Life-Threatening Hemangioma

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1 Riunione Rimini 19 Maggio 2006 Life-Threatening Hemangioma Patrizia Dall Igna

2 Life-Threatening? Local compression or displacement of adjacent critical organs Congestive cardiac failure Acute respiratory distress Platelet consumption (Kasabach-Merritt Syndrome)

3 Kasabach-Merritt Syndrome (KMS)

4 Syndrome? In 1940 Kasabach and Merritt described a male infant with a discolored, indurated mass on his left thigh, that rapidly grew and affected the entire left leg, scrotum, abdomen and thorax Association of hemangioma, thrombocytopenia, coagulopathy

5 Pathophysiology Presumed to be that of platelet trapping

6 Pathophysiology How platelets become trapped not clear Physical entrapment Adhesion to abnormally proliferating endothelium within the hemangioma (Gilon, 1959)

7 Pathophysiology The PLT are consumed in the process, with release of PLTderived growht factor, a mitogen. Increased thrombin generation occur, followed by the development of DIC Continued consumption of platelet and clotting factors along with initiation of fibrinolysis results in intralesional bleeding with rapid enlargement of hemangioma and so the cycle continues

8 Histology Histological types most frequently reported Kaposiform HemangioEndothelioma Tufted Angioma (previously termed angioblastoma)

9 Emangioendotelioma Kaposiforme Rare Rapid growth (KHE) Trunk, retroperitoneum, visceral involvement, extremities, head-neck Irregular, infiltrating nodules of compressed vessels Spindle cells con spazi rounded with hyaline granules, stippled hemosiderin and small vacuoles Microthrombi Large lymphatic channels P. North, SPP 2004

10 while resembling JH, KHE notably shows no tendency to spontaneously involute Kaposiform Hemangioendothelioma: A study of 33 cases emphasizing its pathologic, immunophenotypic, biologic uniqueness from juvenile hemangioma Am J Surg Pathol, 2004

11 Histology Many reported cases (including hepatic hemangioma, multiple splenic hemangiomas, diffuse neonatal hemangiomatosis) did not have KHE/TA histology (Longeville 1997, Hoeger 1995, Ryard 1991) However KMS is not a complication of classic hemangioma of infancy but of KHE (Enjolras 2000, Lyons 2004)

12 Management No one treatment modality as been established as consistently efficacious

13 Management No single modality is favored over others, and many regimens have been investigated, with variable success

14 Key to correct thrombocytopenia To treat the tumor responsible for platelet trapping

15 Supportive therapy Should not focus on the thrombocytopenia PLT should not be given unless the patient is actively bleeding or is being prepared for an operation Transfused PLT are quickly consumed by the tumor, with a halflife of between 1 and 24 hours Degranulating PLT release proangiogenic protein that stimulate the tumor and increase permeability by vascular endothelial growth factor

16 Treatment options Surgical excision rarely possible Compression therapy (bandaging, pneumatic) particularly useful for limb lesions Arterial embolization has been effective, but feeder vessels are often small in KHE and embolization usually provides temporary improvement Risks: Ischemic damage/ infarction of vital organs, worsening of hematologic parameters

17 Risoluzione dei sintomi sistemici dopo 2 mesi Progressiva riduzione di volume della lesione Limitazione funzionale dell articolazione del ginocchio sinistro

18 Pharmacologic treatment Corticosteroids Most patients respond to corticosteroids within a few days Prednisolone 2-3 mg/kg/die Approximately one-third are non-responders Higher doses of 5 mg/kg/die have been used effectively and megadose therapy using 30 mg/kg/die for 3 days tailing off over 4-5 weeks had good effect in 15 cases Mechanism of action poorly understood (antimitotic drug)

19 Pharmacologic treatment Interferon α2a, α2b IFN works as antiproliferative/antiangiogenic agent: it decreases endothelial cell proliferation by downregulating bfgf (blocking production of factors that stimulate angiogenesis, such as fibroblast growht factor-2 and vascular endothelial growht factor) Onset of action slower than that of steroids: a response with a standard dose of 3 millions/m 2 /die seen within 1-2 weeks, but can take up to a months

20 Pharmacologic treatment Interferon α2a, α2b Therapy is stopped after a few weeks if no response is seen or continued for several months according to clinical progress Difficult to know how much IFN is contributing to the overall response or whether spontaneous involution has occurred simultaneously

21 Pharmacologic treatment Interferon α2a, α2b Collateral effects Influenzalike symptoms Elevations aminotransferase levels Renal failure Neurologic effects (lethargia, spastic paraplegia)

22 Sarkar (Boston) Plast reconstr Surg 1997 Interferon Used successfully in a large number of steroids non-responders (Ezekowitz 1992, Hatley 1993, McArthur 1995, Powell 1999) but reported also as a failure in others (Teillac-Hamel 1992) 14 children 6 significant decrease 2 stable disease 6 no response Avarage time of response 4 weeks Treatment avarage duration 21 (+/-12) weeks Frevel E J Pediatr Surg month old boy with giant cutaneous hemangioma Steroids poor response Interferon tumor regression and resolution coagulopathy

23 Greinwald Arch Otolaryng Head Neck Surg 1999 Interferon 19 children (massive or life-threatening) 8 significant decrease Szymic-Kantorowicz E J Pediatr Surg, 2005 Interferon 8 children (high risk) 7 significant decrease 1 dead 3 substantial decrease 5 intermediate response 3 no response Treatment avarage duration 10.2 months de la Hunt J Ped Surg, month old girl (posterior, lateral abdominal wall) Prednisolone (2 mg/kg), Interferon Cod liver oil and Prednisolone (4 mg/kg) no bleeding for 2 weeks but Cushing and still thrombocytopenia Pentoxifylline started at 15 months e gradually reduxed in 5 years

24 Wananukul, Int J Dermatology m, Abdominal wall 6 y, Abdomen, leg 2 m, arm 6 w, leg 2 m, cheek,mandib 1 m, intrabd 1 m, chest wall 2 m, back 9 y, abd wall, leg 5 m, back Predinisolone, Dipyridamole Predisolone, dipyridamole Predn, dipyr, IFN Predn, dipyr, IFN Predn, dipyr, IFN Predn, dipyr, IFN Predn, dipyr, IFN Predn, dipyr, IFN,VBL Predn, dipyr, IFN,VCR Predn, dipyr, IFN, embolization Tapered off in 12 months Tapered off in 8 m Death Death Tapered off in 12 m Tapered off in 18 m Tapered off in 12 m Tapered off in 5 m Tapered off in 24 m Tapered off in 12 m

25 Pharmacologic treatment Chemotherapy Good response of several steroid non-responders with Vincristine (1-2 mg/m2/weekly) (Enjolras 2000, 2004) Cyclophosphamide (10 mg/kg/die for 3 days each month) used succesfully in a particular resistant case (Perez-Payarols 1995) Good effect of a combination chemotherapy with VAC (Vincristine, Actinomicine, Cyclophosphamide) in a patient with recurrent bony lesions and a second patient with unresectable KHE

26 Haisley-Royster, J Ped Hematol Oncol, 2002 Vincristine 15 children (KMS) 13 significant decrease in size Avarage time of response 4 weeks Treatment avarage duration 21 (+/-12) weeks Hu, J Ped Hemtol Oncol, 1998 VAC 1 girl (leg enlarging hemagioma) Response after first cycle

27 Enjolras Archives de Pediatrie, 2004 Vincristine (after failure of steroids and steroids+ifn; in 2 cases as first line treatment) Masashi Taki Pediatrics International, children 6 head-neck, 2 liver, 1 disseminated Vincristine (after failure of steroids, IFN, RT, arterial embolization) 7 clear clinical response 2 slow response Treatment average duration months 1 child head-neck Treatment duration 24 months

28 Mulliken, Ezekowitz N Engl J Med, 2004 Newborn girl with large, superficial cutaneous mass of the thorax and KMS Prednisone 3 mg/kg/die: no response Combination therapy: Cyclophosphamide + Vincristine + Interferon Within 4 days PLT count rose, lesion regressed Maintenance therapy with Interferon for 6 months

29 Radiotherapy Radiosensitivity demonstrated since 1940s Previously one of the mainstays of treatment rarely considered as first line therapy nowadays due to late effects Effective when used in conjunction with steroids (Miller Orton, 1992) Attempts to use low-dose RT in the multimodal treatment

30 Radiotherapy Shin (Corea), Pediatrics International cases in 20 years 3 resection (1 after steroids) 3 alive 34 steroids 3 good, 1 lost 2 interferon 2 good 25 radiotherapy 22 good 1 dead 2 lost 3 radiotherapy + interferon 2 good, 1 dead Interferon followed by RT (200 cgy/die for 3 days) Median follow-up 6 years; no disease RT-related

31 Radiotherapy Hesselmann Br J Radiol 2002 Newborn male with huge hemangioma of the upper right cervical region and KMS Prednisolone (5 mg/kg/die) no effect after 2 weeks Simultaneously: Radiotherapy (total dose of 9.5 Gy in 5 fractions) + Interferon Tumor response and increase PLT count within 4 weeks

32 El Dessouky M J Ped Surg 1988 Review of 153 cases Radiotherapy as sole therapy or in combination with steroids yelded the lowest mortality rate Dutton, Plowman Br J Radiol 1991 Anomalous aggressive radioresistant hemangioma may occur Frevel Eur J Pediatr m old boy, giant cutaneous hemangioma Poor response corticosteroids IFN Tumor regression with RT

33 Pharmacologic treatment Anticoagulants (heparine) Antiplatelet (ticlopidine, pentossifilline) Antifibrinolitic agents (ε-aminocaproic acid, tranexamic acid) Their use in an attempt to control the consumptive process is controversial Little evidence of benefit Delicate balance between thrombosis, fibrinolysis and hemorrage may be altered

34 Experimental therapies Antiangiogenetic agents Antiangiogenic agents (IL12, CM101, CA1, vitaxin) have entered phase II clinical trials; Marmistat and antivascular endotelial growth factor monoclonal antibody have entered phase III. None is freely available for clinical use Thalidomide currently under study in Kaposi sarcoma and hepatocarcinoma Good response with angiogenesis inhibitor angiostatin in murine hemangioendotelioma (Lanutti 1997)

35 KMS - Management options (Br J Hematol, 2001) Isolated, accessible lesions Refer to surgeon Isolated, unresectable lesions Refer to interventional radilogist (?) Diffuse or multiple lesions First line therapy: PREDNISOLONE INTERFERON Deterioration No Improvement after 1-2 weeks Yes Add: 1) The other, untried first line therapy (Prednisolone or Interferon) 2) Second line adjuvant therapy Alternative first line therapy (Prednisolone or Interferon) Further deterioration Continue first line therapy Third line therapy Experimental therapies

36 F, 3 mesi KHE retroperitoneale con KMS Terapia Chirurgica: 1 biopsia, 3 exeresi incomplete Medica: Metilprednisolone, Interferone, Ciclofosfamide Decesso

37 F, 4 mesi Anemia, melena Emangioma infantile a manicotto attorno all aorta addominale e alle aa. iliache e che sembra interessare anche parte del mesentere. Biopsia Terapia Prednisone (ogni tentativo di riduzione della dose è seguito da ripresa delle emorragie gastrointestinali), Vincristina (7 cicli) A 5 mesi da stop CT: un po ridotta l iperintensità del segnale mesenterico da presenza di formazione angiomatosa nota che comunque persiste ancora discretamente estesa

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40 F, 3 mesi Dispnea, inappetenza, febbricola, melena Lesione mediastino anteriore e medio, retroperitoneo, inglobante aorta e tripode celiaco, e a contatto con i poli renali superiori No istologia Terapia Chirurgica: Posizionamento di drenaggi pleurici bilaterali e catetere intrapericardico Medica: Metilprednisolone, Desametasone, Interferone, Ciclofosfamide, Vincristina Decesso

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42 Questions

43 What kind of therapy? Is the biopsy really necessary?

44 Does formulation of therapeutic guidelines make any sense?

45 yet the numbers of reported cases remains small and many have appeared in clinical studies without accompanying illustrations Kaposiform Hemangioendothelioma: A study of 33 cases emphasizing its pathologic, immunophenotypic, biologic uniqueness from juvenile hemangioma Am J Surg Pathol, 2004

46 Serum level of vascular endothelial growth factor in proliferating hemangiomas is significantly higher than that in involuting hemangiomas or vascular malformation The serum level of vascular endothelial growth factor may be useful in differentiating hemangiomas and judging the efficacy of therapy.

47 Biopsy is important Differential diagnosis Infantile hemangioma KHE Malignant tumors KHE may residue after resolution of KMS and deserves careful follow-up

48 ..alla prossima riunione

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53 Treatment options Experimental therapies Laser therapy in rapidly proliferating superficial cutaneous hemangioma (Barlow 1996) Pegylated recombinant human megakaryocyte growth and development factor used in murine model of KMS with reduction of tumor size and recovery PLT count (Verheul 1999)

54 Treatment options First line therapy Simple single lesions: Surgical excision, embolization Diffuse, extensive disease Prednisolone 2-3 mg/kg/die (increasing to 5 mg/kg/die) α-interferon 3 millions/m 2 /die Second line therapy (if no response) Vincristine 1-5 mg/m2 weekly for 4 weeks Localized radiotherapy Combination chemotherapy (Vincristine, Cyclophosphamide) Antifibrinolitic,or antiplatelets agents Experimental therapies