Clonal T-Cell Receptor γ-Chain Gene Rearrangements in Differential Diagnosis of Lymphomatoid Papulosis From Skin Metastasis of Nodal Anaplastic Large-Cell Lymphoma FREE

Anaplastic large-cell lymphoma (ALCL) is a peripheral CD30⁺ T-cell non-Hodgkin lymphoma. The following 2 types of ALCL are recognized by the World Health Organization lymphoma classification: (1) systemic nodal ALCL and (2) primary cutaneous ALCL, which with lymphomatoid papulosis (LyP) and borderline cases constitute the spectrum of primary cutaneous CD30⁺ T-cell lymphoproliferative disorders (LPDs). The difference in prognosis and treatment make the distinction between the LyP and nodal ALCL very important. For LyP, prognosis is excellent, with a 5-year survival of 98%,¹ whereas survival is only 15% to 45% for anaplastic lymphoma kinase 1 (ALK-1) –negative ALCL.^2- 3 Anaplastic large-cell lymphoma is a monoclonal LPD. When LyP arises in the setting of ALCL, it would be expected to share the same T-cell receptor γ-chain gene rearrangement (TCR- γR) as the subclone of the original tumor.^4- 5

We herein describe a patient who developed waxing and waning crops of cutaneous papules and nodules typical of LyP following systemic nodal ALCL. Because of the identical histologic features of type C LyP and ALCL, differentiation between metastatic nodal ALCL and LyP presented a significant challenge. However, molecular studies (TCR- γR by means of polymerase chain reaction analysis) from skin and nodal specimens demonstrated 2 distinct clones, allowing us to confirm the suspected diagnosis of LyP and avoid aggressive therapy for this patient.

A 54-year-old white man presented with a 2 ½-year history of periodic outbreaks of pink papules and nodules on his trunk. Six years before this visit, the patient developed a right inguinal mass that was found to be a completely effaced lymph node with large transformed lymphocytes, abundant eosinophilic cytoplasm, eccentrically located nuclei, and anaplastic features, surrounded by sclerosis. Large cells demonstrated staining for CD45 (weak), CD3 (weak), CD2 (weak), CD4, and CD30, but were negative for CD20, CD79a, ALK-1, CD5, CD7, CD8, CD56, CD57, T-cell restricted intracellular antigen (TIA-1), granzyme, and epithelial membrane antigen (EMA) (Figure 1). His staging workup at that time included bone marrow biopsy, positron emission tomography, and computed tomography, all of which were negative for involvement with the disease. The disease was classified as being stage I (Ann Arbor staging) ALK-1 –negative ALCL. The patient had received 6 cycles of the CHOP regimen (cyclophosphamide, doxorubicin, vincristine [Oncovin], and prednisone administered in 21-day cycles) with a complete response as judged by continually negative findings on positron emission tomography. Field radiation therapy (30.6 Gy in 17 fractions) was also delivered to the right inguinal and pelvic region.

Three and a half years after the initial diagnosis of and therapy for ALCL, he developed a cutaneous nodule over the right clavicle; he felt well without any weight loss or B-symptoms. The skin biopsy findings revealed a dense CD30⁺ lymphocytic infiltrate. Positron emission tomography performed at the same time did not find any evidence of systemic involvement. Diagnosis of metastatic nodal ALCL was made by his oncologist. The CHOP regimen of chemotherapy was offered, but the patient preferred watchful waiting. For the next 2 years of regular follow-up, intermittent nonulcerated papules and nodules appeared ( ≤3 cm in diameter) on different parts of the body. During the course of 2 to 3 months, with the use of topical corticosteroids, the lesions regressed without scarring.

On examination, the patient was a well-appearing, well-nourished white male in no distress. His skin examination revealed numerous, erythematous to violaceous, discrete monomorphous papules and nodules with superficial erosion ranging from 0.5 to 2.5 cm above the left clavicle, near upper medial border of the right scapula, left lumbar area, and midback. These nodules were well circumscribed, firm, and nontender (Figure 2A and B). Results of the histopathological examination showed a dense dermal infiltrate with epidermal involvement (Figure 2D and E). Atypical lymphocytes showed expression of CD3 (Figure 2C), CD30 (Figure 2F), Ki-67, and CD2; diminished expression of CD8, CD4, CD5, and CD7; and negative findings for EMA, CD20, ALK-1, CD56, CD57, granzyme, and TIA-1. The TCR- γR polymerase chain reaction analysis was performed for both specimens (the cutaneous nodule of the recent presentation and the original lymph node removed 6 years ago) using oligonucleotide primers for the V1-8, V9, V10, V11, and J1/2 regions and using an assay that discriminates homoduplex from heteroduplex products. The absence of similar bands in the 2 distinct tissue specimens was demonstrated by using the same primer sets. A distinct leading edge band was observed with the V1-8 primer set for the skin biopsy specimen (Figure 3A). This band was absent in the lymph node specimen, which demonstrated a different leading edge band with the V9 primer set (Figure 3B). The presence of positive bands with different primer sets is consistent with the presence of 2 different clones in the skin and lymph node specimens.

Lymphomatoid papulosis affects men roughly twice as frequently as women.⁶ The typical clinical picture includes multiple waxing and waning ulcerative papules and nodules, which spontaneously and completely regress with or without scarring. Lymphadenopathy and systemic involvement are absent.⁷ In nearly all cases of histologically supported CD30⁺ LPD, the clinical scenario is of utmost importance, whereas the molecular testing is helpful in further supporting the clinical impression.

Several studies have shown that when LyP coexists with systemic CD30⁺ lymphoma, CD30⁺ LyP cells appear to be of the same clone as the coexisting lymphoma.^8- 10 A previous publication suggested that secondary LyP may arise as a subclone of the original lymphoma via acquisition of additional mutations that can alter its clinical, histologic, and immunophenotypic characteristics.⁴ We found a clone in the LyP nodules that was different from the clone identified in the original lymph node involved with ALCL, which suggested that LyP was not a skin metastasis or other manifestation of nodal ALCL.

Although interpretation of immunohistochemical stains may be subject to individual variation, we observed subtle differences in staining patterns between the skin (LyP) and node (ALCL) specimens. The nodal lesion showed strong CD30 and CD4 but weak CD3 expression; the skin showed strong CD30 and CD3 but weak CD4 staining. Together with the demonstration of a distinct clone, this observation may support a different origin of LyP in our patient.

The spectrum of CD30⁺ T-cell LPDs presenting in the skin include LyP, primary cutaneous ALCL, large-cell transformation of mycosis fungoides, metastatic nodal ALCL, and rare variants of Hodgkin lymphoma with additional coexpression of CD3. Genetic, immunophenotypic, and clinical differences separate systemic and cutaneous ALCL into 2 different entities, with systemic ALCL constituting 2% to 8% of non-Hodgkin lymphoma in adults and 10% to 15% in children.¹¹

The histopathological features of LyP are extremely variable and in part correlate with the age of the skin lesion undergoing biopsy. Several histologic subtypes of LyP have been described¹² that represent a spectrum with overlapping features. Besides classic types A, B, and C, a new subtype resembling primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T-cell lymphoma¹³ was described recently. It was emphasized before that some cases reported in the past as febrile ulceronecrotic pityriasis lichenoides et varioliformis acuta with atypical and/or CD30⁺ lymphocytes may in fact be a peculiar variant of LyP as well.¹⁴ Type C LyP demonstrates a monotonous population or large clusters of large CD30⁺ T cells with relatively few admixed inflammatory cells. Large atypical cells of LyP are diploid¹⁵ and rapidly cycling, as evidenced by nuclear staining with Ki-67,¹⁶ rather than being postmitotic as previously believed. Clonally rearranged T-cell receptor genes have been detected in 40% of LyP lesions,¹⁷ with a higher incidence of TCR- γR in type C LyP.¹⁸

Positive findings for TCR- γR are commonly seen in ALCL and mycosis fungoides. Findings of TCR- γR are infrequently positive in Hodgkin lymphoma, which commonly expresses CD15.¹⁹ Most cases of LyP, despite a benign course, show clonal rearrangements. Single-cell analysis of CD30⁺ cells in LyP demonstrated a common clonal T-cell origin.²⁰ However, the origin of monoclonal cells seems to be dependent on the type of LyP. A small study performed by Gellrich et al²¹ demonstrated that the 54% of small CD3⁺ T cells vs 22% of the large CD30⁺ cells were monoclonal in type A LyP. Thus, the source of the clonal population in the present case of type C LyP is unknown. In 10% to 20% of cases, LyP can precede, coexist with, or follow systemic lymphoma. In cases with evolution to malignancy, T cells have been shown to retain the same TCR- γR as the associated LyP.

Given the poor outcome of metastatic ALK-1 –negative ALCL, aggressive multiagent chemotherapy is often required, whereas the benign and protracted course of LyP does not demand assertive measures. There is no curative therapy for LyP, so the main goal of the management is to control symptoms and maintain the clinical response to improve quality of life. Several studies^22- 23 demonstrated that low-dose methotrexate sodium (10-15 mg or less given weekly) is an effective and well-tolerated treatment for LyP. Systemic multiagent chemotherapy provides a response rate comparable to that of a low dose of methotrexate (86.7% and 87.5%, respectively).²⁴ At the same time, the risk for adverse events with systemic multiagent chemotherapy is disproportionally high and provides no additional benefit. Misdiagnosis of LyP as ALCL remains a leading cause of administration of systemic chemotherapy for LyP. In a retrospective case series of 84 patients with LyP, 30 patients who received systemic chemotherapy or radiotherapy were misdiagnosed as having ALCL. The authors discussed a common scenario in which a patient with a single lesion underwent a complete excision that displayed alarming histologic findings consistent with ALCL, resulting in aggressive treatment.²⁴ Thus, an accurate diagnosis is necessary to avoid inappropriately aggressive systemic chemotherapy.

Davis et al⁹ proposed a stem cell hypothesis wherein subclones of an occult abnormal T-cell clone acquired independent genetic abnormalities to produce LyP, ALCL, Hodgkin lymphoma, or mycosis fungoides in the same patient. This model explains the observation of LyP before, during, or after ALCL.⁵ Putative lymphocyte precursors in the bone marrow could have low mitotic activity, a characteristic feature of the neoplastic stem cells, which may explain the frequent recurrence of LyP after even successful chemotherapy for lymphoma.²⁵ The appearance of 2 different clones does not exclude the stem cell hypothesis. The hypothetical stem cell could be at a stage of differentiation before T-cell receptor gene rearrangement, that is, it could be capable of giving rise to T cells with multiple different T-cell receptor gene rearrangements.

The results of TCR- γR polymerase chain reaction analysis were helpful in that identification of 2 separate clones supported our clinical impression of 2 separate processes in our patient. The search for new diagnostic markers of CD30⁺ LPD is currently ongoing. Recently, several publications reported that multiple myeloma oncogene 1,²⁶ BCL2,²⁷ and tumor necrosis factor receptor –associated factor 1²⁸ could be of use in differential diagnostics of CD30⁺ LPD. However, the results of these studies are unconfirmed or conflicting.²⁹ In this case, the patient treatment would rely on careful clinical monitoring of disease behavior.

Our case reinforces the utility of TCR- γR studies in the assessment of primary vs secondary LPD. Further molecular studies of coexisting LyP and ALCL should be attempted to aid in differentiation of these entities to provide appropriate treatment to the patients.