Cutaneous pseudolymphoma

it comprises group of lesions simulating cutaneous lymphoma both clinically and histopathologically but does not meet the criteria for malignancy.

1. Cutaneous pseudolymphoma presenter : dr. sheikh tousif reza moderator: dr. Jayaprakash shetty k

2. Historical aspects Cutaneous pseudolymphoma (CPL) was first described under the term sarcomatosis cutis by Kaposi in 1891. In 1923, Bilerstein coined term lymphocytoma cutis Term lymphadenosis benigna cutis was introduced by bafverstedt in 1943 In 1967, Lever introduced term pseudolymphoma of Spiegler and Fendt Subsequently,Caro and Helwig in 1969 introduced term cutaneous lymphoid hyperplasia

3. Definition A process that simulates lymphoma, primarily histologically but sometimes clinically, which at the time of diagnosis appears to have a benign biologic behaviour and does not satisfy criteria for malignant lymphoma.

4. This is a heterogeneous group of dermatoses with clinical manifestations varying from tumor -like nodes to flat cell infiltrates. It does not refer a specific disease It does not imply anything about the cause But , it implies a process of accumulation of lymphocytes in the skin in response to variety of known and unknown stimuli.

5. Classification of cutaneous pseudolymphoma Cutaneous T-cell pseudolymphoma i ) Band like pattern ii) Nodular pattern Cutaneous B cell pseudolymphoma i ) Nodular pattern

6. Cutaneous T-cell pseudolymphoma (Band pattern) i ) Idiopathic ii) Lymphomatoid drug eruptions (mc) iii) Lymphomatoid contact dermatitis iv) Nodular scabies v) Actinic retinioid vi) Lymphomatoid papulosis (type B) vii) Clonal

7. Cutaneous T-cell pseudolymphoma (Nodular pattern) i ) Anticonvulsant induced pseudolymphoma syndrome ii) Persistent nodular arthropod bite reaction iii) Nodular scabies (mc) iv) Acral pseudolymphomatous angiokeratoma v) Lymphomatoid papulosis (type A)

8. Cutaneous B-cell pseudolymphoma (Nodular pattern) i ) Idiopathic lymphocytoma cutis ii) Borrelial lymphocytoma cutis iii) Tatto induced lymphocytoma cutis iv) Post-herpes zoster scar lymphocytoma cutis v) Lymphocytoma cutis caused by antigen injections/acupuncture vi) Persistent nodular arthropod-bite reactions vii) Lymphomatoid drug eruptions viii) Acral pseudolymphomatous angiokeratoma ix) Clonal

9. causes of cutaneous pseudolymphoma 1. Drugs 2. Foreign agents : tattoo dyes, insect bites, scabies, injection of arthropod venom, vaccinations, contactants , trauma, acupuncture 3 . Infections: B. burgdorferi , varicella zoster, HIV 4. Photosensitivity 5. Idiopathic

10. lymphamatoid drug eruptions It can be divided into 2 categories a) Anticonvulsant induced pseudolymphoma syndrome b) Cutaneous lymphoma induced by drug other than anticonvulsants.

11. lymphamatoid drug eruptions within 2 to 8 weeks Clinical triad Eosinophilia Hepatosplenomegaly Lesions disappear after discontinuing the drug. Fever Lymphadenopathy Erythematous eruptions Widespread erythematous papules,plaques or nodules

12. pathogenesis of lymphomatoid drug eruptions Significant stimulation of drug induced blastic transformation of lymphocytes Impaired ability of T-suppressor lymphocytes to suppress B-cell differentiation and immunoglobulin production Increase in the relative and absolute number of peripheral T lymphocytes

13. Prototypic reaction pattern resembles mycosis fungoides but also lymphocytoma cutis and follicular mucinosis . In anti- convulsant induced pseudolymphoma syndrome, the lymph node may show focal necrosis, eosinophilic and histiocyte infiltration. Acanthosis Minimal spongiosis Epidermotropic lymphocytes

14. Lymphomatoid contact dermatitis Pruritic , generalized, discrete and confluent, erythematous , scaly papules, and plaques. Similar histologic features of Mycosis fungoides . Etiologic elements: gold, nickel and paraphenylenediamine Superficial lymphocytic dermatitis Spongiosis Edema in papillary dermis

15. Persistent nodular arthropod-bite reactions and nodular scabies. Multiple pruritic firm erythematous to red-brown papules and nodules Elbows, abdomen, genitalia, and axillae . Pathogenesis thought to be a delayed-type hypersensitivity reaction

16. Acanthosis Perivascular and interstitial infiltrate

17. Acral pseudolymphomatous angiokeratoma 2 to 16 yrs Unilateral eruption of 1 to 5 mm, red or violaceous , discrete, irregularly shaped, angiomatous papules with hyperkeratotic collars present on acral regions. Variant of the persistent nodular arthropod reactions. Raised , scaly, undulating lesion

18. Top heavy pattern infiltrates Secondary follicles with germinal centre Thick walled blood vessels with plump endothelial cells

19. Actinic reticuloid Severe, chronic, persistent, pruritic photosensitive dermatosis . Red, scaly, lichenoid , papules, plaques and nodules on light exposed skin. Leonine facies with deep furrows in lichenified skin may develop. Generalized lymphadenopathy

20. Acanthosis Exocytosis of lymphocytes multinucleated fibroblasts Thick walled blood vessels Vertically oriented coarse collagen bundles parallel to the rete ridges

21. Lymphamatoid papulosis Criteria to diagnose are : a) Multiple ulcerative papulonodules b) Waxing and waning of lesions c) Less than 3 cm during 3 months of observation. d) Absence of lymphadenopathy and systemic involvement Five subtypes: A,B,C,D,E

22. Type A : most common, wedge-shaped infiltrate comprising large pleomorphic and anaplastic CD30 lymphocytes.The admixed inflammatory infiltrate consists of histiocytes , neutrophils , and eosinophils

23. Type B : Band like infiltrate

24. Type C : CD 30+ cells with fewer inflammatory cells CD 30+ cells > 50%

25. Type D : prominent epidermotropism of atypical small- and medium-sized CD8 and CD30 pleomorphic lymphocytes. CD 8+

26. Type E : Angioinvasive type, thrombi, vascular invasion and cause necrosis and ulceration.

27. jessner lymphocytic infiltration of the skin Asymptomatic, Non-scaly, erythematous papules or plaques Predominantly on face and neck,upper trunk or arms of several months duration Majority of cases occur in middle aged adults

28. Deep perivascular infiltration, may extend to subcutis Normal epidermis

29. Idiopathic lymphocytic cutis Sites of invovement Also known as cutaneous lymphoid hyperplasia, pseudolymphoma of Spiegler and Fendt , lymphodenosis benigna adenoisis Both localized and generalized forms Face 70% Chest 36% Upper 25% extremities Multiple erythematous firm papules on the tip of the nose

30. Well defined “top-heavy” nodular infiltrate in the upper dermis

31. Borrelial lymphocytoma cutis Borrelia burgdorferi infection Vector : Ixodes ricinus tick 0.6 to 1.3% reported in lyme disease Predilection site : ear lobule, nipple and areola, nose and scrotal region Blue-red plaque or nodule , 1 to 5 cm

32. Thin grenz zone in upper dermis Dense, diffuse infiltrate of small and large lymphocytes admixed with occasional histiocytes and plasma cells.

33. Vaccination induced cutaneous pseudolymphoma Appear at the site of vaccination Reactive B-cell growth pattern with many histiocytes These histiocytes have granular eosinophilic to basophilic cytoplasm representing intracellular aluminium deposits.

34. Pseudolymphoma folliculitis Solitary nodule on a face Dense lymphocytic infiltrate in dermis and subcutaneous fat The walls of hair follicles are enlarged and irregular Their epithelium is blurred by lymphocytic infiltrates

35. Kimura ‘s disease Single or multiple nodules upto 10 cm in diameter Head and neck – most common Peripheral eosinophilia and regional lymphadenopathy

36. Abundant number of eosinophils in germinal centre Germinal centre formation in deeper dermis

37. Castleman’s disease Also referred to as angiofollicular lymph node hyperplasia First described by Benjamin Castleman in 1956 Types of Castleman’s disease Unicentric and Multicentric Hyaline vascular , Plasmacytic and Mixed cellularity variety based on histopathology HIV associated

38. Unicentric Castleman’s disease Marked vascular proliferation with hyalinization broad mantle zone consisting of a concentric layering of lymphocytes resulting in an onion-skin appearance

39. Multicentric castleman’s disease Interfollicular region shows diffuse plasma cell infiltration Eosinophilic deposits of fibrin and immune complexes

40. Small plaque psoriasis Small, flat, erythematous lesions seem indistinguishable from those of conventional mycosis fungoides .

41. Superficial infiltrate in papillary dermis Intradermal lymphocytes

42. Idiopathic follicular mucinosis Slightly erythematous patch on the lumbal region follicular distribution of the lesions

43. Dense perifollicular lymphoid infiltrates Hair follicle Focal deposition of mucin Intraepithelial lymphocytes

44. Lupus erythematosus Lupus erythematosus profundus , also referred as lupus erythematosus panniculitis . Dermal subcutaneous interface shows intense inflammatory infiltrate Adipose tissue hyalinization

45. Pigmented purpuric dermatosis Dense lymphohistiocytic infiltrate is present in the superficial dermis in a band-like fashion spongiosis Extravasated RBCs near the venules

46. Perniosis (chilblains) Abnormal inflammatory response to cold Seen commonly in acral locations Papillary dermal edema Superficial and deep perivascular lymphocytic infiltration

47. Swollen Endothelial cells and show infiltration by lymphocytes Medium-sized vessels infiltrated by lymphocytes

48. Histologic patterns of cutaneous pseudolymhoma Histologic diagnosis of CPL depends on two considerations (1) the architectural pattern of the infiltrate and (2) the composition and cytologic condition of the cells that comprise the infiltrate. Patterns of the infiltrate in CPL: a bandlike pattern and a nodular pattern

49. Histologic patterns of cutaneous t-cell pseudolymhoma Mostly band like pattern similar to mycosis fungoides . Blurring of the dermoepidermal junction. variable acanthosis and minimal spongiosis . Epidermotropism of lymphocytes, with occasional Pautrier microabscess like collections.

50. Histologic features of cutaneous B-cell pseudolymphoma Nodular or diffuse infiltrate of lymphocytes Infiltrates involve the papillary dermis Germinal centers are divided into 2 types a) small cell nodular form - typical germinal centre and lacks cellular pleomorphism . b) large cell nodular form- large pleomorphic lymphocytes and frequent mitotic figures.

51. Immunohistochemical studies (1) overexpression or deletion of certain markers in certain populations of lymphocytes, (2) the presence of so-called immature markers or determinants, (3) the presence of antigens expressed solely by malignant lymphoid cells

52. Immunohistochemical features of cutaneous t-cell pseudolymphoma Most are CD4+ with the exception of actinic reticuloid and HIV related cutaneous PL which are CD8+. Lymphomatoid papulosis show CD30+. In lymphomatoid papulosis , large atypical lymphocytes are CD30+. Loss of pan-T-cell markers (CD2, CD3, CD5) described in CTCL has not been reported in CTPL. loss of CD7 , a common finding in CTCL, is rare in CTPL

53. Immunohistochemical features of cutaneous B-cell pseudolymphoma Expression of polyclonal light chains i.e. mixture of kappa and lambda in pseudolymphoma in contrast to lymphoma in which one light chain predominates. MT2/CD45RA and Anti-bcl-2 protein monoclonal antibodies are also useful markers in distinguishing primary cutaneous follicular lymphomas from CBPL with germinal centers .

54. Clonality “ Polyclonality signifies benign, monoclonality signifies malignant”- however is not absolute. Monoclonality has been demonstrated in some benign or reactive conditions, such as Lymphomatoid papulosis , pityriasis lichenoides et varioliformis acuta , and cutaneous lymphoid hyperplasia.

55. The finding of clonal T- or B-cell populations in Cutaneous pseudolymphoma suggests that gene rearrangement analysis cannot be used as an absolute criterion in the differentiation between CPL and cutaneous lymphoma. Presence of clonality must be interpreted in the context of the clinicopathologic and immunohistochemical features of cutaneous lymphoproliferative processes

56. Ct-cell pl vs c t-cell lymphoma Features T cell psedo T cell lymphoma Presentation Localized Generalized Clinical course Spontaneous remission Progressive Epidermotropism Mild Present Spongisis +++++ Minimal Pautrier microabscess -------- +++++ Lymphocytes Small/benign looking Large/ atypical CD2,CD3,CD5 +++++ ---------- Loss of CD7 Rare Common TCR rearrangement 10-19% 90%

57. Cb -cell pl vs c b-cell lymphoma Cutaneous B cell psedo Cutaneous B cell lymphoma Acanthosis ++++ Acanthosis ----- Top heavy infiltrate Bottom heavy infiltrate Indian filing ------ Indian filing ++++ Mixed infiltrates of lymphocyte Monomorphous population Mitoses few Mitoses ++++ 65% with germinal center 10-20% with germinal center Multinucleated giant cell++ Multinucleated giant cell -- Preservation of adnexa Destruction of adnexa Vascular proliferation ++ Vascular proliferation --- Stromal fibrosis ++++ Stromal fibrosis ---

58. modern classification of cutaneous pseudolymphoma 1. Rijlaarsdam and Willemze’s classification 2. Burg and Braun- Falco classification

59. rijlaarsdam and willemze’s classification 1. Cutaneous T-cell pseudolymphoma a) Primarily with stripe-like infiltration Lymphomatoid drug eruptions Lymphomatoid contact dermatitis Actinic reticuloid Nodular scabies Idiopathic forms Clonal

60. b) Primarily with nodular infiltration Drug induced Persistent nodules after insect bites Nodular scabies 2. Cutaneous B-cell pseudolymphoma Cutaneous lymphocytoma from Borrelia burgdorferi Cutaneous lymphocytoma after antigen injection Cutaneous lymphocytoma resulting from tatoo Cutaneous lymphocytoma after Herpes Zoster Idiopathic Clonal

61. Burg&Braun-Falco ; Kerl&Smole classification A) Infiltration from non-lymphoid cell - Neuroblastoma ,Merkel cell carcinoma B) Neoplasm rich in lymphocytes - Cutaneous lymphadenoma (variant of trichoblastoma ) C) Stroma reaction in epithelial displasia and malignant neoplasms of the soft tissues

62. D) Diseases which are not directly related to the skin - Rosai-Dorfmann’s disease, Castleman’s disease, Kikuchi’s disease E) Classical dermatological diseases resembling cutaneous lymphoma - atypical lymphocyte lobular , panniculitis , lymphomatoid dermatitis, lymphomatoid folliculitis . F) Specific cutaneous pseudolymphoma units - angiolymphoid hyperplasia with eosiniphilia ,Kimura’s disease, APACHE

63. Recent advances Genotypic analysis has made a major contribution in the last decade. Now many pseudolymphomas are considered cutaneous lymphomas: a) regressing atypical histiocytosis b) granulomatous slack skin disease c) pagetoid reticulosis Cutaneous T-cell lymphoma

64. Clinical course and Management 1. Anti- convulsant induced pseudolymphoma Usually regress after 3-4 weeks of withdrawal lymphoma has been reported following a period of many years of drug therapy. Phenytoin 2. Other lymphomatoid drug eruption - complete resolution within 1 to 8 weeks after discontinuation of the causative drug.

65. 3. Lymphomatoid contact dermatitis Topical corticosteroids Avoidance of the responsible allergens 4. Nodular scabies Antiscabetic therapy is often ineffective Spontaneous resolution occurs frequently Intralesional corticosteroids are beneficial

66. 5. Actinic reticuloid A several-month course of azathioprine leads to a remission in about two thirds of patients Cases of actinic reticuloid progressing to lymphoma have been reported Various combinations of photochemotherapy , UVB phototherapy, systemic corticosteroids, azathioprine , and cyclosporine may be beneficial

67. 6. Lymphomatoid papulosis disappear without treatment in 3 to 6 weeks lymphomas develop in 10% to 20% of patients Malignant evolution cannot be predicted by clinical or histologic features, T-cell receptor gene rearrangement, or DNA flow cytometry Continued observation is essential Mycosis fungoides 38% Hodgkin’s lymphoma 24% CD30+ anaplastic large cell lymphoma 32%

68. 5. Borrelial lymphocytoma penicillin 1 gm orally three times daily or doxycycline 100 mg orally twice daily for 2 weeks. Although, B. burgdorferi -associated Cutaneous B-cell Lymphoma has been reported.

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70. 4. Kiyohara T et.al. Linear acral pseudolymphomatous angiokeratoma of children (APACHE): Further evidence that APACHE is a cutaneous pseudolymphoma . J am acad dermatol . Feb 2003;48:15-7. 5. Shtilionova S, Drumeva P, Balabanova M, Krasnaliev . JofIMAB . 2010;16(3):100-1. 6. Kutlubay Z, Pehlivan O, Engin B. Cutaneous peudolymphomas . J Turk Acad Dermatol . 2012;6:1-7. 7 Rosai J. Rosai and Ackerman’s Surgical Pathology. 10 th Edition. New York: Mosby; 2011.

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