—  SPECIALTY CONFERENCE  —

Dermatopathology

Case 2 - Anaplastic Large Cell Lymphoma with Pseudoepitheliomatous Hyperplasia

A. Neil Crowson
Regional Medical Lab
Tulsa, OK


Click on each slide thumbnail image for an enlarged view
The CD30-positive Lymphoproliferative Disorders
The spectrum of CD30 positive lymphoproliferative disorders encompasses lymphomatoid papulosis (LYP), primary cutaneous and secondary CD30+ve anaplastic large cell lymphoma (ALCL), borderline CD30 positive lymphoproliferative disorder, Hodgkin's disease (HD) either primarily or secondarily involving the skin, mycosis fungoides (MF) with large cell transformation, CD30+ve large B cell lymphoma and CD30+ve lymphomatoid drug reactions. In one study that addressed the spectrum of CD30 positive cutaneous lymphoproliferative lesions, ALCL comprised 45% of cases, LYP 17% of cases, borderline lesions 16% of cases, non-Hodgkin's lymphoma of the nonanaplastic subtype 20% and HD 1% of cases (Paulli). This likely represents a form of selection bias, however, as a study from MCP Hahnemann University, New York University, and the University of Califormia, San Francisco over a 3 year period showed ALCL to represent a mere 0.9% of newly registered cutaneous lymphoma patients, while 13% of patients had LYP, 3% had peripheral T-cell lymphoma, 4% had B-cell lymphoma, and the overwhelming majority represented mycosis fungoides/Sezary syndrome (80%) (Zackheim). Lymphomatoid hypersensitivity reactions in the context of persistent arthropod bite reactions, cutaneous herpes and paramyxovirus infection and chemotherapy and other drug reactions may manifest reactive CD30 positive lymphoid infiltrates.

The diverse spectrum of cutaneous lesions associated with CD30 expression reflects the nature of the CD30 molecule and the inherent diversity of cells in which it can be expressed including mitotically active cells of monocytic, B cell or T cell lineage. The expression of CD30 does not equate with a neoplastic event and can be identified in a minority of reactive T or B lymphocytes and in lymphocytes exposed to transforming viruses such as Epstein Barr virus (EBV) and HTLV1. It was first detected on Reed-Sternberg (RS) cells of HD but has since been described in stimulated or transformed peripheral blood T or B cells, T cell and B cell lymphoma lines, and myeloid cell lines. In paraffin embedded tissue, an epitope of the CD30 molecule which is preserved following formalin fixation is detected with the BerH2 antibody; Ki-1, a monoclonal antibody raised against an HD cell line in 1982, is an antibody which detects a much greater proportion of the CD30 molecule on frozen tissue and hence is a more sensitive assay for CD30 expression. Ki-1 was subsequently shown to be expressed by a minority of small lymphoid cells found in the parafollicular regions of normal lymph nodes. The Ki-1 antigen, now designated the CD30 cluster, is part of the tumor necrosis factor family. The gene encoding the CD30 molecule is found on chromosome 1p36.


Case 2 - Figure 1 - There is a lichenoid infiltrate which is devoid of atypical lymphocytes. The epidermis shows mild hyperplasia.
Case 2 - Figure 2 - The second biopsy shows marked epidermal hyperplasia and a sheet like dermal lymphoid intiltrate.
Case 2 - Figure 3 - The keratinocytes are markedly atypical, as are large , non-cohesive cells in the dermis.



Case 2 - Figure 4 - A cytokeratin immunostain (AE1/3) decorates the epidermis but spares the dermal infiltrate.
Case 2 - Figure 5 - A CD30 immunostain strongly decorates the atypical dermal mononuclear cell infiltrate.
Case 2 - Figure 6 - There is dot-like accentuation of CD30 expression in the Golgi region.



Case 2 - Figure 7 - A CD20 preparation decorates background small lymphoid forms.
Case 2 - Figure 8 - An anaplastic lymphoma kinase (ALK) preparation is negative.
Case 2 - Figure 9 - A CD3 preparation strongly decorates small mature background T-cells; the larger cells show progressive loss of staining.
Lymphomatoid Papulosis (LYP)
First described by McCauley in 1968, LYP is a distinctive syndrome characterized by recrudescent eruption of nodules or papules which clinically follow a benign course despite a worrisome histology. Clinical criteria currently used to diagnose LYP are 1. Multiple papules or nodules; 2. Spontaneous regression or waxing and waning of lesions that often heal with a scar; 3. No evidence that skin lesions progressively grow to a diameter larger than 3 cm during 3 months of observation without treatment; and 4. Absence of lymphadenopathy. Many articles suggest that 10 to 20% of cases manifest concurrent or subsequent development of lymphomas include mycosis fungoides, anaplastic Ki-1 lymphoma, and Hodgkin's disease. Recent reports indicate the actuarial cumulative risk approaches 80%. Lesions manifest no sex predilection (Kadin) and can occur at any age from infancy to the eighth decade (Wang) with the median age being in the fourth or fifth decades (Wang, Kadin). The incidence ranges from 1.2 - 1.9 per million in New England (Wang). The overall prognosis in those patients who have LYP and then develop lymphoma relates to the presence or absence of extracutaneous disease; those patients with extracutaneous disease have a worse prognosis. Willemze first recognized two distinct variants: type A and type B. Those patients who have or subsequently develop MF usually have type B LYP while those patients with CD30 positive lymphoma or Hodgkin's disease have type A LYP (Beljaards). It appears that progression of lymphomatoid papulosis to malignant lymphoma is a more frequent occurrence in males (Beljaards).

Pathology
The histology of LYP depends upon the age of the lesion biopsied (Kadin). Early lesions show only a sparse, non-descript perivascular lymphoid infiltrate, while the characteristic atypical morphology is seen in the fully-developed, mature lesion. With respect to the latter, two distinct morphologies are described as "type A" and "type B" lesions (Willemze). The former comprise wedge-shaped superficial and deep perivascular infiltrates which include both small lymphoid forms and atypical large lymphocytes mimicking Reed-Sternberg cells and their variants. At a light microscopic level both variants show a prominent angiocentric mononuclear cell infiltrate which expands the vessel wall with resultant luminal attenuation. Ischemic alterations of the overlying epidermis may be seen. Mural or luminal fibrin deposition is not observed. There is concomitant erythrocyte extravasation within the dermis and epidermis. In the type A lesion the dominant cell around and within the vessel walls is a large lymphoreticular cell in the 20 to 30 micron range with abundant lightly staining cytoplasm; the cells have round, oval and or reniform nuclei with an open chromatin pattern and a prominent basophilic nucleolus. Most of the cells are mononuclear although occasional binucleated forms can be seen. In some cases there is hypereosinophilia of the cytoplasm with senescent alteration of the nucleus resulting in a morphology reminiscent of the mummified cell encountered in Hodgkin's disease. Mitoses are numerous. There is a polymorphous inflammatory background comprising eosinophils and neutrophils with leukocytoclasia. The infiltrate extends deep and can expand the adventitial dermis of the eccrine coil and pilosebaceous unit. Epidermotropism is minimal to absent. Fully-developed type A lesions of two or three weeks' age frequently contain numerous histiocytes, neutrophils and eosinophils, with the granulocyte component forming sheets in the superficial dermis and frequently manifesting exocytosis, eventuating in epidermal necrosis, ulceration and formation of a neutrophil-containing scale-crust (Willemze). Neutrophils may pack the blood vessels; fibrinoid necrosis and erythrocyte extravasation may be seen (Willemze) and fibrosis may result. The so-called "type B" lesions mimic MF histologically, with band-like infiltrates of small, irregularly-contoured lymphoid forms in close apposition to the undersurface of the epidermis. Pautrier's micro-abscesses are unusual in both types of lesion and their presence should raise consideration of MF. The so-called "type C" lesion shows nodules of CD30+ve cells cognate to anaplastic large cell lymphoma but sparing the subcutis.

Phenotypic and molecular studies
Lymphomatoid papulosis is a lymphoproliferative disorder. A study of patients with LYP uncomplicated by lymphoma showed through PCR amplification that a single Vβ-7 transcript of identical size was present in each lesion in the majority. When the dominant band from each excised lesion was removed from the gel, reamplified and directly sequenced, it was confirmed that monoclonality from multiple lesions of patients with LYP is derived from a single transformed T cell. This study also showed via the method of semiquantitative PCR and DNA sequencing that the atypical lymphocytes in lesions of LYP and lymphoma were identical [1].

Immunophenotypically most large atypical lymphocytes of types A and B LYP exhibit pan T cell and T-helper antigen expression (ie CD3,4+5). Both the large atypical cells of type A LYP and the large cerebriform cells of type B LYP express activation markers HLADR, TAC (the antigen for the interleukin-2 receptor), transferrin receptor (T9) and Ki-67. Phenotypic abnormality is revealed in both subtypes of LYP by virtue of diminished expression of the pan T cell antigens Leu-1 and/or CD7/Leu-9. The cells show variable Ki1 expression but are frequently –ve in type B LYP.

Lymphomatoid papulosis has a unique position amidst the primary T cell lymphoproliferative syndromes by virtue of a cytomorphology, phenotypic and molecular profile suggesting a malignant neoplastic process while its clinical course is typical of benign disease, being one of spontaneous regression. LYP expressing CD8-positivity is unusual [6, 29] . The basis of its categorization as a form of neoplasia lies in the identification of clonality, features of an aberrant phenotype as defined by a significant diminution in CD7 and CD62l and perhaps most convincingly the identification of a single T cell clone in lesions of LYP, primary cutaneous CD30+ve ALCL and Hodgkin lymphoma. We have encountered 4 cases of LYP with a CD8 phenotype, in all of which lesions followed a classical clinical course.

Treatment
Methotrexate (MTX) appears to the treatment of choice for more severe cases of LYP. The effectiveness of MTX relates to its inhibitory effect on DNA synthesis, anti-inflammatory effects or both. The atypical lymphocytes seen in LYP and Ki1 lymphoma manifest a high mitotic activity and hence it would seem likely that methotrexate significantly inhibits the proliferation of these cells especially during the initial phase of lesional development. The recommended dosage is 10 to 25 mg every 1 to 4 weeks. The major side effect is hepatic fibrosis; liver biopsies with treatment guidelines similar to those used for psoriasis patients should be employed.

Borderline CD30 Positive Lymphoproliferative Disorders
There are cases that manifest borderline morphologic features between ALCL and LYP, with lesions clinically compatible with the latter. The hallmarks light microscopically include a cohesive growth of atypical cells in the depths of the lesion however more superficially the infiltrate of atypical cells is arranged in small clusters and as well there are numerous admixed inflammatory cells including granulocytes. The absolute distinction between ALCL and LYP can be difficult, prompting a diagnosis of borderline C30+ve lymphoproliferative disease.

Anaplastic Ki1 Lymphoma
At the other end of the spectrum of CD30 positive lymphoproliferative disorders is Ki-1 positive lymphoma. Stein and coworkers in 1985 recognized a distinctive large cell hematopoietic neoplasm associated with extensive lymph node effacement manifesting sinusoidal accentuation. The neoplastic cell population is typically of T-cell or null-cell phenotype. There is heterogeneity in terms of the morphologic spectrum of the lesion with cells ranging from small forms to large highly atypical sarcomatoid variants. There are four main variants: the common type (classic), giant cell-rich or pleomorphic, small cell, and lymphohistiocytic or Hodgkin's disease-like. There are other unusual variants including neutrophil rich, eosinophil rich, sarcomatoid, and signet ring. Although one recognizes these morphologic variants, there is no clear cut clinical difference between the various subtypes except with respect to the small cell variant which often has a leukemic picture (Kinney) and a more aggressive clinical course. An alternative classification scheme reflects anaplastic lymphoma kinase (ALK) expression; specifically the lymphomas are categorized according to the presence or absence of ALK. The vast majority of primary cutaneous ALCL's are ALK-ve; ALK–ve tumors tend to occur in older individuals and have a much worse than do ALK+ve forms.

CD30+ve ALCL in the skin may represent a primary cutaneous lymphoma, may represent secondary involvement in the setting of primary nodal Ki1 positive lymphoma, or may develop in the setting of another form of lymphoma, specifically Hodgkin's disease, MF, and other forms of post thymic T cell lymphoma (Kinney). Primary cutaneous ALCL arises denovo in the skin with the median age of presentation being 60 years. Lesions usually present as solitary tumors manifesting variable ulceration but may exhibit multicentricity. Approximately 25% of patients with ALCL showed lesional regression. The absolute distinction between ALCL and LYP may be difficult, but in LYP the lesions are multiple, small, and have a tendency for spontaneous regression; extracutaneous spread does not occur. In contrast in primary cutaneous ALCL the lesions may be solitary, may not regress and may manifest extracutaneous dissemination. Secondary ALCL may arise in the progression of other lymphomas including peripheral T cell lymphoma, Hodgkin's disease, MF and LYP. The acquisition of CD30 expression in a previously CD 30-ve lymphoma is considered a poor prognostic sign.

Some authors note that the presence of a solitary lesion greater than 3 centimeters, persistence without spontaneous regression, and the presence of significant lymphadenopathy probably indicate malignant lymphoma and/or progression of lesions of LYP into ALCL. Such criteria might be construed as overly stringent in that there are published series addressing the clinical features of ALCL with lesions smaller than 2 centimeters and where only 63% had a solitary lesion while the remainder had multiple lesions. Others have used a 2 centimeter cut off as distinguishing lymphoma from LYP. Regression is only marginally helpful as it may be seen in both conditions [4]. The cases that most frequently undergo regression are the so-called borderline cases which are those which manifest overlap features between CD30 positive lymphoma and LYP.

Molecular basis of anaplastic Ki-1 lymphoma
The questions arise as to what molecular events are responsible for the spontaneous regression of some cases of CD30 positive lymphoma and what events lead to lesional progression eventuating in death. A transforming growth factor (TGF)-β receptor designated TBRII is a multifunctional polypeptide which regulates cell proliferation and differentiation; its main effect is one of growth inhibition. Cell culture lines derived from a lesion of Ki1+ve lymphoma do not show an inhibitory growth response to TGFβ, the apparent basis being a point mutation in TBRII, leading to inhibition of the wild-type receptor, rendering the cell resistant to the inhibitory effects of TBRII [13].

Lymph node based CD30+ve large cell lymphomas of either T cell or null cell lineage manifest a characteristic translocation, namely t(2;5)(p23;q35) and express the NPM-ALK hybrid protein detected by the antibody ALK1. This distinctive translocation was first described in 1989. Five years later the translocation site was cloned by Morris et al and it was shown that the chromosomal rearrangement fuses part of the nucelophosmin gene on chromosome 5q35 to a portion of the ALK gene on chromosome 2p23 generating a chimeric molecule and a unique 80-kDa NPM ALK fusion protein. The incidence of this translocation ranges from 15% to 80% of cases of ALCL in the hands of different authors. The translocation has been detected in some peripheral T-cell lymphomas other than classical Ki1+ve ALCL and in some diffuse large cell B cell lymphomas. In addition a cryptic abnormality has been detected that is easily recognized using fluorescence in situ hybridization : inv (2)(p23q35). The result is distinctive ALK protein expression restricted to the cytoplasm of the neoplastic cells. ALK protein expression is held to be an independent positive prognostic variable based upon retrospective analyses [10]. The principle methods of detection of ALK are through RT in situ PCR, cytogenetics, and immunohistochemistry.

Expression of ALK is seen in a small minority of cases of LYP and primary CD30+ve ALCL (i.e. less than 10% of cases) with several studies not detecting its presence in any cases. In contrast the rate of t(2:5) is higher in lymph node-based CD30+ve lymphomas with a prevalence of about 40%. There is a suggestion that the t(2:5) may be more common in cutaneous lesions derived from younger patients. The findings suggest that lymph node based CD30+ve lymphoproliferative disease is distinct from its cutaneous counterpart.

Pathology
There are five distinct histomorphologic forms of ALCL [10]. Most common in our hands are the pleomorphic variant, comprising large cells with wreath-like giant cells, and the monomorphic variant comprising sheets of monotypic medium or large cells. The lymphohistiocytic variant has numerous admixed reactive histiocytes. The small cell variant shows scattered large atypical cells as described above, but the dominant cell is a small to intermediate sized lymphocyte that demonstrates nuclear contour irregularities including the presence of polylobate or floret-like forms; the cells have clear cytoplasms and distinct cytoplasmic membranes. Sarcomatoid and signet ring variants of ALCL are rare. There are two cytologic lymphocyte types that ought to prompt recognition of Ki1+ve ALCL [4]. Type I cells are polygonal forms between 10 and 30 microns in diameter and exhibit a distinct pink-staining cell membrane. Their angulated cell borders imparts a squamoid appearance to the cell. The nuclei are usually round to oval but can show irregular foldings. The chromatin is dispersed as coarse clumps, associated with large areas of clearing. Nucleoli are large and multiple. The cytoplasm is abundant and is pale to lightly amphophilic in quality. The type II cell is monomorphous, measuring 15 to 50 microns in diameter with a round to oval, lobulated, reniform or horseshoe shaped nucleus that may be centrally placed with a prominent paranuclear hof. The chromatin is irregularly clumped and shows less clearing than the type I cell. The cytoplasm is abundant and deeply amphophilic or basophilic. The cells may contain multiple nuclei, oftentimes in a wreath like arrangement and/or resembling those cells encountered in HD.

Pathologically CD30-positive lymphoma differs from LYP by virtue of a predominance of CD30 positive cells with greater than 75% of cells having a large anaplastic morphology. In contrast, in LYP the CD30 positive cells are noted amidst a dominant polymorphous inflammatory cell background. Features suggestive of evolution from LYP into CD30 positive lymphoma include a further loss of pan T cell marker expression, extension into the subcutis and a greater proportion of atypical cells relative to the inflammatory cell background with focal effacement of the dermal architecture by sheets of atypical cells. In addition to the sheet like pattern of growth there is striking angiocentricity. Pseudoepitheliomatous hyperplasia occurs in 20 to 30% of all cases of CD30+ve ALCL; the presence of this phenomenon in lesions of LYP has not been previously reported [20].

Phenotypic studies
Most cases of Ki1+ve lymphoma exhibit a T cell or null cell phenotype, with a small minority having a B cell phenotype. The basis of their classification as ALCL is due to co-expression of CD30, EMA, and the demonstration of a t(2;5) translocation. However, the B cell variant, clearly representing the least frequent of the immunophenotypic subgroups, is prognostically similar to other forms of large cell B cell lymphoma. The expression of activation antigens is very common including T9, HLA-DR, and Tac. They may show an aberrant T cell phenotype by virtue of CD3 negativity. Unlike Hodgkin's disease the cells are CD45 positive and are Leu-M1 (CD15) negative. In addition, there is evidence of cytotoxic potential. In nodal Ki1 positive lymphomas, the cytotoxic characteristics are revealed by virtue of the presence of cytotoxic cell associated antigens including CD8, CD56, CD57, and the cytotoxic granular proteins perforin and T-cell restricted intracellular antigen-1 (TIA-1), the latter a 15-kDa cytotoxic granule associated membrane protein expressed in natural killer cells and cytotoxic T-lymphocytes that was first characterized by Anderson et al in 1990 and that reacts with 20-36% of peripheral bood T-lymphocytes, being strongly expressed by NK cells and CD8+ cytolytic T-cells and less strongly by CD4+ve cells. Since then several studies have shown that the expression of these cytotoxic proteins are seen in a spectrum of lymphoma including NK-cell lymphomas, rare cases of Hodgkin's lymphoma, Ki1+ve ALCL and certain distinctive forms of peripheral T cell lymphoma including subcutaneous T cell lymphoma, hepatosplenic, and intestinal lymphoma. In primary cutaneous Ki1+ve ALCL's granzyme B and TIA's have been observed while in CD30-ve primary cutaneous large T-cell lymphomas the neoplastic cells usually do not express these proteins [14].

In the small cell variant, the smaller lymphoid cells are typically CD30 negative nevertheless there is a clonal loss of one of the pan-T cell antigens especially CD3 and as well expression of the NPM-ALK protein may be seen. In those cases of null phenotype expression of CD11b and CD13 has been observed (Simonitsch). ALK positivity is seen in only 15% and 30% of the Hodgkin like and giant cell forms respectively while ALK positivity is seen in 80 to 100% of classic small cell and lymphohistiocytic variants.

In those null-cell ALCL's gene rearrangement studies nevertheless do demonstrate a rearrangement of the T cell β-receptor [5] and even in these lymphomas there is expression of various cytotoxic proteins including granyme, perforin, and TIA-1. It would appear that a certain percentage of these tumors also may represent true NK cells in light of the expression of the NK cell associated marker CD56 in some cases of ALCL in concert with the failure to detect TCR gene rearrangements.

Primary Cutaneous Hodgkin's Disease
Although exceptional cases of primary cutaneous Hodgkin's disease (HD) occur, most cases of cutaneous HD represent secondary involvement; even this is a rare event in patients with advanced disease. In most instances the skin lesions represent a direct extension from extensive mediastinal disease. To diagnose primary cutaneous HD there must be no evidence of extracutaneous HD at 6 months follow-up. Histologically there is a background infiltrate of small mature lymphocytes producing a morphology reminiscent of benign reactive lymphoid hyperplasia as seen in lesions of lymphocytoma cutis, but with scattered Reed Sternberg (RS) like cells present that demonstrate the typical CD30+ve/CD15+ve/CD45-ve phenotype. Some patients may have disease limited to the skin while others may develop nodal HD several years after the initial cutaneous presentation.

Lymphocyte rich classic HD is a form of CD30+ve HD with two recognized variants: a diffuse and a nodular form. The nodular form has also fallen under the alternative appellation of follicular HD. The classic appearance is one of expanded follicles composed predominantly of mantle zone lymphocytes in the absence of sclerosis. Within the expanded mantle zones are scattered RS cells and their variants; the diagnosis is suspected due to the presence of these scattered RS cells in a benign-appearing follicle. Prognostically lymphocyte rich forms of classical HD likely do better than either mixed cellularity or nodular sclerosing variants. The histology closely resemble nodular lymphocyte predominant HD.

Phenotypic Studies
The molecular and phenotypic profile for HD is characterisic; specifically the RS like cells are typically of B cell derivation. Occasionally a null phenotype exists; less than 2% of cases are of T cell derivation. The RS cells are typically EMA-ve despite expression of CD30 and CD15.

Primary Cutaneous CD30 Positive T Cell Rich B Cell Lymphoma
We have encountered patients with CD30+ve 10CBCL. In one patient presenting with a solitary scalp nodule there was an ensuing indolent course with no recurrence following complete removal. In the other case in whom the morphology was dominated by sheets of transformed cells, the lesions were multiple; the follow up in this case is only a matter of weeks and to date we are not aware of extracutaneous disease in this patient. The diagnosis was difficult as the neoplastic component was obscured by the reactive inflammatory infiltrate. Integral to the diagnosis was a high level of suspicion based on the clinical presentation in concert with the morphologic identification of a minor cell populace which demonstrated morphologic features that one associates with a CD30 positive lymphoproliferative disease. Specifically, the cells manifested large eosinophilic multilobate or irregularly notched nuclei; the traditional round, oval and regular undulating contours manifested by transformed reactive cells were not encountered. Phenotypically the cells resembled a marginal zone phenotype by virtue of being CD20+ve and CD10-ve with co-expression of CD43 along with CD23 and CD5 negativity. The differential diagnosis of the inflammatory cell rich case was primarily with primary cutaneous HD however the co-expression of CD45 and the absence of CD15 expression did not support this diagnosis. A form of extracutaneous CD30 positive large B cell lymphoma dominated by sheets of transformed cells has been previously described and is to be distinguished from both Ki1+ve ALCL and HD; prognostically they behave no differently than other forms of large B cell lymphoma. In the one multicenter study on cutaneous CD30 positive lymphoproliferative disease only 2 out of 17 cases in the CD30 positive non-Hodgkin's disease category were of B cell phenotype. The cells had a polymorphic centroblastic morphology and or/ had a hybrid morphology including immunoblasts, centroblast-like cells and RS-like cells comprising the dominant infiltrate. These uncommon lymphomas were designated as CD30 positive non-anaplastic large cell B cell lymphomas.

Lymphomatoid CD30+ve Drug Reactions
We have encountered cases of lymphomatoid drug eruptiosn in which a significant number of CD30 +ve lymphocytes was observed, mainly in a perivascular array. In particular, 5 of 15 cases of lymphomatoid drug reaction, all showing clonal rearrangement of TCR- g , manifested CD30+ve large cells in the dermis [18]. These drug-associated atypical cutaneous lymphoid proliferations manifested heterogenous clinical presentations included papular dermatitis, purpuric lesions, infiltrative plaques resembling MF and erythroderma. Light microscopically, the lesions manifested lymphoid atypia which assumed angiocentric, lichenoid or eczematous patterns, interstitial granulomatous inflammation, or atypical pigmentary purpura, all patterns previously described in drug associated cutaneous lymphomatoid hypersensitivity reactions [2, 3, 19] .

The implicated drug classes were those previously associated with lymphomatoid drug reactions, including minocycline and its analog erythromycin, ACE inhibitors, antidepressants, anticonvulsants, antihistamines, anti-hypertensive blocking agents including b-blockers, calcium channel blockers, lipid lowering agents, and a -antagonists In vitro studies have shown depression of T-cell function with antihistamines, b-blockers, antidepressants, lipid lowering agents, sex steroid related drugs, and calcium channel blockers.

Most cases demonstrated histological features useful in the distinction of lymphomatoid hypersensitivity from malignant lymphoma including directed migration of lymphocytes into suprapapillary plates, a site of preferential antigenic processing, eosinophilic spongiosis, papillary dermal edema and the presence of intraepidermal lymphocytes which were less atypical than those in the dermis. Cases of MF can manifest one or more of the aforesaid features and not all of these features are seen in every case of lymphomatoid hypersensitivity. Although the light microscopic overlap between lesions of MF and drug induced lymphomatoid hypersensitivity suggests that phenotypic and genotypic analyses would be logical diagnostic adjuncts, in this study those analyses suggested MF over a reactive process, and were therefore misleading.

In MF and other forms of post thymic CTCL, the neoplastic cells are of T cell lineage, and typically express CD2, CD3, CD4 and CD5. The T-helper (Th) lineage of the neoplastic lymphocytes is suggested by virtue of a CD4/8 ratio which exceeds 4:1 and by CD4 expression by cytologically atypical cells. In our CD30+ve lymphomatoid drug reactions, most cases studied showed a CD4/8 ratio which exceeded 4:1. In a few cases the intraepidermal lymphoid population was predominated by CD8 positive lymphocytes while the dermal lymphocytes mainly expressed CD4, findings characteristic of a type IV immune reaction with combined delayed type hypersensitivity and cellular cytotoxic features. This differential localization of CD8 and CD4 lymphocytes to the epidermis and dermis characteristic of a reactive process was only present in a minority of cases.

The neoplastic lymphocytes of MF often manifest deletions of the pan T cell markers CD7 and CD62 K. Therefore, CD7 and CD62 K expression in less than 50% of an infiltrate has been held to indicate MF; the greater the diminution of expression, the more specific is the finding. As CD62 K is only demonstrable in frozen tissue and there is rarely a deletion of CD2 and CD5 in lesions of MF, the lack of CD7 expression has been held by some authors to be an important phenotypic indicator of CTCL. However, 16 of 19 biopsies in our recent series exhibited reduced CD7 expression in only 50% or less of the infiltrate. The number of T cells expressing CD7 was 30% or less in 5 cases, a profile indistinguishable from CTCL. In 2 cases, there was also a significant reduction in CD62 K expression. Although the aforementioned pattern of pan T cell marker deletion could be construed as being compatible with MF, there are subpopulations of reactive T lymphocytes which do not express CD7 or CD62 K, including memory T-cells. The expression of CD7 and CD62 K by lymphocytes correlates inversely with HLADR expression. CD62 K or L-selectin is a member of a group whose cluster designations are CD62 K, CD62 E (E-selectin), and CD62 P (P-selectin). L-selectin is expressed on blood monocytes, blood neutrophils, subsets of natural killer cells and T and B lymphocytes including those of naïve phenotype, but not cells of Th1 memory subtype, and is shed from the surface of activated leukocytes. Hence T lymphocytes lacking both CD7 and CD62 K would be expected in type IV antigen driven inflammatory processes.

References

  1. Chott A, Vonderheid EC, Olbricht S, Miao N, Balk S, Kadin M. The same dominant T cell clone ins present in multiple regressing skin lesions and associated T cell lymphomas of patients with lymphomatoid papulosis. J Invest Dermatol 1996;106;696-700.

  2. Crowson AN, Magro CM. Atypical pigmentary purpura : A clinical, pathological and genotypic study of 40 cases Hum Pathol 1999;30(9):1104-12.

  3. Crowson AN, Magro CM. The pathology of cutaneous drug eruptions (monograph). St. Louis: CV Mosby. Curr Probl Dermatol 2002;14(4):117-146.

  4. Demierre M, Goldberg L, Kadin M, Koh H. Is it lymphoma or lymphomatoid papulosis? J Am Acad Dermatol 1997;36:765-772.

  5. Foss H-D, Anagostoupoulos I, Araujo I et al. Anaplastic large-cell lymphomas of T-cell and null-cell phenotype express cytotoxic molecules. Blood 1996;88:4005-4011.

  6. Fukunaga M, Masaki T, Ichihashi M, Ueda M. CD8-positive primary cutaneous anaplastic large cell lymphoma with a fair prognosis.Acta Derm Venereol. 2002;82(4):312-4.

  7. Grau RH, Hall TC, Crowson AN, Clark SJ. Pseudocarcinomatous Hyperplasia in the Setting of CD30+ve Anaplastic Large Cell lymphoma: A report of 2 cases (abst) . J Am Acad Dermatol 2004;50:p262

  8. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf-Peeters, Falini B, Gater KC. A revised European American classification of lymphoid neoplasms: A proposal from the international Lymphoma Study group. Blood 1994;84;1361.

  9. Kinney MC, Collins RD, Greer JP, Whitlock JA, Sioutos N, Kadin ME. A small cell predominant variant of primary Ki-1 (CD30) T-cell lymphoma. Am J Surg Pathol 1993;17:859.

  10. Kinney MC, Kadin ME. The pathologic and clinical spectrum of anaplastic large cell lymphoma and correlation with ALK gene dysregulation. Am J Clin Pathol 1999 Jan;111(1 Suppl 1):S56-67.

  11. Krenacs L Wellmann A, Sorbara L et al. Cytotoxic cell antigen expression in anaplastic large cell lymphomas of T- and null-cell type and Hodgkin disease: evidence for distinct cellular origin. Blood 1997:89;980-989.

  12. Krishman J, Tomaszewaki M, Kao GF. Primary cutaneous CD30-positive anaplastic large cell lymphomas: report of 27 cases. J Cutan Pathol 1993;1511-34.

  13. Knaus P, Lindemann D, DeCoteau J, Perlman R, Yankelev H, Hille M, Kadin M, Lodish H. A dominant inhibitory mutant of the type II transforming growth factor B receptor in the malignant progression of a cutaneous T-cell lymphoma. Mol Cell Biol 1996;16:3480-3489.

  14. Kumar S, Kingma D, Weiss W et al. Primary cutaneous Hodgkin's disease with evolution to systemic disease. Am J Surg Pathol 1996:26; 754-759.

  15. Kummer JA, Vermeer MH, Dukers D, Meijer CJ, Willemze R. Most primary cutaneous CD30-positive lymphoproliferative disorders have a CD4-positive cytotoxic T-cell phenotype. J Invest Dermatol 1997 Nov;109(5):636-40.

  16. Liang X, Golitz L, Smoller BR et al. Association of expression of CD44v6 with systemic anaplastic large cell lymphoma. Am J Clin Pathol 2002;117:276-282.

  17. Macaulay WL. Lymphomatoid papulosis: a continuing self-healing eruption, clinically benign-histologically malignant. Arch Dermatol 1968;97:23-30.

  18. Magro CM, Crowson AN, Kovatich AJ, Burns F. Drug-induced reversible lymphoid dyscrasia: A clonal lymphomatoid dermatitis of memory and activated T cells. Hum Pathol 2003; (in press).

  19. Magro CM, Crowson AN. Drug-induced immune-dysregulation as a cause of atypical cutaneous lymphoid infiltrates : A hypothesis. Hum Pathol 1996;26:125-132.

  20. Scarisbrick JJ, Calonje E, Orchard G et al Pseudoepitheliomatous change in lymphomatoid papulosis and primary cutaneous CD30 lymphoma: a clinicopathologic and immunohistochemical study of 6 patients. J Am Acad Dermatol 2001;44:239-247

  21. Scwarting R, Gerdes J, Durkop H, Falini B, Pilwei A, Stein H. Ber H-2: a new anti-Ki1 (CD30) monoclonal antibody directed at a formalin-resistant epitope. Blood 1989;74;1678-1689

  22. Stein H, Mason DY, Geredes J. The expression of the Hodgkin's disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood 1985;66:848-858.

  23. Vonderheid E, Sajjadian A, Kadin M. Methotrexate is effective therapy for lymphomatoid papulosis and other primary cutaneous CD30-positive lymphoproliferative disorders. J Am Acad Dermatol 1996;34:470-481.

  24. Willemze R, Scheffer E, Van Vloten W, Meijer CM: Lymphomatoid papulosis and Hodgkin's disease: are they related? Arch Dermatol Res 1982;275:159-167.

  25. Willemze R, Beljaards RC. Spectrum of primary cutaneous CD30 (Ki-1) positive lymphoproliferative disorders. J Am Acad Dermatol 1993;28:973-980.

  26. Wood GS, Stricker JG, Denea D et al. Lymphomatoid papulosis expresses immunophenotypes associated with T cell lymphoma but not inflammation. J Am Acad Dermatol 1986;15:444-458.

  27. Wood G, Hardman D, Boni R et al. Lack of t(2;5) or other mutations resulting in expression of anaplastic lymphoma kinase catalytic domain in CD30+ primary cutaneous lymphoproliferative disorders and Hodgkin's disease. Blood 1996;88:1765-1770.

  28. Wood G. Analysis of the t(2:5) (p23;q35) translocation in CD30+ primary cutaneous lymphoproliferative disorders and Hodgkin's disease. Leukemia and Lymphoma 1997;29:93-101.

  29. Wu WM, Tsai HJ. Lymphomatoid papulosis histopathologically simulating angiocentric and cytotoxicT-cell lymphoma: a case report. Am J Dermatopathol. 2004 Apr;26(2):133-5.

  30. Zinzani PL, Bendand M, Martell M, et al. Anaplastic large cell lymphoma: a clinical and prognostic evaluation of 90 adult patients. J Clin Oncol 1996;14:955-962.