Primary Systemic Anaplastic Large-Cell : A Case Report Louis Siegel, DO,* Suzanne Sirota-Rozenberg, DO, FAOCD**

*Dermatology Resident, 2nd year, St. John’s Episcopal Hospital, Far Rockaway, NY **Program Director, Dermatology Residency Program, St. John’s Episcopal Hospital, Far Rockaway, NY

Disclosures: None Correspondence: Louis Siegel, DO; [email protected]

Abstract Primary systemic anaplastic large cell lymphoma is a rare malignancy. This case report describes a patient presenting with cutaneous metastasis and illustrates the importance of differentiating cutaneous from systemic lymphomas.

Introduction have multiple coalescing, red to dark-red nodules in year. A CT scan of the head, chest, and abdomen Lymphomas are divided into two categories: the right inguinal area (Figure 1) and right medial/ demonstrated diffuse and hepatic Hodgkin lymphomas and non-Hodgkin lymphomas posterior proximal leg, with foul-smelling, greenish and bony metastases. Two 3 mm punch skin (NHL). Anaplastic large-cell lymphoma (ALCL) discharge in the latter. In addition, small red papules were performed (one from the right inguinal area and is a non-Hodgkin T-cell lymphoma characterized and nodules were present on the left medial superior one from the chest). About a week after the by anaplastic cytology and the persistent expression chest (Figure 2), and multiple hyperpigmented warty report (Figure 3) and (Table of the CD30 antigen. This antigen is expressed on papules and plaques were scattered on the back. Also 1), which indicated ALCL, the patient’s condition activated T and B cells. noted were enlarged, firm lymph nodes -- biaxillary, began to deteriorate. The oncologist planned to start right supraclavicular, and bilateral inguinal – some of outpatient with the CHOP regimen According to the 2008 World Health Organization which were not mobile. (WHO) classification, ALCL is divided into systemic ALCL and primary cutaneous ALCL. The On initial laboratory studies, the patient was noted most common type of cutaneous T-cell lymphoma to be slightly anemic, with a of 11.9 g/ (CTCL) is . Cutaneous dL. When trended with labs from the previous two B-cell lymphomas are less common, making years, a steady decrease was noted over the previous up approximately 20% to 25% of all cutaneous lymphomas. Primary cutaneous ALCL, one of the CD30+ T-cell lymphoproliferative disorders, which includes , represents about 9% of cutaneous lymphomas.1 While lymphomatoid papulosis is regarded by most authorities as an indolent disorder, 4% to 25% of patients may have an associated history of lymphoma. The three most commonly associated lymphomas are primary cutaneous ALCL, and mycosis Figure 3. Diffuse Reed-Sternberg-like cells, fungoides. These lymphomas can be seen prior to, 2 with mitotic figures. concurrent with or after lymphomatoid papulosis.

Systemic ALCL is further classified as either anaplastic Table 1. ALCL immunohistochemical analysis lymphoma (ALK)-positive or ALK-negative. Results Systemic ALCL often has a chromosomal translocation t(2;5) that results in constitutive expression of ALK. AE1/AE3 Negative The translocation fuses ALK, a tyrosine kinase, with ALK-1 Negative a ubiquitous intracellular protein. Subsequently, ALK expression is under the control of the other protein’s BCL-2 Negative promoter, leading to gross overexpression. Most BCL-6 Negative systemic cases of ALCL are ALK-positive; ALK- Figure 1. Multiple, red to dark, coalescing 3 CD2 Negative negative cases have a dismal . nodules in right inguinal region. CD3 Positive Case Report CD4 Negative A 71-year-old male presented to the emergency department from his nursing home with a chief CD5 Negative complaint of a “rash on the chest and groin.” The CD7 Negative patient gave varying answers regarding the rash’s time frame but indicated the groin rash had begun CD8 Negative months prior, and the chest rash was more recent. The CD10 Negative patient denied pain at the site of the groin rash, and he reported pain at the site of the chest rash. He denied CD20 Negative pruritus, , , changes in weight, and CD30 Positive increased . In the nursing home, he received CD43 Positive topical steroid cream, topical antifungal cream and oral fluconazole, none of which improved his condition. CD56 Negative His past medical history included hypertension, Cyclin D1 Negative benign prostatic hyperplasia, constipation, GERD, schizoaffective disorder, and parkinsonism. He was Ki-67 80% unsure about any family history of . MUM-1 Positive On physical examination, the patient was alert and Figure 2. Clustered red papules and nodules on S100 Negative oriented to person, place and year. He was noted to left superior medial chest. TdT Negative

SIEGEL, SIROTA-ROZENBERG once the patient was stable enough for discharge. References However, the patient’s renal function decreased, and 1. Swerdlow A, Campo E, Harris NL, et al. World he began to third-space fluids. In accordance with Health Organization Classification of Tumours of the patient’s and family’s wishes, a do-not-resuscitate Hematopoietic and Lymphoid Tissue. Lyon: IARC order (DNR) was established. Soon afterward, the Press; 2008. patient’s blood pressure began to decrease. He was unable to be stabilized and expired. 2. Beljaards RC, Willemze R. The prognosis of patients with lymphomatoid papulosis associated Discussion with malignant lymphomas. Br J Dermatol. 1992 Internationally, the incidence of systemic ALCL is Jun;126(6):596-602. 2% to 8% of adult non-Hodgkin lymphoma (NHL) cases and up to 30% of childhood NHL cases. 3. Bennani-Baiti N, Ansell S, Feldman Patients with ALK-negative systemic ALCL are AL. Adult Systemic Anaplastic Large Cell often older and have worse prognoses than patients Lymphoma: Recommendations for Diagnosis and with ALK-positive systemic ALCL. Cutaneous Management. Expert Rev Hematol. 2016;9(2):137- metastasis occurs in approximately 20% of cases 50. and is more common in ALK-negative cases.4,5 4. Ferreri AJ, Govi S, Pileri SA, Savage KJ. Anaplastic The differential diagnosis includes other metastatic large cell lymphoma, ALK-negative. Crit Rev , disseminated deep fungal infection and Oncol Hematol. 2013 Feb;85(2):206-15. other types of lymphomas. The three most common causes of cutaneous metastasis in men, from most 5. Ferreri AJ, Govi S, Pileri SA, Savage KJ. common to least common, are , colon 6 Anaplastic large cell lymphoma, ALK-positive. Crit cancer and melanoma. By far the most common Rev Oncol Hematol. 2012 Aug;83(2):293-302. cause of cutaneous metastasis in women is breast cancer. Deep fungal infections are more likely to 6. Wong CY, Helm MA, Helm TN, Zeitouni N. disseminate to the skin in an immunocompromised Patterns of skin metastases: a review of 25 years’ individual. Many types of lymphomas can present experience at a single cancer center. Int J Dermatol. on the skin primarily or secondarily. Our patient’s 2014 Jan;53(1):56-60. skin findings were most prominent overlying the right inguinal nodes, which were enlarged and firm, 7. Schmitz N, Trumper L, Ziepert M, et al. suggesting a high likelihood of cutaneous metastasis. Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with Currently, and immunohistochemistry, T-cell lymphoma treated in studies of the German including ALK, are unreliable in distinguishing High-Grade Non-Hodgkin Lymphoma Study between ALK-positive and ALK-negative cases. Group. Blood. 2010 Nov;116(18):3418-25. ALK is rarely positive in primary cutaneous ALCL, but in primary systemic ALCL it is positive in 50% 8. Pro B, Advani R, Brice P, et al. Brentuximab to 80% of cases. Therefore, staging is mandatory vedotin (SGN-35) in patients with relapsed or in all cases, with complete imaging and laboratory refractory systemic anaplastic large-cell lymphoma: tests. This differs from the typical workup for results of a phase II study. J Clin Oncol. 2012 Jun mycosis fungoides, where complete imaging is 20;30(18):2190-6. usually performed only in the presence of tumors and/or lymphadenopathy. 9. Gambacorti-Passerini C, Messa C, Pogliani EM. in anaplastic large-cell lymphoma. N As with many types of systemic NHL, patients often Engl J Med. 2011 Feb;364(8):775-6. present with more widespread disease, as did our patient. Currently, the CHOP (, hydroxydaunorubicin, oncovin, ) regimen is the most commonly used. CHOP is also used for multi-focal primary cutaneous ALCL. A recent German study showed possible benefit with the addition of to CHOP in patients with ALK.7 , a CD30 antibody linked to a cytotoxic antitubulin agent, is approved by the U.S. Food and Drug Administration (FDA) for relapsed/refractory systemic ALCL. Currently, multiple phase 3 trials are in progress to evaluate this agent for second-line treatment.8 ALK-positivity in systemic disease is now being targeted with the ALK inhibitor crizotinib. Crizotinib is already indicated for cases of ALK-positive non-small cell lung cancer.9 Conclusion It is crucial to differentiate between cutaneous ALCL, which has a favorable prognosis, and systemic ALCL. The same holds true for many types of B-cell lymphomas and their cutaneous counterparts. The five-year survival rate for primary cutaneous ALCL is around 90%, and some cases regress without intervention. The prognosis for ALK-negative systemic ALCL, on the other hand, is dismal, ranging from 15% to 45%.3 This distinction can be complicated by cutaneous metastasis presenting from systemic disease.

PRIMARY SYSTEMIC ANAPLASTIC LARGE-CELL LYMPHOMA: A CASE REPORT