible single to multiple nucleoli admixed with smaller lymphoid cells ( Fig. 1A). The tumour cells were seen infiltrating adipose tissue ( Fig. 1B). No nodular architecture or germinal centres were noted. Low power magnification examination of the three pieces of lung tissue from the transbronchial biopsy revealed diffuse distension of the alveolar septa and perivascular areas mimicking interstitial pneumonia ( Fig. 2A). However, on higher magnification, the presence of large atypical mononuclear cells within the capillaries of the alveolar septa as well as arterioles and veins in the bronchiolar regions with similar cytological features as those described in the eyelid nodule betrayed the diagnosis of IVL (Fig. 2B). No infarction, haemorrhage, fibrinous exudates or collections of alveolar macrophages were seen. Vascular intimal fibroelastosis and adjacent interstitial lymphoplasmacytic infiltrates were not observed.
Six strips of liver tissue examined disclosed a sparse infiltrate of similar large neoplastic cells within the small blood vessels as well as in the sinusoids ( Fig. 3). Although there was steatosis, there was no evidence of parenchyma destruction, cholestasis, hepatitis or cirrhosis. No tumour cells were seen in the stroma of the portal tracts. In fact, the quantum of malignant lymphoid infiltrate was so low that a definitive diagnosis was only rendered in conjunction with immunohistochemical stains. On immunohistochemistry, the tumour cells in all three specimens stained strongly for CD45 and pan B cell marker, CD20. The tumour cells stained negatively for pan T cell markers, CD2 and CD3. The stains for CD5 and CD10 were also negative in the tumour cells. CD34-positive endothelial cells were seen to enclose the malignant lymphoid cells within the lumina of the blood vessels of the lung and liver. The light microscopy and immunohistochemistry findings corroborated the diagnosis of diffuse large B cell lymphoma of the soft tissue of the eyelid with subsequent IVL of the lung and liver.
DISCUSSION Primary pulmonary presentation of IVL lacking neurological and cutaneous symptoms and manifestations is very rare.7,8 Review of the literature,2,7– 16 including our current case, discloses only 16 cases of histologically proven IVL with primary or predominant pulmonary symptoms occurring in adults averaging 40–79 years of age, with the mean age being 61 years and median being 59.5 years. The male to female ratio is 1.7:1. Often the patients present with dyspnoea, cough or chest pain associated with fever. One
84
Pathology ( 2002 ), 34, February
GOH et al.
( A)
( B)
Fig. 2 ( A) Malignant large lymphoid cells distending the blood vessels in peribronchiolar region and alveolar septa mimicking interstitial pneumonia ( H&E, original magnification, ´100). ( B) Mononuclear cells within the lumina of the blood vessels in the lung staining positively for CD20 ( ABC, original magnification, ´200 ).
patient subsequently developed acute respiratory distress.10 Radiologically, the patients present commonly with pulmonary reticulonodular infiltrates and, on pulmonary function tests, the usual finding is that of decreased diffusing capacity most likely as the result of vascular plugging by neoplastic lymphoid cells. On morphology, one case of small non-cleaved non-Burkitt’s lymphoma,10 one case of anaplastic large cell lymphoma7 and 10 cases of large cell lymphomas 7– 9,13,15,16 have been documented. In the remaining four cases, the morphological appearance was
Fig. 3 CD20-positive neoplastic cells lying within the lumen of the central vein and sinusoidal spaces of the liver. Note the lack of parenchymal destruction and presence of steatosis ( ABC, original magnification, ´200 ).
not stated.2,11,12,14 The most common immunophenotype is B cell2,7,9 –11,13 –16 with a single report of CD30 anaplastic large cell lymphoma.7 Primary pulmonary IVL shows an aggressive clinical course, with 56.25% of patients dying of the disease within 9 months of diagnosis.7– 12,14 18.75% who were reported to be alive showed evidence of remnant disease.2,15 Only 25% of patients were alive without evidence of disease,8,13,16 implying that chemotherapy offers a hope of cure.2 On histology, the differential diagnoses of IVL include metastatic carcinoma, metastatic melanoma, leukaemia, sarcoma and angiocentric or lymphomatoid granulomatosis. Careful light microscopic examination with adjunctive immunohistochemistry and clinical correlation will usually enable separation of the different entities.8 Lymphomatoid granulomatosis reveals angioinvasion and angiodestruction, features not characteristic of IVL where neoplastic cells are seen in the lumina of the blood vessels usually associated with viable surrounding tissue devoid of obvious ischaemic damage.4 Intravascularly disseminated angiosarcoma, a fairly new entity, may be confused with IVL and, in such an instance, the demonstration of endothelial markers such as CD31 and negative staining for leucocyte common antigen on immunohistochemistry will be pivotal in favouring a diagnosis of angiosarcoma.17 Interestingly, apart from our case, none of the pulmonary cases cited above is associated with an antemortem diagnosis of liver IVL. In our case, the presence of deranged liver transaminase levels implicates hepatic disease which was confirmed on liver biopsy. The presence of sinusoidal involvement, as in this report, has been described in hepatic IVL6 and, in this instance, the angiotropic nature of the neoplastic lymphoid cells contrasts with other forms of nonHodgkin’s lymphoma which have a tendency to involve the portal tracts with nodular infiltration,18 a feature notably absent in our case. In fact, hepatic IVL has been suspected
INTRAVASCULAR LYMPHOMATOSIS
on occasions where the initial biopsy reveals only a sinusoidal infiltrate of malignant cells with subsequent liver sections from autopsy showing an intravascular pattern, confirming the presence of IVL.6 The presence of a sparse lymphoid infiltrate in the liver in our case indicates the necessity of careful light microscopic examination in corroboration with a panel of immunohistochemistry stains in a patient with a previous history of lymphoma presenting with raised serum liver transaminase levels. Almost all the cases of IVL with primary lung symptoms have not shown any preceding non-intravascular lymphoma.7 Apart from our report, there is only one case where solid lymphoma preceded the angiotropic disease and, in this instance, both the initial breast tissue and subsequent IVL of the lung revealed small, non-cleaved non-Burkitt’s lymphoma. 10 It is unclear at this point whether IVL represents a distinct lymphoma arising from small blood vessels19 or dissemination from a pre-existing solid/nonintravascular lymphoma.20 Generally, most cases of IVL do not show any evidence of simultaneous solid lymphoma at postmortem examination, giving weight to the consideration of the former.21 Furthermore, the fact that IVL may manifest 2 months22 to 5 years 23 following a diagnosis of solid lymphoma suggests that it is unlikely that IVL is the consequence of vascular dissemination of a solid lymphoma.21 However, as illustrated in our case as well as others, 10,21 the similar morphological and immunohistochemical features of the tumour cells in the initial solid lymphoma and subsequent IVL will logically presuppose a common histogenetic origin. Hopefully, clonal arrangement studies will resolve this issue in the future. AC KN OW LED GEM ENTS We thank Dr Ivy Sng and other colleagues in the department for the diagnostic help rendered. We also thank our clinical colleagues involved in the management of the patient. Address for correspondence: Dr K. L. Chuah, Department of Pathology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore. E-mail: [email protected] g
References 1. Pfleger L, Tappeiner J. Zur Kenntnis der systemisierten Endotheliomatose der cutanen Blutgefasse ( Reticuloendotheliose? ). Hautarzt 1959; 10 : 359– 63. 2. Demirer T, Dail DH, Aboulafia DM. Four varied cases of intravascular lymphomatosis and a literature review. Cancer 1994; 73: 1738–45. 3. DiGiuseppe JA, Nelson WG, Seifter EJ, et al. Intravascular of lymphomatosis: a clinicopathologic study of 10 cases and assessment of response to chemotherap y. J Clin Oncol 1994; 12: 2573– 9.
85
4. Ferry JA, Harris NL. Atlas of Lymphoid Hyperplasia and Lymphoma. Philadelphia, PA: WB Saunders, 1997; 126– 8. 5. Chan JKC. Tumors of the lymphoreticular system including spleen and thymus. In: Fletcher CDM, editor. Diagnostic Histopathology of Tumors. London: Churchill Livingstone, 2000; 1165. 6. Murase T, Nakamura S, Kawauchi K, et al. An Asian variant of intravascular large B-cell lymphoma: clinical, pathological and cytogenetic approaches to diffuse large B-cell lymphoma associated with haemophagocytic syndrome. Br J Haematol 2000; 111: 826– 34. 7. Ko YH, Han JH, Go JH, et al. Intravascular lymphomatosis: a clinicopathological study of two cases presenting as an interstitial lung disease. Histopathology 1997; 31: 555– 62. 8. Yousem SA, Colby TV. Intravascular lymphomatosis presenting in the lung. Cancer 1990; 65: 349–53. 9. Curtis JL, Warnock ML, Conrad DJ, et al. Intravascular angiotropic large-cell lymphoma ( ‘malignant angioendotheliomatosis ’) with small vessel pulmonary vascular obstruction and hypercalcaemia. West J Med 1991; 155: 72–6. 10. Gabor EP, Sherwood T, Mercola KE. Intravascular lymphomatosi s presenting as adult respiratory distress syndrome. Am J Hematol 1997; 56: 155– 60. 11. Kamesaki H, Matsui Y, Ohno Y, et al. Angiocentric lymphoma with histologic features of neoplastic angioendotheliomatosis presenting with predominant respiratory and hematologic manifestations. Am J Clin Pathol 1990; 94: 768–72. 12. Remberger K, Nawrath-Koll I, Gokel JM, et al. Systemic angioendo theliomatosis of the lung. Pathol Res Pract 1987; 182: 265–74. 13. Stroup RM, Sheibani K, Moncada A, et al. Angiotropic ( intravascular) large cell lymphoma. Cancer 1990; 66: 1781– 8. 14. Synder LS, Harmon KR, Estensen RO. Intravascular lymphomatosi s ( malignant angioendotheliomatosi s) presenting as pulmonary hypertension. Chest 1989; 96: 1199–200. 15. Takamura K, Nasuhara Y, Mishina T, et al. Intravascular lymphomato sis diagnosed by transbronchial lung biopsy. Eur Resp J 1997; 10: 955–7. 16. Walls JG, Hong YG, Cox J, et al. Pulmonary intravascular lymphomatosis. Presentation with dyspnea and air trapping. Chest 1999; 115: 1207– 10. 17. Lin BTY, Weiss LM, Battifora H. Intravascularly disseminated angiosarcoma : true neoplastic angioendotheliomatosis? Report of two cases. Am J Surg Pathol 1997; 21: 1138–43. 18. Walz-Mattmuller R, Horny HP, Ruck P, et al. Incidence and pattern of liver involvement in haematological malignancies. Pathol Res Pract 1998; 194: 781– 9. 19. Molina A, Lombard C, Donlon T. Immunohistochemical and cytogenetic studies indicate that malignant angioendotheliomatosis is a primary intravascular ( angiotropic) lymphoma. Cancer 1990; 66: 474– 9. 20. Kayano H, Katamaya I. Primary hepatic lymphoma presenting as intravascular lymphomatosis. Arch Pathol Lab Med 1990; 114: 580– 4. 21. Evert M, Lehringer-Polzin M, M¨obius W, et al. Angiotropic large-cell lymphoma presenting as pulmonary small vessel occlusive disease. Hum Pathol 2000; 31: 879–82. 22. Theaker JM, Gatter KC, Esiri MM, et al. Neoplastic angioendothelio matosis – further evidence supporting lymphoid origin. Histopathology 1986; 10: 1261–70. 23. L´opez-Gil F, Roura M, Umbert I, et al. Malignant proliferative angioendotheliomatosis or angiotropic lymphoma associated with a soft-tissue lymphoma. J Am Acad Dermatol 1992; 26: 101–4.
CASE
REPORT
INTRAVASCULAR LYMPHOMATOSIS OF THE LUNG AND LIVER FOLLOWING EYELID LYMPHOMA IN A CHINESE MAN AND REVIEW OF PRIMARY PULMONARY INTRAVASCULAR LYMPHOMATOSIS SENG GEOK NICHOLAS GOH , KHOON LEONG CHUAH
AND
PUAY HOON TAN
Department of Pathology, Singapore General Hospital, Singapore
Summary Intravascular lymphomatosis (IVL) is characterised by an almost exclusive intravascular proliferation of malignant lymphoid cells, with the diagnosis often made only when the illness is in its terminal phase or at autopsy. We detail a case of IVL affecting the lung and liver of a 49-year-old Chinese man presenting primarily with lung symptoms and incidental findings of abnormal serum transaminase levels, the antemortem diagnosis being established on transbronchial lung biopsy and percutaneous liver biopsy specimens, respectively. Histology disclosed CD20 + CD5 CD10 malignant large mononuclear B cells within the lumina of the blood vessels of the affected organs as well as sinusoids of the liver. Significantly, the patient had a history of large B cell lymphoma affecting the eyelid 18 months prior to the angiotropic disease, suggesting a possible link between the more common types of non-Hodgkin’s lymphoma and IVL. A brief review of all cases of primary pulmonary intravascular lymphomatosis is also presented. Key words: Intravascular lymphomatosis, eyelid, lung, liver. Received 5 February, revised 23 May, accepted 4 June 2001
INTRODUCTION In 1959, Pfleger and Tappeiner coined the term ‘angioendotheliomatosis proliferans systemisata’ for what was thought to represent a malignant endothelial cell disorder.1 This term is now replaced by ‘angiotropic lymphoma or intravascular lymphomatosis’ ( IVL), since malignant lymphoid cells play a central role in the pathogenesis of this disease, featuring proliferation of neoplastic lymphoid cells confined within the lumina of small arteries, veins and capillaries with no or minimal involvement of the adjacent parenchymal tissue.2 – 4 The most common immunophenotype of this rare variant of large cell lymphoma5,6 is B cell with occasional reports of T cell as well as anaplastic large cell.5 Interestingly, a subset of intravascular B cell lymphoma expresses CD5.5 While the diagnosis of IVL can be confidently clinched on histology, the clinical presentation of IVL is often variable, with the diagnosis often made when the disease is at its advanced stage or at postmortem examination.2 Often, IVL exhibits cutaneous or neurological manifestations. This case report details the antemortem histological findings of IVL affecting the lung and liver of a 49-year-old Chinese
man presenting mainly with pulmonary symptoms and with a previous history of large B cell lymphoma of the left eyelid.
CASE REPORT A 49-year-old Chinese cobbler, a non-smoker, presented with pyrexia of 3 weeks duration associated with cough, chills and rigors. There were no specific complaints referable to nervous and hepatobiliary systems or skin. Significantly, there was a history of a locally confined large B cell nonHodgkin’s lymphoma of the left eyelid 18 months prior to the current admission, for which he was treated with chemotherapy and radiotherapy. Apart from a temperature of 39°C, physical examination of all systems was normal. Besides increased monocyte levels, the patient had normal blood counts and serum electrolyte levels. Liver function tests revealed normal bilirubin and total serum protein levels with slight hypoalbuminaemia. Significantly, there was a 2– 4-fold increase in the serum alkaline phosphatase, alanine transaminase and aspartate transaminase levels, suggesting a mixed hepatocellular and cholestatic injury. The serum lactate dehydrogenase and g-glutamyl transferase levels were markedly raised, being 5938 U/l ( normal range 180–380) and 363 U/l ( normal range 9– 41), respectively. Microbiology investigations for bacterial and fungal organisms as well as viruses on blood, urine and sputum samples were negative. Chest X-ray and CT scan of the lung disclosed an ill-defined pulmonary infiltrate in the left upper zone. No mediastinal or hilar lymphadenopath y was noted. Except for a small 1-cm cyst in the left hepatic lobe, CT scans of the abdomen and pelvis were essentially normal, showing no obvious lymphadenopathy. CT scan of the head was unremarkable . Bone marrow trephine aspirate and biopsy revealed no malignancy. No obvious abnormalities were noted on subsequent bronchoscop y. Bronchoalveolar lavage specimens submitted for microbiological investigation were negative for fungi and mycobacteria. Transbronchial lung biopsy was carried out in the same setting. In view of the raised transaminase levels, a percutaneous liver biopsy was also performed. Following the histological diagnosis of the liver and lung specimens, the patient was given a course of chemotherapy consisting of cisplatin, Ara-C and dexamethasone. This resulted in diminution but not resolution of the pulmonary interstitial infiltrates on repeat chest X-ray a week later. Serum liver transaminase levels also dropped to slightly above normal about 2 weeks later. Two months after the diagnosis of IVL, the patient is alive but still has persistent pyrexia associated with elevated hepatic transaminase levels and without any respiratory symptoms.
MATERIALS AND METHODS The block and slides of the initial left eyelid biopsy were retrieved for study. Tissues obtained from the percutaneous liver and transbronchial lung
ISSN 0031–3025 printed/ISSN 1465– 3931 online/02/010082 – 04 © 2002 Royal College of Pathologists of Australasia DOI:10.1080/00313020120105705
INTRAVASCULAR LYMPHOMATOSIS
( A)
83
( B)
Fig. 1 ( A) Excision specimen from left eyelid showing diffuse proliferation of large lymphoid cells with enlarged irregular nuclei and discernible nucleoli ( arrow ) admixed with smaller lymphoid cells ( H&E, original magnification, ´400 ). ( B) Antibodies against CD20 decorating the tumour cells which are infiltrating fat. Note the mitotic figure ( ABC, original magnification, ´400 ).
biopsies were received, fixed in formalin and processed for routine haematoxylin and eosin sections. From formalin-fixed paraffin-embedded tissues, 4-mm sections were stained with antibodies against CD2 ( 1:40; Neomarkers, USA) , CD3 ( 1:100; Dako, Denmark), CD5 ( 1:20; Novocastra, UK), CD10 ( 1: 60; Novocastra ), CD20 ( 1:80; Dako ), CD34 ( 1:30; Novocastra) and CD45 ( 1:15; LCA, Dako) using the avidin–biotin complex ( ABC) method with the microwave antigen retrieval technique, except for CD20 where the pressure cook method was employed. Appropriate positive and negative controls were used throughout .
RESULTS Sections from the previous left eyelid nodule which measured 2.5 cm in diameter showed a diffuse infiltrate of large lymphoid cells with scanty basophilic cytoplasm, vesicular nuclei and discernible single to multiple nucleoli admixed with smaller lymphoid cells ( Fig. 1A). The tumour cells were seen infiltrating adipose tissue ( Fig. 1B). No nodular architecture or germinal centres were noted. Low power magnification examination of the three pieces of lung tissue from the transbronchial biopsy revealed diffuse distension of the alveolar septa and perivascular areas mimicking interstitial pneumonia ( Fig. 2A). However, on higher magnification, the presence of large atypical mononuclear cells within the capillaries of the alveolar septa as well as arterioles and veins in the bronchiolar regions with similar cytological features as those described in the eyelid nodule betrayed the diagnosis of IVL (Fig. 2B). No infarction, haemorrhage, fibrinous exudates or collections of alveolar macrophages were seen. Vascular intimal fibroelastosis and adjacent interstitial lymphoplasmacytic infiltrates were not observed.
Six strips of liver tissue examined disclosed a sparse infiltrate of similar large neoplastic cells within the small blood vessels as well as in the sinusoids ( Fig. 3). Although there was steatosis, there was no evidence of parenchyma destruction, cholestasis, hepatitis or cirrhosis. No tumour cells were seen in the stroma of the portal tracts. In fact, the quantum of malignant lymphoid infiltrate was so low that a definitive diagnosis was only rendered in conjunction with immunohistochemical stains. On immunohistochemistry, the tumour cells in all three specimens stained strongly for CD45 and pan B cell marker, CD20. The tumour cells stained negatively for pan T cell markers, CD2 and CD3. The stains for CD5 and CD10 were also negative in the tumour cells. CD34-positive endothelial cells were seen to enclose the malignant lymphoid cells within the lumina of the blood vessels of the lung and liver. The light microscopy and immunohistochemistry findings corroborated the diagnosis of diffuse large B cell lymphoma of the soft tissue of the eyelid with subsequent IVL of the lung and liver.
DISCUSSION Primary pulmonary presentation of IVL lacking neurological and cutaneous symptoms and manifestations is very rare.7,8 Review of the literature,2,7– 16 including our current case, discloses only 16 cases of histologically proven IVL with primary or predominant pulmonary symptoms occurring in adults averaging 40–79 years of age, with the mean age being 61 years and median being 59.5 years. The male to female ratio is 1.7:1. Often the patients present with dyspnoea, cough or chest pain associated with fever. One
84
Pathology ( 2002 ), 34, February
GOH et al.
( A)
( B)
Fig. 2 ( A) Malignant large lymphoid cells distending the blood vessels in peribronchiolar region and alveolar septa mimicking interstitial pneumonia ( H&E, original magnification, ´100). ( B) Mononuclear cells within the lumina of the blood vessels in the lung staining positively for CD20 ( ABC, original magnification, ´200 ).
patient subsequently developed acute respiratory distress.10 Radiologically, the patients present commonly with pulmonary reticulonodular infiltrates and, on pulmonary function tests, the usual finding is that of decreased diffusing capacity most likely as the result of vascular plugging by neoplastic lymphoid cells. On morphology, one case of small non-cleaved non-Burkitt’s lymphoma,10 one case of anaplastic large cell lymphoma7 and 10 cases of large cell lymphomas 7– 9,13,15,16 have been documented. In the remaining four cases, the morphological appearance was
Fig. 3 CD20-positive neoplastic cells lying within the lumen of the central vein and sinusoidal spaces of the liver. Note the lack of parenchymal destruction and presence of steatosis ( ABC, original magnification, ´200 ).
not stated.2,11,12,14 The most common immunophenotype is B cell2,7,9 –11,13 –16 with a single report of CD30 anaplastic large cell lymphoma.7 Primary pulmonary IVL shows an aggressive clinical course, with 56.25% of patients dying of the disease within 9 months of diagnosis.7– 12,14 18.75% who were reported to be alive showed evidence of remnant disease.2,15 Only 25% of patients were alive without evidence of disease,8,13,16 implying that chemotherapy offers a hope of cure.2 On histology, the differential diagnoses of IVL include metastatic carcinoma, metastatic melanoma, leukaemia, sarcoma and angiocentric or lymphomatoid granulomatosis. Careful light microscopic examination with adjunctive immunohistochemistry and clinical correlation will usually enable separation of the different entities.8 Lymphomatoid granulomatosis reveals angioinvasion and angiodestruction, features not characteristic of IVL where neoplastic cells are seen in the lumina of the blood vessels usually associated with viable surrounding tissue devoid of obvious ischaemic damage.4 Intravascularly disseminated angiosarcoma, a fairly new entity, may be confused with IVL and, in such an instance, the demonstration of endothelial markers such as CD31 and negative staining for leucocyte common antigen on immunohistochemistry will be pivotal in favouring a diagnosis of angiosarcoma.17 Interestingly, apart from our case, none of the pulmonary cases cited above is associated with an antemortem diagnosis of liver IVL. In our case, the presence of deranged liver transaminase levels implicates hepatic disease which was confirmed on liver biopsy. The presence of sinusoidal involvement, as in this report, has been described in hepatic IVL6 and, in this instance, the angiotropic nature of the neoplastic lymphoid cells contrasts with other forms of nonHodgkin’s lymphoma which have a tendency to involve the portal tracts with nodular infiltration,18 a feature notably absent in our case. In fact, hepatic IVL has been suspected
INTRAVASCULAR LYMPHOMATOSIS
on occasions where the initial biopsy reveals only a sinusoidal infiltrate of malignant cells with subsequent liver sections from autopsy showing an intravascular pattern, confirming the presence of IVL.6 The presence of a sparse lymphoid infiltrate in the liver in our case indicates the necessity of careful light microscopic examination in corroboration with a panel of immunohistochemistry stains in a patient with a previous history of lymphoma presenting with raised serum liver transaminase levels. Almost all the cases of IVL with primary lung symptoms have not shown any preceding non-intravascular lymphoma.7 Apart from our report, there is only one case where solid lymphoma preceded the angiotropic disease and, in this instance, both the initial breast tissue and subsequent IVL of the lung revealed small, non-cleaved non-Burkitt’s lymphoma. 10 It is unclear at this point whether IVL represents a distinct lymphoma arising from small blood vessels19 or dissemination from a pre-existing solid/nonintravascular lymphoma.20 Generally, most cases of IVL do not show any evidence of simultaneous solid lymphoma at postmortem examination, giving weight to the consideration of the former.21 Furthermore, the fact that IVL may manifest 2 months22 to 5 years 23 following a diagnosis of solid lymphoma suggests that it is unlikely that IVL is the consequence of vascular dissemination of a solid lymphoma.21 However, as illustrated in our case as well as others, 10,21 the similar morphological and immunohistochemical features of the tumour cells in the initial solid lymphoma and subsequent IVL will logically presuppose a common histogenetic origin. Hopefully, clonal arrangement studies will resolve this issue in the future. AC KN OW LED GEM ENTS We thank Dr Ivy Sng and other colleagues in the department for the diagnostic help rendered. We also thank our clinical colleagues involved in the management of the patient. Address for correspondence: Dr K. L. Chuah, Department of Pathology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore. E-mail: [email protected] g
References 1. Pfleger L, Tappeiner J. Zur Kenntnis der systemisierten Endotheliomatose der cutanen Blutgefasse ( Reticuloendotheliose? ). Hautarzt 1959; 10 : 359– 63. 2. Demirer T, Dail DH, Aboulafia DM. Four varied cases of intravascular lymphomatosis and a literature review. Cancer 1994; 73: 1738–45. 3. DiGiuseppe JA, Nelson WG, Seifter EJ, et al. Intravascular of lymphomatosis: a clinicopathologic study of 10 cases and assessment of response to chemotherap y. J Clin Oncol 1994; 12: 2573– 9.
85
4. Ferry JA, Harris NL. Atlas of Lymphoid Hyperplasia and Lymphoma. Philadelphia, PA: WB Saunders, 1997; 126– 8. 5. Chan JKC. Tumors of the lymphoreticular system including spleen and thymus. In: Fletcher CDM, editor. Diagnostic Histopathology of Tumors. London: Churchill Livingstone, 2000; 1165. 6. Murase T, Nakamura S, Kawauchi K, et al. An Asian variant of intravascular large B-cell lymphoma: clinical, pathological and cytogenetic approaches to diffuse large B-cell lymphoma associated with haemophagocytic syndrome. Br J Haematol 2000; 111: 826– 34. 7. Ko YH, Han JH, Go JH, et al. Intravascular lymphomatosis: a clinicopathological study of two cases presenting as an interstitial lung disease. Histopathology 1997; 31: 555– 62. 8. Yousem SA, Colby TV. Intravascular lymphomatosis presenting in the lung. Cancer 1990; 65: 349–53. 9. Curtis JL, Warnock ML, Conrad DJ, et al. Intravascular angiotropic large-cell lymphoma ( ‘malignant angioendotheliomatosis ’) with small vessel pulmonary vascular obstruction and hypercalcaemia. West J Med 1991; 155: 72–6. 10. Gabor EP, Sherwood T, Mercola KE. Intravascular lymphomatosi s presenting as adult respiratory distress syndrome. Am J Hematol 1997; 56: 155– 60. 11. Kamesaki H, Matsui Y, Ohno Y, et al. Angiocentric lymphoma with histologic features of neoplastic angioendotheliomatosis presenting with predominant respiratory and hematologic manifestations. Am J Clin Pathol 1990; 94: 768–72. 12. Remberger K, Nawrath-Koll I, Gokel JM, et al. Systemic angioendo theliomatosis of the lung. Pathol Res Pract 1987; 182: 265–74. 13. Stroup RM, Sheibani K, Moncada A, et al. Angiotropic ( intravascular) large cell lymphoma. Cancer 1990; 66: 1781– 8. 14. Synder LS, Harmon KR, Estensen RO. Intravascular lymphomatosi s ( malignant angioendotheliomatosi s) presenting as pulmonary hypertension. Chest 1989; 96: 1199–200. 15. Takamura K, Nasuhara Y, Mishina T, et al. Intravascular lymphomato sis diagnosed by transbronchial lung biopsy. Eur Resp J 1997; 10: 955–7. 16. Walls JG, Hong YG, Cox J, et al. Pulmonary intravascular lymphomatosis. Presentation with dyspnea and air trapping. Chest 1999; 115: 1207– 10. 17. Lin BTY, Weiss LM, Battifora H. Intravascularly disseminated angiosarcoma : true neoplastic angioendotheliomatosis? Report of two cases. Am J Surg Pathol 1997; 21: 1138–43. 18. Walz-Mattmuller R, Horny HP, Ruck P, et al. Incidence and pattern of liver involvement in haematological malignancies. Pathol Res Pract 1998; 194: 781– 9. 19. Molina A, Lombard C, Donlon T. Immunohistochemical and cytogenetic studies indicate that malignant angioendotheliomatosis is a primary intravascular ( angiotropic) lymphoma. Cancer 1990; 66: 474– 9. 20. Kayano H, Katamaya I. Primary hepatic lymphoma presenting as intravascular lymphomatosis. Arch Pathol Lab Med 1990; 114: 580– 4. 21. Evert M, Lehringer-Polzin M, M¨obius W, et al. Angiotropic large-cell lymphoma presenting as pulmonary small vessel occlusive disease. Hum Pathol 2000; 31: 879–82. 22. Theaker JM, Gatter KC, Esiri MM, et al. Neoplastic angioendothelio matosis – further evidence supporting lymphoid origin. Histopathology 1986; 10: 1261–70. 23. L´opez-Gil F, Roura M, Umbert I, et al. Malignant proliferative angioendotheliomatosis or angiotropic lymphoma associated with a soft-tissue lymphoma. J Am Acad Dermatol 1992; 26: 101–4.