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Cutaneous Lymphomas and Cutaneous Signs of Systemic Lymphomas
Key Points
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Cutaneous lymphomas represent a heterogeneous group of malignant lymphomas arising primarily in the skin.
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Most cutaneous lymphomas are listed as separate entities in the World Health Organization classification of hematologic malignancies.
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Differentiation of primary cutaneous lymphomas from extracutaneous lymphomas with secondary skin manifestations is paramount, as management of patients is different.
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In some cases, only accurate staging investigations allow differentiation of primary cutaneous lymphomas from their nodal counterparts, as clinical, histological, and phenotypic features may be similar.
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In extranodal lymphomas, besides specific skin manifestations the skin may be the site of several nonspecific symptoms and/or disorders (e.g., generalized pruritus, Sweet’s syndrome, pyoderma gangrenosum, etc.).
Malignant lymphomas may affect the skin both primarily (i.e., without extracutaneous disease at presentation) and secondarily (i.e., as specific manifestations of a primary extracutaneous—usually nodal—lymphoma). Differentiation of primary from secondary cutaneous lymphomas is paramount, as staging investigations, treatment modalities, and prognosis are different. In fact, the World Health Organization (WHO) classification of hematologic neoplasia recognizes several types of primary cutaneous lymphomas, the most frequent being mycosis fungoides (MF) ( Table 20-1 ). In addition to specific skin manifestations of hematologic malignancies, many non-neoplastic cutaneous conditions may be variably associated with systemic lymphomas, the most important of them being briefly discussed at the end of this chapter and summarized in Table 20-2 .
TABLE 20-1
Cutaneous Lymphomas Included in the World Health Organization (WHO) Classification
| Mycosis Fungoides |
|---|
| Sézary syndrome Adult T-cell leukemia/lymphoma ∗ Primary cutaneous CD30+ lymphoproliferative disorders
Subcutaneous panniculitis-like T-cell lymphoma |
∗ These entities are not always primary cutaneous, but may arise in the skin in the absence of systemic manifestations (i.e., negative staging at presentation).
† This category includes cases commonly classified as cutaneous marginal zone lymphoma, which in the WHO classification has been lumped together with other extranodal variants of the disease.
TABLE 20-2
Mucocutaneous Signs and Symptoms Frequently Associated with Systemic Lymphomas and Leukemias ∗
| Associated with Tumor-Induced or Treatment-Related Bone Marrow Suppression and Resulting Cytopenia |
| Pallor |
| Purpura, especially petechial |
| Gingival hemorrhage; epistaxis; prolonged bleeding after minor injuries |
| Oral ulcerations in neutropenic patients |
| Associated with either Tumor-Specific or Treatment-Related Immune Dysregulation |
| Opportunistic infections; unusual presentations of common infections (e.g., vegetating lesions, prolongued duration of self-limited disease, severe manifestations of otherwise banal infections) |
| Associated with Autoantibodies Produced by the Hematologic Neoplasm |
| Paraneoplastic pemphigus † |
| Associated with Deposition of Amyloid Protein |
| Cutaneous amyloidosis |
| Crystal storing histiocytosis |
| Associated with Paraproteinemia but without Deposition of M-protein |
| Scleromyxedema |
| Scleredema |
| Normolipemic plane xanthoma |
| Necrobiotic xanthogranuloma |
| POEMS syndrome |
| AESOP syndrome |
| Schnitzler’s syndrome |
| Other Conditions (Exact Mechanism and Pathogenesis of Skin Lesions Not Known) |
| Generalized idiopathic pruritus ‡ |
| Sweet’s syndrome (acute febrile neutrophilic dermatosis) § |
| Bullous pyoderma gangrenosum |
| Acquired ichthyosis |
| Cutaneous and/or systemic sarcoidosis || |
∗ Many of these conditions may be observed in different settings other than hematologic neoplasms; some are mostly, but not invariably, associated with an underlying lymphoproliferative disorder.
† Associated mostly with B-cell lymphomas and leukemias.
‡ May be observed in Hodgkin’s lymphoma (HL), as well as less frequently in other types of non-Hodgkin’s lymphoma (NHL); it may represent the first clinical manifestation of the disease.
§ As paraneoplastic disorder observed mostly in patients with myelogeneous leukemia and related conditions; skin lesions may harbor neoplastic cells of the underlying condition.
|| Sarcoidosis may antedate the diagnosis of NHL (“sarcoidosis-lymphoma syndrome”) or arise during the course of the disease.
Primary Cutaneous Lymphomas
Primary cutaneous lymphomas represent a heterogeneous group of lymphoproliferative disorders affecting the skin. By definition a primary cutaneous lymphoma does not show extracutaneous involvement at presentation (Sézary syndrome [SS] represents an exception, as involvement of the blood is a prerequisite for the diagnosis). Table 20-1 summarizes the entities included in the WHO classification. Precise diagnosis and distinction from similar entities involving the skin secondarily is crucial in order to manage patients properly.
Primary Cutaneous T-Cell Lymphomas
Mycosis Fungoides
MF represents by far the most common type of primary cutaneous T-cell lymphoma (CTCL) and of cutaneous lymphoma in general, accounting for almost half of all cases. It is defined as a tumor composed of small/medium-sized, epidermotropic T-helper lymphocytes. The disease is characterized by a chronic course with prolonged survival. The incidence is around 6–7 cases/10 6 , with regional variations and with a regular increase in recent decades. Although adults, especially elderly, are usually affected, MF represents the most common cutaneous lymphoma in children and adolescents as well.
Clinically, lesions of MF can be divided morphologically into patches, plaques, and tumors. Morphology is commonly used to classify the disease in three clinical stages according to the presence of corresponding lesions (patch, plaque, and tumor stage), with a good correlation with prognosis (this is a good “rule of thumb” to discuss with patients and guides discussion of available treatment options, but of course a more precise staging system should be applied—see below). So-called plaque and tumor stages probably should be considered together as a more aggressive phase of the disease, compared to the chronic course of patch-stage disease. Pruritus is often a prominent symptom in all stages of the disease, and may be very difficult to treat. The diagnosis of MF is based mainly on clinicopathologic correlation. Immunohistochemical and molecular analyses offer adjunctive information that should be integrated with the clinicopathologic assessment.
The precise characterization of the early phases of MF is still a matter of debate, and terms such as “parapsoriasis en plaques” or large plaque parapsoriasis are used differently to denote either a non-neoplastic condition that may progress to MF, or an early manifestation of the disease. In this stage the disease presents with variably large erythematous patches commonly located in sun-protected areas. Loss of elastic fibers and atrophy of the epidermis may confer on the lesions a wrinkled appearance. Notwithstanding the discussion on the nosology of “parapsoriasis en plaques,” patients with early MF should not undergo extensive staging investigations (only clinical examination with assessment of percentage of body involvement and of superficial lymph nodes), and should be managed in a nonaggressive way.
Plaques of MF are characterized by infiltrated, variably scaling, reddish-brown, indurated lesions. Typical patches are usually observed contiguous to plaques or at other sites of the body. Tumors in MF may be observed in the absence of other lesions, or in combination with patches and plaques. They may be solitary or, more often, localized or generalized. Tumors, as the sole manifestation of MF, except as relapsed disease are highly unusual, and a tumor d’emblee diagnosis would require exclusion of cutaneous anaplastic large cell lymphoma, or a nodule of lymphomatoid papulosis, or pleiomorphic small/medium CD4+ lymphoma, NK/T cell lymphoma, etc. Ulceration is common. Erythroderma can develop in the course of the disease, rendering distinction from SS difficult. Patients with infiltrated plaques, tumors, or erythroderma should be screened for extracutaneous involvement (laboratory investigations, sonography of lymph nodes, computed tomography and/or positron emission tomography scan of chest, abdomen and pelvis, bone marrow biopsy, examination of the peripheral blood).
Staging for MF is performed according to a system proposed by a joint working group of the International Society of Cutaneous Lymphoma (ISCL) and the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force ( Table 20-3 ).
TABLE 20-3
Staging of Mycosis Fungoides (MF) and Sézary Syndrome (SS) according to the International Society of Cutaneous Lymphoma (ISCL) and the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force
Adapted from Olsen et al. Blood 2007;110:1713–1722.
| Skin |
|
| Lymph Nodes |
|
| Visceral |
|
| Blood |
|
| Stage |
| IA T1N0M0B0,1 IB T2N0M0B0,1 |
| II T1,2N1,2M0B0,1 IIB T3N0–2M0B0,1 |
| III T4N0–2M0B0,1 IIIA T4N0–2M0B0 IIIB T4N0–2M0B1 |
| IVA1 T1–4N0–2M0B2 IVA2 T1–4N3M0B0–2 IVB T1–4N0–3M1B0–2 |
∗ For skin, patch indicates any size skin lesion without significant elevation or induration. Presence/absence of hypo- or hyperpigmentation, scale, crusting, and/or poikiloderma should be noted.
† For skin, plaque indicates any size skin lesion that is elevated or indurated. Presence or absence of scale, crusting, and/or poikiloderma should be noted. Histologic features such as folliculotropism or large cell transformation (>25% large cells), CD30+ or CD30−, and clinical features such as ulceration are important to document.
‡ For skin, tumor indicates at least one 1-cm diameter solid or nodular lesion with evidence of depth and/or vertical growth. Note total number of lesions, total volume of lesions, largest size lesion, and region of body involved. Also note if histologic evidence of large cell transformation has occurred. Phenotyping for CD30 is encouraged.
§ For node, abnormal peripheral lymph node(s) indicates any palpable peripheral node that on physical examination is firm, irregular, clustered, fixed, or 1.5 cm or larger in diameter. Node groups examined on physical examination include cervical, supraclavicular, epitrochlear, axillary, and inguinal. Central nodes, which are not generally amenable to pathologic assessment, are not currently considered in the nodal classification unless used to establish N3 histopathologically.
|| For viscera, spleen and liver may be diagnosed by imaging criteria.
¶ For blood, Sézary cells are defined as lymphocytes with hyperconvoluted cerebriform nuclei. If Sézary cells cannot be used to determine tumor burden for B2, then one of the following modified International Society of Cutaneous Lymphoma criteria along with a positive clonal rearrangement of the T-cell receptor may be used instead: (1) expanded CD4+ or CD3+ cells with CD4:CD8 ratio of 10 or more, (2) expanded CD4+ cells with abnormal immunophenotype including loss of CD7 or CD26.
# A T-cell clone is defined by polymerase chain reaction or Southern blot analysis of the T-cell receptor gene.
Many clinical and/or histopathologic variants of MF have been described. Three of them are mentioned in the WHO classification, namely, pilotropic MF, localized pagetoid reticulosis, and granulomatous slack skin. While localized pagetoid reticulosis and granulomatous slack skin show a chronic course and good prognosis (patients with localized pagetoid reticulosis may undergo long-standing complete remission), pilotropic MF seems to be characterized by a more aggressive course than the “conventional” variants of the disease. A thorough discussion of these variants is beyond the scope of this chapter. Granulomatous slack skin may be viewed as a subset of MF, but there is ample evidence that it may be more appropriately viewed as a syndrome that may result from a variety of hematologic diseases—up to 50% are associated with Hodgkin’s, and other reports include non-Hodgkin’s, MF, acute myelogenous leukemia, and Langerhans histiocytosis. Granulomatous slack skin shares many features with MF but it is not clear that it should always be considered to represent MF.
Prognosis and selection of proper treatment for MF depends on the stage of the disease (as well as on previous treatments). Most patients will never require aggressive therapy and can be managed with skin-directed options (e.g., psoralen and ultraviolet A, retinoids, etc.). Systemic chemotherapy is usually effective only for short periods, and recurrences are the rule. Large numbers of systemic, partly experimental therapies have been tested in the last decades (indirectly showing that no treatment option is giving a true chance for cure). In recent years several independent studies showed that patients with advanced stage disease may be treated successfully with allogeneic stem cell transplantation.
Sézary Syndrome
SS is characterized clinically by pruritic erythroderma, generalized lymphadenopathy, and the presence of circulating malignant T lymphocytes. It is considered as a disease distinct from MF, and prognosis is much worse (5-year survival of about 20% to 30%). Diagnostic criteria include the presence of the same monoclonal population of T lymphocytes within the peripheral blood and the skin, of at least 1000 circulating Sézary cells/mm 3 , of an expanded CD4+ population in the peripheral blood resulting in a markedly increased CD4:CD8 ratio, of an increased population of CD4+/CD7– cells or CD4+/CD26–in the peripheral blood, and of the loss of T-cell antigens such as CD2, CD3, and CD5. Although SS is considered a leukemic variant of CTCL, the bone marrow is usually not affected in early phases.
Patients present with a variably rapid onset of erythroderma and lymph node enlargement. The erythroderma is characterized by intense pruritus and scaling, and the pruritus may be intractable. Complete staging investigations should be performed upon a confirmed diagnosis of SS ( Table 20-3 ). Since many non-neoplastic disorders may present with erythroderma (e.g., psoriasis, drug eruptions, etc.), accurate diagnostic investigations are crucial in order to manage patients properly. It is also crucial to remember that in a distinct proportion of patients (up to 50%) a precise diagnosis is not possible (“idiopathic” erythroderma, “red man syndrome”). Some of these patients eventually progress to clear-cut SS. At the present state of knowledge, however, patients with “idiopathic” erythroderma should not be treated aggressively (symptomatic treatment of associated symptoms such as pruritus, regular controls to monitor the disease). Extracorporeal photopheresis has been successfully used to treat both overt SS and idiopathic erythroderma, but the efficacy tends to be limited in time, and patients with advanced disease usually show progression in spite of treatment. As in advanced MF, allogeneic stem cell transplantation may represent a successful option for patients with SS as well.
Primary Cutaneous CD30+ Lymphoproliferative Disorders (pcCD30+LD)
pcCD30+LD include lymphomatoid papulosis (LyP) and cutaneous anaplastic large cell lymphoma (cALCL). These diseases are considered as two ends of a spectrum without clear-cut boundaries. In many cases precise classification can be achieved only upon careful clinicopathologic correlation. Both LyP and cALCL arise predominantly in adults, but LyP is the second most frequent type of cutaneous lymphoma in children after MF. pcCD30+LD are characterized by a very good prognosis, and should be clearly separated from nodal ALCL with cutaneous involvement, as treatment and prognosis are completely different.
cALCL usually presents with solitary, commonly ulcerated tumors ( Fig. 20-1 ). Partial regression may be observed. LyP, on the other hand, is a disease characterized by recurrent crops (“waxing and waning”) of papules and small nodules that may ulcerate leaving a scar ( Fig. 20-2 ). The typical duration of each single lesion is 4 to 8 weeks, and the patients present usually with polymorphous lesions due to the appearance of new lesions while old ones are resolving. This peculiar clinical aspect represents the most important single diagnostic criterion, as histopathologic features of LyP and cALCL may overlap. In typical cases differentiation is not a problem; so-called “borderline” cases, however, may be impossible to classify precisely in one or the other category of pcCD30+LD. In particular, regional LyP (that is, LyP confined to a single area of the body) and cALCL with satellite lesions (i.e., cALCL with tumors surrounded by small “satellites”) may be indistinguishable from one another both clinically and histopathologically. There are no phenotypic or molecular tools that allow a precise classification in these cases, and a diagnosis of pcCD30+LD is appropriate if a distinction cannot be made. Histopathologically, many cases of LyP and cALCL can be separated easily from one another, but in some instances a precise distinction may be impossible. Thus, accurate clinicopathologic correlation should be considered the standard for precise classification of pcCD30+LD.
Staging investigations are not necessary in patients with a confirmed diagnosis of LyP, but should be carried out for those with cALCL or borderline cases. Examination of the regional lymph nodes is paramount, as well as biopsy of suspicious lymph nodes.
It is particularly important to clearly separate cALCL from nodal ALCL with secondary skin involvement. In this context, anaplastic lymphoma kinase (ALK) is negative in the vast majority of cases of cALCL. It is crucial to underline that secondary skin involvement may be observed both in ALK+ and ALK− nodal ALCL, thus a negative staining for ALK is not a surrogate for staging investigations in patients with cALCL. While secondary skin manifestations of nodal ALCL are usually characterized by a bad prognosis and require aggressive treatment, cALCL is an indolent disease that should be managed by surgical excision and/or local radiotherapy.
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