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Littoral cell angioma: review of the literature and case report.

BACKGROUND

Littoral cell angioma (LCA), first described by Falk et al. in 1991, (1) is a rare primary vascular neoplasm unique to the spleen that originates from littoral cells that normally line the sinus channels of the splenic red pulp. Although initially thought to be an extremely rare pathology of the spleen, there have been an increasing number of LCA cases reported in the English language literature. Until now, less than 100 cases have been reported. The etiology and prevalence of LCA is still unclear partly due to the rarity of cases. The association of LCA with internal organ cancers, specifically lymphoma, has been reported. (1) In the cases of patients with histories of lymphoma or other cancers, the accurate diagnosis of LCA as the cause of the splenomegaly is challenging and would make the splenectomy an unavoidable diagnostic option. In this article, we present a case of LCA in a patient with non-Hodgkin B-cell lymphoma and alpha thalassemia trait, which to our knowledge, is the first report of the coexistence of LCA and thalassemia and only the second case of LCA and marginal zone non-Hodgkin B-cell lymphoma. (2) We review the literature and discuss the radiology and pathology findings of this case in comparison with the previously reported cases.

CASE PRESENTATION

A 49-year-old African-American male with a past medical history of the alpha thalassemia trait who had a three-year history of marginal zone monocytoid B-cell non-Hodgkin lymphoma (NHL), which was diagnosed on a lymph node and bone marrow biopsies, had a longstanding splenomegaly with symptoms of fever, night sweats, fatigue, weight loss, mild abdominal pain, and early satiety. At the time of referral, his spleen was palpable 10 cm below the costal margin and persisted, despite the patient undergoing chemotherapy. Laboratory at presentation was significant for microcytic anemia, thrombocytopenia, and low iron studies. Previous genetic study had revealed deletion of the alpha globin gene (alpha thalassemia trait) with no pathogenic beta globin gene mutation in the patient. Serum Protein Electrophoresis before chemotherapy was consistent with alpha thalassemia trait with no evidence of gammopathies. A repeat bone marrow biopsy reported a normocellular bone marrow with no evidence of involvement by a B-cell lympho-proliferative disorder. Computed tomography (CT) scan at that time showed splenomegaly and numerous transiently visualized well-circumscribed hypovascular splenic lesions. The patient was very much in favor of undergoing a splenectomy, so an open total splenectomy was performed. He was discharged home 18 days post-operation after a tenuous hospital course due to postsurgical complications.

Pathologic Findings of the Case

The surgically excised specimen was an enlarged spleen that weighed 1,338. (4) grams and measured 25 x 12 x 8 cm with white-to-red-tan fibrous tissue with shaggy adhesions and hemorrhagic clots on the surface. The spleen was serially cross-sectioned and reveals no obvious white lesions. There were small nodular hemorrhagic areas within the splenic pulp that ranged from 0.5 to approximately 4 cm (Figure 1-A). Microscopic exam of the spleen showed an unencapsulated, well-circumscribed vascular lesion (Figure 1-B) comprising anastomosing vascular channels resembling splenic sinuses (Figure 1-C), which were lined by plump endothelial cells, in some areas demonstrating hemophagocytosis. Some endothelial cells were detached into vascular spaces. No sclerosis or atypia was seen (Figure 1-D). Immunohistochemistry studies were consistent with littoral cell angioma. CD31 (Figure 1-F), CD68, and factor VIII-related antigen (Figure 1-E) highlighted the lesion. CD34, CD21, and CD8 were negative. Mixed T and B lymphocytes were identified with CD3 and CD20. HHV-8 staining was also negative.

Imaging Findings of the Case

CT characteristics of the case included an enlarged spleen with hardly visible focal lesions on the unenhanced or delayed CT phases. However, on the portal venous phase, multiple small, ovoid low-attenuated nodules were evident. These lesions ranged in size from 0.2 to 6.0 cm. Delayed filling of the nodules eventually made them isodense on the excretory phase (Figure 2). The nuclear medicine liver spleen scan with Tc-99m sulfur colloid was useful to show splenomegaly and colloid shift with an increased spleen to liver ratio suggestive of hypersplenism (Figure 3). FDG-PET-CT scan showed splenomegaly, modest diffuse physiologic FDG activity with a subtle nonspecific parenchymal heterogeneity (Figure 4).

DISCUSSION AND LITERATURE REVIEW

Endothelial cells lining the vascular sinuses of the spleen (normal littoral cells) are quite unique as they exhibit both phagocytic and hematopoietic properties. (1) Neoplasia of these cells results in the formation of a littoral cell angioma (LCA), which exhibits histological and molecular features consistent with both endothelial and histiocytic cell types. Normal splenic littoral cells can react to any unknown antigenic stimuli with proliferation and increasing phagocytic activity as a result of their unusual elongated cytoplasmic surface and basement membrane discontinuity. So, tumoral littoral cells possess dual immunophenotypic characteristics, as they have both vasculoendothelial and monohistiocytic cell markers. (1,3,4)

Although initially classified under benign primary vascular neoplasms of the spleen, LCA is no longer considered as an absolutely benign lesion. Falk et al. reported a case series including one patient with LCA demonstrating liver and brain disease dissemination that responded to cytotoxic chemotherapy. (1) Moreover, association of LCA with other malignancies, such as thyroid, (5) lung, (6) brain, (6) colorectal, (7) renal, (7) pancreatic, (7) hepatic, (8) hematologic, (1,2,9) ovarian, (8) testicular, leiomyosarcoma, (10) and melanoma, (10) is another piece of supporting evidence for avoiding categorization of LCA as a completely benign disease.

Studies have demonstrated that LCA has two subtypes with potentially malignant properties, littoral cell angiosarcoma (11) and littoral cell hemangioendothelioma. (12) These variants may present with distant metastasis, and their histologic examination can reveal malignant features, such as abnormal architecture, abundant mitotic figures, nuclear atypia, and necrosis. (1,3,4) Interestingly, it has been revealed that LCA also has an association with different congenital and immunological conditions, such as inflammatory bowel disease, (1) Wiskott-Aldrich syndrome, (13) Epstein syndrome, (14) lymphocytic colitis, SLE, (15) ankylosing spondylitis, psoriasis, (16) Gaucher's disease, (17) myelodysplastic syndrome, (9) chronic glomerulonephritis, and aplastic anemia. (18)

A relationship between LCA and immune system abnormalities has been proposed recently. Development of LCA following chronic immunosuppression after renal transplant (19) and complete resolution of fever following surgical splenic resection may provide interesting hints. (20) Development of LCA after treatment of Crohn's disease and pulmonary sarcoidosis with anti-TTNF agents have been reported and suggest a role for tumor necrosis factor alpha in the pathogenesis of this disease. (21)

Clinically, LCA patients can manifest with different signs or symptoms. More than 55% of patients are asymptomatic and incidentally discovered by imaging or surgical procedures being performed for other purposes. LCA patients can present with symptoms and signs of hypersplenism and bicytopenia (anemia and thrombocytopenia). Splenomegaly is not uncommon in LCA patients, and they can present with LUQ pain, fullness, and early satiety. Constitutional symptoms, such as fever, fatigue, weight loss, and anorexia, can be the only manifestation of LCA in some cases. (1,3,7)

The majority of LCA tumors are benign, but given their malignant potential and possible concomitant malignancies, a diagnostic and therapeutic splenectomy seems essential. Fine needle aspiration and percutaneous ultrasound-guided core biopsy of the lesion has been reported with equivocal diagnostic results. Also, there have been cases of LCA and littoral cell angiosarcoma (11) reported to present as splenic rupture and hemoperitoneum.

Although some imaging characteristics of LCA make the differential diagnosis much narrower, there is no imaging modality that can show a pathognomonic imaging pattern to reach the definitive diagnosis. Depending on the imaging modality and protocol used, LCA may show an appearance similar to that of a wide variety of more common conditions. The following conditions may show characteristics similar to that of LCA and when appropriate, should be included in the differential diagnosis: hemangioma, hamartoma, sclerosing angiomatoid nodular transformation (SANT), hemangioendothelioma, hemangiopericytoma, angiosarcoma, lymphoma, and metastatic disease. (1,3,4,6-8) On ultrasonography, LCA may show a mottled echo texture with multiple or solitary heterogeneous hyperechoic masses. (16) On unenhanced CT, the nodular lesions of LCA are usually indiscernible unless complicated by hemorrhage; however, with the addition of intravenous contrast, LCA can be visible as multiple low attenuation lesions on a background of normal enhancing spleen during the portal venous phase, and on delayed images, can become iso-attenuating with the normal enhancing spleen due to delayed filling with contrast. (7) On MRI, the nodular lesions of LCA are usually hypointense on both T1-weighted and T2-weighted sequence images, owing to the presence of hemosiderin as a result of hemophagocytosis by neoplastic cells. However, in another study, LCA manifested on MRI as T1-hypointense and T2-hyperintense lesions, an appearance related to insignificant siderosis, seen in less than 50% of LCA cases. (10) After the administration of IV gadolinium-based contrast, the lesions may demonstrate internal linear enhancement during the portal venous phase on T1-weighted sequences which become iso-intense on the delayed images, an enhancement curve similar to that of that described for CT. (10) Tc-99m-labeled red blood cell scintigraphy scan may show LCA lesion to be "cold." RBC scan can be useful to differentiate splenic lesions from splenic hemangiomas.

As mentioned before, although the imaging studies are helpful, the definitive diagnosis of LCA is only possible postoperatively by histopathology and immunohistochemical studies. Macroscopically, LCA in an excised spleen can be diffuse or nodular (solitary or multiple nodules), but often the gross cut-surface of the spleen shows nodules with blood or blood products. Nodules can be spongy or cystic with different colors, such as purplish dark or light red, brownish black, or even white, depending on the chronicity of the blood in the lesion. On microscopic exam, the tumor is not encapsulated but is well-circumscribed and has distinct borders. There are closely packed and congested blood-filled anastomotical sinusoidal vascular channels with focal, projecting, papillary fronds and multiple cystic spaces. These spaces are lined with tall or cuboidal endothelial cells, with vesicular nuclei and pale eosinophilic cytoplasm that have no evidence of mitotic activity, necrosis, or nuclear atypia. The tumor cells contain hemosiderin deposits and hyaline globules. Specifically, they stain positively with Perls' Prussian Blue iron staining for hemosiderin, suggesting erythrophagocytosis. The typical and characteristic immunohistochemical pattern of the LCA is as follows: CD31, CD68, CD163, CD21, and Factor VIII antigen positive; but CD34 and CD8 negative. Normal littoral cells express CD8 so it can be positive in hemangioma, angiosarcoma, and hamartoma, but the lining cells of LCA do not express CD8. CD21 expression is unique to the LCA cases; however a peculiar CD21-negative case of LCA was reported in 2009 by Colovic' et al. (22) CD68 is a histiomonocytic marker and can be positive (KP1 staining) in LCA and diffuse hemangioma, but it is usually negative in malignant variants of LCA. Vimentin, factor VIII Ag, and CD31 positivity often suggests the endothelial origin of the tumor cells and can be seen in LCA. Other immunohistochemical staining methods for endothelial or histiocytic lineage might be positive in LCA cases due to their dual immunophenotypic characteristics. Lysozyme, OKM1, S-100, Mac387, and HAM-56 are among those with histiomonocytic lineage positivity, BMA 120, von Willebrand factor, and UEA-1 lectin with endothelial lineage positivity. Indexes such as MIB-1, which shows mitotic activity, and Ki-67, which indicates proliferation rate, are likely to be very low in littoral cell angioma. (1,3,4,8,13)

After reviewing more than 80 English articles, it is interesting to note that although an increasing number of LCA cases have been reported, there are still numerous questions that need to be addressed. In the current report, a case of LCA was discussed that was associated with lymphoma and thalassemia. Imaging modalities like ultrasound, CT, MRI, scintigraphy, and PET can assist with diagnosis; however, ultimate diagnosis of LCA is only achieved by microscopic examination of the lesion tissue. The optimal method of extracting the lesion specimen is controversial, as in some of the previous studies, and fine needle aspiration or core needle biopsy has been preferred to splenectomy. In this report, however, the coexistence of lymphoma and long history of hypersplenism have made splenectomy inevitable. As the entity of littoral cell angioma of the spleen becomes more prevalent after two decades of its existence in medicine, long-term follow-up of these patients can be promising in finding more information about this disease.

CONCLUSION

To our knowledge, this is the first report on coexistence of LCA and thalassemia and the second report of LCA and marginal zone non-Hodgkin B-cell lymphoma. While ultimate diagnosis of LCA is only achieved by microscopic examination of the splenic tissue, imaging modalities can be very helpful in the diagnosis of LCA. Although the optimal method of extracting the spleen specimen is controversial, generally fine needle aspiration or core needle biopsy has been preferred to splenectomy. In cases similar to the current case, the coexistence of lymphoma, thalassemia, along with persistence of splenomegaly despite chemotherapy, and long history of hypersplenism may make splenectomy the only available option for further evaluation. As more cases of LCA are being recognized, long term surveillance of these patients should be evaluated and discussed in detail.

ACKNOWLEDGEMENT

The authors would like to thank Mr. John Cyrus who provided us editorial assistance.

REFERENCES

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(2.) Chatelain D, Bonte H, Guillevin L, Balladur P, Flejou JF. Small solitary littoral cell angioma associated with splenic marginal zone lymphoma and villous lymphocyte leukemia in a patient with hepatitis C infection. Histopathology 2002; 41(5):473-5.

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(5.) Mohan V, Jones RC, Drake AJ 3rd, Daly PL, Shakir KM. Littoral cell angioma presenting as metastatic thyroid carcinoma to the spleen. Thyroid 2005; 15(2):170-5.

(6.) Bisceglia M, Sickel JZ, Giangaspero F, et al. Littoral cell angioma of the spleen: an additional report of four cases with emphasis on the association with visceral organ cancers. Tumori 1998;84(5):595-9.

(7.) Levy AD, Abbott RM, Abbondanzo SL. Littoral cell angioma of the spleen: CT features with clinicopathologic comparison. Radiology 2004; 230(2):485-90.

(8.) Bi CF, Jiang LL, Li Z, Liu WP. Littoral cell angioma of spleen: a clinicopathologic study of 17 cases. Zhonghua Bing Li Xue Za Zhi 2007; 36(4):239-43.

(9.) Bierenbaum J, Alapat DV, Godinez C, et al. Littoral cell angioma: a correctable cause of progressive pancytopenia in a patient with myelodysplastic syndrome. Leuk Res 2010; 34(4):e117-9.

(10.) Bhatt S, Huang J, Dogra V. Littoral cell angioma of the spleen. AJR Am J Roentgenol 2007; 188(5):1365-6.

(11.) Rosso R, Paulli M. Littoral cell angiosarcoma: a truly malignant tumor. Am J Surg Pathol 2004;28(9):1255.

(12.) Fernandez S, Cook GW, Arber DA. Metastasizing splenic littoral cell hemangioendothelioma. Am J Surg Pathol 2006;30(8):1036-40.

(13.) Heese J, Bocklage T. Specimen fine-needle aspiration cytology of littoral cell angioma with histologic and immunohistochemical confirmation. Diagn Cytopathol 2000; 22(1):39-44.

(14.) Sallah S, Gonzalez P, Maia DM, Kelekis N, Semelka R. Littoral cell angioma in a patient with Epstein syndrome. Acta Haematol 1997; 98(2):113-5.

(15.) Mac New HG, Fowler CL. Partial splenectomy for littoral cell angioma. J Pediatr Surg 2008; 43(12):2288-90.

(16.) Goldfeld M, Cohen I, Loberant N, et al. Littoral cell angioma of the spleen: appearance on sonography and CT. J Clin Ultrasound 2002; 30(8):510-3.

(17.) Forest F, Duband S, Clemenson A, Peoc'h M. Traumatic subcapsular splenic hematoma revealing littoral cell angioma and Gaucher's disease. Ann Hematol 2010; 89(10):1061-2.

(18.) Tholouli E, Roulson JA, Byers R, Burton I, Liu Yin JA. Littoral cell angioma of the spleen in a patient with severe aplastic anaemia. Haematologica 2003; 88(11):ECR33.

(19.) Tan YM, Chuah KL, Wong WK. Littoral cell angioma of the spleen. Ann Acad Med Singapore 2004; 33(4):524-6.

(20.) Fadare O, Hileeto D, Mariappan MR. Pathologic quiz case: multiple splenic lesions in a bacteremic patient. Littoral cell angioma of the spleen. Arch Pathol Lab Med 2004; 128(10):1183-5.

(21.) Cordesmeyer S, Putzler M, Titze U, Paulus H, Hoffmann MW. Littoral cell angioma of the spleen in a patient with previous pulmonary sarcoidosis: a TNF-a related pathogenesis? World J Surg Oncol 2011;9:106.

(22.) Colovic' R, Suvajdzic' N, Grubor N, Colovic' N, Terzic' T. Atypical immunophenotype in a littoral cell angioma. Vojnosanit Pregl 2009;66(1):63-5.

Navid Mokhtari, MD; Alireza Hamidian Jahromi, MD; Nestor Dela Cruz, MD; Aaron Woodward, MD; Daniel Do, MD; Jaiyeola O. Thomas-Ogunniyi, MD; Guillermo Sangster, MD

Drs. Mokhtari and Hamidian Jahromi are with the Department of Surgery at Louisiana State University Health Sciences Center in Shreveport. Drs. Dela Cruz and Thomas-Ogunniyi are with the Department of Pathology at LSUHSC-Shreveport. Drs. Woodward, Do, and Sangster are with the Department of Radiology at LSUHSC-Shreveport.
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Author:Mokhtari, Navid; Jahromi, Alireza Hamidian; Dela Cruz, Nestor; Woodward, Aaron; Do, Daniel; Thomas-O
Publication:The Journal of the Louisiana State Medical Society
Article Type:Case study
Date:Nov 1, 2013
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