AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Cutaneous CD30⁺ (Ki-1) anaplastic large-cell lymphoma (cutaneous CD30⁺ ALCL) is clinically and pathologically heterogeneous, leading to some difficulty in its diagnosis and classification. Expression of CD30 (an activation marker for B or T cells) in more than 75% of neoplastic cells characterizes this group of lymphoproliferative disorders.

Based on clinical manifestations, cutaneous CD30⁺ ALCL can be subdivided mainly into a primary cutaneous form without extracutaneous involvement at presentation or a systemic form with secondary skin involvement at presentation. The primary cutaneous form (see History) generally has a better prognosis than the systemic form with secondary skin involvement. Sometimes (in up to 25% of cases), spontaneous regression of the primary cutaneous form occurs despite high-grade anaplastic cytology of neoplastic lymphocytes.

Cutaneous CD30⁺ ALCL can be further classified into different groups according to histologic features (eg, pleomorphic, immunoblastic, monomorphic, small-cell predominant, Hodgkin disease–related, and other less common variants); immunophenotype (eg, T, null, B, rarely B and T); and other clinical features, such as ALCL arising in patients who are HIV positive and ALCL occurring after another lymphoproliferative process (eg, lymphomatoid papulosis, mycosis fungoides, Hodgkin disease). The primary cutaneous form is composed of predominantly anaplastic morphology type, though pleomorphic and immunoblastic morphology types can infrequently be seen.

Pathophysiology

Cytogenetic studies and subsequent cloning of the translocation t(2;5) have shown a high degree of association with systemic forms of CD30⁺ ALCL. This genetic abnormality is not specific for anaplastic morphologic features and is more common in the monomorphic and small-cell variants. However, the t(2;5) is relatively rare in the primary cutaneous form of ALCL. This points to a molecular etiology of primary cutaneous CD30⁺ ALCL distinct from that of extracutaneous (systemic form) CD30⁺ lymphoproliferative disease.

This translocation creates a novel fusion protein, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), which has transforming properties in vitro and can cause large-cell lymphoma in vivo when transfected into murine bone marrow. NPM-ALK expression is most often seen in young patients with the monomorphic or small-cell variant of ALCL who present with advanced-stage disease and have tumors with a CD30⁺, T- or null-cell phenotype. It is less frequently detected in older patients and in ALCL of pleomorphic histology.

The neoplastic cells are CD30⁺ positive and typically have a T-helper phenotype (ie, CD3⁺, CD4⁺). Cells are usually CD8^-. Pan–T-cell antigens may be partially lost. Monoclonal rearrangement of the TCR gene is observed in most cases. However, Bonzheim et al recently reported that only 2 (4%) of 47 ALCLs expressed TCR-beta protein. Moreover, both TCR-beta(+) ALCLs lacked CD3 and ZAP-70 (ie, molecules indispensable for the transduction of cognate TCR signals). Thus, defective expression of TCRs is a common characteristic of all types of ALCL, which may contribute to the dysregulation of intracellular signaling pathways controlling T-cell activation and survival.

CD30 is a protein in the tumor necrosis factor receptor superfamily. CD30 must be expressed in more than 75% of cells for the diagnosis. The primary cutaneous form is typically CD15^-.

CD95 (FAS protein that induces apoptosis) expression is preferentially expressed at high levels in all primary cutaneous forms of CD30⁺ lymphomas and suggests that CD95 may play a role in the regression of CD30⁺ skin lesions.

No clear-cut distinction exists clinically or histologically between some expressions of lymphomatoid papulosis and the primary cutaneous form of CD30⁺ ALCL. This discrimination may be artificial in some cases because 10% of cases of lymphomatoid papulosis progress to the clear-cut primary cutaneous form of CD30⁺ ALCL.

Frequency

United States

The frequency of CD30⁺ ALCL in the United States is not known.

International

CD30⁺ ALCL comprise approximately 5% of all non-Hodgkin lymphoma (NHL). The primary cutaneous form of CD30⁺ ALCL makes up about 10% of the total primary cutaneous lymphoproliferative disorders and is the second most common primary cutaneous lymphoproliferative disorder after mycosis fungoides.

Mortality/Morbidity

The 5-year survival rate is 90% for the primary cutaneous form of CD30⁺ ALCL. The prognosis of the systemic form with secondary cutaneous involvement depends on the expression of the ALK protein. Patients with expression of ALK have a 5-year survival rate ranging from 70-80%. The 5-year survival rate in patients without ALK expression ranges from 15-30%.

Sex

The male-to-female ratio is 3:2.

Age

Patients with primary cutaneous forms of ALCL are generally older (median age, 61 y) than patients with the systemic form of ALCL (median age, 24 y) and, in contrast to the latter group, do not show a bimodal age distribution.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• The primary cutaneous form is defined by skin-only involvement without systemic dissemination at presentation. Draining regional lymph node involvement occurs in approximately 25% of patients with only skin lesions. Whether the patients only showing draining regional lymph node involvement should be considered to have a primary cutaneous form remains controversial.
• Patients with widespread systemic and cutaneous disease at first presentation should be considered to have the systemic form with skin involvement.

Physical

• Patients usually present with solitary or ulcerating nodules or tumors.
• Lesions are typically reddish brown and indurated.
• Involvement of the draining regional lymph nodes occurs in approximately 25% of patients. (This does not appear to be associated with a worse prognosis.)

Causes

In the systemic form of CD30⁺ ALCL, t(2;5), resulting in a novel fusion protein (NPM-ALK), may play an important role for the development of disease. The primary cutaneous form, however, does not commonly show this translocation, and the etiology remains unknown.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Primary CD30^- T-cell large cell lymphoma (T-LCL)
Primary cutaneous Hodgkin disease
Granulocytic sarcoma
Viral infection

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Molecular diagnostic techniques and cytogenetic studies
• • Most cases have clonally rearranged T-cell receptor genes.
  • The t(2;5) translocation has shown a high degree of association with systemic forms of CD30⁺ ALCL; however, it is relatively rare in the primary cutaneous form of ALCL.
  • Reverse transcriptase-polymerase chain reaction (RT-PCR) can be performed to detect the t(2;5) translocation for diagnostic purposes or for monitoring of minimal residual disease.

Imaging Studies

• CT scan of the chest and the abdomen may be performed for staging of lymphoma and for differentiating the primary cutaneous form from the systemic form involving the skin. The latter has systemic lymphadenopathy other than regional lymphadenopathy associated with skin lesions.

Procedures

• A skin biopsy may be performed.
• A bone marrow biopsy may be performed for staging.

Histologic Findings

Cutaneous CD30⁺ ALCL consists of diffuse nonepidermotropic infiltrates with cohesive sheets of large CD30⁺ tumor cells. In most cases, the tumor cells may have the characteristic morphology of anaplastic cells, showing round, oval, or irregularly shaped nuclei; prominent (eosinophilic) nucleoli; and abundant cytoplasm. Less commonly, tumor cells have a pleomorphic or immunoblastic appearance. Reactive lymphocytes are often present at the periphery of the lesions. In some cases, numerous inflammatory cells (eg, T cells, eosinophils, neutrophils) and relatively few CD30⁺ cells may be observed (lymphomatoid papulosis [LyP]–like histology). Epidermal hyperplasia may be prominent in such cases.

Immunophenotypically, most neoplastic lymphocytes have a unique CD4⁺, CD8^-, and cytotoxic T-cell phenotype (TIA-1 and granzyme B+), with variable loss of pan–T-cell antigens (eg, CD2, CD3, CD5). CD30 must be expressed by most (>75%) of the neoplastic cells. The neoplastic lymphocytes in the primary cutaneous form are usually epithelial membrane antigen (EMA) negative in contrast to the systemic form.

LyP and cutaneous CD30⁺ lymphoma are closely related conditions in which large atypical lymphocytes that have similar immunophenotypic features occur.

In LyP, the lesions are papules and nodules that spontaneously involute. Two polar histologic patterns (type A and type B) occur in which the large atypical cells resemble those of Hodgkin disease and mycosis fungoides, respectively, but, in many cases, features of both types are present, either separately or in the same lesions. Type C LyP includes lesions that show sheets of atypical mononuclear cells with little admixed inflammatory cells, a histologic picture that is difficult to separate from classic CD30⁺ ALCL. Variants of LyP include cases with a perifollicular distribution and those with lymphocytic vasculitis or dermal mucin deposits.

LyP is associated with a long benign course of frequent regression of papular lesions. The risk of developing a malignant lymphoma is approximately 10-20%.

A loss of response to transforming growth factor-beta, which normally dampens cellular proliferation, favors a diagnosis of CD30⁺ ALCL instead of LyP. A recent study shows that CCR3 was expressed by atypical lymphoid cells in 10 (83%) of 12 cases of ALCL, but in only 5 (38%) of 13 cases of LyP. CXCR3 was expressed in 11 (85%) of 13 cases of LyP, but in only 1 (8%) of 12 cases of ALCL. CCR4 was expressed in 11 (92%) of 12 cases of ALCL, but in only 2 (15%) of 13 cases of LyP. RANTES was strongly expressed by lymphoma cells in ALCL (11 [92%]of 12), but was weak or sporadic in LyP (7 [54%] of 13). These markers may be useful to differentiate ALCL from LyP in difficult cases. Lesions of LyP typically show clonal TCR rearrangements; therefore, this is not a useful test to differentiate between these entities.

The term borderline case refers to cases in which a discrepancy between the clinical features and the histologic appearance exists. These include cases with the clinical presentation of a CD30⁺ ALCL but with histologic features suggestive of LyP, and, conversely, cases with recurrent, self-healing skin lesions, that on histologic examination, show a rather uniform proliferation of large CD30⁺ tumor cells with only a few admixed inflammatory cells, which is characteristic of a CD30⁺ ALCL. The presence of these cases indicates that CD30⁺ ALCL and LyP are parts of a spectrum of primary cutaneous CD30⁺ lymphoproliferative disorders. The distinction between LyP and the primary cutaneous form of CD30⁺ ALCL is not always possible on the basis of histologic criteria. Thus, the clinical appearance and the course are used as decisive criteria for the definite diagnosis and the choice of treatment.

Primary CD30^- T-LCL is generally associated with a poor prognosis.

Primary cutaneous Hodgkin disease probably does exist as a rare, often deep-seated, nodular disorder that usually has a good prognosis. Reed-Sternberg cells in Hodgkin disease are CD15⁺ in addition to CD30⁺.

The authors' observation indicates that CD30 may be positive in rare cases of granulocytic sarcoma, though the staining intensity is weaker than that seen in CD30⁺ ALCL.

CD30⁺ lymphocytes can be found in certain viral infections, such as human T-lymphotropic virus type I, HIV, hepatitis B and C viruses, Epstein-Barr virus, and Parapoxvirus infection.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Radiation therapy is the preferred treatment of solitary or localized skin disease.
• Generalized skin lesions may respond to methotrexate.
• Multiagent chemotherapy, such as F-MACHOP regimen (see detailed information in the reference by Fanin cited in the Bibliography), should be considered only in patients with systemic disease. The issue of how to treat patients with local nodal disease is somewhat more controversial, and some may consider multiagent chemotherapy in these patients (see detailed information in the reference by Bekkenk cited in the Bibliography).
• Recently, anti-CD30 monoclonal antibody has been used experimentally for patients in whom multichemotherapy failed.

Surgical Care

Simple excision may be considered for solitary or localized skin lesions.

Consultations

• Consult a hematologist/oncologist for chemotherapy evaluation.
• Consult a radiation oncologist for therapy.

Diet

No limitation on diet is necessary.

Activity

No limitation on activity is necessary.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals are to reduce morbidity and to prevent complications.

Drug Category: Chemotherapeutic agents

Methotrexate is the choice of single-agent chemotherapy, if necessary.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Arrange for follow-up care to look for any new skin lesions or lymphadenopathy.
• Obtain a CBC count if the patient is undergoing chemotherapy.

Complications

• Chemotherapy drugs are myelosuppressive.

Prognosis

• Generally, CD30⁺ has a favorable clinical course (5-y survival rate of 90%) for the primary cutaneous form with occasional spontaneous regression (up to 25% of cases) of the skin lesions. The systemic form has a worse prognosis than the primary cutaneous form. The primary cutaneous CD30^- large-cell lymphoma also has a much worse prognosis (5-y survival rate of 15%) than that of the primary cutaneous form of CD30⁺ ALCL.
• Primary cutaneous disease, spontaneous regression, absence of extracutaneous involvement, and younger age at onset (£60 y) have been suggested to be associated with a better prognosis.
• The expression of either NPM-ALK transcripts or ALK protein is not correlated with prognosis or age in the primary cutaneous form of CD30⁺ cutaneous lymphoproliferations; however, expression of either NPM-ALK transcripts or ALK protein indicates a better prognosis in the systemic form of ALCL.
• Prior studies have suggested that the stage of disease may be more important than the cytologic subtype.
• CD30 ligand expression is detected in regressing lesions only and indicates a better prognosis. Cutaneous CD30⁺ ALCL developing from preexistent mycosis fungoides are often associated with a poor prognosis (5-y survival rate of 10-30%).
• Regional lymph node involvement is not necessarily associated with an unfavorable prognosis.
• P53 expression by immunohistochemistry is not associated with spontaneous regression, extracutaneous spreading, or survival.

Patient Education

• Regular follow-up care is indicated for possible relapse or recurrent disease.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to properly treat this condition is a pitfall. Overtreatment of this indolent lymphoma may expose patients to unnecessary complications.

Special Concerns

• Local excision may be an alternative to radiation therapy for solitary lesions in either pregnant patients or pediatric patients.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Bekkenk MW, Geelen FA, van Voorst Vader PC, Heule F, Geerts ML, van Vloten WA, et al. Primary and secondary cutaneous CD30(+) lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment. Blood. Jun 15 2000;95(12):3653-61. [Medline].
• Bonzheim I, Geissinger E, Roth S, Zettl A, Marx A, Rosenwald A, et al. Anaplastic large cell lymphomas lack the expression of T-cell receptor molecules or molecules of proximal T-cell receptor signaling. Blood. Nov 15 2004;104(10):3358-60. [Medline].
• de Bruin PC, Beljaards RC, van Heerde P, Van Der Valk P, Noorduyn LA, Van Krieken JH, et al. Differences in clinical behaviour and immunophenotype between primary cutaneous and primary nodal anaplastic large cell lymphoma of T-cell or null cell phenotype. Histopathology. Aug 1993;23(2):127-35. [Medline].
• Duncan LM. Cutaneous lymphoma. Understanding the new classification schemes. Dermatol Clin. Jul 1999;17(3):569-92. [Medline].
• Fanin R, Sperotto A, Silvestri F, Cerno M, Geromin A, Stocchi R, et al. The therapy of primary adult systemic CD30-positive anaplastic large cell lymphoma: results of 40 cases treated in a single center. Leuk Lymphoma. Sep 1999;35(1-2):159-69. [Medline].
• Kempf W, Dummer R, Burg G. Approach to lymphoproliferative infiltrates of the skin. The difficult lesions. Am J Clin Pathol. Jan 1999;111(1 Suppl 1):S84-93. [Medline].
• Kinney MC, Kadin ME. The pathologic and clinical spectrum of anaplastic large cell lymphoma and correlation with ALK gene dysregulation. Am J Clin Pathol. Jan 1999;111(1 Suppl 1):S56-67. [Medline].
• Kummer JA, Vermeer MH, Dukers D, Meijer CJ, Willemze R. Most primary cutaneous CD30-positive lymphoproliferative disorders have a CD4-positive cytotoxic T-cell phenotype. J Invest Dermatol. Nov 1997;109(5):636-40. [Medline].
• LeBoit PE. Lymphomatoid papulosis and cutaneous CD30+ lymphoma. Am J Dermatopathol. Jun 1996;18(3):221-35. [Medline].
• Mori M, Manuelli C, Pimpinelli N, Mavilia C, Maggi E, Santucci M, et al. CD30-CD30 ligand interaction in primary cutaneous CD30(+) T-cell lymphomas: A clue to the pathophysiology of clinical regression. Blood. Nov 1 1999;94(9):3077-83. [Medline].
• Paulli M, Berti E, Boveri E, Kindl S, Bonoldi E, Gambini C, et al. Cutaneous CD30+ lymphoproliferative disorders: expression of bcl-2 and proteins of the tumor necrosis factor receptor superfamily. Hum Pathol. Nov 1998;29(11):1223-30. [Medline].
• Paulli M, Berti E, Rosso R, Boveri E, Kindl S, Klersy C, et al. CD30/Ki-1-positive lymphoproliferative disorders of the skin--clinicopathologic correlation and statistical analysis of 86 cases: a multicentric study from the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Project Group. J Clin Oncol. Jun 1995;13(6):1343-54. [Medline].
• Shehan JM, Kalaaji AN, Markovic SN, Ahmed I. Management of multifocal primary cutaneous CD30 anaplastic large cell lymphoma. J Am Acad Dermatol. Jul 2004;51(1):103-10. [Medline].
• Tomaszewski MM, Lupton GP, Krishnan J, May DL. A comparison of clinical, morphological and immunohistochemical features of lymphomatoid papulosis and primary cutaneous CD30(Ki-1)-positive anaplastic large cell lymphoma. J Cutan Pathol. Aug 1995;22(4):310-8. [Medline].
• Vergier B, Beylot-Barry M, Pulford K, Michel P, Bosq J, de Muret A, et al. Statistical evaluation of diagnostic and prognostic features of CD30+ cutaneous lymphoproliferative disorders: a clinicopathologic study of 65 cases. Am J Surg Pathol. Oct 1998;22(10):1192-202. [Medline].
• Vonderheid EC, Sajjadian A, Kadin ME. Methotrexate is effective therapy for lymphomatoid papulosis and other primary cutaneous CD30-positive lymphoproliferative disorders. J Am Acad Dermatol. Mar 1996;34(3):470-81. [Medline].
• Willemze R, Beljaards RC. Spectrum of primary cutaneous CD30 (Ki-1)-positive lymphoproliferative disorders. A proposal for classification and guidelines for management and treatment. J Am Acad Dermatol. Jun 1993;28(6):973-80. [Medline].
• Willemze R, Kerl H, Sterry W, Berti E, Cerroni L, Chimenti S, et al. EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood. Jul 1 1997;90(1):354-71. [Medline].
• Yamaguchi T, Ohshima K, Karube K, Kawano R, Nakayama J, Suzumiya J, et al. Expression of chemokines and chemokine receptors in cutaneous CD30+ lymphoproliferative disorders. Br J Dermatol. May 2006;154(5):904-9. [Medline].

Article Last Updated: Feb 27, 2007