—  SPECIALTY CONFERENCE  —

Hematopathology

Case 3 - Cutaneous Lymphoid Hyperplasia

Mark R. Wick
University of Virginia Health Science Center
Charlottesville, VA


Click on each slide thumbnail image for an enlarged view
Introduction
The seminar case demonstrates a dense infiltrate of lymphoid cells that occupies most of the dermis, but there is no effacement of adnexal structures or vascular destruction or permeation. The cellular population is rather polymorphous, with no obvious nuclear atypia, and numerous eosinophils are apparent. The lesion is best characterized as cutaneous lymphoid hyperplasia, and an arthropod bite response was suggested as a possible etiology. However, a fair proportion of lesions with the specified morphologic features turn out to be idiopathic, with no clearly identifiable pathogenesis.

One of the most maddening problems with which pathologists may be confronted is the evaluation of whether a cutaneous lymphoid infiltrate is benign or malignant. In the former group, one has such lesions as Jessner's infiltrate, dermal or subcutaneous lupus erythematosus, lymphadenoma benigna cutis, lymphocytoma cutis (of Spiegler-Fendt), chronic lichenoid and spongiotic dermatitides, drug-induced pseudolymphomas, actinic reticuloid, inflammatory pseudotumor, Kikuchi's disease, and cutaneous lymphoid hyperplasia, not further specified. These have been summarized in a thorough review by Smoller & Glusac. Malignant lymphoid lesions of the skin that may be deviously bland-looking are also quite common among selected members of the small-lymphocytic, small cleaved-cell, and mixed small & large-cell categories. Immunohistologic evaluation is variably effective at resolving differential diagnostic problems and can be applied best after subclassification of the constituent disorders into three broad groups, as discussed below. Genotypic analyses, using either Southern blot or polymerase chain reaction (PCR)-based technology, also contribute in a meaningful way to determinations of clonality in this setting. Rearrangements of the immunoglobulin heavy-chain genes are often present in B-cell lymphomas, and T-cell malignancies most commonly demonstrate rearrangements of the T-cell beta and gamma receptor genes.

Because the differential diagnosis between cutaneous lymphoid hyperplasias and malignant lymphomas is largely predicated upon such morphological adjuncts in many cases, I have elected to devote all of the ensuing discussion to them. Conventional morphological features used to discriminate between benign and malignant lymphoid infiltrates in the skin have been well-covered by Banks, and will not be recounted here.


Case 3 - Figure 1 - This clinical photograph shows a violaceous nodular lesion of the right earlobe.
Case 3 - Figure 2 - In this photomicrograph, one sees a vaguely nodular lymphoid infiltrate that occupies much of the dermis.
Case 3 - Figure 3 - A partially follicular nature for the lymphoid infiltrate is better-seen in this photograph.


Case 3 - Figure 4 - The lymphoid infiltrate is polymorphous in this area.
Case 3 - Figure 5 - Notable stromal vascularity is apparent. The lymphoid cells in this field demonstrate modest nuclear atypia.


Case 3 - Figure 6 - Eosinophils are admixed throughout the infiltrate, as shown here.
Case 3 - Figure 7 - Modest nuclear atypia is again evident in this photomicrograph.

Epidermotropic Infiltrates Resembling Mycosis Fungoides
Selected drug-induced pseudolymphomatous infiltrates, chronic lichenoid & spongiotic dermatitides, and actinic reticuloid are those conditions that principally have the capacity to mimic mycosis fungoides (MF) histologically. This is so because they may feature the presence of grouped lymphocytes in the epidermis as well as the dermal interstitium, and such cells commonly demonstrate at least a modest degree of "activation" and nuclear atypia. Nearly universally, these elements are also T-cells, as are the proliferating cells of MF.

If it is available, frozen tissue can be studied immunohistologically to assess the presence or absence of an "aberrant" T-cell phenotype. The latter is said to be defined by the loss of one or more "pan-T-cell" determinants (CD2,3,5, & 7), or by the coexpression of antigens that are usually mutually exclusive (e.g., both CD4 and CD8 in the same cell population). CD7 is the pan-T-cell antigen cluster that is most often lost in MF, which is characteristically a proliferation of CD4+ cells. Nonetheless, this is not a universal finding in cutaneous T-cell lymphoma, and it has been reported in benign inflammatory conditions as well. On the other hand, actinic reticuloid and most other chronic dermatitides do usually retain pan-T-cell markers and, with rare exceptions, are comprised predominantly of CD8+ lymphocytes. Drug-induced pseudo-MF may have an immunophenotype like that of chronic spongiotic dermatitis, or it may simulate the profile of MF perfectly. If the latter fact is disheartening, it is made moreso by the knowledge that even genotyping studies may show T-cell receptor gene rearrangements in drug-related pseudolymphomas which are like those observed in MF. In the final analysis, withdrawal of all medications-- within feasible boundaries-- and continued clinical surveillance over time may be the only means whereby pseudo-MF and true cutaneous T-cell lymphoma (CTCL) can be distinguished from one another in selected cases.

Paraffin sections are much less suitable substrates for the immunohistologic separation of benign and malignant T-cell infiltrates of the skin. This is so because the "pan-T-cell" antibodies that can be applied to fixed tissues (e.g., anti-CD3;CD5, CD43, and CD45R0 are not as sensitive or specific as those used with frozen sections; moreover, potential paraffin section markers of T-cell subsets were, until very recently, limited. In some studies, CD4-positive intraepidermal lymphoid infiltrates which also show concurrent negativity for CD3, CD43, or CD45R0 are more often seen in MF than in benign T-cell infiltrates of the skin. CD8-preponderance also would argue against a diagnosis of MF. Nevertheless, these observations usually require further validation before they can be applied clinically in individual cases.

Deep Lymphoid Infiltrates Simulating Small-Cell or Mixed B-Cell Lymphomas
Generally speaking, "bulky" deep lymphoid infiltrates of the dermis and subcutis raise the specter of a B-cell lymphoma, rather than one of CTCL or peripheral T-cell lymphoma . Some of the former conditions are relatively easy to dispatch in short order as benign disorders, because they are comprised principally of T-lymphocytes or show an admixture of B- and T-cells. Such lesions include Jessner's infiltrates, active cutaneous lupus erythematosus, and inflammatory cutaneous "pseudotumors" . However, other infiltrates such as lymphadenoma benigna cutis, lymphocytoma cutis, and follicular variants of cutaneous lymphoid hyperplasia (CLH) do, in fact, contain a large number of B-lymphocytes and are capable of causing substantial diagnostic consternation .

Frozen section- based or in-situ hybridization studies are helpful if they show restriction of lambda or kappa light chain immunoglobulin expression by the constituent B-cells . By convention, this profile must demonstrate a ratio of at least 10:1 with respect to one light chain over the other.

Other determinants also may be helpful in separating B-cell lymphomas from variants of CLH in paraffin sections. B-cell lymphoma is the likely diagnosis when CD20 and/or CD79a are coexpressed with CD43 by the same population of lymphocytes; when > 75% of the infiltrate mark as B-cells; and when >30% of the cells are positive for proliferating cell nuclear antigen (PCNA) or Ki-67. The diagnostic standard for such conclusions has been the clinical outcome of study cases after long-term surveillance.

The utility of other markers-- particularly the bcl-2 and bcl-6 proteins-- has been analyzed in several studies of cutaneous lymphoid infiltrates. The first moiety is an inhibitor of apoptosis, and it is preferentially overexpressed in malignant lymphoid cells that demonstrate a t(14;18) chromosomal translocation as seen most characteristically in nodal follicular lymphomas. However, it would appear that bcl-2 has rather limited differential diagnostic usefulness in the context of cutaneous follicular lymphoproliferations. Many examples of CLH, CTCL, and various non-follicular lymphomas of the skin are bcl-2-positive, and, conversely, <50% of follicular lymphomas demonstrate that marker in the skin. As expected, however, follicular CLH is bcl-2-negative.

Bcl-6 has demonstrated utility as a marker of cutaneous follicular lymphomas (CFLs). For example, a study by Hoefnagel et al. found bcl-6-positivity in all examples of primary CFLs. Interestingly, those authors observed that CD10-- another putative follicular marker-- was absent in almost all CFLs, whereas benign follicular proliferations expressed both bcl-6 and CD10. However, contrary results were obtained on that point by Mirza and colleagues and deLeval et al., who observed CD10-reactivity in the great majority of CFLs.

These variable immunohistologic findings, the usual absence of the t(14;18) in CFLs, and a relatively low incidence of rearranged immunoglobulin heavy chain gene (in roughly 50% of cases) in those tumors makes consistent recognition of primary follicular lymphoma problematic in the skin, even with modern technology. Ultimately, clincial followup may be the only way of making a firm diagnosis. Even that avenue of assessment is less-than-definitive, because CFLs often respond well to local treatment (e.g. irradiation) and many patients have long-term remissions.

All of these issues contribute to a conclusion-- with which I agree-- made by Nihal et al., espousing the stance that CLH cannot necessarily be distinguished from CFL, marginal-zone lymphoma of the skin, "cutaneous immunocytoma," and other malignant lymphoproliferative lesions. They are instead believed to exist on a continuum, making regular surveillance of "CLH" patients a prudent step in management.

Cutaneous Large-Cell Lymphoproliferations Simulating Lymphoma
Occasional examples of CLH may contain such a strikingly high number of reactive immunoblasts that they mimic the microscopic appearance of a nodular B-cell lymphoma of the large-cell type. Similarly, Kikuchi's disease-- a rare benign lymphoproliferative disorder that it much more often seen in Asia than in the U.S.-- is also comprised by large atypical lymphoid elements that may cause confusion with a malignant process.

In the first of these scenarios, that of florid immunoblast-rich CLH, the benefit is realized of routinely applying a broad panel of immunostains. These demonstrate a large number of B-cells among the large-cell population, but they also show the presence of normal follicular mantles, interfollicular zones rich in T-cells, and accentuation of Ki-67-reactivity in the central aspects of the follicular aggregates. In other words, the results mirror those seen in lymph nodal hyperplasia. Molecular analysis characteristically shows a polytypic lymphoid population as well. It should also be remembered with caution that CD30-- a marker that may be associated with some large-cell lymphomas-- is also potentially seen in benign immunoblastic proliferations in the skin and elsewhere. Hence, the presence of this determinant should never be used as sole support for a diagnosis of lymphoid malignancy. Kikuchi's disease (KD) features the presence of large, atypical mononuclear cells in the dermis, admixed with neutrophils and zones of necrosis; as such, it is a potential imitator of a subtype of anaplastic large-cell lymphoma. However, KD is apparently a true histiocytic proliferation; it is correspondingly labeled by the monoclonal antibody MAC-387 and those in the CD68 group (e.g., KP-1), but not by CD20 or pan-T-cell reagents. Inasmuch as examples of cutaneous "malignant histiocytosis" have essentially vanished in the wake of nosological reclassification occasioned by new technologies, the latter findings constitute strong evidence for the presence of a benign disorder.

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