Marginal zone B‐cell lymphoma
Primary cutaneous marginal zone B cell lymphoma (PCMZL) is one of the most common types of cutaneous B cell lymphoma (fig 14).1,2,3
Similar cases used to be classified as cutaneous immunocytoma.3
In addition, it seems likely that cases reported as primary cutaneous plasmacytoma also represent PCMZLs with prominent plasma cell differentiation.1
In this context, it should be added that in the past many cases of PCMZL were considered to be pseudolymphomas of the skin, and that only accurate phenotypic and genotypic analyses and follow‐up data have allowed these cases to be reclassified correctly.24
Figure 14Marginal zone B cell lymphoma. Grouped reddish papules and small nodules on the upper arm.
Clearly, in most cases of PCMZL neoplastic lymphocytes constitute only a minority of the infiltrate, which is dominated by reactive T lymphocytes and B lymphocytes (often with formation of reactive germinal centres), commonly admixed with eosinophils.3,24
In addition, the neoplastic population in most cases is not monomorphous, but comprises cells with different morphology (marginal zone cells, lymphoplasmacytoid cells and plasma cells). The neoplastic cells are often arranged at the periphery of large nodules of reactive lymphocytes, giving a characteristic biphasic appearance to the lesions (dark in the centre of the nodule, paler at the periphery; fig 15). The most important stainings for confirmation of the diagnosis of PCMZL, besides routine stainings for T lymphocytes and B lymphocytes, are those for the immunoglobulin light chains, for MIB‐1/Ki‐67, and for Bcl‐6. It is often easy to demonstrate monoclonality by immunohistochemistry; on the other hand, negativity for Bcl‐6 in the marginal zone cells (centrocyte‐like cells) helps in the distinction from cutaneous follicle centre lymphoma.25
Staining for MIB‐1/Ki‐67 shows the characteristic arrangement of the proliferating cells at the margin of the nodules (fig 16). Routine molecular analyses detect monoclonality in slightly more than half of the cases. Thus, lack of monoclonality does not rule out PCMZL.
Figure 15Marginal zone B cell lymphoma. (A) Large lymphoid nodules with reactive germinal centres; and (B) marginal zone cells with larger nuclei and clear cytoplasm at the periphery of the nodules.
Figure 16Marginal zone B cell lymphoma. Staining for MIB‐1/Ki‐67 highlights the proliferating cells at the margin of the nodule.
In countries endemic for Borrelia burgdorferi
infection, PCR analyses may show the presence of Borrelia
DNA in roughly 20% of cases of PCMZL.26,27
Although the percentage is small, these patients can be managed by non‐aggressive antibiotic treatments, thus rendering this analysis useful as a routine. Molecular analyses by the fluorescence in situ hybridisation technique show chromosomal abnormalities in <50% of cases, and cannot yet be considered to be a routine diagnostic investigation.28,29
Distinction from reactive infiltrates may be very difficult in some cases. I sometimes use the term “atypical lymphoid proliferation” to refer to lesions in which the diagnosis is not clear cut. Patients are put on short‐term controls, and eventual biopsies of new lesions are examined.
Cutaneous follicle centre lymphoma
Primary cutaneous follicle centre lymphoma (PCFCL) can present with a purely follicular, purely diffuse or mixed pattern of growth. The follicular and mixed patterns are morphologically indistinguishable from nodal follicular lymphoma. On the other hand, some cases with a diffuse pattern of growth would be classified as diffuse large B cell lymphoma in organs other than the skin, but should be classified as PCFCL at a cutaneous site.1
It is usually possible to make a diagnosis of PCFCL, follicular type, on morphological criteria alone, based on the atypical features of the follicles (lack of or reduced mantle zone, lack of or reduced number of tingible body macrophages, lack of polarisation of the follicle; fig 17).25,30
Many of these cases occur in the head and neck regions. The cells are constantly positive for Bcl‐6 (and usually positive for CD10) and do not express Bcl‐2, a major difference with nodal follicular lymphomas.1,30,31,32
When present, Bcl‐2 expression is usually confined to a minority (<30%) of the neoplastic cells, and only rarely shows the strong positive characteristic of nodal follicular lymphoma.3,33
The finding of Bcl‐2 positivity in a follicular lymphoma at cutaneous sites should raise the strong suspicion of a secondary cutaneous lymphoma.
Figure 17Cutaneous follicle centre lymphoma, follicular. (A) Atypical follicle showing lack of polarisation and tingible body macrophages; and (B) negativity of a lymphoid follicle for Bcl‐2.
Cases with a mixed follicular‐diffuse pattern show features similar to those discussed earlier. Cases presenting with a purely diffuse pattern of growth are characterised by predominance of medium‐large cleaved cells (large centrocytes) and may be misdiagnosed as cutaneous diffuse large B cell lymphoma. Although positivity for Bcl‐6 is the rule, CD10 is often negative in these cases. The main criteria for differential diagnosis from diffuse large B cell lymphoma, leg type, include predominance of cleaved cells over round cells, and lack of Bcl‐2 and MUM‐1 expression (in PCFCL, MUM‐1 is either negative or expressed by a small minority of neoplastic cells; fig 18).34
The clinical aspect of these cases is also helpful, as most of them present with the features of so‐called Crosti's lymphoma (tumours and nodules on the trunk, usually the back, surrounded by erythematous papules and patches; fig 19).
Figure 18Cutaneous follicle centre lymphoma, diffuse. (A) Dense, diffuse lymphoid infiltrates without follicular structures; (B) predominance of large cleaved cells; (C) positivity for Bcl‐6; and (D) staining for MUM‐1 shows positivity (more ...)
Figure 19Cutaneous follicle centre lymphoma, diffuse. Erythematous plaques and nodules on the trunk (picture of so‐called Crosti's lymphoma).
An important differential diagnosis of PCFCL is lymphocytoma cutis induced by B burgdorferi
infection. Germinal centres in Borrelia
lymphocytoma are often atypical, completely lacking a mantle zone (tingible body macrophages, though, are abundant).35
The confluence of such naked follicles can even simulate the picture of a large B cell lymphoma.36
In >80% of cases Borrelia
lymphocytoma involves the nipple, earlobe or genital region.35
Thus, at these body sites Borrelia
lymphocytoma should be ruled out before rendering a diagnosis of cutaneous lymphoma.
In some cases, PCFCL of the diffuse type shows predominance of spindled and bizarre cells, simulating the picture of a spindle‐cell neoplasm.37
These cases can be accurately diagnosed by a combination of morphological and phenotypical (CD20 and Bcl‐6) criteria.
Standard molecular analyses are of limited value in the diagnosis and differential diagnosis of PCFCL. Data obtained with DNA microarrays showed that the genetic signature of PCFCL, diffuse type, differs from that of diffuse large B cell lymphoma, leg type.38
These analyses, however, are far from being routine in the evaluation of cutaneous lymphomas.
Primary cutaneous diffuse large B cell lymphoma, leg type
This entity got its name because most cases (>80%) occur on the legs (fig 20).1,3,34,39
Sections of primary cutaneous diffuse large B cell lymphoma, leg type, catch your eye because of the dense, monomorphous infiltrates of large round cells (immunoblasts and centroblasts; fig 21). Dermatopathologists should be aware that primary cutaneous diffuse large B cell lymphoma, leg type, may show focal epidermotropism with “Pautrier's”‐like intraepidermal collections of atypical lymphocytes.3
These cases should not be mistaken histopathologically for a T cell lymphoma.
Figure 20Diffuse large B cell lymphoma, leg type. Multiple reddish nodules and plaques on the lower leg.
Figure 21Diffuse large B cell lymphoma, leg type. (A) Dense, diffuse infiltrate of lymphoid cells; (B) predominance of large round cells (immunoblasts); (C) positivity of all neoplastic cells for Bcl‐2; and (D) MUM‐1.
Besides cell morphology, stainings for B cell and T cell markers as well as for Bcl‐2 and MUM‐1 should be carried out to confirm the diagnosis. Primary cutaneous diffuse large B cell lymphoma, leg type, shows strong positivity for Bcl‐2 and MUM‐1, in contrast with PCFCL, diffuse type (fig 21).34
Bcl‐6 does not provide differential diagnostic clues, as it is positive in most cases of both PCFCL and primary cutaneous diffuse large B cell lymphoma, leg type. Cases with prominent round‐cell morphology and negative staining for Bcl‐2 are classified as diffuse large B cell lymphoma, other, but may represent a phenotypic (Bcl‐2) variation of primary cutaneous diffuse large B cell lymphoma, leg type, or a morphological (round‐cell) variation of PCFCL, diffuse type.34
Although in the past it has been suggested that Bcl‐2 expression is related to prognosis in cutaneous large B cell lymphomas,40
it seems that the prognostic value disappears completely once the cases are classified correctly.34
The number of lesions, location on the leg and round‐cell morphology, too,41
are devoid of any prognostic value once the cases are classified properly.34
However, it seems that cases of PCFCL, diffuse type, arising on the legs may have a worse prognosis than those arising at other body sites.34
Analyses by fluorescence in situ hybridisation show a wide spectrum of chromosomal abnormalities in primary cutaneous diffuse large B cell lymphoma, leg type.42
Most of these aberrations are similar to those observed in nodal diffuse large B cell lymphomas.
Primary cutaneous diffuse large B cell lymphoma, other
Only cases that do not fit into the previous categories, mainly Bcl‐2‐negative examples of diffuse large B cell lymphomas with round‐cell morphology are termed as primary cutaneous diffuse large B cell lymphoma, other.34
These cases are a small minority of cutaneous B cell lymphomas. Other rare cases such as plasmablastic lymphomas seen in patients with HIV or in the setting of iatrogenic immunosuppression should be classified according to criteria used for haematological neoplasms.3,43
For practical purposes, these cases are rarely encountered in the normal routine.
Intravascular large B cell lymphoma is also rare.1,3
The morphological diagnosis is relatively easy, as neoplastic cells are arranged in clusters stuffing dilated blood vessels in the dermis and superficial subcutis. These cases should always be analysed by immunohistology, as in rare cases the neoplastic cells are not B lymphocytes but T or natural killer cells, and morphology alone does not enable these variants to be differentiated. It is interesting to note that intravascular large B cell lymphoma occurs often at the site of cherry haemangiomas and that the diagnosis in some of these cases has been made by accidental biopsy of the haemangioma.44,45
CD4/CD56 haematodermic neoplasm (blastic natural killer cell lymphoma)
This is a controversial entity closely related to myelogenous leukaemia, but with a peculiar and repeatable phenotype.1,3
It was previously termed “blastic NK cell lymphoma”. The disease often presents in the skin, and in about half of the patients is confined to it at presentation (fig 22).20
Figure 22CD4/CD56 haematodermic neoplasm. Characteristic “bruise‐like” tumour.
The histopathological specimens are characterised by dense, monomorphous infiltrates of medium‐sized cells (fig 23). The epidermis is always spared and the subcutaneous tissues are consistently involved. The main differential diagnoses, on morphology, are lymphoblastic lymphoma and myelogenous leukaemia. A complete phenotyping is required to classify these cases correctly. Neoplastic cells are positive for CD4, CD56, CD123, terminal deoxynucleotidyl transferase (TdT) (often focally), and negative for T cell and B cell markers, CD1a, CD10, CD30, CD57, TIA‐1 and myeloperoxidase (fig 23). The combination of CD4 and CD56 positivity is so striking that it has been used to term this entity; useful clues for diagnosing are positivity for TdT and the negativity for TIA‐1 in the context of CD56 positivity (stainings for CD4 on paraffin wax sections may be equivocal). Molecular analyses of the TCR and IgH gene rearrangement are negative in these cases, and positivity rules out the diagnosis of CD4/CD56 haematodermic neoplasm.
Figure 23CD4/CD56 haematodermic neoplasm. (A) Monomorphous infiltrate of medium‐large blastic cells positive for (B) terminal deoxynucleotidyl transferase, (C) CD4 and (D) CD56.
Other lymphomas of the skin
Extracutaneous (usually nodal) lymphomas may present with secondary spread to the skin. In many instances, morphological aspects are similar to those of the cutaneous counterparts (eg, ALCL and follicle centre lymphoma); thus, complete staging investigations belong to the routine management of these patients. Some cases, on the other hand, do not have a “primary cutaneous” counterpart. The most important are B cell chronic lymphocytic leukaemia and B lymphoblastic lymphoma. Lesions of B cell chronic lymphoblastic leukaemia are characterised by dense, homogenous infiltrates of small lymphocytes.46
It is possible to confirm the diagnosis by immunohistology, showing an aberrant CD20/CD5/CD43 positive phenotype. Molecular analyses show the presence of a monoclonal population of B lymphocytes in most cases. B cell chronic lymphocytic leukaemia may present at sites of cutaneous inflammation (eg, at sites of previous herpes simplex 1/2 or herpes zoster, or at sites of Borrelia
B lymphoblastic lymphoma may include the skin secondarily, and in some patients may even present in the skin without manifest systemic disease (staging investigations negative).49
Morphologically, there are dense, diffuse infiltrates of monomorphous medium‐sized cells, focally arranged in a “mosaic stone” pattern. The so‐called “starry sky” pattern can also be observed, but is less frequent in the skin than in the lymph nodes. Phenotypic analyses show positivity for CD20, CD10 and TdT, and in some cases for CD34. For practical purposes, it is useful to carry out a staining for TdT in cases presenting morphologically with monomorphous proliferations of medium‐sized lymphoid cells. No reactive conditions are evident where you can expect positivity with this marker, and a positive staining clearly points to a precursor lymphoma or leukaemia.
In conclusion, diagnosis and differential diagnosis of cutaneous lymphoproliferative disorders rests on careful correlation of histopathological features with the clinical aspects. Whenever you encounter a tumoral lymphoid lesion with a T phenotype, make sure to rule out mycosis fungoides before making a diagnosis of some rare type of cutaneous T cell lymphoma, and remember that mycosis fungoides in tumour stage can present with every possible morphological–phenotypical pattern. We must be wary of false negative results when carrying out immunohistology: external positive controls, in my experience, do not suffice, and internal positive controls should always be checked for. In skin biopsies, they are available for most antibodies used routinely (eg, normal nerves are stained by CD56 antibody). A staining for κ or λ should not be interpreted as negative unless we find at least a few positive cells in our “negative” section. Positivity for a given marker does not allow diagnosis: CD56, for example, is positive in some cases of conventional early mycosis fungoides, in many γ/δ T cell lymphomas, in natural killer cell/T cell lymphoma, nasal type, and in some cases of LyP and ALCL, as well as in CD4/CD56 haematodermic neoplasm, and the immunohistochemical results need to be evaluated carefully with a panel of antibodies. Molecular analyses of the TCR and IgH genes are a valuable tool, but should never be evaluated out of the clinicopathological context. Finally, new molecular methods such as fluorescence in situ hybridisation and microarrays, though very promising, do not yet belong to the routine histopathological diagnosis of cutaneous lymphoproliferative disorders.