Dermatologic manifestation of haematologic diseases

1. Dermatologic manifestation of haematologic diseases By Ghada Fawzy …. Assistant Lecturer

2. Cutaneous manifestation of blood diseases: • Coagulation disorders • Anaemia • Plasma-Cell Disorders and Dysproteinemias • Mastocytosis • Myeloproliferative disorders • Leukaemia • Purpura

3. 1- Coagulation Disorders: A- Antiphospholipid syndrome • acquired, multisystemic disorder characterized by recurrent thromboses in the arterial system, venous system, or both. • classified into 2 groups: primary and secondary. • Secondary type is often associated with SLE and infrequently with other diseases, such as lymphoproliferative disorders, autoimmune diseases, infections (eg, syphilis, HIV, hepatitis C), and drugs (eg, procainamide, quinidine, hydralazine, phenytoin, chlorpromazine). • Serologic markers are antiphospholipid antibodies, lupus anticoagulant, and anticardiolipin.

4. A- Antiphospholipid syndrome • The primary diagnostic criteria: • arterial thrombosis • venous thrombosis • recurrent fetal loss • thrombocytopenia. One of the listed primary criteria is required for diagnosis, combined with a • sustained elevated titer of IgG, anticardiolipin or lupus anticoagulant.

5. A- Antiphospholipid syndrome • Cutaneous manifestations: • livedo reticularis • necrotizing vasculitis • livedo vasculitis • Thrombophlebitis • cutaneous ulceration and necrosis • erythematous macules • purpura, ecchymoses, painful skin nodules • subungual splinter hemorrhages. • Differential diagnoses: • Cryoglobulinemia • warfarin-induced necrosis • purpura fulminans • emboli to the skin • thrombocythemia, protein C deficiency, Sneddon syndrome, and skin ulcers in patients with sickle cell anemia or hemolytic anemia. • In some lesions, hemosiderin deposition can make differentiation from Kaposi sarcoma difficult.

6. Treatment: • anticoagulant (esp. warfarin) and antiplatelet agents. • immunotherapy only in SLE or catastrophic vascular occlusion syndrome (eg, corticosteroids, pulse cyclophosphamide, plasmapheresis, gamma-globulin infusions, IVIG), despite this aggressive approach, the mortality remains high. • Potential new approaches rituximab and hydroxychloroquine • prophylaxis: low-dose aspirin in patients with persistent lupus anticoagulant or high levels of IgG anticardiolipin. • The protective effect of hydroxychloroquine against thrombosis has been reported in patients with SLE.

8. B- Warfarin induced skin necrosis • uncommon serious complication of oral anticoagulation therapy. • occur in 0.01-0.1% of patients. • 85% of patients are women. • common affected sites are the breasts, buttocks, thighs, and abdomen because of the abundance of small dermal blood vessels in fatty tissue. • The initial symptom sensation of pain or cold in the affected area, followed by a well-demarcated erythematous lesion that progresses to bullae formation and full-thickness skin necrosis. Areas of erythematous flush may become edematous and have a peau d'orange effect. The eschar may eventually slough or require extensive surgical debridement. • Most cases occur within the first week of warfarin administration

9. B-Warfarin induced skin necrosis • Biopsy: fibrin deposition in the small veins and postcapillary venules in dermis and subcutis, with hemorrhage and diffuse necrosis in the dermis and the subcutaneous fat. Absence of arterial thrombosis is another characteristic feature. • DD: necrotizing fasciitis, venous gangrene, pyoderma gangrenosum, and cholesterol embolization syndrome. • Patients at risk: receiving large, rapidly loading doses of warfarin, those with a previous episode, protein C or protein S deficiency, or antiphospholipid syndrome • avoiding excessive initial doses of warfarin, and administering vitamin K in the early stages can prevent warfarin-induced skin necrosis. • TTT: oral anticoagulation discontinued, reverse the anticoagulation with plasma, in patients with protein C deficiency, concentrates of protein C have been used. Anticoagulation with heparin should be continued until the necrotic lesions heal. • Despite treatment, approximately 50% of patients ultimately require skin grafting.

10. 2-Cutaneous Manifestations of Anemia • Pallor of the skin and mucocutaneous membranes can be a sign of severe anemia of any cause (hemoglobin <7 g/dL) A- Iron deficiency anemia • Nails: fragile, longitudinal ridges, nail-plate alterations follow, with the development of koilonychia, a spoonlike convexity. • In iron deficiency anemia, reduced oxygen availability is believed to diminish disulfide bond formation, which reduces nail-plate pliability. • angular stomatitis, alterations in tongue papillae, either a change to the filiform type or atrophy • Diffuse hair thinning. Changes in hair quality, increased splitting, dryness, and dullness, are infrequently observed

11. koilonychia

12. B-Pernicious anemia • No distinct cutaneous findings occur in pernicious anemia. • The deep-red, cobblestone-appearing tongue may be a late manifestation. • With excess production of unconjugated bilirubin, the skin tends to have a yellowish hue. • autoimmune phenomena tend to occur together, pernicious anemia may be associated with autoimmune thyroiditis, hypoparathyroidism, and Addison disease. Late-onset vitiligo is reported in as many as 10% of patients with pernicious anemia.

13. C- Sickle cell anaemia: • leg ulcers, usually in the ankle area over the medial or lateral malleoli, are the most common 25% • The incidence is low in children younger than 10 years because of the protective effect of persistent fetal hemoglobin. Other risk factors for developing leg ulceration are anemia, male sex, combined HLA-B35 and HLA-Cw4, and antithrombin III deficiency. • the causes of leg ulceration can be divided into 3 categories: • reduction in blood supply to the skin (infarction being the primary cause) • local edema • minor trauma. • The size of the ulcers varies from a few millimeters to large lesions. The onset is spontaneous, with prodromal pain.

14. C- Sickle cell anaemia:

15. C- Sickle cell anaemia: • A history of an insect bite or intravenous cannulation • Secondary infections, mostly with Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus species are most common. • Systemic infections, osteomyelitis, and tetanus are rare complications. • resistant to healing and tend to be recurrent they may be associated with venous incompetence. • Wearing properly fitting shoes, using insect repellents to prevent ulceration, wearing elastic support stockings.

16. C- Sickle cell anaemia: • Therapy for leg ulcers involves: • gentle debridement • control of local edema (strict bed rest and elevation of the leg), • treatment of infection • blood transfusions to increase hemoglobin level. • Elevation of the fetal hemoglobin level can be achieved by using hydroxyurea, alone or in combination with erythropoietin. • Improvement of leg ulcers was also reported in 2 patients given arginine butyrate. • Skin grafts are advocated for ulcers resistant to more conservative therapy

17. D- Fanconi aneamia • AR: congenital abnormalities, bone marrow failure, and predisposition to malignancy. Patients have an increased incidence of spontaneous chromosomal abnormalities. • By the end of childhood, patients with Fanconi anemia develop hypoplastic bone marrow • Skin findings consist of several abnormalities of pigmentation. • café au lait spots, mostly present at birth. • Diffuse hyperpigmentation, which can also be an acquired phenomenon because of iron overload accompanying multiple transfusions, is present early in life. • hypopigmented macules. • A number of malignancies have been reported particularly myelogenous leukemia. Many individuals die of aplastic anemia. Bone marrow transplantation has been used successfully.

18. 3- Plasma-Cell Disorders and Dysproteinemias • Diseases associated with monoclonal immunoglobulin or light-chain production can cause skin findings. • Skin lesions can be directly related to the abnormal protein production (acting as cold agglutinins or cryoglobulins or causing an increase in viscosity). • Skin diseases (eg, cutaneous plasmacytoma or polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes [POEMS] syndrome) can be observed with clonal plasma cell proliferation. Light-chain deposition in the skin can be a part of the spectrum of symptoms of amyloidosis.

19. A- Cryoglobulinemia • Cryoglobulins are serum immunoglobulins complexed with other immunoglobulins or proteins that reversibly precipitate in cold temperatures.  • Cryoglobulinemia is associated with: • palpable purpura in parts of the body exposed to cold temperatures • Raynaud phenomenon • acral hemorrhagic necrosis • Arthralgia • neurologic manifestations • glomerulonephritis. • severity of the symptoms reflects the serum concentration and the temperature at which cryoglobulins precipitate.

20. A- Cryoglobulinemia • The classification: • Type I cryoglobulins are monoclonal immunoglobulins, usually IgG or IgM, Patients usually have an underlying B-cell malignancy, such as chronic lymphatic leukemia (CLL), multiple myeloma, or B-cell-type non-Hodgkin lymphoma (NHL). it affects the skin, kidneys, and bone marrow. Cutaneous manifestations can precede extracutaneous manifestations by decades. • Mixed cryoglobulinemias consist of type II and type III cryoglobulins. • Type II cryoglobulins are mixed cryoglobulins; 1 component is monoclonal, and 1 component is polyclonal. accounts for 40-60% of cases.can be associated either with B-cell malignancies or with autoimmune disorders, persistent viral infections such as hepatitis C and HIV infection. • Type III cryoglobulins are polyclonal immunoglobulins that form a cryoprecipitate with polyclonal IgG or a nonimmunoglobulin serum component.it can be classified as an immune complex disease. Type III cryoglobulinemia accounts for 40-50% of cases and is not associated with any particular hematologic disorder. Patients with this type of cryoglobulin have an autoimmune process or an infection (eg, with hepatitis B, hepatitis C, or Epstein-Barr virus).

22. Raynaud’s phenomenon:

23. B- Hyperviscosity syndrome • significant increase in the viscosity of whole blood: • which may result from an increased number of cellular blood elements, as in myeloproliferative disorders (eg, polycythemia vera, essential thrombocythemia) • a large amount (>3 g/dL) of monoclonal proteins (mostly the IgM type) in the blood. • may manifest as mucous membrane bleeding, retinopathy, cardiac failure, and neurologic disturbances. • For symptoms to develop, blood viscosity must increase at least 4-fold. • A bleeding tendency can also be explained by clotting-factor antibodies and/or platelet dysfunction because of surface coating by immunoglobulins. • Plasma exchange in patients with severe neurologic impairment. • chemotherapy directed to the underlying dysglobulinemia is not administered.

24. C- Cold agglutinin disease • Cold agglutinins are antibodies, mostly the IgM type, that are directed against the I/i antigens on the surface of RBCs. Cold agglutinins are able to agglutinate RBCs, usually below the body temperature. • Cold agglutinins can be divided into 2 types: monoclonal, which occurs in the idiopathic form and associated with B-cell proliferation, and polyclonal, which accompanies infectious diseases, especially Mycoplasma pneumoniae infection.  • CP: episodes of hemolytic anemia, hemoglobinuria, and cold-provoked vaso-occlusive phenomena. • The most common cutaneous manifestations are acrocyanosis and Raynaud phenomenon. Livedo reticularis, cold-induced urticaria, petechiae, ecchymoses, and hemorrhagic bullae have also been described. Skin ulceration or necrosis is unusual. • Jaundice and/or pallor can follow a severe episode of hemolysis.

25. Acral areas (eg, earlobes, nose, distal extremities) are commonly affected • Symptoms associated with agglutination are quickly reversible on warming. • The severity of the clinical manifestation does not appear to be related to the agglutinin titer. • On microscopic evaluation, dilatation of dermal vessels is extensive, with thinning of vascular walls and without evidence of vasculitis. Eosinophilic thrombi or fibrin can occlude some capillaries. • In patients with small-vessel thrombosis induced by cold agglutinin disease, the differential diagnoses must include disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), warfarin (Coumadin)–induced skin necrosis, cryofibrinogenemia, and paroxysmal nocturnal hemolysis (PNH).

26. The best treatment of is avoidance of cold temperatures. • In contrast to the treatment of other hemolytic anemias, steroids and splenectomy have no role in the treatment of hemolytic anemia due to cold agglutinins. • Cytotoxic agents, such as cyclophosphamide and chlorambucil, may be useful in selected patients to reduce the production of antibody. • Anti-CD20 (rituximab [Rituxan]) has been effective in treating patients with cold agglutinin disease that did not respond to conventional therapies. • Plasmapheresis should be reserved for patients with ongoing severe hemolysis, severe acrocyanosis

27. D- Plasmacytoma • Neoplasms originating from mature secretory B lymphocytes (plasma cells) • Multiple myeloma arises from bone-marrow plasma cells and typically manifests as osteolytic lesions on the skull, vertebrae, ribs, pelvis, and proximal long bones. Anemia, kidney dysfunction, hypercalcemia, and susceptibility to bacterial infections frequently accompany multiple myeloma. • Monoclonal peaks of immunoglobulin are found on electrophoresis and occasionally accompanied by light chains in the urine. • Several nonspecific lesions, including amyloidosis, cold urticaria, alopecia, pigmentation, and Raynaud phenomenon, are associated with multiple myeloma. Follicular hyperkeratosis, most prominent on the nose, is considered a sign of paraneoplastic myeloma.

29. Cutaneous plasmacytoma • nontender, smooth, cutaneous or subcutaneous nodules 1-5 cm in diameter. The lesions are flesh- or plum-colored and can become crusted or ulcerated. mostly distributed on the extremities, trunk, and face. • secondary cutaneous plasmacytomas in multiple myeloma. Lesions may develop as a direct extension of underlying bone lesions, or, more frequently, they manifest as metastatic foci. • Primary cutaneous plasmacytomas with no evidence of involvement of other tissues are exceedingly rare. • dermis and the subcutaneous tissues are infiltrated by plasma cells that vary in maturity. Plasma cells can be distinguished from benign plasma cell proliferation (cutaneous plasmacytosis) on the basis of their monoclonality (presence of only kappa light chains or only lambda light chains). • Immunoglobulins produced may be of any type, but immunoglobulin A (IgA) appears to be frequently found.

30. E- POEMS syndrome • Polyneuropathy was present in all patients and was usually sensorimotor in nature. • Organomegaly: hepatomegaly (82%), lymphadenopathy (65%), or splenomegaly (39%). • Endocrinopathy occurred as impotence (78%) or gynecomastia (68%), amenorrhea (68%) . Other abnormalities were glucose intolerance, hyperthyroidism, hyperprolactinemia, and adrenal insufficiency. • M protein (abnormal monoclonal antibody) • Skin lesions: diffuse hyperpigmentation, thickening with sclerodermoid changes, Hypertrichosis, less common Digital clubbing, white fingernails, sicca syndrome, acrocyanosis, plethora, hemangiomas , telangiectasias , and Raynaud phenomenon. • Patients have bony lesions, but unlike those in multiple myeloma, the bony lesions are mostly osteosclerotic. • Solitary osteosclerotic lesions can be treated with local radiation, Widespread systemic disease requires treatment with systemic chemotherapy. Melphalan and prednison, hematopoietic stem cell transplantation

31. F- Amyloidosis: • Classification: amyloid light-chain momoclonal protein (AL) and serum protein A amyloidosis (AA). • AA-type amyloidosis (secondary systemic amyloidosis) is usually associated with a chronic inflammatory process, such as rheumatoid arthritis, chronic osteomyelitis, tuberculosis, or leprosy. Although the deposition of amyloid in the skin is common in AA, this deposition rarely leads to clinically apparent skin lesions. • AL-type amyloidosis is the primary form and includes forms associated with multiple myeloma and Waldenström macroglobulinemia. AL commonly affects the skin. The most characteristic skin lesions are nonpruritic, nontender, shiny, waxy papules, which commonly develop on the eyelids, also know as raccoon eyes. Lesions can also be present in the skin folds, the retroauricular folds, the anogenital region, or the oral mucosa. Subcutaneous nodules or plaques are also described.

32. Purpura occurs due to deposition of amyloid in blood vessel walls, which results in the extreme fragility of skin vessels. frequently found on the eyelids of patients with AL-type amyloidosis. • Scalp involvement may be evident with hair loss. • Mucocutaneous changes in the oral cavity can include rubbery papules, petechiae, and ecchymoses macroglossia,dysphonia and dysphagia, xerostomia, resulting from salivary gland infiltration • AL amyloid deposition is also responsible for peripheral neuropathy, carpal tunnel syndrome, orthostatic hypotension (autonomic neuropathy), congestive heart failure, and nephrotic syndrome.

34. 4- Mastocytosis: • Mastocytosis is a disorder of mast cell proliferation that has both cutaneous features and systemic features. The most frequent site is the skin, although mast cell hyperplasia can occur in the bone marrow, liver, spleen, lymph nodes, GI tract, and skeletal system.

35. Mastocytosis: • WHO classification: • cutaneous mastocytosis: This includes nodular, maculopapular (urticaria pigmentosa or telangiectasia macularis eruptive perstans), and diffuse cutaneous mastocytosis. This is limited to the skin in the absence of involvement of other organs. • Indolent mastocytosis: This includes smoldering systemic mastocytosis and isolated bone marrow mastocytosis. Good prognosis • Systemic mastocytosis: This occurs with an associated hematologic non–mast cell lineage disorder. • Aggressive systemic mastocytosis: Patients have lymphadenopathy with blood or tissue eosinophilia. • Mast cell leukemia: Patients are grouped as those with more than or those with less than 10% mast cells in the peripherabl blood. • Mast cell sarcoma • Extracutaneous mastocytoma

36. Mastocytosis: • mastocytomas may be present at birth, they mostly appear within the first 3 months of life; they are rarely described in adults. • Lesions are solitary or multiple but few in number. They appear as macules or papules and are yellowish to tan.

37. Urticaria pigmentosa

38. telangiectasia macularis eruptiva perstans:

39. Treatment: • In extensive cutaneous disease unresponsive to other forms of treatment, PUVA can be used, which can decrease the pruritus and whealing of urticaria pigmentosa in adults, but relapses within 3-6 months after cessation of therapy are common • Aggressive systemic mastocytosis is commonly treated with interferon alfa-2b and/or glucocorticoids or cladribine. • Mast cell leukemia is treated similarly to patients with acute leukemia. Even with aggressive chemotherapy, patients with mast cell leukemia have a poor prognosis, and bone marrow transplantation can be considered.

40. 5- Meyloproliferative disorders: A- Polycythemia vera • increase of circulating RBCs that causes an increase in hematocrit values higher than 55% characterizes polycythemia vera. • can be accompanied by a moderate increase in leukocytes and, less frequently, by thrombocytosis. • Skin changes are characteristic: Ruddiness and occasionally cyanosis, affecting mostly the face, neck, and distal parts of the extremities. Less frequent changes are telangiectasias and bleeding gums. Rosacea and purpura can be present. • Pruritus, which is triggered by a bath or a shower and which lasts up to 1 hour, is a typical symptom in patients with polycythemia vera. • The degree of pruritus is not related to the severity of the disease. • H1 and H2 blockers is indicated because elevation of the histamine levels corresponds with symptoms. failure of the pruritus to respond to antihistamine suggests that an increased histamine level is not the sole factor in symptom development. Patients with polycythemia vera often have iron deficiency • use of selective serotonin reuptake inhibitors (SSRIs) in patients with polycythemia vera in whom pruritus responded favorably.

41. A- Polythycemia vera: • Can cause erythromelalgia (a form of paroxysmal vasodilatation affecting the skin): intense burning sensation, pain, and increased local skin temperature. These paroxysms may last minutes to days and may be relieved by cooling. They are rapidly reversed with antiplatelet therapy and preservation of arterial pulses. Livedo reticularis • abnormal arachidonic acid metabolism occurs in the platelets in persons with polycythemia vera. • responds well to low-dose aspirin 50-100 mg/d and to a reduction in the platelet count. • Ttt: maintain the hematocrit below 45% (0.45) in men and 42% (0.42) in women. Phlebotomy alone is effective, • Patients at high risk for thrombosis should receive supplemental hydroxyurea • Interferon-alfa used in patients with refractory pruritus, in high-risk women of childbearing potential, and in patients whose condition is refractory to all other treatments.

42. B- Cutaneous myelofibrosis • myeloproliferative disorder with a clonal proliferation of defective stem cells in the bone marrow. • The hallmark of myelofibrosis is extramedullary hematopoiesis, which rarely presents as a cutaneous form. • Overproduction of abnormal megakaryocytes produces excess amounts of platelet-derived growth factor, which is a stimulus for fibroblast proliferation and collagen production. • it may manifest as erythematous plaques, nodules, erythema, ulcers, or bullae. Microscopy of cutaneous lesions (dermal and subcutaneous nodules) shows infiltrates of mature and immature myeloid cells, erythroid precursors, and a predominance of megakaryocytes. Marked production of reticulin fibers is typical. • Neutrophilic dermatoses can be a presenting or a complicating feature of myelofibrosis, and it can progress to bullae or pyoderma gangrenosum.

43. C- Hydroxyurea-induced skin changes • Hydroxyurea is probably the medication most commonly used to treat polycythemia vera and essential thrombocythemia. • The most frequent skin disorders were skin dryness ,melanonychia, actinic keratosis ,leg ulcers increased skin pigmentation ,and squamous cell cancer . • Other manifestations include alopecia (rare), facial and peripheral edema, gangrene, nail and/or skin atrophy, scaling, and violet papules.

44. 6- LEUKAEMIA: specific lesions • Leukemia cutis, represents localized or disseminated skin infiltration by blast cells. • leukemia cutis is a sign of relapse or dissemination of medullary disease. common in people older than 50 years. • associated with acute monocytic leukemia and acute myelomonocytic leukemia, but it can be observed in chronic leukemia, including the leukemic phase of non-Hodgkin lymphoma and hairy cell leukemia. • Skin pain, tenderness, and pruritus are usually absent. Most commonly, lesions are discrete, firm, violaceous or red-brown papules, nodules, or plaques. On occasion, ulcerative lesions or hemorrhagic bullae are observed.

46. Sweet syndrome: • acute febrile neutrophilic dermatosis: painful, erythematous, cutaneous tender plaques with an irregular pseudovesicular surface, not pruritic. Central clearing may appear. Common on the face, neck, and upper or lower extremities. • Mucous membranes can be affected, usually accompanied by fever, elevated ESR, and leukocytosis. • dense dermal infiltrate of neutrophils without vasculitis characterize Sweet syndrome. • mostly idiopathic, except for 10-20% of cases, which are associated with hematopoietic malignancies (eg, acute myelogenous leukemia [AML], myelodysplastic syndrome, lymphoproliferative disorders, multiple myeloma). Rare cases have been associated with solid malignancies (mostly of genitourinary origin).

49. 7- purpura: Purpura divided into 4 groups based on the characteristics (eg, size, shape, depth) of blood extravasation: • Petechiae: are superficial, pinpoint (<3 mm), red or purple, nonblanching macules that mostly occur in dependent areas. Petechiae imply a platelet-related condition or vessel disease. • Ecchymoses are larger than 3 mm, flat, and observed with notable extravasation commonly known as a bruise. Ecchymoses initially form an irregular purple patch, which eventually turns yellow and fades. • Vibices are purpuric lesions that are linear and are mostly caused by scratching. • Hematomata are deeper collections of blood in the skin. Fluctuation is often palpated.