Case 4 -
CD15+/CD30+ Peripheral T Cell Transformation of Mycosis Fungoides
Eric D. Hsi
Cleveland Clinic Foundation
Click on each slide thumbnail image for an enlarged view
A 42 y.o. woman with a remote history of Hodgkin lymphoma in 1988 presented to a surgeon in October of
2003 with adenopathy. The patient was well until 6 months prior to this when she developed axillary
lymphadenopathy. She also reported having night sweats for the last month and pruritis. Physical
examination showed axillary, cervical, and supraclavicular lymphadenopathy. A cervical lymph node was
biopsied. H&E images and CD15 and CD30 immunostains are shown. A diagnosis of classical HL was
Case 4 - Figure 1 - Lymph node biopsy, H&E, low magnification. Note effacement of lymph node and sclerosis.
Case 4 - Figure 2 - Lymph node biopsy, H&E high magnification. A mixed infiltrate is present with lymphocytes, plasma cells, occasional eosinophils, and atypical large cells. Reed-Sternberg like cells are present.
Case 4 - Figure 3 - Lymph node biopsy, H&E high magnification. A mixed infiltrate is present with lymphocytes, plasma cells, occasional eosinophils, and atypical large cells. Reed-Sternberg like cells are present.
Shortly after the lymph node biopsy was performed, a forearm skin biopsy was also done. In the
interim, a more detailed history and physical was performed. Review of systems revealed a pruritic skin
rash predominantly in the axillae for 20 years and a dry cough. Physical examination showed the
previously mentioned lymphadenopathy and erythematous plaques on the forearms and legs. A CBC was
performed and showed a mild thrombocytosis (460 x 109/l) but was otherwise normal.
The skin biopsy revealed a dense upper dermal lymphoid infiltrate composed of small and intermediately
sized lymphocytes, some of which demonstrated nuclear irregularity and deep clefts. The infiltrate was
band-like but infiltration of the epidermis was present. Some of these lymphocytes displayed a
cytoplasmic clearing or "halo" effect along the dermal-epidermal junction and collections of several
lymphocytes in the epidermis were present. Immunophenotyping showed the vast majority of lymphocytes
expressed CD3 and CD4 but lacked CD20, CD8, and CD7. PCR studies for T-cell receptor gamma gene (TCG) rearrangement showed two dominant peaks by capillary electrophoresis at 230
and 241 base pairs. These pathologic features were felt to be compatible with cutaneous T-cell lymphoma
(mycosis fungoides, MF).
The same molecular analysis was also then performed on the lymph node biopsy and an identical pattern
was seen in the capillary gel electropherogram. Given this information, the patient was interpreted to
likely have a long history of undiagnosed mycosis fungoides with transformation to a large cell
peripheral T-cell lymphoma expressing CD15 and CD30.
CD15+/CD30+ peripheral T-cell transformation of mycosis
fungoides (clonally related).
This case illustrates some interesting clinical and histopathologic points that serve to confound the
pathologist. From a histopathologic standpoint this case demonstrates CD15 and CD30 expression that is
misleading, particularly within the context of a history of Hodgkin lymphoma. A twist is added with the
subsequent skin biopsy findings and the elicited history of the long-standing skin rash that makes it
possible to postulate a pre-existing cutaneous T-cell lymphoma. The addition of the molecular genetic
information, indicating that the two processes are related, highlights the fact that cutaneous T-cell
lymphoma such as mycosis fungoides can have a prolonged and indolent course (often with nonspecific
pathologic findings) followed by transformation to a CD30+ large T-cell lymphoma. A brief discussion of
these pathologic and clinical features follows.
The lymph node biopsy shows a numerous large transformed cells with vesicular chromatin and variably
prominent nucleoli. In some sections, a vague nodularity with some sclerosis is seen. Scattered Hodgkin
and Reed-Sternberg-like cells are present but certainly are only a minority of the cells. There is a
background of small lymphocytes, neutrophils and eosinophils. Immunophenotyping showed these large
atypical cells are CD15+/CD30+. Many of these larger cells appear to lack CD45RB and CD3 expression.
However, close examination shows some large mononuclear cells to be positive for CD3 and CD45RB. Given
the history of Hodgkin lymphoma, consideration of recurrent Hodgkin lymphoma is not unreasonable.
Although we now know that classical Hodgkin lymphoma originates from B-cells, unusual cases of T-cell
origin have been reported.
At this point, the possibility of coexistent/pre-existent MF was not entertained. The skin biopsy,
however, showed fairly typical pathologic features of MF. The immunophenotype (CD3+, CD4+, CD7-, CD8-)
and TCG PCR results all supported MF. The clinical features of longstanding
rash on the trunk, pruritis, and lesions now on the extremities are consistent with a cutaneous T-cell
lymphoma such as MF.
MF is the most common primary cutaneous T-cell lymphoma. It presents most commonly in middle age to
older adults (median age 57 years, 1.7 M:F ratio) with patches and plaques in a "bathing trunk"
distribution. The natural history is long with an indolent clinical course. The median overall survival
is 11.4 years with a disease specific survival at 10 years of 74%. Important prognostic factors include
age, T-classification, and presence of extracutaneous dieases.  The clinical and
histopathologic features can mimic other inflammatory lesions and diagnosis may take
This difficulty is well-known and the clinical conundrums have recently been
highlighted by the description of a clinically inapparent form ("invisible mycosis
There are reported cases of Hodgkin lymphoma and mycosis fungoides occurring in the same patient with
varying permutations of one lymphoma before the other or simultaneous occurrence.
cases, however, were reported prior to the ability to perform detailed immunophenotyping and molecular
genetic studies such as T-cell receptor gene rearrangement studies in fixed tissues. More recent studies
suggest different cells of origin for the two disease occurring in the same patient.
The molecular studies in this case strongly support a common clonal origin for these two
histopathologically disparate cases.
Transformation of mycosis fungoides to higher cytologic grade lesions has been well described. In a
recent series, transformation was estimated to occur in approximately 10% of cases when defined as large
cells comprising at least 25% of the infiltrate or the presence of nodules of large cells. The
transformed lesions occurred first in the skin after a median of 6.5 years from diagnosis. 
Other series differ somewhat in these figures, perhaps due to selection bias. For example, Salhany et al
reported a transformation rate of 18% with a median time to transformation of 12 months.  Of
note, 7 of 17 cases showed transformation at the time of diagnosis, similar to the current case.
Extracutaneous transformation was the initial site of transformation in 41%.  Histologic
features vary but the cells are usually large (8-35 um) with oval nuclei, prominent nucleoli, and
moderate amounts of cytoplasm and can be classified as peripheral T-cell lymphoma, unspecified.
Occasionally, the transformed cells have nuclear irregularity or can resemble anaplastic large cell
lymphoma. Reed-Sternberg like cells may be seen in some cases but are a minority of the
Histologic grouping into pleomorphic medium and large T-cell lymphoma,
T-immunoblastic, and anaplastic large cell lymphoma has been described.  When occurring in
skin, tumors are often present and lack epidermotropism.  All series describe a poor
prognosis associated with transformation, particularly with extracutaneous disease.
Immunophenotypically, the transformed lymphoma cells are usually CD4+ T-cells and express pan-T cell
antigens such as CD3. Pretransformation phenotype can be maintained but phenotypic drift occurs with
loss of some T-cell associated antigens and even changes in the CD4 or CD8 expression pattern can
occur.  CD30 expression is seen in a substantial proportion of cases
Strong expression (>75% of cells) can be seen in 15% of cases. The
expression of CD30, particularly in the majority of large cells brings up the potential diagnosis of
anaplastic large cell lymphoma. ALK expression has not been reported in this setting. When CD30+ large
cell transformation occurs in skin, a simultaneous primary cutaneous ALCL is also a consideration.
Distinction is important given the excellent prognosis of primary cutaneous ALCL.  If the
lesion is clinically distinct from the MF lesions or if the two processes can be shown to be clonally
unrelated, a separate diagnosis would be supported. Ultimately, only the clinical course may reveal the
difference between cutaneous ALCL and transformed CD30+ MF. 
The expression of CD15 on many of the atypical cells in the lymph node confounded the issue of whether
the lymph node biopsy represented Hodgkin lymphoma. CD15 antibodies recognize Lewis X antigen. It is
expressed in various epithelia and myeloid cells and expression of CD15 is useful in the diagnosis of
classical Hodgkin lymphoma since approximately 85% of cases express CD15 on Hodgkin and Reed-Sternberg
(HRS) cells. However, it is also expressed in other hematolymphoid malignancies including acute
lymphoblastic leukemias (particularly those with MLL rearrangements), acute myeloid leukemias, and rare
cases of B-cell non-Hodgkin lymphoma.
CMV-infected cells mimicking HRS cells have also
been shown to express CD15.  More relevant to this case, CD15 has also been reported to be
expressed in some post-thymic T-cell lymphomas.  In the setting of transformation of MF,
strong CD15 expression has been reported in 3/17 cases. 
Recently, this phenomenon has been documented in two studies that specifically report cases of
peripheral T-cell lymphomas that express both CD30 and CD15.
Gorczyca and colleagues
reported 9 cases of T-cell lymphomas, including 2 cases of ALK+ anaplastic large cell lymphoma, that
coexpressed these markers that are typically seen in classical HL.  The median age of their
patients was 62 years with a 2:1 male predominance. Barry et al reported an additional 11 patients with
a remarkably similar median age of 62 years and male predominance.  8/11 showed nodal
disease and two had primarily cutaneous disease. Importantly, one group of 5 patients had histologic
features that closely mimicked classical HL, with a mixed inflammatory infiltrate and HRS-like cells.
The remaining cases had features more in keeping with peripheral T-cell lymphoma but also had a
proportion of neoplastic cells that coexpressed CD15 and CD30. T-cell monoclonality could be
demonstrated in the majority of cases (9 of 11) and Epstein-Barr virus was not detected. These two
reports remind us that CD15 and CD30, while seen commonly in the HRS cells of classical HL, can be
coexpressed in T-cell lymphomas. The histopathologic features in such cases may also mimic HL.
This case is interpreted as a CD30+/CD15+ T-cell lymphoma that appears to represent a transformation
of an undiagnosed cutaneous T-cell lymphoma (MF). It illustrates how the expression of CD15 can be
misleading, particularly with the clinical history (albeit unconfirmed) of HL, and how the evolving
clinical and pathologic findings combine to help resolve diagnostic difficulties. The combined
pathologic findings, clinical features, and application of molecular genetic studies make it possible to
render an appropriate diagnosis.
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