Tertiary Lymphoid Organs in Lymphatic Malformations

Andrew Kirsh

Sharon Cushing

Eunice Chen

Stephen Schwartz

Jonathan Perkins

Background

Examine lymphatic malformation lymphoid aggregates for the expression of tertiary lymphoid organ markers. Determine how lymphoid aggregate density relates to lymphatic malformation clinical features.

Methods and Results

Retrospective cohort study. Tissue and clinical data were reviewed from 29 patients in the Vascular Anomaly Database who represented the spectrum of head and neck lymphatic malformations and had >5 years of follow-up. Archived formalin-fixed, paraffin-embedded lymphatic malformation tissue was immunohistochemically stained with antibodies for tertiary lymphoid organ markers, which included follicular and mature myeloid dendritic cells, high endothelial venules, segregated B and T-cells, lymphatic endothelial cells, and lymphoid homing chemokines (CXCL13, CCL21). Lymphoid aggregate density (count/mm^{) was quantified by 2 independent, blinded reviewers. Lymphoid aggregate density and lymphatic malformation clinical features were characterized using analysis of variance. Larger lymphatic malformation tissue lymphoid aggregates stained consistently for tertiary lymphoid organ markers. In oral cavity and neck specimens from the same patients (}n = 9), there were more tertiary lymphoid organ in oral cavity than in neck specimens (p = 0.0235). In lymphatic malformation neck tissue, de Serres stage 4 lymphatic malformations displayed the highest tertiary lymphoid organ density. No significant association was seen between tertiary lymphoid organ density and other clinical features.

Conclusion

This study demonstrates that some lymphoid aggregates within lymphatic malformations represent tertiary lymphoid organs. There was an association between tertiary lymphoid organ density and lymphatic malformation location. Further study is required to define the role of lymphoid neogenesis and tertiary lymphoid organ formation in lymphatic malformation pathogenesis.

^{Division of Pediatric Otolaryngology, Seattle Children's Hospital, Seattle, Washington.}

^{Department of Otolaryngology, Head and Neck Surgery, University of Washington, Seattle, Washington.}

^{Department of Surgery, Section of Otolaryngology Head and Neck Surgery, Dartmouth Hitchcock Medical Center, Hanover, New Hampshire.}

^{Department of Pathology, University of Washington, Seattle, Washington.}

^{Corresponding author.}

Presented in part at the American Society of Pediatric Otolaryngology Meeting, Las Vegas, Nevada, May 1, 2010.

Address correspondence to: Jonathan A. Perkins, DO, Seattle Children's Hospital, Division of Pediatric Otolaryngology-Head and Neck Surgery, 4800 Sand Point Way NE, P.O. Box 5371, MS W-7729, Seattle, WA 98105-0371. E-mail:gro.snerdlihcelttaes@snikrep.nahtanoj

Abstract

Background

Examine lymphatic malformation lymphoid aggregates for the expression of tertiary lymphoid organ markers. Determine how lymphoid aggregate density relates to lymphatic malformation clinical features.

Methods and Results

Conclusion

Abstract

References

1. Kennedy TL. Whitaker M. Pellitteri P, et al. Cystic hygroma/lymphangioma: A rational approach to management. Laryngoscope. 2001;111:1929–1937.[PubMed]
2. Filston HCHemangiomas, cystic hygromas, and teratomas of the head and neck. Semin Pediatr Surg. 1994;3:147–159.[PubMed][Google Scholar]
3. Wernher A Angeborenen Kysten-Hydrome und die Ihnen verwandten. Giessen, Germany: G.F. Heyer, Vater; 1843. pp. 79–91. [PubMed][Google Scholar]
4. de Serres LM. Sie KC. Richardson MA. Lymphatic malformations of the head and neck. A proposal for staging. Arch Otolaryngol Head Neck Surg. 1995;121:577–582.[PubMed]
5. Raveh E. de Jong AL. Taylor GP, et al. Prognostic factors in the treatment of lymphatic malformations. Arch Otolaryngol Head Neck Surg. 1997;123:1061–1065.[PubMed]
6. Chen EY. Hostikka SL. Oliaei S, et al. Similar histologic features and immunohistochemical staining in microcystic and macrocystic lymphatic malformations. Lymphat Res Biol. 2009;7:75–80.[PubMed]
7. Perkins JA. Maniglia C. Magit A, et al. Clinical and radiographic findings in children with spontaneous lymphatic malformation regression. Otolaryngol Head Neck Surg. 2008;138:772–777.[PubMed]
8. Yaita T. Onodera K. Xu H, et al. Histomorphometrical study in cavernous lymphangioma of the tongue. Oral Dis. 2007;13:99–104.[PubMed]
9. Fleming JN. Hostikka SL. Chen EY, et al. Plasmacytoid dendritic cells and interferon levels are increased in lymphatic malformations. Otolaryngol Head Neck Surg. 2008;139:671–676.[PubMed]
10. Dowd CN. XI. Hygroma cysticum colli: Its structure and etiology. Ann Surg. 1913;58:112–132.
11. Aloisi F. Pujol-Borrell R. Lymphoid neogenesis in chronic inflammatory diseases. Nature Rev. 2006;6:205–217.[PubMed]
12. Xie Q. Chen L. Fu K, et al. Podoplanin (d2-40): A new immunohistochemical marker for reactive follicular dendritic cells and follicular dendritic cell sarcomas. Int J Clin Exp Pathol. 2008;1:276–284.
13. Raymond I. Al Saati T. Tkaczuk J, et al. CNA.42, a new monoclonal antibody directed against a fixative-resistant antigen of follicular dendritic reticulum cells. Am J Pathol. 1997;151:1577–1585.
14. Carlsen HS. Haraldsen G. Brandtzaeg P, et al. Disparate lymphoid chemokine expression in mice and men: No evidence of CCL21 synthesis by human high endothelial venules. Blood. 2005;106:444–446.[PubMed]
15. Ranuncolo SM. Polo JM. Dierov J, et al. Bcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR. Nature Immunol. 2007;8:705–714.[PubMed]
16. Goestch EHygroma colli cysticum and hygroma axillare: Pathologic and clinical study and report of twelve cases. Arch Surg. 1938;36:394–479.[PubMed][Google Scholar]
17. Nacionales DC. Weinstein JS. Yan XJ, et al. B cell proliferation, somatic hypermutation, class switch recombination, and autoantibody production in ectopic lymphoid tissue in murine lupus. J Immunol. 2009;182:4226–4236.
18. Dieu-Nosjean MC. Antoine M. Danel C, et al. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol. 2008;26:4410–4417.[PubMed]
19. Shields JD. Kourtis IC. Tomei AA, et al. Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Science (New York) 2010;328:749–752.[PubMed]
20. Thaunat O. Kerjaschki D. Nicoletti A. Is defective lymphatic drainage a trigger for lymphoid neogenesis? Trends Immunol. 2006;27:441–445.[PubMed]
21. Gommerman JL. Browning JL. Lymphotoxin/light, lymphoid microenvironments and autoimmune disease. Nature Rev. 2003;3:642–655.[PubMed]
22. Chen SC. Vassileva G. Kinsley D, et al. Ectopic expression of the murine chemokines CCL21a and CCL21b induces the formation of lymph node-like structures in pancreas, but not skin, of transgenic mice. J Immunol. 2002;168:1001–1008.[PubMed]
23. Fan L. Reilly CR. Luo Y, et al. Cutting edge: Ectopic expression of the chemokine TCA4/SLC is sufficient to trigger lymphoid neogenesis. J Immunol. 2000;164:3955–3959.[PubMed]
24. Luther SA. Bidgol A. Hargreaves DC, et al. Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis. J Immunol. 2002;169:424–433.[PubMed]
25. Luther SA. Lopez T. Bai W, et al. BLC expression in pancreatic islets causes B cell recruitment and lymphotoxin-dependent lymphoid neogenesis. Immunity. 2000;12:471–481.[PubMed]
26. Mounzer RH. Svendsen OS. Baluk P, et al. Lymphotoxin-alpha contributes to lymphangiogenesis. Blood. 2010;116:2173–2182.
27. Ruddell A. Mezquita P. Brandvold KA, et al. B lymphocyte-specific c-Myc expression stimulates early and functional expansion of the vasculature and lymphatics during lymphomagenesis. Am J Pathol. 2003;163:2233–2245.
28. Padwa BL. Hayward PG. Ferraro NF, et al. Cervicofacial lymphatic malformation: Clinical course, surgical intervention, and pathogenesis of skeletal hypertrophy. Plastic Reconstr Surg. 1995;95:951–960.[PubMed]
29. Hartl DM. Roger G. Denoyelle F, et al. Extensive lymphangioma presenting with upper airway obstruction. Arch Otolaryngol Head Neck Surg. 2000;126:1378–1382.[PubMed]
30. Perkins JA. Tempero RM. Hannibal MC, et al. Clinical outcomes in lymphocytopenic lymphatic malformation patients. Lymphat Res Biol. 2007;5:169–174.[PubMed]
31. Tempero RM. Hannibal M. Finn LS, et al. Lymphocytopenia in children with lymphatic malformation. Arch Otolaryngol Head Neck Surg. 2006;132:93–97.[PubMed]