CUTANEOUS PSEUDOLYMPHOMA

PRESENTER : DR. SHEIKH TOUSIF REZA MODERATOR: DR. JAYAPRAKASH SHETTY K

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

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.

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.

CLASSIFICATION OF CUTANEOUS PSEUDOLYMPHOMA

Cutaneous T-cell pseudolymphoma i) Band like pattern ii) Nodular pattern Cutaneous B cell pseudolymphoma i) Nodular pattern

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

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)

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

CAUSES OF CUTANEOUS PSEUDOLYMPHOMA1. 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

LYMPHAMATOID DRUG ERUPTIONS It can be divided into 2 categories a) Anticonvulsant induced pseudolymphoma

syndrome b) Cutaneous lymphoma induced by drug other

than anticonvulsants.

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

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

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

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

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

• Acanthosis• Perivascular and interstitial infiltrate

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

• Top heavy pattern infiltrates• Secondary follicles

with germinal centre• Thick walled blood vessels with plump endothelial cells

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

• Acanthosis

• Exocytosis of lymphocytes• multinuc-

leated fibroblasts • Thick walled blood vessels

Vertically oriented coarse colla-gen bundles parallel to the rete

ridges

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

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

Type B: Band like infiltrate

Type C: CD 30+ cells with fewer inflammatory cells

CD 30+ cells > 50%

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

CD 8+

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

JESSNER LYMPHOCYTIC INFILTRATION OF THE SKIN• Asymptomatic,• Non-scaly, erythema-

tous papules or plaques• Predominantly on

face and neck,upper trunk or arms of several months duration• Majority of cases oc-

cur in middle aged adults

Deep perivascular infiltration, may ex-tend to subcutis

Normal epi-dermis

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 erythemat-ous

firm papules on the tip

of the nose

Well defined “top-heavy” nodular infiltrate in the

upper dermis

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

Thin grenz zone in up-

per dermis

Dense, diffuse infiltrate of small and large lymphocytes

admixed with occasional histiocytes and plasma cells.

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.

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

KIMURA ‘S DISEASE

Single or multiple nodules upto 10 cm in diameter Head and neck – most common Peripheral eosinophilia and regional

lymphadenopathy

Abundant number of eosinophils in germinal centre

Germinal centre forma-tion in deeper dermis

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

UNICENTRIC CASTLEMAN’S DISEASE

Marked vascular proliferation

with hyalinization

broad mantle zone consist-ing of a concentric layering

of lymphocytes resulting in

an onion-skin appearance

MULTICENTRIC CASTLEMAN’S DISEASE

Interfollicular region shows diffuse plasma cell infiltration

Eosinophilic deposits of fib-

rin and immune

complexes

SMALL PLAQUE PSORIASIS

Small, flat, erythemat-ous lesions seem

indistinguishable from those of

conventional mycosis fungoides.

Superficial

infiltrate in papillary dermis

Intradermal lympho-

cytes

IDIOPATHIC FOLLICULAR MUCINOSIS

Slightly erythemat-ous patch on

the lumbal region

follicular distribution of the lesions

Dense perifollicular lymphoid infiltrates

Hair follicle

Focal depos-ition of mucin

Intraepithelial lymphocytes

LUPUS ERYTHEMATOSUS Lupus erythematosus profundus , also referred as

lupus erythematosus panniculitis.

Dermal subcutaneous interface shows

intense inflammatory infiltrate

Adipose tissue hyalinization

PIGMENTED PURPURIC DERMATOSIS

Dense lymphohistiocytic infiltrate is present in the superficial dermis in a band-like fashion

spongiosis

Extravasated RBCs near the venules

PERNIOSIS (CHILBLAINS) Abnormal inflammatory response to cold Seen commonly in acral locations

Papillary dermal ed-ema

Superficial and deep perivascular

lymphocytic infiltra-tion

Swollen Endothelial cells

and show infiltration by lymphocytes

Medium-sized ves-sels infiltrated by

lymphocytes

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

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.

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.

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

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

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.

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.

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

CT-CELL PL VS C T-CELL LYMPHOMAFeatures T cell psedo T cell lymphoma

Presentation Localized Generalized Clinical course Spontaneous

remissionProgressive

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%

CB-CELL PL VS C B-CELL LYMPHOMACutaneous 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 centerMultinucleated giant cell++ Multinucleated giant cell --Preservation of adnexa Destruction of adnexa Vascular proliferation ++ Vascular proliferation ---Stromal fibrosis ++++ Stromal fibrosis ---

MODERN CLASSIFICATION OF CUTANEOUS PSEUDOLYMPHOMA

1. Rijlaarsdam and Willemze’s classification2. Burg and Braun-Falco classification

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

b) Primarily with nodular infiltration - Drug induced- Persistent nodules after insect bites- Nodular scabies2. 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

BURG&BRAUN-FALCO; KERL&SMOLE CLASSIFICATION

A) Infiltration from non-lymphoid cell

- Neuroblastoma ,Merkel cell carcinomaB) Neoplasm rich in lymphocytes

- Cutaneous lymphadenoma (variant of trichoblastoma)

C) Stroma reaction in epithelial displasia and malignant neoplasms of the soft tissues

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

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

Cu-taneous T-cell lymph-

oma

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.

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

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

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%

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.

REFERENCES 1. Ploysangum T, Breneman DL, Mutasim DF.

Cutaneous pseudolymphomas. J Am Acad Dermatol. June 1998;38(6):877-98.

2. Bergman R. Pseudolymphoma and cutaneous lymphoma:Facts and controversies. Clinics of Dermatology. 2010;28:568-74.

3. Cerroni L. Lymphoproliferative lesions of skin. J Clin Pathol 2006;59:813–26.

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.

10th Edition. New York: Mosby; 2011.

8. Elder DE. Lever’s Histopathology of Skin. 11th

Edition: Lippincott Williams and Wilkins;2014.9. Sternberg SS, Mills SE, Carter D. Sternberg’s

diagnostic surgical pathology. 5th Edition. Philadelphia:Wolters Kluwer Health/Lippincott Williams & Wilkins;2010.

10. Slater D. Cutaneous pseudolymphoma. Underwood J, Pignatelli M. Recent Advances in Histopathology 22. London:Royal Society of Medicine Press Ltd;2007.