CUTANEOUS PSEUDOLYMPHOMA

CUTANEOUS PSEUDOLYMPHOMA

cutaneous pseudolymphomas are benign lymphocytic proliferations that simulate cutaneous malignant lymphomas clinically and/or histopathologically. The term pseudolymphoma is not specific but is merely descriptive as it encompasses reactive skin conditions with different aetiologies, pathogeneses, clinicopathological presentations and behaviours. Cutaneous pseudolymphomas are traditionally divided into T- and B-cell pseudolymphomas according to the histopathological and immunophenotypical features, although in many conditions this distinction is artificial. For example, pseudolymphomas induced by drugs may present with either a T- or a B-cell pattern and the same drug may induce different patterns in different patients. Thus, in what follows we classify cutaneous pseudolymphomas according to specific clinicopathological entities. 1

Pseudolymphoma (PSL) is not a specific disease but rather an inflammatory response to known or unknown stimuli that results in a lymphomatous-appearing but benign accumulation of inflammatory cells. In cutaneous pseudolymphoma, resemblance to lymphoma is usually most apparent histologically, but some examples may also mimic lymphoma clinically. When known, the inciting agent should be included within the diagnosis of cutaneous pseudolymphoma. The term pseudolymphoma without modification should be reserved for idiopathic cases. 2


Localized, nodular pseudolymphomas are more common and typically mimic. A variety of specific diseases are sometimes referred to as pseudolymphomas simply because they may resemble lymphoma. These disorders often show broad patches and plaques and often mimic cutaneous T-cell lymphoma. Examples include actinic reticuloid, lymphomatoid contact dermatitis, and lymphomatoid drug eruptions. 2,3


No frequency data are available for cutaneous pseudolymphoma; the condition is uncommon but not rare. Pseudolymphoma is not associated with mortality. Localized variants rarely result in morbidity other than minor pain or pruritus. Rare cases of cutaneous pseudolymphoma have been described in which the pseudolymphoma has evolved into cutaneous lymphoma. 2,4


Cutaneous pseudolymphomas affect all age groups with a predilection of Borrelia-induced B-pseudolymphomas in children and young adults, whereas drug induced T-pseudolymphomas more frequently are seen in adults. Even though Borrelia-induced pseudolymphomas may be precursors for B-cell lymphomas of the skin, in general cutaneous pseudolymphomas are selfregressing and do not affect survival. 4,5


We reported cutaneous pseudolymphoma on right elbow in thirthy five years old woman. Lesion is a nodule, reddish brown and solitary. Patient has minimally pruritus and painless. We presented this case in light of cytology findings. On Fine Needle Aspiration Biopsy (FNAB) smear showed hight cellularity composed polymorphous inflammatory cells such as lymphocyte predominant, lymphoblast and plasma cells. Also seen were few irregularly lymphoblast with large nuclei.

Definition

Pseudolymphomatous drug eruption due to captopril, marked by erythematous to purple papules, patches, and plaques.

Cutaneous Pseudolymphoma, also known as Cutaneous lymphoid hyperplasia, Borrelial lymphocytoma, Lymphadenosis benigna cutis, Lymphocytoma cutis, Pseudolymphoma of Spiegler and Fendt, Sarcoidosis of Spiegler and Fendt, Spiegler–Fendt lymphoid hyperplasia, and Spiegler–Fendt sarcoid refers to a groups of benign cutaneous disorders characterized by collections of lymphocytes, macrophages, and dendritic cells in the skin. 3,6

Conditions included in this groups are: 3,6

· Cutaneous lymphoid hyperplasia with nodular pattern
Cutaneous lymphoid hyperplasia with bandlike and perivascular patterns
Jessner lymphocytic infiltrate of the skin

Etiology

Most cases are idiopathic. Known inciting agents include tattoo dyes, jewelry (eg, gold earrings), insect bites, medications, folliculitis, trauma, vaccinations, other injectables (eg, liquid silicone), irritants, and infection (eg, varicella-zoster virus, Borrelia species, molluscum contagiosum). 2,6,7

This erythrodermic pseudolymphoma (T-cell pattern) typifies drug-induced pseudolymphoma, which is most often secondary to anticonvulsant therapy.

Pathophysiology

In persons with pseudolymphoma, lymphocytes and other inflammatory cells are recruited to the skin in response to known or unknown stimuli.

Most cases are idiopathic. Cases of cutaneous pseudolymphoma with known etiology include reactions to tattoo dyes, jewelry (especially gold), insect bites, medications, folliculitis, trauma, infections, vaccinations, and contactants. A discrete subset of pseudolymphoma, borrelial lymphocytoma, primarily occurs in Europe in areas endemic for the tick Ixodes ricinus. Borrelial lymphocytoma is a response to infection by Borrelia burgdorferi subsp afzelius conferred by a tick bite. Another subset of pseudolymphoma is the result of an unusual systemic response to medications, typically anticonvulsants. 2






Clinical features


The clinical manifestations of cutaneous pseudolymphomas are protean. The lesions are often solitary although they may be regionally clustered or generalized in distribution. Cutaneous pseudolymphomas may also show the features of generalized erythroderma. The course of pseudolymphomas varies considerably. The lesions may persist for weeks, months or even years; they may resolve spontaneously and they may recur unpredictably. 2 Several variants of cutaneous pseudolymphoma exist, presenting with different clinical symptoms. 4

· Pseudolymphoma (PSL) with predominant T-cell infiltrates (T-PSL)

· Lymphocytic infiltration (idiopathic or drug induced)


· Palpable migratory arciform erythema

· Lymphomatoid contact dermatitis

· Actinic reticuloid

· Persistent nodular arthropod-bite reactions

· Inflammatory molluscum contagiosum

The original description of lymphocytic infiltration (idiopathic or drug induced cutaneous T-cell pseudolymphoma) given by Jessner and Kanof in 1953 is still valid today. 4


The lesions are flat, discoid, more or less elevated, pinkish to reddish brown, starting as small papules, expanding peripherally, sometimes clearing in the centre, sometimes showing a circinate arrangement. The surface is smooth, occasionally uneven. There is no follicular hyperkeratosis as seen in discoid lupus erythematosus, which may be simulated. There may be only one, a few, or numerous lesions. 3,4,8

Although 90% of reported patients with pseudolymphoma are white, racial predilection has not been established. In reported cases of localized pseudolymphoma, the female-to-male ratio is approximately 2:1. 4

No significant epidemiologic data are available regarding entities in the T-cell pattern pseudolymphoma spectrum. Individuals of any age may be affected, but localized, nodular pseudolymphoma is most common in early life. The mean age of onset is 34 years. Two thirds of patients are younger than 40 years at the time of biopsy.

Approximately 8% of cases involve patients younger than 18 years. Borrelial pseudolymphoma is more common in children than in adults. 2

Patients with B-cell pattern pseudolymphoma present with a nodule or a group of discrete nodules, usually with minimal associated symptoms. Occasionally, cases present with pruritus or pain. Patients with a T-cell pattern of cutaneous pseudolymphoma usually present with broader patches, which are often symptomatic. 2,8

Physical Examination

Examination of patients with a B-cell pattern of pseudolymphoma usually reveals a single nodule, from one to several centimeters in diameter. Although the lesions may be soft, they are more often firm. Typically, the lesions are red to purple in color, but they may show no coloration. Approximately three quarters of cases of cutaneous pseudolymphoma are localized. The remaining cases usually show grouped papules in a single defined region. More disseminated cases are rare. 2

The most common site of involvement in cutaneous pseudolymphoma is the face (70%), followed by the chest and the upper extremities. Cutaneous pseudolymphoma lesions are infrequent below the waist. Sites of predilection for borrelial pseudolymphoma include the earlobe, the nipple, the areola, the nose, and the scrotum (sites of low skin temperature). 2

Patients with T-cell pattern pseudolymphoma typically present with broad, erythematous patches and/or plaques, as shown in the image below. Pseudolymphomatous actinic reticuloid affects sun-exposed areas. Lymphomatoid contact dermatitis demonstrates lesions in areas where the inciting agent has come in contact with the skin. 2

Classification

Classification of cutaneous pseudolymphomas.show in table 1.


Clinicopathologic condition

Simulated malignant lymphoma

· Actinic Reticuloid

· Lymphomatoid contact dermatitis

· Lymphomatoid drug reaction, T cell type

· Solitary T-cell pseudolymphoma (‘unilesional mycosis fungoides’)

· Lichenoid (‘lymphomatoid’) keratosis

· Lichenoid pigmented purpuric dermatitis

· Lichen sclerosus

Mycosis Fungoides/ Sezary Syndrome

Atypical lymphoid infiltrates (CD30+) associated with:
· Orf – Milkers nodule

· Herpes simplex &

· Molluscum contagiosum

· Arthropod (insect) reactions (including nodular scabies)

Lymphomatoid papulosis / Anaplastic large cell lymphoma – CD30+

lupus panniculitis

Subcutaneous T-cell lymphoma

Lymphocytoma cutis

B B cell lymphomas

· Follicle center lymphoma

· Marginal zone B-cell lymphoma

· Large B-cell lymphoma
· Lymphomatoid drug reaction, B cell type

· Pseudolymphoma after vaccination

· Pseudolymphoma in tattoos

· Pseudolymphoma caused by Hirudo medicinalis therapy

· Follicle center lymphoma
· Marginal zone B-cell lymphoma

· Morphoea, inflammatory stage

· Syphilis (secondary)

 Marginal zone B-cell lymphoma

· Jessner's lymphocytic infiltrate

· Chronic lymphocytic leukaemia, B cell type

· Inflammatory pseudotumour
· Plasmacytoma

· Marginal zone B-cell lymphoma


Histopathology


Histological criteria for the diagnosis of cutaneous pseudolymphomas include two main features: 2


1. The architectural pattern of the infiltrates


2. The cellular composition of those infiltrates, which frequently show a mixed character.


These histological features then need to be compared carefully with the immunophenotypical data obtained on routinely fixed, paraffin-embedded sections. The recent introduction of polymerase chain reaction (PCR) analysis of the rearrangement of the T-cell receptor (TCR) and immunoglobulin heavy-chain (JH) genes allows the clonality of cutaneous T- and B-cell infiltrates to be established. 1,9

Although, as a rule, malignant lymphomas reveal a monoclonal population of lymphocytes whereas pseudolymphomas show a polyclonal infiltrate, it must be underlined that demonstration of monoclonality may be lacking in true malignant lymphomas and that a distinct proportion of cutaneous pseudolymphomas harbour a monoclonal T- or B-cell population. In this context, it must be clearly stated that differentiation of benign from malignant lymphoid infiltrates of the skin is possible only after a careful synthesis and integration of the clinical, histopathological, immunophenotypical and molecular features. In some cases, only careful follow-up will reveal the true diagnosis. 1

In recent years, the presence of CD30+ large blasts has been observed in the skin in several reactive conditions including various viral infections (orf, milker’s nodule, molluscum contagiosum, viral warts, herpes simplex, herpes zoster), arthropod reactions, scabies and drug eruptions. CD30+ cells have also been observed in lesions of hidradenitis and rhynophyma, as well as at the sites of cutaneous abscess and of injury caused by red sea coral. The finding may be related, at least in part, to improved methods of antigen demasking and immunohistochemical staining of routinely fixed, paraffin-embedded sections of tissue. 1,9,10

Besides the presence of large atypical CD30+ cells, the histology in these lesions reveals the typical changes of the specific underlying disorder. Moreover, in these reactive conditions CD30+ lymphocytes are scattered throughout the infiltrate and are usually not arranged in clusters or sheets as observed in lymphomatoid papulosis or cutaneous anaplastic large cell lymphoma. 1,9,10

However, in some cases differentiation may be very difficult or even impossible on histological and immunohistochemical grounds alone. Unlike the situation in lymphomatoid papulosis and cutaneous anaplastic large cell lymphoma, gene rearrangement studies in CD30+ pseudolymphomas reveal the presence of a polyclonal population of T lymphocytes. 1,9,10


PSL with predominant B-cell infiltrates


Lymphadenosis benigna cutis (LABC), the prototype of this group of BPSL-is synonymous with lymphocytoma cutis. In Europe it is most commonly caused by infection with Borrelia burgdorferi after a tick bite (Ixodes ricinus). However other microbiological

(medicinal leeches, Hirudo medicinalis), physical or chemical agents as well may induce lymphocytoma-like reactions. 4

Two thirds of all lesions are situated on the head, tending to occur on the ear lobes. Other predilections are the nose as well as the nipples, the inguinal area and scrotum. Usually the lesion is a solitary papule or nodule, but several disseminated lesions may occur as well. 4

Microscopic examination shows a nodular dermal infiltrate with reactive follicles. In addition, there is a rather diffuse infiltrate containing T cells, histiocytes, eosinophils and polyclonal plasma cells. The presence of macrophages containing ingested nuclear material (tangible body macrophages) within the follicles producing a “starry sky” pattern is a common feature in B-PSL and a hallmark of all reactive germinal centres.

The infiltrate is predominantly located in the upper and mid dermis, but may extend into the deep dermis. Small groups of lymphoid cells between collagen bundlesmay be observed at the periphery of the lesions. This is a helpful histological criterion in the differentiation from cutaneous B-cell lymphoma, in which the nodular infiltrate shows convex rather than concave sharply demarcated borders. Phenotypically a polyclonal B-lymphocytic infiltrate without light chain restriction of the infiltrate is found in most cases. The cells express the phenotype of mature B-cells (CD 20, CD 79a). In BPSL, regular and sharply demarcated networks of CD21+ follicular dendritic cells are present, whereas in CBCL these networks are irregularly shaped. 4

Acral pseudolymphomatous angiokeratoma of children (APACHE) is a rare benign pseudolymphomatous disorder occurring mainly in children. The typical clinical presentation is multiple (up to 40), asymptomatic, small papules located unilaterally on the fingers, toes and hands. Their colour is usually red-violet, accounting for their angiomatous appearance. Histologically the dermis contains a moderately to very dense, non-epidermotropic infiltrate composed of small well-differentiated lymphocytes admixed with a few plasma cells, histiocytes, and giant cells. Blood vessels show prominent plump endothelial cells. Immunohistochemically the cellular infiltrate represents a mixture of polyclonal mature T- and B-lymphocytes.4

Inflammatory pseudotumour (IPT) or plasma cell granuloma, inflammatory myofibroblastic pseudotumour, refers to a spectrum of idiopathic benign conditions with unknown etiology that can develop in various organs and deep tissues, particularly in the lung. Cutaneous IPT occurs as a solitary, slowly growing, tender nodule measuring 1-3 cm in diameter. Irrespective the anatomic location, the lesions share common histological features, showing well circumscribed proliferation of myofibroblasts/fibroblasts expressing smooth muscle actin (SMA) and vimentin, a mixed cell infiltrate containing high numbers of plasma cells with prominent germinal centres dispersed throughout the lesion. The plasma cellsare polyclonal and are seen in the interfollicular areas (plasma cell granuloma) 21. Later stages show marked fibrosis/sclerosis with thick collagen bundles arranged in concentric whorls. 4


Histological variations include presence of high endothelial venules, admixture of eosinophils, calcification, psammoma bodies, and presence of large polygonal myofibroblasts (vimentin+, CD15-, CD30-) with single, double or multiple nuclei and prominent eosinophilic nucleoli resembling Reed-Sternberg cells. 4

Differential diagnosis of cutaneous IPT includes lymphoma, angiolymphoid hyperplasia with eosinophilia and Kimura and infectious dermatoses (mycobacteria, deep fungal infections). The later stages of cutaneous IPT should be distinguished from erythema elevatum diutinum, granuloma faciale and dermatofibroma with lymphoid infiltrate.

PSL with mixed and unclassified infiltrates

There are reactive lymphocytic infiltrates in the context of other skin disorders that can be referred to as pseudolymphomatous reactions in an even broader sense. Neoplasms, especially squamous cell carcinoma, basal cell carcinoma, and malignant melanoma, or naevi (halo [Sutton] naevi) may show a dense mononuclear infiltrate, composed of T cells or of B cells, sometimes with follicle formation, with polyclonal plasma cells being numerous especially in head and neck localizations. 4


Therapy

The therapy of pseudolymphomas depends on the specific diagnosis, and includes surgical excision, topical steroids, intralesional steroids, cryotherapy, antiviral treatment and radiation treatment. 1,2

Prognosis and predictive factors

The prognosis of cutaneous pseudolymphomas by definition is excellent, showing spontaneous regression of the lesions after cessation of the causative factor or due to treatment with nonaggressive treatment modalities. However there is a potential for some cutaneous pseudolymphomas to progress to cutaneous B-cell lymphoma (CBCL), or to cutaneous T-cell lymphoma (CTCL). 4


REFERENCES


1. Cerroni L, Gatter BM K, Kerl H. An illustrated guide to Skin Lymphoma (e-Book), Pseudolymphomas of the skin. Blackwell Publishing; 1998(2): 157-76.

2. J Ko Ch, Meyerle JH, Glusac EJ. Pseudolymphoma, cutaneous. 2010 [cited on 2010, Augustus 8]. Available from: http://www.medscape.com/

3. Cutaneous lymphoid hyperplasia. 2010 [cited on 2010, Augustus 8]. Available from: http://www.wikipedia.com/

4. Burg G, et all. Lymphoid infiltrates of the skin mimicking lymphoma (cutaneous pseudolymphoma). In: DeLellis R, Lloyd RV, Heitz PU, Eng Ch. (Editors). World Health Organization (WHO) Pathology and Genetics of The Skin Tumours. IARCS Press; Lyon; 2004: 212-14.

5. Cutaneous pseudolymphoma. 2009 [cited on 2010, Augustus 7]. Available from: http://www.dermnetnz.org/ndzs.html.
6. Lymphocytoma cutis. 2010 [cited on 2010, Augustus 8]. Available from: http://www.skinpatient.com.
7. Horn TD, Hiatt KM. Cutaneous Toxicities of Drugs. In: Elder DE, Elenitsas R, Johnson Jr BL, Murphy GF. Lever’s Histopathologyu of The Skin. Lippincott Williams & Wilkins; 2005(9): 331-2.
8. White CR. Nodular and Diffuse Dermatitis. In: Grant-Kels JM (Editor). Color Atlas of Dermatopathology (e-Book). Informa Healthcare; New York; 2007: 98-9.
9. Skin Pseudolymphoma. 2007 [cited on 2010, August 9]. Available from: http://www.thedoctorsdoctor.com/

10. Immunohistological features of the various skin components. 2009 [cited on 2010, Augustus 7]. Available from: http://www.histopathologyindia.net


11. Ackerman AB. Histologic Diagnosis of Inflammatory Skin Diseases: A Methode by Pattern Analysis. Henry Kimpton Publisher; 1978: 442.