CUTANEOUS PSEUDOLYMPHOMA

Moderator : Dr Ram Singh Meena

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

Pseudolymphoma is process of accumulation of lymphocytes in skin in response to a variety of known and unknown stimuli

It simulates lymphoma, primarily histologically but sometime clinically,which at time of diagnosis appear to have a benign biological behavior and do not satisfy criteria for malignant lymphoma

EPIDEMIOLOGY

Mortality/Morbidity Pseudolymphoma is not associated with mortality.

Localized variants rarely result in morbidity other than minor pain or pruritus.

Race Although 90% of reported patients of CPL are white In localized CPL, F:M ratio is 2:1. No significant epidemiologic data are available CTPL Age Individuals of any age may be affected, but

localized, nodular CPL is MC in early life. Mean age of onset is 34 years. 2/3 of patients are

younger than 40 years at time of biopsy. Borrelial pseudolymphoma is more common in

children than in adults

CLASSIFICATION Rijlaarsdam & Willemze’s classification based on

clinical and morphologicalcriteria. 1. Cutaneous T-cell pseudolymphomas

A) Primarily with stripe-like infiltration (the majority of cases)

Lymphomatoid drug eruption (most cases); Lymphomatoid contact dermatitis; Actinic reticuloid; Nodular scabies (individual cases); Idiopathic forms; Clonal cutaneous T-cell pseudolymphomas. B) Primarily with nodular infiltration (a small percentage of the cases) Drug-induced – mainly by anti-convulsive drugs Persistent nodules after insect bites; Nodular scabies (the majority of cases).

2. Cutaneous B-cell pseudolymphomas (with nodular infiltration) Cutaneous lymphocytoma from Borrelia

burgdorferi; Cutaneous lymphocytoma after antigens

injection; Cutaneous lymphocytoma resulting from

tattoo; Cutaneous lymphocytoma after Herpes zoster; Idiopathic forms; Clonal cutaneous B-cell pseudolymphomas

Classification of Cutaneous Pseudolyphomas(2012)Clinicopathologic Subtype Predominan

tLymphoid Subset

PredominantLocalization

Major Associated Findings

Cutaneous lymphoid hyperplasia

B and T cell Reticular dermis

Kimura’s disease B and T cell Subcutis Lympadenopathy

Angiolymphoid hyperplasia with eosinophilia

B and T cell Reticular dermis Eosinophilia

Castleman disease B and T cell Subcutis Lympadenopathy, POEMSsyndrome

Pseudo mycosis fungoides T cell Papillary dermis &Epidermis

Lymphomatoid contact dermatitis

T cell Papillary dermis &Epidermis

Contact allergen

Lymphocytic infiltration of the skin (Jessner’s disease)

T cell Perivascular &periadnexial dermis

Clinicopathological subtypes

Depending on predominant cell type in infiltrate,cutaneous pseudolymphomas are divided into two major categories.

1.Mixed B and T cell pseudolymphoma. cutaneous lymphoid hyperplasia, Kimura's disease, angiolymphoid hyperplasia with eosinophilia, Castleman disease

2. T cell pseudolymphoma pseudo mycosis fungoides, lymphomatoidcontact dermatitis, Jessner’s lymphocytic infiltration of the skin

Wood GS. Inflamatory diseases that simulate lymphomas: Cutaneous lymphomas. Ed.Wolf K, Goldsmith L, Gilchrest B, Paller A, Leffell D. In. Fitzpatrick’s Dermatology in General Medicine. 7th edition

CUTANEOUS LYMPHOID HYPERPLASIA Also Known as Spiegler-Fendt sarcoid,

Lymphocytoma cutis, lymphadenosis benigna cutis & cutaneous lymphoplasia

World-wide distribution and affects all races and ethnic groups.

Both adults and children Females >males CLH is characterized by a relatively dense

lymphoid infiltrate, centered in the reticular dermis, that is usually B-cell rich and may resemble lymphoma clinically and/or histopathologically

In most cases of CLH is idiopathic but in some there is an identifiable trigger.

These include foreign agents such as: Tattoo dye,Insect bites,Scabies, Stings and spider bites

Vaccinations Desensitisation injections Trauma Acupuncture Gold earring piercing Infections with :-Borrelia burgdorferi (Lyme

disease), Varicella zoster (chickenpox) and Human immunodeficiency virus (AIDS virus).

Drugs

Drugs capable of inducing cutaneous pseudolymphomas

Class Drugs

Anticonvulsants

AntidepressantsNeurolepticsTranqulizers (anxiolitics)ACE-inhibitorsβ-blockersH2- blockersCalcium antagonistsAntirheumatic drugsCytostaticsAntibioticsAntihistaminesAntiarrhythmic drugsDiureticsAntilipemic drugsSexual steroidsLocal drugs

Phenytoin, carbamazepine, phenobarbital, trimethadone, primidone, butobarbitol, methsuximide, phensuximideAmitriptyline, fluoxetine, doxepin, desipramine, lithiumChlorpromazine, thioridazine, promethazine(clonazepam, lorazepam)

Captopril, enalapril, benazeprilAtenolol, labetololCimetidine, ranitidineVerapamil, diltiazem Aspirin, phenacetin, D-penicillamin, allopurinolCyclosporin, methotrexatePenicillinDiphenhydramineProcainamideHydrochlorothiazide, ModureticLovastatinEstrogen, progesterone Menthol, etheric oils

Approach to CLH Clinical history should elicit information

about Duration and symptomatology of lesions, Nature and pace of clinical progression, Past treatment, Local and systemic exposure to foreign

antigens, Including medications and personal or family

history about other lymphoproliferative disorders.

It also include review of systems focusing on so called lymphoma B symptoms

GPE :-with special attention to type and distribution of skin lesions and to status of peripheral lymph nodes, liver and spleen.

Scanning tests such as a CBC, Routine biochemistry screening and chest radiography help to exclude extra cutaneous involvement.

Computed tomography of chest, abdomen and pelvis, as well as bone marrow aspiration and biopsy.

Biopsy can be performed from abnormally enlarged lymph nodes

Lesional skin biopsy is an essential part of diagnostic evaluation

Cutaneous lesions of CLH present most commonly as a solitary nodule or can appear as a localized array of nodules, papules and plaques.

Head, neck, extremities, breast and genitalia are common predilection sites.

Lesions have a doughy to firm consistency & range from red- brown to violaceous in color

Lesions may be pruritic or asymptomatic

HPE of CLH lesions reveals dense, nodular and diffuse lymphoid infiltrate that is concentrated in t reticular dermis.

Epidermis is normal and separated from underlying infiltrate by a narrow grenz zone of uninvolved papillary dermis.

Lesions of CLH include generally a mixed B and T cell lymphocytes. However, various types of histiocytes, including macrophages, dermal dentritic cells, Langerhans cells are scattered throughout infiltrate.

Other cells are sometimes admixed, including plasma cells, eosinophils, mast cells, neutrophils and histiocytic giant cells.

Plasma cells and eosinophils are particularly common in arthropod induced reactions

CLH:-Infiltrate is wedge shaped and taper out in its deeper portion reactive lymphoid

follicles containing pale germinal centre

Lyphoid follicle in the dermis contain pale germinal centers surrounded by darker

mmantle zone

Algorithm for the differential diagnosis of typical CLH mixed B-cell/T-cell type, clonal CLH, and CBCL. CLH, cutaneous lymphoid hyperplasia; CBCL,

cutaneous B-cell lymphoma; IPOX, immunoperoxidase; IGH, immunoglobulin H; GR, gene rearrangement; PCR, polymerase chain reaction

Histologic differentiating features between CPL &CBCL

CPL CBCL

Prominent acanthosis Minimal or no acanthosisTop heavy infiltrate (75%) dermalinfiltrate with perivascular &periappendageal preference

Bottom-heavy infiltrate(65%)diffuse infiltrate that dissects

collagen & may involve the subcutis

Organized immune response (e.g., follicles with germinal centers, etc.); heterogeneous cellular constituency

65% with germinal centers

No organized immune response cellular monomorphism often present10%-20% with germinal centers

No or few mitoses Mitoes may be numerousNo necrosis en masse Necrosis en masse (sometime)Multinuleated gaint cells No multinuleated gaint cells

&granulomaLymphoid infiltrate with no

apoptotic cells Lymphoid infiltrate puching borders with infiltrating borders apoptotic cells

Preservation of adnexae Destruction of adnexaeVascular proliferation No vascular proliferationStromal fibrosis Little or no stromal fibrosis

LYMPHOMATOID DRUG ERUPTIONS

Also known as drug-induced CPL or drug- induced pseudolymphoma syndrome

Divided in two major categories:- 1. Induced by anticonvulsants 2. Induced by other drugs

Anticonvulsants- induced pseudolymphoma syndrome

Develops during first 2 to 8 weeks of drug intake, but can occur from 5 daysup to 5 years of phenytoin therapy

Black>white patients Clinically, most patient have triad of fever,

lymphadenopathy, and an erythemic eruptionin association with hepatosplenomegaly, blood eosinophilia

Lymphadenopathy can localized or generalized Skin manifestations appear as single papule or

widespread erythematous papules, plaques and nodules, but occasionally, lesions may be generalized.

MC offenders are phenytoin,primidone,mephenytoin and trimethadione

Anticonvulsant-induced pseudolymphoma syndrome in a 16-year-old boy

erythrodermic pseudolymphoma drug-induced pseudolymphoma, secondary to anticonvulsant therapy

2.CUTANEOUS PSEUDOLYMPHOMAS INDUCED BY DRUGS OTHER THAN

ANTICONVULSANTS

Occur one month to one year following the administration of therapy

M=F Localized papules together with single or

multiple nodules and plaques, generalized papulonodular lesions and exfoliating erythrodermia resembling Sezàry’s syndrome

Eg:-Neuroleptics,ACE-inhibitors,β-blockers, Antihistamines, Cytotoxic

Pathogenesis of lymphomatoid drug eruptions

Immunological function is reduced and immune control is impaired, leading to abnormal proliferation of lymphocytes, increased function of T-suppressors and hypogammaglobulinemia

Studies of these patients show1. Relative increase in absolute number of

peripheral T-lymphocytes by 85-95 %2. Significant stimulation of drug-induced

blastic tranformation of lymphocytes 3. Impaired ability of T-suppressor lymphocyte

to suppress B-cell differentiation and immunoglobulin production

Persistent nodular arthropod-bite reations and nodular scabies

CBPL or CTPL can develop as a result of scabies or arthropod bite

Clinically, multiple pruritic firm erythematous to red-brown papule and nodule MC on genitalia,abdomen,axillae and elbows

Nodule following scabies may persist for many months after adequate anti-scabietic therapy

It is thought to be due to delayed-type hypersensitivity reaction to componant of mite

Persistent nodular arthropod-bite reations

nodular scabies

Acral pseudolymphomatous angiokeratoma

It is known by its acronym APACHE – Acral Pseudolymphomatous Angiokeratoma of Children

Apache etiology remains unknown howeverpossibility that it is a hypersensitivity

reaction to insect bites Clinically characterized by presence of 10 to

40 violet-erythematic papules, diameter ranges from 1 to 4 mm, and which are asymptomatic, located unilaterally, generally with acral distribution

Occurring more often between 2 and 13 years of age

Histological studies of Apache reveal an epidermis of normal aspect and a dense well-differentiated lymphocyte infiltrate in the dermis, amongst connective tissue structures, not affecting skin appendage.

Such histopathological aspect configures lymphocyte proliferation,associate with no nuclear atypia.

Asymptomatic papules in the right forearm,measuring approximately 3 mm in diameter

Leukocyte infiltrate with predominance oflymphocytes

Treatment

Cutaneous lymphoid hyperplasia related to infection with B. Burgdorferi, antibiotic therapy with cephalosporins

Excision,glucocorticoids (topical, intralesional, and systemic), cryotherapy, antimalarials, minocycline and radiation therapy have all been used with various successes.

Laser therapy and photodynamic therapy

Comparison of clinicopathological changes between Kimura’s disease and ALHE

Clinical features

Kimura’s disease ALHE

Sex Young adult male predominance

Middle-aged female

Age Mean range 27-40 Mean 35 years

Presentation & site

as solitary or multiple nodules up to 10 cm in diameter centered in subcutis, MC involving head and neck

present with smaller,more superficial intradermal papulo-nodules that are typically unilateral. Also involve Salivary glands & resional lymph nodes(reactive)

Regional L N enlargement

LN often show histological evidence of involvement

Uncommon, show reactive changes only

Peripheral bloodeosinophilia

Present in majority of cases Occurs in about 20 % of cases

Course Progressive, becoming stationary after years. Recurrence is common 15%-40%, but there is no fatality.Rarely, association with a nephrotic syndrome

Benign lesion which recurs in about 30%of cases. Recurrence is rare ifexcision is complete

Histological features

Kimura’s disease ALHE

Outline Usually non-circumscribed Often circumscribed except dermal lesions

Lymphoidcomponent

Abundant lymphocytes and plasma cells; lymphoid follicles are always found

Sparse to heavy infiltrate of lymphocytes & plasma cells, with or without lymphoid Follicles

Eosinophils Moderate to abundant; eosinophilic abscesses

Sparse to abundant; eosinophilic abscess is rare

Vascular proliferation

Some stromal vascularity with unremarkable endothelial cells

Prominent vascular proliferation with large epitheloid/ histiocytoid endothetial cells,evidence of underlying vascular malformation may evident

fibrosis Prominent Absent or limited

showing severe facial disfiguration from mass effect(kimura disease)

Histopathologic features of Kimura's disease. A, Scanning view shows prominent germinal center formation. B,Higher magnification of a

germinal center with abundant number of eosinophils. C, Focally, blood vessels may show prominent endothelial cells with vacuolated cytoplasm

Histologic section with hematoxylin and eosin staining showing nodular vascular proliferation and inflammatory infiltrate. High power (inset) shows lymphoid proliferation with plasma cells

and eosinophils

Vascular channels lined by epithelioid endothelial cells with abundant

pink cytoplasm(ALHE)

TreatmentFIRST LINE Excision, Topical corticosteroids, Tntralesional corticosteroids (5-40 mg/ml,

monthly)SECOND LINE Topical tacrolimus ointment, Systemic corticosteroids (60/ 40/ 20 mg PO

tapers, 5 days each), Cyclosporine (2.5- 4mg/kg/day), Local radiation, Vinblastine (15 mg/week IV), Intravenous immunoglobulins

Also referred to as angiofollicular lymph node hyperplasia

First described by Benjamin Castleman in 1956

follicular hyperplasia of lymph nodes with abnormally increased interfollicular vascularity

Can be associated with Kaposi's sarcoma (KS), non-Hodgkin's lymphoma, Hodgkin's lymphoma, and POEMS syndrome

Types of CD

Unicentric and Multicentric Hyaline vascular , Plasmacytic and

Mixed cellularity variety based on histopathology

HIV associated

Unicentric CD

More common Presents as slow growing solitary mass

typically located in the mediastinium or mesenteries.

No constitutional sm-s Not associated with progression to

malignancy Treated by surgical resection with

excellent results Histologicaly Unicentric CD is of hyaline

vascular variety

Follicles show abnormal germinal centers with marked vascular proliferation and hyalinization.Center of

follicle is usually depleted of lymphocytes and shows follicular dendritic cells.Follicle is surrounded by a broad

mantle zone consisting of a concentric layering of lymphocytes resulting in an onion-skin appearance. Follicles are frequently penetrated radially by a sclerotic blood vessel

Multicentric CD Median age 50-60’s ( younger if HIV+) Widespread lymphadenopathy Hepatosplenomegaly Can present with systemic sm-s: fatigue, fever,

wt loss, night sweats (overproduction of IL-6). Severe peripheral edema, anemia,

hypoalbumenia, peripheral neuropathy Also can be associated with:-autoimmune

hemolytic anemia,multiple myeloma, amyloidoisis,Pemphigus & POEMS syndrome

Diagnosis by biopsy: Histologicaly usually of the plasmacytic type or mixed cellularity variety

 show diffuse plasma cell proliferation in interfollicular region.Image shows a small follicle in the center with eosinophilic deposits of fibrin and immune complexes

HIV association

More likely to be associated with Multicentric Castleman’s Disease

More likely to be caused by HHV8 Associated with poor prognosis and

progression to malignancy Initiation of HAART may lead to fulminant

multicentric CD

Associated Malignancies

Kaposi's sarcoma (up to 70% in HIV+/HHV+)

Non-Hodgkin's lymphoma (15-20% of pt)

Hodgkin's lymphoma (both MCD & UCD)

POEMS syndrome

Therapy for Multicentric CD

Steroids (15-20% eff, not in HIV+) IV Ig Antivirals (acylovir/gancyclovir/foscarnet)

in HIVand HHV8 + population Rituximab (complete remission in few

cases) CHOP or CVAD (90% eff) Anti-IL6 or anti-IL6 receptor antibody. Thalidomide (anecdotal)

Pseudo Mycosis Fungoides Eruptions mimicking mycosis fungoides

occur typically in adults. Both genders can be affected. Pseudo T cell lymphomas may arise

spontaneously or may occur in association with B cell chronic lymphocytic leukemia

Also associated with ingestions of various drugs, including hydantoins, carbamazepine and antihistamines.

The lesions present clinically as one or a few plaques on the trunk or extremities.

1.Lesion during drug therapy2.Lesion after discontinuation of drug

Histopathologically, there is a papillary dermal, band-like infiltrate containing mostly atypical lymphocytes with clefted and cerebriform nuclei.

Compared with mycosis fungoides,epidermotropism is typically far less prominent and Pautrier’s microabscess-like aggregates are rare.

Most cases contain polyclonal T cells In the differential Lichenoid drug eruptions, Lymphomatoid contact dermatitis, Chronic radiodermatitis, Secondery syphilis

Pautrier microabcess–like appearancecan be seen

First line of therapy Drug discontinuation Treatment of underlying disorder when an

associated specific disease is detected Excision for isolated lesions, Topical and systemic corticosteroids, Ultraviolet B phototherapy and PUVA

therapies

Lymphomatoid Contact Dermatitis LCD is a chronic and persistent allergic contact

dermatitis Lymphomatoid contact dermatitis was described

originally in four patients with persistent allergic contact dermatitis proven by patch testing

Responsible agents include gold, nickel and para-phenylenediamine.

Characterizedby generalized pruritic red, scaly papules and plaques

Histopathologically, superficial lymphocytic dermatitis that contains foci of spongiosis simulating appearance of cutaneous T cell lymphomas

Frequently there is edema in papillary dermis in lymphomatoid contact dermatitis, this finding is usually absent in mycosis fungoides

Avoidance of the responsible allergic agents leads to eventual resolution of condition.

A search for offending agent via patch testing

Therapy firstly Elimination of a suspected allergic agent,

later topical corticosteroids, pimecrolimus and tacrolimus ointments

There is a superficial and deep perivascular infiltrate of lymphocytes and eosinophils. Some lymphocytes extend to a hyperplastic epidermis where there is spongiosis, a few individual necrotic keratinocytes, and parakeratosis with serum. There is no evidence of lymphocytic atypia

Jessner Lymphocytic Infiltration of the Skin

Jessner lymphocytic infiltrate commonly present with 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

Histologically ,epidermis usually is normal In dermis, a moderately dense superficial and

deep perivascular lymphocytic infiltrate.Lymphocytic infiltrate may also be perifollicular or may extend into subcutis.

Higher magnification reveals a predominance of small mature lymphocytes. Large lymphoid cells, plasma cells, or plasmacytoid monocytes may occasionally be present and eosinophils and neutrophils are absent.

Differential diagnosis:- Polymorphous light eruption, Discoid lupus erythematosus, Well-differentiated lymphocytic lymphoma & Lymphocytoma cutis

Histopathologic features of Jessner's lymphocytic infiltration of skin: absence of epidermal and

dermoepidermal junction abnormalities

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