Version May 2024
INTRODUCTION — The clinical and histologic diagnosis of cutaneous lymphoproliferative disorders is one of the most vexing issues in dermatology and dermatopathology, despite significant advances in their classification, pathogenesis, and treatment [1]. An international registry of patients with mycosis fungoides, the most common cutaneous T cell lymphoma, reported that 86 percent of patients experienced a delay in diagnosis, with a median delay of three years [2]. During this period, patients typically undergo numerous skin biopsies, which, in the absence of definite histopathologic criteria for cutaneous lymphoma, may be interpreted by the pathologist as "atypical lymphocytic infiltrate" or "atypical lymphocytic proliferation." This nonspecific but potentially serious diagnosis is often a source of anxiety and frustration for both the patient and the clinician.
This topic will discuss the definition of atypical lymphocytic infiltrate, the difficulties in differentiating reactive lymphocytic infiltrates from early lymphoma from the pathologist and clinician perspective, and the management of patients who receive this ambiguous diagnosis. Mycosis fungoides and other cutaneous lymphoproliferative disorders are discussed separately.
●(See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)
●(See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome".)
●(See "Primary cutaneous marginal zone lymphoma".)
●(See "Primary cutaneous large B cell lymphoma, leg type".)
●(See "Primary cutaneous follicle center lymphoma".)
●(See "Primary cutaneous T cell lymphomas, rare subtypes".)
●(See "Cutaneous T cell pseudolymphomas".)
●(See "Cutaneous B cell pseudolymphoma".)
●(See "Lymphomatoid papulosis".)
●(See "Primary cutaneous anaplastic large cell lymphoma".)
DEFINITION — The term "atypical lymphocytic infiltrate" describes the histologic finding of a dermal infiltrate of atypical lymphocytes admixed with cytologically banal, reactive-appearing lymphocytes in a pattern that is suggestive of lymphoma or leukemia. Cytologic characteristics that suggest lymphocytic atypia include (picture 1):
●Increased cell size
●Nuclear hyperchromasia
●Nuclear shape (eg, cleaved, folded, cerebriform) that deviates from the typical round morphology of normal lymphocytes
Histologic patterns that suggest a lymphoproliferative disorder include:
●Dense band-like infiltrate of lymphocytes within the superficial dermis
●Dense and diffuse lymphocytic infiltrate
●Exocytosis of lymphocytes into the overlying epidermis or adnexa in the absence of spongiosis
●Nodular aggregates of lymphocytes reminiscent of germinal centers
The term "atypical lymphocytic infiltrate" is generally used when the pathologist cannot reliably differentiate a reactive from a malignant lymphoproliferative disorder on histopathologic grounds alone [3]. In cases where the histologic features are strongly suggestive of malignancy (eg, necrosis, angioinvasion, angiodestruction, diffuse cytologic atypia) but are not entirely consistent with one of the entities included in the current classification of cutaneous lymphomas, the clinician should be alerted that strict clinical and histopathologic monitoring is needed to identify the type of lymphoproliferative disorder and start appropriate treatment.
DIFFICULTIES IN THE DIAGNOSIS OF CUTANEOUS LYMPHOMA — The diagnosis of cutaneous lymphoma based solely upon histologic features may be extremely difficult, particularly in the early stage of disease [4]. Much of the difficulty stems from the absence of specific markers that can identify a lymphocyte as malignant. In addition, there are numerous conditions that simulate cutaneous lymphoma (eg, drug reactions, inflammatory, and autoimmune skin diseases) or may represent precursor diseases, blurring the line between reactive and malignant lymphoid proliferation (table 1) [3,5-9].
Technical issues such as poor tissue handling during the biopsy procedure, insufficient specimen size, poor processing, and inadequate clinical history also may preclude a precise diagnosis. When a definitive diagnosis cannot be made, it is often more appropriate for the pathologist to render a diagnosis of "atypical lymphocytic infiltrate" rather than label the patient with a possibly life-threatening condition.
DIFFERENTIATING REACTIVE FROM MALIGNANT LYMPHOPROLIFERATIVE DISORDERS
Pathologist perspective
Histologic clues — Various histologic clues suggest either a malignant or reactive process [1,3]. For instance, the presence of lymphocyte exocytosis into the epidermis without associated spongiosis suggests mycosis fungoides (picture 2) rather than a reactive dermatosis. In the latter, spongiosis is prominent, whereas lymphocytic exocytosis, if present, is usually limited (picture 3).
Likewise, if a B cell lymphoma is suspected, the presence of a "bottom-heavy" infiltrate (picture 4) and abnormalities in germinal center architecture (lack of tingible-body macrophages, lack of germinal center polarity, lack of mantle zone, expanded marginal zone, etc) are more consistent with a malignant process than with a B cell pseudolymphoma (picture 5). (See "Cutaneous B cell pseudolymphoma".)
However, despite histologic clues, immunohistochemical staining patterns, and molecular data, pathologists are often left without a definitive diagnosis. In such situations, the best approach is to describe the salient histopathologic features and provide the clinician with an extensive differential diagnosis based upon the synthesis of the various findings. In addition, a direct discussion of the case with the clinician may be extremely helpful to both parties, especially if the possibility of a lymphoproliferative disorder was not clinically suspected.
Immunophenotyping — Immunohistochemical detection of specific cellular proteins is commonly used to support or refute the initial histologic diagnosis [10,11]. Common immunohistochemical markers for cutaneous lymphoproliferative disorders are listed in the table (table 2). However, the interpretation of immunohistochemical findings may be difficult, as illustrated in the examples below:
●Atypical lymphocytes often lose expression of markers that are present on their reactive, benign counterparts. As an example, the loss of the T cell markers CD7, CD2, and CD5 may be found in T cell lymphoma. However, a diminished expression of these markers, especially CD7, is by no means specific and can be observed in numerous reactive processes [12]. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Immunophenotyping'.)
●Expression of markers not commonly observed in reactive infiltrates can also be cause for concern. CD30, a marker of activated lymphocytes, is the hallmark of CD30+ lymphoproliferative disorders, including lymphomatoid papulosis and anaplastic large-cell lymphoma. However, CD30 positive cells may be observed in viral infections, drug reactions, arthropod bites, scabies, and inflammatory dermatoses [13]. (See "Lymphomatoid papulosis" and "Primary cutaneous anaplastic large cell lymphoma".)
●The pattern of marker expression is also important. As an example, several markers, including BCL-6, CD10, human germinal center associated lymphoma (HGAL), and LIM-only transcription factor 2 (LMO2), are normally expressed by germinal center B lymphocytes. The presence of B cells expressing these markers outside of germinal centers raises a concern for malignancy, namely primary cutaneous follicle center B cell lymphoma or systemic follicular B cell lymphoma with secondary skin involvement. Likewise, a predominance of intraepidermal CD4+ T lymphocytes over CD8+ T lymphocytes is suggestive of mycosis fungoides. (See "Primary cutaneous follicle center lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Immunophenotyping'.)
Molecular analysis — Molecular techniques play a key role in the diagnosis of lymphoid neoplasms. Each T and B cell expresses a single T cell receptor (TCR) or immunoglobulin (Ig), respectively. In most reactive lymphocytic infiltrates, T and/or B cells express a variety of TCRs and Igs consistent with polyclonality. In contrast, in lymphoma, the cell population results from the clonal expansion of a single aberrant cell that expresses a single TCR or Ig.
The TCR and Ig genes are composed of several separate regions that are combined during maturation (ie, variable [V], diversity [D], and joining [J]) (figure 1) and vary from one individual to another. During the maturation process, one D region is selected and combined with one J region. This pair is then joined to a single V region. By combining the regions in various configurations, the immune system is able to recognize and respond to the extraordinary diversity of proteins to which an individual is exposed over a lifetime. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T cell receptor generation' and "Immunoglobulin genetics".)
There are four TCR genes: TCR-alpha, TCR-beta, TCR-gamma, and TCR-delta. T cells express either TCR-alpha and TCR-beta or TCR-gamma and TCR-delta. The pair of resulting proteins (TCR-alpha/beta or TCR-gamma/delta) combines to form the TCR protein that resides on the cell surface. Although cells only express two of the TCR genes, all of the genes undergo rearrangement of V, D, and J regions during the maturation process. Of note, the TCR-delta gene resides within the TCR-alpha gene and is lost during rearrangement.
The detection of the various V, J, and D regions is usually performed by polymerase chain reaction (PCR)-based methods, which have largely replaced the Southern blotting technique used in early studies. PCR primer sets are designed to detect the various regions of the TCR-alpha, TCR-beta or TCR-gamma genes, the last two of which are the most commonly used. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Polymerase chain reaction' and "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Southern and Northern blotting'.)
Clonality is present when a single V-D-J region is detected. It is important to note, however, that clonality does not equate to malignancy. Clonal T cell and B cell populations have been detected in numerous benign or reactive processes [14-17]. In addition, pseudoclonality (ie, clonal populations that fail to be detected on repeat analysis) has been detected in benign T and B cell processes that histologically resemble lymphoma [18,19]. Pseudoclonality is most commonly seen when only a small population of B cells is present.
Diagnostic accuracy — The sensitivity of molecular tests is not 100 percent. The ability of the assays to detect a clonal population of cells in clinically proven cutaneous lymphoma varies across studies, ranging from 50 to 90 percent [20,21]. Some of this variation is related to the methods used [22]. A protocol for both T cell and B cell processes (BIOMED-2) is used by many laboratories to provide some degree of standardization [23-25].
The detection of clonality may be hindered when the lymphocytic infiltrate is sparse, as in early disease. In addition, mutations may occur within the PCR primer binding sites, especially in B cell malignancies, preventing the amplification and detection of the clone.
Performing two complementary assays (TCR-gamma and TCR-beta or IGH and IGK) on a specimen has been shown to increase sensitivity [26,27]. In addition, next-generation sequencing techniques have shown an increased sensitivity of T cell clone detection over traditional methods [28]. Specificity can be increased by performing clonality studies on specimens from two or more distinct cutaneous lesions [29]. The presence of the same clone at distinct clinical sites is highly suggestive of malignancy. Finally, in situations in which there is a high risk for false-positive results, such as when the lymphocytic infiltrate is sparse or reacting to a limited number of antigens (eg, allergic contact dermatitis, scabietic dermatitis), clonality studies should be repeated at least twice to avoid the detection of pseudoclonality.
Clinician perspective — The clinical diagnosis of cutaneous lymphoma, especially in the setting of early disease, is extremely difficult [30]. The cutaneous lesions of early mycosis fungoides may mimic numerous benign dermatoses and may respond temporarily to topical corticosteroids. Cutaneous B cell lymphomas often present as nonspecific nodules or plaques suggestive of a cyst or basal cell carcinoma. (See "Basal cell carcinoma: Epidemiology, pathogenesis, clinical features, and diagnosis".)
Despite these challenges, the astute clinician can often alert the pathologist to the possibility of a lymphoproliferative disorder and confirm or refute the pathologist's suspicions.
Skin examination — A full-body skin examination is essential in the evaluation of a patient with suspected lymphoproliferative disorder. Clinical features that suggest a diagnosis of mycosis fungoides include the presence of atrophic, poikilodermatous patches or plaques in geographic, asymmetric patterns and preferential localization of lesions in sun-protected sites. The presence of a nodular lesion on the earlobe, nipple, or scrotum is highly suggestive of Borrelia burgdorferi-associated cutaneous pseudolymphoma [31]. Such clinical clues should always be relayed to the pathologist with an accompanying detailed clinical differential diagnosis. (See "Cutaneous B cell pseudolymphoma" and "Clinical manifestations of Lyme disease in adults", section on 'Borrelial lymphocytoma'.)
Skin biopsy — Providing an adequate tissue sample for histopathologic examination is crucial for the diagnosis of lymphoproliferative disorders. Biopsies should be performed after cessation of any topical therapies, except emollients, for at least two weeks to prevent any treatment-related dampening of the histologic features. It is also important to avoid lesions with significant secondary changes (eg, from scratching or irritation). Biopsying two or more distinct clinical lesions may increase the chance of detecting specific histologic features and improve the accuracy of clonality studies. (See 'Molecular analysis' above.)
Although small punch or shave biopsies may provide sufficient material for diagnosis, incisional or punch biopsies ≥5 mm in diameter are preferred, since important diagnostic and prognostic features (eg, depth of involvement, folliculotropism, follicular mucinosis) may be missed with a small or superficial biopsy. (See "Skin biopsy techniques".)
Skin specimens are generally fixed in formalin, as the majority of ancillary studies (eg, immunohistochemistry, PCR-based gene rearrangement studies) can be performed on formalin-fixed tissue. If flow cytometry is to be performed, the specimen should be provided to the laboratory on saline-soaked gauze or, preferably, in Roswell Park Memorial Institute medium.
MANAGEMENT — Several questions arise when a patient receives a diagnosis of atypical lymphocytic infiltrate:
●What additional steps should the clinician undertake to further clarify the diagnosis?
Further clarifying the diagnosis largely depends upon a detailed correlation of histopathologic and clinical features. Several algorithms incorporating clinical and immunohistochemical findings have been proposed for the diagnosis of cutaneous lymphoproliferative disorders in their earliest stages (table 3) [4,12]. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Diagnostic algorithm'.)
Direct discussions between the clinician and the pathologist are essential. Some patients may benefit from evaluation in a multidisciplinary clinic specialized in cutaneous lymphoma [32]. In many of these clinics both the clinician and the pathologist assess the patients and the differential diagnosis is discussed at the bedside. Laboratory or imaging studies typically do not play a role in the evaluation of the patient with suspected lymphoproliferative disorder, since they are expected to be negative in the early stages of the disease.
●What should the patient be told regarding his or her diagnosis and prognosis?
Receiving a diagnosis of atypical lymphocytic infiltrate can produce significant anxiety and frustration in a patient. The clinician should discuss with the patient the difficulties in differentiating early lymphoproliferative disorders from reactive conditions and the need of clinical follow-up and repeat biopsies. It is also important to reassure patients that the prognosis of early stage primary cutaneous lymphoma is generally excellent with little effect on their general health, minimal risk for progression to more aggressive disease, and a long-term life expectancy that is similar to that of the general population [33]. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome".)
●How should the patient be treated?
A "watch and wait" approach with conservative, symptomatic treatment is the most appropriate in patients with a diagnosis of atypical lymphocytic infiltrate. Topical corticosteroids are most commonly used. Intralesional injections of corticosteroids may be useful for localized nodular or plaque-like lesions.
Phototherapy, especially narrowband ultraviolet (NBUVB) therapy, may be a therapeutic option for patients with widespread skin involvement. (See "UVB phototherapy (broadband and narrowband)".)
Systemic immunosuppressive agents should not be used for the treatment of patients with atypical lymphocytic infiltrate. There are several reports of nonspecific dermatoses treated with cyclosporine who later transformed into aggressive T cell lymphomas [34-36].
A close clinical follow-up with a low threshold for repeat biopsy is required for all patients with a diagnosis of atypical lymphocytic infiltrate. We typically see patients every three to four months. The frequency of follow-up visits may be reduced if clinical improvement is noted or the condition remains stable. Patients should be educated to alert the clinician for more urgent evaluation if a change in their condition occurs.
SUMMARY AND RECOMMENDATIONS
●Definition – The term "atypical lymphocytic infiltrate" is generally used when the pathologist cannot reliably differentiate a reactive from a malignant lymphoproliferative disorder on histopathologic grounds alone. It describes the histologic finding of a dermal infiltrate of atypical lymphocytes admixed with cytologically banal, reactive-appearing lymphocytes in a pattern that is suggestive of lymphoma or leukemia. (See 'Definition' above.)
●Diagnostic approach – Clinicians suspecting a cutaneous lymphoproliferative disorder should provide adequate tissue samples for histopathologic examination, immunophenotyping, and molecular studies. Incisional or punch biopsies ≥5 mm in diameter taken from two or more distinct lesions may increase the chance of a correct diagnosis. (See 'Histologic clues' above and 'Immunophenotyping' above and 'Molecular analysis' above.)
●Management – Communication between the pathologist and the clinician, as well as between the clinician and the patient, is essential for the management of patients with a diagnosis of atypical lymphocytic infiltrates of the skin. A "watch and wait" approach with symptomatic treatment of the skin lesions is appropriate for most patients. (See 'Management' above.)
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