Cutaneous T-Cell Lymphoma Workup

Updated: Jun 23, 2017
  • Author: Lauren C Pinter-Brown, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Workup

Approach Considerations

For mycosis fungoides, clinical features, the history of the disease, and histomorphologic and cytomorphologic findings yield clues that lead to a diagnosis in most cases. However, demonstration of a dominant T-cell clone in skin biopsy specimens by a molecular assay (ie, Southern blot, polymerase chain reaction [PCR]) constitutes an additional diagnostic criterion to distinguish cutaneous T-cell lymphoma from inflammatory dermatoses.

For a diagnosis of Sézary syndrome, one or more of the following criteria should be present [3] :

  • An absolute Sézary cell count of least 1000 cells/µL
  • Demonstration of immunophenotypic abnormalities (an expanded CD4 + T-cell population that results in a CD4/CD8 ratio of more than 10; loss of any or all of the T-cell antigens CD2, CD3, CD4, and CD5; or loss of both CD4 and CD5)
  • Demonstration of a T-cell clone in the peripheral blood by molecular or cytogenetic methods - Flow cytometry may be useful for the differential diagnosis of precursor and peripheral T-cell and NK-cell lymphomas [4]

Following a diagnostic algorithm for the evaluation and diagnosis of erythroderma due to cutaneous T-cell lymphoma, versus erythroderma resulting from "reactive" causes, may be helpful. [74]

Perform the following tests in the diagnostic workup of mycosis fungoides:

  • Conduct a complete blood count (CBC) with differential, and review the buffy coat smear for Sézary cells
  • Look for liver-associated enzyme abnormalities; abnormal transaminase values may indicate hepatic involvement
  • Obtain uric acid and lactate dehydrogenase (LDH) levels, since uric acid and LDH are markers of bulky and/or biologically aggressive disease
  • Conduct a flow cytometric study of the blood (include available T-cell–related antibodies) to detect a circulating malignant clone and to assess immunocompetence by quantifying the level of CD8-expressing lymphocytes
  • Consider human immunodeficiency virus (HIV) and HTLV-I testing

Reflectance confocal microscopy

Reflectance confocal microscopy as an investigational technique in mycosis fungoides may highlight junctional atypical lymphocytes, architectural disarray, and spongiosis. [75]

Imaging studies

Chest radiography

Perform chest radiography to determine whether there is lung involvement.

CT scanning

Computed tomography (CT) scanning of the abdomen and pelvis may be performed in patients with advanced mycosis fungoides (stage IIB to stage IVB) or in patients with clinically suspected visceral disease.

PET scanning

Positron emission tomography (PET) scanning to determine visceral involvement can be considered in individual cases.

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Polymerase Chain Reaction Assay

Consider obtaining polymerase chain reaction (PCR), Southern blot testing of the blood, or both if detecting a circulating clone of malignant cells in the blood will change medical management. Ideally, the abnormal clonal T-cell gene rearrangement detected in the blood should match that found in the skin. However, T-cell gene rearrangement by itself will not allow the physician to make a diagnosis of mycosis fungoides or Sézary syndrome. Disorders that are considered benign (eg, lymphomatoid papulosis) can have T-cell gene rearrangement.

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Genetic Testing

Neoplastic mycosis fungoides cells have a mature CD3+, CD4+, CD45RO+, CD8- memory T-cell phenotype. Rarely, otherwise-classic mycosis fungoides may have a CD4-, CD8+ mature T-cell phenotype. [76] An aberrant phenotype, such as a loss of pan–T cell antigens (eg, CD2, CD3, CD5), is not unusual.

An identical phenotype is seen in granulomatous slack skin syndrome and Sézary syndrome. Clonal T-cell receptor gene rearrangements are detected in most mycosis fungoides cases. [77]

Many structural and numerical chromosomal abnormalities have been described in the advanced stages of mycosis fungoides, but recurrent, mycosis fungoides–specific chromosomal translocations have not been identified. Chromosomal loss at 10q and abnormalities in P15, P16, and TP53 tumor suppressor genes are often evident with mycosis fungoides.

The neoplastic T cells in pagetoid reticulosis may have either a CD3+, CD4+, CD8- phenotype or a CD3+, CD4-, CD8+ phenotype, with CD30 often being expressed. [78]

Genetic features show T-cell receptor genes to be clonally rearranged in persons with mycosis fungoides, granulomatous slack skin syndrome, or Sézary syndrome. Demonstration of clonal T cells in the peripheral blood is an important diagnostic criterion that allows differentiation between Sézary syndrome and benign forms of erythroderma. [3]

Recurrent chromosomal translocations are not detected in persons with Sézary syndrome, but complex karyotypes are common, as is a consistent pattern of identical chromosomal abnormalities in Sézary syndrome as seen in mycosis fungoides. [79]

The neoplastic T cells in adult T-cell leukemia/lymphoma express a CD3+, CD4+, CD8- phenotype, with CD25 being highly expressed. [42] T-cell receptor genes are clonally rearranged; clonally integrated HTLV-1 genes are present and are useful in differentiating between chronic or smoldering variants of adult T-cell leukemia/lymphoma and classic mycosis fungoides or Sézary syndrome.

Panniculitis-like T-cell lymphoma shows an alpha/beta+, CD3+, CD4-, CD8+ T-cell phenotype, with expression of cytotoxic proteins. [29] CD30 and CD56 are not expressed. Neoplastic T cells do show clonal T-cell receptor gene rearrangements, although neither specific genetic abnormalities nor EBV has been identified.

Nasal-type extranodal NK/T-cell lymphoma has neoplastic cells that express CD2, CD56, and cytoplasmic CD3.

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Biopsy

Perform a skin punch biopsy, which is submitted on sodium chloride–soaked gauze to allow for fixation and snap freezing.

Perform a bone marrow examination only if the patient has proven blood or nodal involvement.

Perform a lymph node biopsy if the nodes are palpable. In a study by Pai et al, the investigators determined that fine-needle aspiration (FNA) biopsy combined with immunophenotyping and T-cell receptor gamma chain PCR (TCR-gamma PCR) assay was “significantly useful” in evaluating lymphadenopathy in patients with mycosis fungoides or, specifically, Sézary syndrome, “especially for triaging lymph nodes that would otherwise not be sampled or for evaluating multiple lymph nodes." [80]

In the study, the investigators assessed a series of 11 FNA biopsy specimens from 10 patients with mycosis fungoides or Sézary syndrome and performed flow cytometric immunophenotyping and TCR-gamma PCR assay on the FNA biopsy material. These were correlated with cytologic findings. [80]

Seven of 10 patients in the study demonstrated "lymph node involvement by cutaneous T-cell lymphoma, with 3 cases exhibiting large-cell transformation and 4 cases exhibiting a small-cell pattern."

Another 6 patients in the study were identified, using flow cytometric immunophenotyping, as having an abnormal T-cell population. In 2 cases—one in which insufficient events were present for evaluation by flow cytometry and one in which flow cytometry was not diagnostic of T-cell lymphoma—TCR-gamma PCR assay demonstrated a clonal T-cell rearrangement. Immunohistochemistry on cell block material revealed classic Hodgkin lymphoma in 2 cases.

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Histology

In the early stages of mycosis fungoides, the histopathology is nonspecific, [81, 82, 83, 84] and the condition is often misdiagnosed as an inflammatory disorder. Early patch mycosis fungoides shows superficial bandlike or lichenoid infiltrates, mainly consisting of lymphocytes and histiocytes.

A few atypical cells with small to medium, highly indented (cerebriform), and sometimes hyperchromatic nuclei are present and are mostly confined to the epidermis (epidermotropism). They tend to colonize the basal layer of the epidermis either as single, often haloed cells or in a linear configuration, [77] especially at the tips of the rete ridges. (See the image below.)

Mycosis fungoides with large, atypical T lymphocyt Mycosis fungoides with large, atypical T lymphocytes in the epidermis and dermis.

When a clear halo surrounds an intraepidermal mononuclear cell singly or in clumps, it is called a Pautrier microabscess. Its presence is suggestive of mycosis fungoides, but it is not necessary for the diagnosis. (See the image below.)

Mycosis fungoides with an epidermal nest of large, Mycosis fungoides with an epidermal nest of large, atypical T cells displaying bizarre, convoluted nuclei surrounded by a clear space (Pautrier microabscess).

To summarize, the histologic criteria for the diagnosis of mycosis fungoides include the following [85] :

  • A bandlike upper dermal infiltrate of lymphocytes and other inflammatory cells, with no grenz zone, is present
  • Epidermotropism of mononuclear cells occurs
  • Little spongiosis of the epidermis is found.
  • Lymphocytes have nuclei that are hyperchromatic and convoluted or cerebriform

Plaque and tumor stages

In mycosis fungoides plaques, the histologic changes are diagnostic; epidermotropism is generally more pronounced than in mycosis fungoides patches. The presence of intraepidermal collections of atypical cells (Pautrier microabscesses) is a highly characteristic feature observed in only a minority of cases (10%).

In the tumor stage, the dermal infiltrates become more diffuse and epidermotropism may be lost. The tumor cells increase in number and size, demonstrating variable proportions of small, medium, and large cerebriform blast cells with prominent nuclei and intermediate forms. Transformation to a diffuse large cell lymphoma of either CD30- or CD30+ phenotype may occur, portending a poor prognosis. Eosinophils, plasma cells, and histiocytes are frequent companions.

Folliculotropic mycosis fungoides

Folliculotropic mycosis fungoides shows a primarily perivascular and periadnexal localization of the dermal infiltrate, with variable involvement of the follicular epithelium by small, medium, or sometimes large hyperchromatic cells with cerebriform nuclei and sparing of the epidermis (folliculotropism instead of epidermotropism). [30]

Most patients have mucinous degeneration of the follicular epithelium (follicular mucinosis)—which is best demonstrated with Alcian blue staining—and an admixture of eosinophils and sometimes plasma cells. Prominent infiltration of both follicular epithelium and eccrine sweat glands is often observed. Similar cases with prominent infiltration of eccrine sweat glands, often seen with alopecia, have been called syringotropic mycosis fungoides. [86] Basaloid folliculolymphoid hyperplasia is a distinctive finding in follicular mycosis fungoides. [87]

Granulomatous mycosis fungoides

Granulomatous mycosis fungoides shows sarcoidal, granuloma annulare–like, or giant cell–rich reactions. Granulomatous slack skin syndrome shows a dermal infiltrate composed of atypical T cells with a dissemination of many multinucleated giant cells containing fragments of elastic fibers.

Pagetoid reticulosis

Pagetoid reticulosis shows a hyperplastic epidermis with marked pagetoid infiltration by atypical, haloed lymphoid cells, singly or arranged in nests. The upper dermis has a mixed infiltrate of lymphocytes or histiocytes.

Sézary syndrome

The histology of Sézary syndrome may be nonspecific, but it is often similar to mycosis fungoides, although the cellular infiltrates in Sézary syndrome are more often monotonous, [88, 89] and epidermotropism may sometimes be absent. Involved lymph nodes have a dense, monotonous infiltrate of Sézary cells with effacement of the normal lymph node architecture, whereas bone marrow infiltrates, when present, are often sparse and mainly interstitial. (See the image below.) [90]

Electron micrograph of a Sézary cell. Electron micrograph of a Sézary cell.

Adult T-cell leukemia/lymphoma

In adult T-cell leukemia/lymphoma, the cutaneous nodules show a superficial or more diffuse infiltration of medium to large T cells with pleomorphic or multilobated nuclei, often with marked epidermotropism. The histologic picture may be the same as that seen with mycosis fungoides. In the smoldering type of adult T-cell leukemia/lymphoma, dermal infiltrates may be sparse, with only slightly atypical cells.

Subcutaneous panniculitis-like T-cell lymphoma

In subcutaneous panniculitis-like T-cell lymphoma, subcutaneous infiltrates simulate a panniculitis and show small, medium, or sometimes large pleomorphic T cells with hyperchromatic nuclei and often many macrophages. [31] The overlying epidermis and dermis are typically not involved. [91] Rimming of individual fat cells by neoplastic T cells is a helpful, although not completely specific, diagnostic feature. [29] Necrosis, karyorrhexis, and cytophagocytosis are common.

Primary cutaneous aggressive epidermotropic CD8

Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma, characterized by a proliferation of epidermotropic CD8+ cytotoxic T cells, has an acanthotic or atrophic epidermis, necrotic keratinocytes, ulceration, and variable spongiosis, sometimes with blister formation. [38, 69] Epidermotropism tends to be marked, ranging from a linear distribution to a pagetoid pattern throughout the epidermis.

This disorder has a beta-F1+, CD3+, CD8+, granzymes-B+, perforin+, TIA-1+, CD45RA+, CD45RO, CD2-, CD4-, CD5-, CD7+/- phenotype. [53, 69] It is usually associated with EBV seronegativity. The lymphoma cells show clonal TCR gene rearrangements, although specific genetic abnormalities have not been described.

Cutaneous gamma/delta-positive T-cell lymphoma

Cutaneous gamma/delta-positive T-cell lymphoma has 3 major histologic patterns of involvement that can be present in the skin; specifically, epidermotropic, dermal, and subcutaneous. [31] More than 1 is often present in the same patient in different biopsy specimens or within a single biopsy specimen. [57] The lymphoma cells are generally medium to large, with coarsely clumped chromatin; large blastic cells with vesicular nuclei and prominent nucleoli are infrequent and apoptosis and necrosis are common, often with angioinvasion. The subcutaneous involvement may demonstrate rimming of fat cells.

Cutaneous gamma/delta-positive T-cell lymphoma cells are generally of beta-F1-, CD3+, CD2+, CD5-, CD7+/-, CD56+ phenotype with strong expression of cytotoxic proteins. [31] Most lack both CD4 and CD8, although CD8 may be expressed in some cases. [57, 92] In frozen-section specimens, the lymphoma cells are strongly positive for TCR -delta. If only paraffin sections are available, the absence of beta-F1 may be used to infer a gamma/delta origin. [93]

The lymphoma cells show clonal rearrangement of the TCR -gamma gene, while TCR -beta may be rearranged or deleted but is not expressed. EBV test results are usually negative. [57]

Primary cutaneous CD4

Histologically, this disorder shows dense, diffuse, or nodular infiltrates within the dermis that have a tendency to infiltrate the subcutis. Epidermotropism is often present focally. A predominance of small/medium-sized pleomorphic T cells may be seen, with a smaller proportion of large pleomorphic cells present. [94]

Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma is a CD3+, CD4+, CD8-, CD30- phenotypic lymphoma. Cytotoxic proteins are generally not expressed, and sometimes there is a loss of pan–T-cell markers. [53] The TCR genes are clonally rearranged. [70]

Nasal-type extranodal NK/T-cell lymphoma

Nasal-type extranodal NK/T-cell lymphoma has dense dermal and often subcutaneous infiltrates with prominent angiocentricity and angiodestruction, often accompanied by extensive necrosis. [54, 95]

Primary cutaneous peripheral T-cell lymphoma, unspecified

Primary cutaneous peripheral T-cell lymphoma, unspecified, shows an aberrant CD4+ T-cell phenotype with variable loss of pan–T-cell antigens. CD30 staining is negative or restricted to a few scattered tumor cells. Rare cases may show coexpression of CD56. Expression of cytotoxic proteins is uncommon. [53]

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Staging of Mycosis Fungoides

Despite the fact that mycosis fungoides and Sézary syndrome are types of non-Hodgkin lymphoma, an entirely different staging system is used for these disorders. The system is based on the particular skin findings and findings of extracutaneous disease that are observed in affected patients, with the stages defined as follows:

  • Stage IA disease (as defined by the tumor, node, metastases, blood [TNMB] system) - Patchy or plaquelike skin disease involving less than 10% of the skin surface area (T1 skin disease)
  • Stage IB - Patchy or plaquelike skin disease involving 10% or more of the skin surface area (T2 skin disease)
  • Stage IIB disease - Tumors are present (T3 skin lesions)
  • Stage III disease - Generalized erythroderma is present
  • Stage IVA1 disease - Erythroderma and significant blood involvement occur [5]
  • Stage IVA2 disease - Lymph node biopsy result shows total effacement by atypical cells (LN4 node) [5]
  • Stage IVB disease - Visceral involvement (eg, liver, lung, bone marrow) occurs

These definitions are denoted in Table 3. Table 4 lists the TNMB stage definitions. Table 5 is a comparison of the 2 systems.

Table 3. Staging of Cutaneous T-Cell Lymphoma (Open Table in a new window)

Stage Skin Lesions Lymphadenopathy Erythroderma Histology
Patches/



plaques



(less than10%)



Plaques/



plaques



(10% or more)



Tumors Lymph Nodes Viscera
IA + - - - - - -
IB + or - + - - - - -
IIA + or - + or - + or - + - - -
IIB + or - + or - + + or - - - -
III + or - + or - + or - + or - + - -
IVA + or - + or - + or - + or - + or - + -
IVB + or - + or - + or - + or - + or - + or - +

Table 4. TNMB Staging of Cutaneous T-Cell Lymphoma (Open Table in a new window)

Stage Class Stage Definition
T



(tumor)



T1 Patches/plaques involving less than 10% of body surface
T2 Patches/plaques involving 10% or more of body surface
T3 Tumor(s) present on skin
T4 Erythroderma
N



(nodes)



N0 No enlarged lymph node present
N1 Enlarged lymph nodes, histologically uninvolved
N2 No enlarged lymph node; 1 or more nodes histologically involved*
N3 Enlarged lymph nodes, histologically involved
M



(metastasis to viscera)



M0 No visceral lesion present
M1 Visceral involvement
B



(blood involvement)



B0 Circulating atypical lymphocytes (Sézary cells) less than 5% of lymphocytes
B1 Circulating atypical lymphocytes 5% or more of lymphocytes (Sézary syndrome)
*Uncommon finding, usually not considered/investigated.

 

Table 5. Comparison of Staging Systems for CTCL (Open Table in a new window)

Clinical Stage TNM (B) Stage
IA T1 N0 M0
IIB T2 N0 M0
IIA T1 N1 M0 T2 N1 M0  
IIB T3 N0 M0 T3 N1 M0  
III T4 N0 M0 T4 N1 M0  
IVA T1 N2 M0 T2 N2 M0 T3 N2 M0 T4 N2 M0
T1 N3 M0 T2 N3 M0 T3 N3 M0 T4 N3 M0
IVB T1 N0 M1 T2 N0 M1 T3 N0 M1 T4 N0 M1
T1 N1 M1 T2 N1 M1 T3 N1 M1 T4 N1 M1
T1 N2 M1 T2 N2 M1 T3 N2 M1 T4 N2 M1
T1 N3 M1 T2 N3 M1 T3 N3 M1 T4 N3 M1
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