—  SPECIALTY CONFERENCE  —

Hematopathology

Case 4 - CD15+/CD30+ Peripheral T Cell Transformation of Mycosis Fungoides

Eric D. Hsi
Cleveland Clinic Foundation
Cleveland, OH


Click on each slide thumbnail image for an enlarged view
Clinical History
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 considered.


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.


Case 4 - Figure 4 - CD30 immunostain highlights large cells.
Case 4 - Figure 5 - CD15 immunostain highlights large cells.


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.

Diagnosis
CD15+/CD30+ peripheral T-cell transformation of mycosis fungoides (clonally related).

Discussion
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. [1, 2]

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. [3] The clinical and histopathologic features can mimic other inflammatory lesions and diagnosis may take years. [3, 4, 5] This difficulty is well-known and the clinical conundrums have recently been highlighted by the description of a clinically inapparent form ("invisible mycosis fungoides"). [6]

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. [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20] Most 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. [12, 14, 18] 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. [21] 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. [22] 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%. [22] 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 cells. [21, 22] Histologic grouping into pleomorphic medium and large T-cell lymphoma, T-immunoblastic, and anaplastic large cell lymphoma has been described. [23] When occurring in skin, tumors are often present and lack epidermotropism. [21] All series describe a poor prognosis associated with transformation, particularly with extracutaneous disease. [21, 22, 24]

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. [21] CD30 expression is seen in a substantial proportion of cases (30-45%). [21, 22] 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. [25] 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. [21]

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. [26, 27, 28, 29, 30] CMV-infected cells mimicking HRS cells have also been shown to express CD15. [31] More relevant to this case, CD15 has also been reported to be expressed in some post-thymic T-cell lymphomas. [32] In the setting of transformation of MF, strong CD15 expression has been reported in 3/17 cases. [22]

Recently, this phenomenon has been documented in two studies that specifically report cases of peripheral T-cell lymphomas that express both CD30 and CD15. [33, 34] 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. [34] 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. [33] 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.

References

  1. Marafioti T, Hummel M, Foss HD et al. Hodgkin and reed-sternberg cells represent an expansion of a single clone originating from a germinal center B-cell with functional immunoglobulin gene rearrangements but defective immunoglobulin transcription. Blood. 2000;95:1443-1450.
  2. Seitz V, Hummel M, Marafioti T et al. Detection of clonal T-cell receptor gamma-chain gene rearrangements in reed-sternberg cells of classic Hodgkin disease. Blood. 2000;95:3020-3024.
  3. Kim YH, Liu HL, Mraz-Gernhard S et al. Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression. Arch Dermatol. 2003;139:857-866.
  4. Kim YH, Hoppe RT. Mycosis fungoides and the Sezary syndrome. Semin Oncol. 1999;26:276-289.
  5. Smith BD, Wilson LD. Management of mycosis fungoides. Part 1. Diagnosis, staging, and prognosis. Oncology (Huntingt). 2003;17:1281-1288.
  6. Pujol RM, Gallardo F, Llistosella E et al. Invisible mycosis fungoides: A diagnostic challenge. J Am Acad Dermatol. 2000;42:324-328.
  7. Harris NL. The relationship between Hodgkin's disease and non-Hodgkin's lymphoma. Semin Diagn Pathol. 1992;9:304-310.
  8. Lipa M, Kunynetz R, Pawlowski D et al. The occurrence of mycosis fungoides in two patients with preexisting Hodgkin's disease. Arch Dermatol. 1982;118:563-567.
  9. Kaufman D, Gordon LI, Variakojis D et al. Successfully treated Hodgkin's disease followed by mycosis fungoides: case report and review of the literature. Cutis. 1987;39:291-296.
  10. van der Putte SC, Toonstra J, Go DM et al. Mycosis fungoides. Demonstration of a variant simulating Hodgkin's disease. A report of a case with a cytomorphological analysis. Virchows Arch B Cell Pathol Incl Mol Pathol. 1982;40:231-247.
  11. Chan WC, Griem ML, Grozea PN et al. Mycosis fungoides and Hodgkin's disease occurring in the same patient: report of three cases. Cancer. 1979;44:1408-1413.
  12. Geldenhuys L, Radhi J, Hull PR. Mycosis fungoides and cutaneous Hodgkin's disease in the same patient: a case report. J Cutan Pathol. 1999;26:311-314.
  13. Beylot-Barry M, Dubus P, Vergier B et al. Meningeal involvement by a transformed mycosis fungoides following Hodgkin's disease. Br J Dermatol. 1999;141:909-913.
  14. Sidwell RU, McLaughlin JE, Jones A et al. Hodgkin Lymphoma in a patient with mycosis fungoides: molecular evidence for separate cellular origins. Br J Dermatol. 2003;148:810-812.
  15. Caya JG, Choi H, Tieu TM et al. Hodgkin's disease followed by mycosis fungoides in the same patient. Case report and literature review. Cancer. 1984;53:463-467.
  16. Brousset P, Lamant L, Viraben R et al. Hodgkin's disease following mycosis fungoides: phenotypic and molecular evidence for different tumour cell clones. J Clin Pathol. 1996;49:504-507.
  17. Bettini R, Quadrelli CM, Masciadra M et al. Hodgkin's disease associated with mycosis fungoides. Haematologica. 1988;73:548.
  18. Kremer M, Sandherr M, Geist B et al. Epstein-Barr virus-negative Hodgkin's lymphoma after mycosis fungoides: molecular evidence for distinct clonal origin. Mod Pathol. 2001;14:91-97.
  19. Bee CS, Blaise YP, Dunphy CH. Composite lymphoma of Hodgkin lymphoma and mycosis fungoides: previously undescribed in the same extracutaneous site. Leuk Lymphoma. 2001;42:543-549.
  20. Park CS, Chung HC, Lim HY et al. Coexisting mycosis fungoides and Hodgkin's disease as a composite lymphoma: a case report. Yonsei Med J . 1991;32:362-369.
  21. Vergier B, de Muret A, Beylot-Barry M et al. Transformation of mycosis fungoides: clinicopathological and prognostic features of 45 cases. French Study Group of Cutaneious Lymphomas. Blood. 2000;95:2212-2218.
  22. Salhany KE, Cousar JB, Greer JP et al. Transformation of cutaneous T cell lymphoma to large cell lymphoma. A clinicopathologic and immunologic study. Am J Pathol. 1988;132:265-277.
  23. Cerroni L, Rieger E, Hodl S et al. Clinicopathologic and immunologic features associated with transformation of mycosis fungoides to large-cell lymphoma. Am J Surg Pathol. 1992;16:543-552.
  24. Dmitrovsky E, Matthews MJ, Bunn PA et al. Cytologic transformation in cutaneous T cell lymphoma: a clinicopathologic entity associated with poor prognosis. J Clin Oncol. 1987;5:208-215.
  25. Beljaards RC, Kaudewitz P, Berti E et al. Primary cutaneous CD30-positive large cell lymphoma: definition of a new type of cutaneous lymphoma with a favorable prognosis. A European Multicenter Study of 47 patients. Cancer. 1993;71:2097-2104.
  26. Arber DA, Weiss LM. CD15: A Review. Appl Immunohistochem 1, 17-30. 1993.
  27. Borkhardt A, Wuchter C, Viehmann S et al. Infant acute lymphoblastic leukemia - combined cytogenetic, immunophenotypical and molecular analysis of 77 cases. Leukemia. 2002;16:1685-1690.
  28. LeBrun DP, Kamel OW, Dorfman RF et al. Enhanced staining for Leu M1 (CD15) in Hodgkin's disease using a secondary antibody specific for immunoglobulin M. Am J Clin Pathol. 1992;97:135-138.
  29. Maynadie M, Campos L, Moskovtchenko P et al. Heterogenous expression of CD15 in acute lymphoblastic leukemia: a study of ten anti-CD15 monoclonal antibodies in 158 patients. Leuk Lymphoma. 1997;25:135-143.
  30. Rudiger T, Ott G, Ott MM et al. Differential diagnosis between classic Hodgkin's lymphoma, T-cell-rich B-cell lymphoma, and paragranuloma by paraffin immunohistochemistry. Am J Surg Pathol. 1998;22:1184-1191.
  31. Rushin JM, Riordan GP, Heaton RB et al. Cytomegalovirus-infected cells express Leu-M1 antigen. A potential source of diagnostic error. Am J Pathol. 1990;136:989-995.
  32. Wieczorek R, Burke JS, Knowles DM. Leu-M1 antigen expression in T-cell neoplasia. Am J Pathol. 1985;121:374-380.
  33. Barry TS, Jaffe ES, Sorbara L et al. Peripheral T-cell lymphomas expressing CD30 and CD15. Am J Surg Pathol. 2003;27:1513-1522.
  34. Gorczyca W, Tsang P, Liu Z et al. CD30-positive T-cell lymphomas co-expressing CD15: An immunohistochemical analysis. Int J Oncol. 2003;22:319-324.