In August 2002, a 78-year-old woman was admitted for severe dehydration and a 13.6-kg weight loss attributed to a 4-month history of chronic diarrhea. On hospital day 4, she was noted to be febrile at 39.3°C. She was started empirically on antibiotics. Blood cultures later grew methicillin-resistant Staphylococcus aureus, and her medication was switched to vancomycin at 1 g intravenously every 24 hours. However, after several days on this antimicrobial regimen, she continued to be febrile and her blood cultures continued to be positive for methicillin-resistant S aureus. Abdominal and pelvic computed tomographic scans were subsequently performed to identify any potential localized sources of the patient's persistent bacteremia. The only abnormal finding of the computed tomographic scan was in the spleen, which had a heterogenous appearance with multiple hypoattenuated lesions that demonstrated minimal peripheral enhancement (Figure 1, arrow). The radiologic impression was that the lesions represented splenic abscesses, and the patient subsequently underwent a splenectomy. The patient continued to be febrile and bacteremic for methicillin-resistant S aureus after her surgery, and resolution of signs was only achieved 2 weeks later. In the interim, she underwent a large bowel biopsy and was diagnosed with lymphocytic colitis as the probable cause of her presenting diarrhea.
The resected spleen was submitted to our laboratory, where it was processed routinely. Grossly, the specimen measured 15 × 12 cm and weighed 310 g. No external surface lesions were apparent. The cut surface showed diffuse, soft, cystic (rarely nodular) lesions throughout the splenic parenchyma, which ranged from 0.3 to 0.7 cm in diameter. A sample from the cystic and solid areas was cultured, and no organisms were identified. For routine microscopic evaluation, multiple sections were fixed in 10% neutral buffered formalin, processed, embedded in paraffin, sectioned, and stained with hematoxylin-eosin, acid-fast bacillus, Brown-Brenn, and fungus Grocott stains. For immunohistochemistry, 4-μm deparaffinized tissue sections were stained with a panel of monoclonal antibodies (CD21, CD31, CD8, CD34, CD68, and S100) using a Dako (Carpinteria, Calif) autostainer based on the avidin-biotin-peroxidase method.
Multiple, large, blood-filled cystic spaces were apparent microscopically at scanning magnification (Figure 2). At higher magnification, these spaces, as well as the intervening stroma, were lined by a layer of tall and polygonal endothelial cells with abundant cytoplasm and vesicular nuclei with prominent nucleoli. In the solid areas (Figure 2, lower field), the lining was characterized by prominent pseudopapillary formations with fibrovascular cores (Figure 3, a and b). The lining cells showed no significant nuclear pleomorphism or mitotic activity. Large numbers of exfoliated histiocyte-like cells with pale nuclei, delicate nuclear membranes, and frequently hemosiderin-laden or vacuolated cytoplasm were present in the cystic spaces.
Immunohistochemically, the lining cells were diffusely and strongly positive for CD31 and CD68, weakly and multifocally positive for CD21 (Figure 4), focally positive for CD8, and negative for CD34 and S100. The aforementioned histochemical stains for microorganisms were negative.
What is your diagnosis?
Pathologic Diagnosis: Littoral Cell Angioma of the Spleen
Most of the currently accepted splenic vascular tumor entities are believed to arise from (or differentiate toward) the conventional endothelial cells of the various vascular structures that richly characterize the spleen. As such, they demonstrate an antigenic immunoprofile (CD34+, CD31+, von Willebrand factor+, Ulex europeaus lectin I+), consistent with a derivation from conventional endothelial cells.1 However, a group of tumors is thought to arise from the specialized endothelial cells that line the splenic sinuses (littoral cells).2 These specialized sinus endothelial cells normally lie on a fenestrated basement membrane and are separated by tight junctional complexes.3 Consistent with the blood filtration function of the splenic sinuses, littoral cells display an endothelial and histiocytic immunophenotype, and in contrast to conventional endothelial cells, they are negative for CD34.
In 1991, Falk et al2 described 17 examples of a distinctive splenic vascular tumor that showed morphologic and immunophenotypical features consistent with a derivation from the splenic littoral cells, and they proposed the designation littoral cell angioma (LCA). Subsequently, at least 33 additional cases have been well-documented in the English literature. Littoral cell angioma occurs over a wide age range, with a median age of 49 years reported in the seminal series by Falk et al.2 There is no gender predilection. Most patients present with splenomegaly of unknown origin, with hypersplenism-associated thrombocytopenia or anemia in approximately 50% of cases.2 In addition to their unique immunophenotype (and presumed histogenesis), LCAs have been segregated from the other vascular tumors because of their potential misinterpretation as angiosarcomas, which was the original file diagnosis in 3 of the 17 original cases.2
Littoral cell angioma was originally classified as a benign tumor.2 However, with the description of additional cases, it has become apparent that LCAs are not always benign, and that the biologic behavior of these tumors may not always be predictable based entirely on morphologic features. This uncertainty stems from 5 cases that showed either clinical or pathologic features suggestive of aggressiveness. In the first case, which the authors designated a “littoral cell angiosarcoma,” 4 an otherwise typical LCA occurring in an 80-year-old man showed significant cytologic atypia and solid areas with high mitotic activity. Therapy was limited to the splenectomy, and the patient was alive with no evidence of tumor recurrence for a limited follow-up period of 4 months. Notably, this lesion was negative for CD68, in contrast to typical cases of LCA. In another case of LCA,2,5 this one without unusual histologic features, tumoral deposits were identified in the retroperitoneal lymph nodes as well as the liver, and eventually in the brain and the lungs. This patient died of widely disseminated, poorly differentiated adenocarcinoma. The contributory role of the vascular lesions (if any) in the patient's death was not clear. The term littoral cell angiomatosis was applied by these authors, descriptively, in reference to the diffuse nature of that tumor.
Another case providing some insight into the potential behavior of these lesions was reported by Ben-Izhak et al.6 In that case, an LCA was resected but recurred 8 years later with hepatic metastases. Microscopically, the only unusual feature was the presence of necrosis; nuclear atypia was described as mild, and mitoses were not evident. That patient died of his disease 4 months after his second exploratory procedure. Based on the relatively indolent clinical course, the lack of obviously malignant pathologic features, a diploid DNA histogram, a low Ki-67 proliferative index, and S-phase fraction, the authors concluded that the lesion was best described as low-grade, and they proposed the term “littoral cell haemangioendothelioma.” Two other cases that were not specifically reported under the littoral cell designation appear to be malignant examples of this tumor.7,8 These 5 cases illustrate that while most patients with LCA will have an indolent course, a subset may not.
Another LCA-associated phenomenon of unclear significance is the apparent association of these tumors with visceral malignancies. The aforementioned example5 is only 1 of 16 reported examples of LCA that were associated with a visceral tumor. The associated malignancies were colorectal adenocarcinoma (n = 3), renal adenocarcinoma (n = 2), pancreatic adenocarcinoma (n = 1), pancreatic neuroendocrine tumor (n = 1), ovarian carcinoma (n = 1), non–small cell lung carcinoma (n = 1), non-Hodgkin lymphoma (n = 4), gastric leiomyosarcoma (n = 1), cutaneous melanoma (n = 1), and testicular seminoma (n = 1).9 These 16 cases constitute approximately one third of all reported cases of LCA, and some authors recommend “close follow-up and careful investigation in search of a second visceral malignancy” in cases of LCA.10 Others attribute the high malignancy-association rate to the incidental discoveries of those malignancies in patients undergoing intensive radiologic investigations for other diseases.1,9 In the current case, the finding of LCA in a bacteremic patient raises the possibility that infectious states may be a component of the etiopathogenesis of these lesions. The splenic sinus endothelia may exist in an altered functional state under certain pathologic conditions requiring increased phagocytic function,1 and infectious states may be one of those conditions. Two of the 17 original patients had fevers of unknown origin, which resolved in both patients following their splenectomies.2 Another patient had hepatitis C.9 However, an alternative and more likely explanation is that the association observed herein was entirely incidental.
References
The authors have no relevant financial interest in the products or companies described in this article.
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