T-CELL lymphomas are the great white whales of hematopathology because:
In cases of morphologically uncertain malignancy, two ancillary methods of establishing
clonality are available. The first is to use molecular techniques such as Southern blotting or PCR to look for a unique, clonal rearrangment of the T-cell receptor gene, which in benign populations exhibits a slightly different rearrangement in each cell. A second method is to demonstrate immunophenotypically that the suspicious population of T-cells uniformly fails to express a pan-T-cell antigen such as CD2, CD3, CD5, or CD7. Some caution is required here, since some reactive T-cell infiltrates, especially in the skin, may be negative for CD7 in many of the cells.
- They are uncommon compared to B-cell lymphomas, comprising only 15% of lymphomas in the United States (they are much more frequent in parts of Asia).
- In cases that are morphologically not clearly malignant, there is no easy way to
assay their clonality comparable to testing for monotypic light chain expression in B-cell cases.
- Compared to B-cell syndromes, there are more T-cell syndromes that shade stealthily from atypical but non-clonal proliferations into clonal malignancies--angioimmunoblastic lymphadenopathy, lymphomatoid papulosis, and others.
Some T-cell lymphomas are malignancies of primitive lymphoid progenitors from the thymus.
Called lymphoblastic lymphomas, they are composed of T-cell blasts that usually various markers or combinations of markers that indicate immaturity. Some cases express terminal deoxynucleotidyl transferase, an enzyme necessary for the rearrangement of the T-cell receptor that occurs early in a T-cells life cycle. Lymphoblastic lymphomas have already been discussed in the previous section.
Mature (Peripheral) T-Cell Neoplasms (PTCL)
Other mature T-cell neoplasms do not nest comfortably in their own pigeon holes and are lumped together as peripheral T-cell lymphomas not otherwise characterized.
These diseases derive from T-cells that have fled the horrors of generation in the central, thymic nursery to join the ranks of the mature immune system billeted in the peripheral lymph nodes. Among the many types are enumerated in the WHO classification are:
Although these lymphomas are a heterogeneous collection, they tend generally to be aggressive diseases. Several of the more common PTCLs are discussed in greater detail below.
Peripheral T-cell Lymphomas Not Otherwise Characterized(PTCL-NOC)
True to their T-cellish nature, PTCL-NOCs (image) initially involve a lymph node in the paracortex and never grow in a true follicular pattern. Four other features often though not always seen are:
The cells often display a range of atypia, with large, atypical forms more frequent in the higher grade cases. The lymphomas home to retroperitoneal sites more commonly than mediastinal ones. Visceral organs and skin, but not the peripheral blood, are also commonly affected. With the exception of one particular cutaneous T-cell lymphoma, mycosis fungoides, skin involvement usually spares the epidermis.
- An admixture of non-neoplastic
inflammatory cells, including plasma cell, eosinophils, epithelioid histiocytes, and
others. This benign component is more frequently seen in lower grade lymphomas, where
some of the malignant T-cells remember how to make cytokines.
Note in the center a large, polylobated cell with moderate amounts of pink to clear cytoplasm.
- Cytoplasm that is moderate or abundant in amount and may be pale or
- Nuclear outlines that are convoluted rather than cleaved.
- Increased vascularity.
Patients, who are mainly adults, usually present with advanced, stage IV lymphoma. A minority of patients will have evidence of prior auto-immune disease. Earlier studies indicated that PTCL-NOCs were diffuse, aggressive lymphomas prognostically similar to their B-cell counterparts. Some later studies, however, predict a worse outcome for patients with T-cell lymphomas.
Immunophenotypically PTCL-NOCs express T-cell antigens. Eighty percent of the lymphomas, however, are immunologically abnormal. One or more T-cell antigen may be aberrantly clonally deleted, of which CD7 is the most common example (see, however, above). In addition, some lymphomas express unnatural combinations of antigens, such as co-expression of CD4 and CD8, or expression of neither. Cases that are clearly lymphomas by morphology are usually branded as T-cell by reactivity for CD2, CD3, CD5, CD7, CD45RO (UCHL1), or CD43. The latter, however, may be seen in other hematopoietic neoplasms.
Because this group is morphologically so diverse, multiple examples of PTCL-NOCs are illustrated here, many of them with skin involvement:
|  Diverse T-Cell Lymphomas |
| Case 1: Lymph node. Unusual striped morphology.
|| Case 2A: Skin. See 2B for progression.
|| Case 2B: Skin. See 2A for earlier invovlement.|
| Case 3A: Skin. See 3B for nodal involvement.
|| Case 3B: Lymph node. See 3A for skin involvement.
|| Case 4A: Skin. See 4B for nodal involvement.|
| Case 4B: Lymph node. See 4A for skin involvement.
|| Case 5A: Lymph node. See 5B for marrow involvement.
|| Case 5B: Bone marrow with PTCL. See 5A
for nodal involvement.|
Mycosis Fungoides/Sezary Syndrome
Mycosis fungoides, called Sezary's syndrome if the malignant lymphocytes circulate in the peripheral blood, is a type of cutaneous T-cell lymphoma. The charcteristic cell is a medium-sized, CD4(+) lymphoid cell with a highly cleaved nucleus and darkly clumped chromatin, typically described as "cerebriform".
In the skin these cells accumulate at the dermal-epidermal junction in a lichenoid infiltrate.
Individual cells drift upward to invade the epidermis without provoking much edema ("epidermotropism"). This presence at the dermal-epidermal junction and involvement of the epidermis distinguishes mycosis fungoides from other cutaneous T-cell lymphomas.
Clinically the disease is usually fairly indolent. Skin involvement may go through
patch, plaque, tumor, and generalized erythroderma stages. Lymph node, blood, or
visceral involvement is a bad sign. If the skin disease is minimal, it may be
bafflingly difficult to distinguish the lymphoma from inflammatory conditions. PCR of the biopsy for a clonally rearranged T-cell receptor may support the diagnosis, although merely inflammatory lesions on rare occasions may yield signs of clonality.
Anaplastic Large Cell Lymphomas (ALCL)
ALCL comes in 2 distinct types: primary cutaneous and systemic. Systemic ACLC most commonly affects young adults; often involves extranodal sites, particularly the skin; and has a high frequency of a characteristic translocation, t(2;5). This translocation results in an NPM/ALK gene combination and a protein product readily detected by the ALK-1 antibody. The prognosis is good, with a 10-year survival of 70-90%. Less commonly systemic cases lack the t(2;5) translocation and are ALK-1(-). These patients tend to be older and have a poorer prognosis.
Primary cutaneous ALCL by definition is not present anywhere besides the skin. It tends to occur more in adults and lacks the t(2;5) translocation. The prognosis for these patients is excellent. The lymphoma may resemble a benign, waxing and waning condition called "lymphomatoid papulosis", and sometimes only continued observation can distinguish the malignant from the benign process.
In both types the characteristic cell has large, often lobated, open nuclei, which may be multiple and assume a wreath-like configuration (also called "horseshoe" or "embryoid") in the cell periphery. Nucleoli are present but not prominent.
By definition the cells are reactive for CD30 (these lymphomas were once called "Ki-1" lymphomas, named after a particular antibody to CD30) and usually other T-cell markers, with CD4 positive more often than CD8. Systemic, though not primary cutaneous, cases are reactive for EMA. This reactivity for what is usually an epithelial marker is unfortunate because the malignant cells, like metastatic carcinoma, tend to expand lymph node sinuses
and to occur in clusters. This low power mimicry of carcinoma is
rendered more treacherous by the fact that some ALCLs are non-reactive for leukocyte common antigen (LCA, CD45) or T-lineage markers. Worst of all, rarely ALCLs have reportedly stained positively for keratin--a set-up for the unwary pathologist to make a misdiagnosis of carcinoma.
Cases that lack lymphoid lineage markers are called "null-cell" type. Some cases with ALCL morphology express B-lineage antigens. At least in the WHO classification these are not considered true ALCLs and are placed in the diffuse large B-cell lymphoma group.
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