CLINICAL PATHOLOGIC CHALLENGE ANSWER
Multiple Scattered Erythematous Nodules and Ulcerations: Answer Amanda F. Marsch, MD* and Jacqueline M. Junkins-Hopkins, MD†
(Am J Dermatopathol 2014;36:677–678)
(Continued from page 667)
ANSWER Concomitant CLL and Melanoma.
DISCUSSION Chronic lymphocytic leukemia (CLL) is the most common leukemia in the United States, accounting for approximately 30% of leukemias found in adults.1 Overall, the risk of secondary cancers in patients with CLL is more than double that of the general population, and secondary cutaneous malignancies are frequent complications in patients with CLL.2 In particular, the risk of skin cancer in these patients is 8-fold higher as compared with the healthy population.3 Moreover, a link between melanoma and CLL has recently been recognized,2 including an increased risk of death from melanoma in these patients. Melanoma patients have a 16-fold increased risk of developing a lymphoma4; conversely, patients with CLL have up to a 7.5 increased incidence of developing malignant melanoma.5 The question one may ask is, which one usually comes first? In a recent study of 55 patients who were diagnosed with both melanoma and lymphoma, 47.3% of patients were concomitantly diagnosed with lymphoma on pathological assessment of lymph nodes for staging of their melanoma.5 However, 40% of patients developed lymphoma subsequent to the diagnosis of melanoma after a median time interval of 41 months. CLL was the most common subtype in these patients. Other similar studies confirm the trend that melanoma generally precedes the diagnosis of CLL instead of the reverse situation.6 Uniquely, in our patient, CLL and melanoma were diagnosed simultaneously from a cutaneous biopsy, which is the first reported case to date. The patient underwent lymph node dissection as part of the management for his melanoma. Several nodes were noted to have an atypical lymphocytic infiltrate, including one that also had nodal melanoma. A diagnosis of small cell lymphoma (SLL) was From the *Department of Dermatology, University of Illinois at Chicago, Chicago, IL; and †Ackerman Academy, New York, NY. The authors declare no conflicts of interest. Reprints: Amanda F. Marsch, MD, University of Illinois at Chicago, 808 S. Wood St, Chicago, IL 60612 (e-mail: [email protected]). © 2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 8, August 2014
confirmed by flow cytometry on an axillary node, which was reported to have 93% of CD19 and CD20 positive B cells, with lambda clonality. CD5 and CD10 were negative in this B-cell population. No evidence of peripheral blood involvement was found. CLL and SLL are essentially the same disease; when the majority of the disease burden involves the blood and bone marrow, the term CLL is used, whereas SLL is reserved for those cases in which the disease burden is located mainly within the lymph nodes. The patient will be followed by oncology. The rising incidence of melanoma and CLL has been attributed to both the inherent immune dysfunction present in CLL7 and with UV exposure. It is well known that patients with CLL have an increased susceptibility to infections, increased incidence of autoimmune conditions, and increased susceptibility to other cancers, independent of receiving chemotherapy for treatment of their CLL. The immune dysfunction seen in CLL involves a variety of aberrations, including a decrease in peripheral blood CD4/CD8 T-cell ratio, abnormal T-cell cytokine secretion profiles, impaired antigenpresenting capabilities, and an increase in regulatory T cells associated with inhibition of antitumor immunity in solid cancers.7 Alterations of the p16 pathway, which inhibit the tumor suppressor gene CDNK4, are common in both lymphomas and melanoma.8 Additional findings common to both entities are mutations in the tumor suppressor gene p53 and Bcl-2.9 Interestingly, peritumoral infiltrates analyzed in nonHodgkin lymphoma patients with nonmelanoma skin cancers showed that approximately 75% of the time, the infiltrates were composed of B-cell leukemia cells.9 The dysfunctional B cells are unable to suppress tumor cell growth, and this has led some authors to believe that these patients have more aggressive tumors heralding a worse prognosis.9 Histopathologically, CLL typically expresses a B-cell phenotype and is CD5+; however, among B-cell CLL, up to 20% do not express CD5, as seen in this case. In a study10 comparing the clinical behavior of CD5+ and CD52 CLL, patients with CD52 CLL were found to have significantly less lymph node involvement, were more frequently stage A according to the Binet classification, and more commonly had isolated splenomegaly at diagnosis. Another study found that CD52 patients with CLL had an overall better prognosis compared with CD5+ patients with CLL, with a significantly longer overall median survival by almost 13 months.11 Cutaneous lesions occur in approximately 25% of patients with CLL,3 the most common presentation being leukemia cutis. At the time of diagnosis of CLL, the skin is the most commonly involved nonlymphoid organ.1 Leukemia www.amjdermatopathology.com |
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cutis in patients with CLL is characterized by either a solitary, grouped, or generalized configuration of papules, plaques, nodules, and/or large tumors. Generally, prognosis of patients with CLL with leukemia cutis is good; however, it is unclear how the combined effects of both having a concomitant melanoma and having a CD52 CLL will affect our patient’s overall prognosis. Given that both CLL and melanoma can be diagnosed concomitantly, and that these patients may have an overall worse prognosis, we present this case to emphasize the importance of being vigilant when assessing lymphoid infiltrates in patients with malignant melanoma. REFERENCES 1. Shanshal M, Haddad RY. Chronic lymphocytic leukemia. Dis Mon. 2012;58:153–167. 2. Royle JA, Baade PD, Joske D, et al. Second cancer incidence and cancer mortality among chronic lymphocytic leukaemia patients: a populationbased study. Br J Cancer. 2011;105:1076–1081. 3. Robak E, Robak T. Skin lesions in chronic lymphocytic leukemia. Leuk Lymphoma. 2007;48:855–865.
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Am J Dermatopathol Volume 36, Number 8, August 2014 4. Riou JP, Ariyan S, Brandow KR, et al. The association between melanoma, lymphoma, and other primary neoplasms. Arch Surg. 1995; 130:1056–1061. 5. Verwer N, Murali R, Winstanley J, et al. Lymphoma occurring in patients with cutaneous melanoma. J Clin Pathol. 2010;63:777–781. 6. Farma JM, Zager JS, Barnica-Elvir V, et al. A collision of diseases: chronic lymphocytic leukemia discovered during lymph node biopsy for melanoma. Ann Surg Oncol. 2013;20:1360–1364. 7. Riches JC, Gribben JG. Understanding the immunodeficiency in chronic lymphocytic leukemia: potential clinical implications. Hematol Oncol Clin North Am. 2013;27:207–235. 8. Gru AA, Lu D. Concurrent malignant melanoma and cutaneous involvement by classical hodgkin lymphoma (CHL) in a 63 year-old man. Diagn Pathol. 2013;8:135. 9. Brewer JD, Christenson LJ, Weenig RH, et al. Effects of chronic lymphocytic leukemia on the development and progression of malignant melanoma. Dermatol Surg. 2010;36:368–376. 10. Cartron G, Linassier C, Bremond JL, et al. CD5 negative B-cell chronic lymphocytic leukemia: clinical and biological features of 42 cases. Leuk Lymphoma. 1998;31:209–216. 11. Efstathiou S, Tsioulos D, Zacharos I, et al. The prognostic role of CD5 negativity in B-cell chronic lymphocytic leukaemia: a case-control study. Haematologia (Budap). 2002;32:209–218.
Ó 2014 Lippincott Williams & Wilkins
Multiple Scattered Erythematous Nodules and Ulcerations: Answer Amanda F. Marsch, MD* and Jacqueline M. Junkins-Hopkins, MD†
(Am J Dermatopathol 2014;36:677–678)
(Continued from page 667)
ANSWER Concomitant CLL and Melanoma.
DISCUSSION Chronic lymphocytic leukemia (CLL) is the most common leukemia in the United States, accounting for approximately 30% of leukemias found in adults.1 Overall, the risk of secondary cancers in patients with CLL is more than double that of the general population, and secondary cutaneous malignancies are frequent complications in patients with CLL.2 In particular, the risk of skin cancer in these patients is 8-fold higher as compared with the healthy population.3 Moreover, a link between melanoma and CLL has recently been recognized,2 including an increased risk of death from melanoma in these patients. Melanoma patients have a 16-fold increased risk of developing a lymphoma4; conversely, patients with CLL have up to a 7.5 increased incidence of developing malignant melanoma.5 The question one may ask is, which one usually comes first? In a recent study of 55 patients who were diagnosed with both melanoma and lymphoma, 47.3% of patients were concomitantly diagnosed with lymphoma on pathological assessment of lymph nodes for staging of their melanoma.5 However, 40% of patients developed lymphoma subsequent to the diagnosis of melanoma after a median time interval of 41 months. CLL was the most common subtype in these patients. Other similar studies confirm the trend that melanoma generally precedes the diagnosis of CLL instead of the reverse situation.6 Uniquely, in our patient, CLL and melanoma were diagnosed simultaneously from a cutaneous biopsy, which is the first reported case to date. The patient underwent lymph node dissection as part of the management for his melanoma. Several nodes were noted to have an atypical lymphocytic infiltrate, including one that also had nodal melanoma. A diagnosis of small cell lymphoma (SLL) was From the *Department of Dermatology, University of Illinois at Chicago, Chicago, IL; and †Ackerman Academy, New York, NY. The authors declare no conflicts of interest. Reprints: Amanda F. Marsch, MD, University of Illinois at Chicago, 808 S. Wood St, Chicago, IL 60612 (e-mail: [email protected]). © 2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 8, August 2014
confirmed by flow cytometry on an axillary node, which was reported to have 93% of CD19 and CD20 positive B cells, with lambda clonality. CD5 and CD10 were negative in this B-cell population. No evidence of peripheral blood involvement was found. CLL and SLL are essentially the same disease; when the majority of the disease burden involves the blood and bone marrow, the term CLL is used, whereas SLL is reserved for those cases in which the disease burden is located mainly within the lymph nodes. The patient will be followed by oncology. The rising incidence of melanoma and CLL has been attributed to both the inherent immune dysfunction present in CLL7 and with UV exposure. It is well known that patients with CLL have an increased susceptibility to infections, increased incidence of autoimmune conditions, and increased susceptibility to other cancers, independent of receiving chemotherapy for treatment of their CLL. The immune dysfunction seen in CLL involves a variety of aberrations, including a decrease in peripheral blood CD4/CD8 T-cell ratio, abnormal T-cell cytokine secretion profiles, impaired antigenpresenting capabilities, and an increase in regulatory T cells associated with inhibition of antitumor immunity in solid cancers.7 Alterations of the p16 pathway, which inhibit the tumor suppressor gene CDNK4, are common in both lymphomas and melanoma.8 Additional findings common to both entities are mutations in the tumor suppressor gene p53 and Bcl-2.9 Interestingly, peritumoral infiltrates analyzed in nonHodgkin lymphoma patients with nonmelanoma skin cancers showed that approximately 75% of the time, the infiltrates were composed of B-cell leukemia cells.9 The dysfunctional B cells are unable to suppress tumor cell growth, and this has led some authors to believe that these patients have more aggressive tumors heralding a worse prognosis.9 Histopathologically, CLL typically expresses a B-cell phenotype and is CD5+; however, among B-cell CLL, up to 20% do not express CD5, as seen in this case. In a study10 comparing the clinical behavior of CD5+ and CD52 CLL, patients with CD52 CLL were found to have significantly less lymph node involvement, were more frequently stage A according to the Binet classification, and more commonly had isolated splenomegaly at diagnosis. Another study found that CD52 patients with CLL had an overall better prognosis compared with CD5+ patients with CLL, with a significantly longer overall median survival by almost 13 months.11 Cutaneous lesions occur in approximately 25% of patients with CLL,3 the most common presentation being leukemia cutis. At the time of diagnosis of CLL, the skin is the most commonly involved nonlymphoid organ.1 Leukemia www.amjdermatopathology.com |
677
Marsch and Junkins-Hopkins
cutis in patients with CLL is characterized by either a solitary, grouped, or generalized configuration of papules, plaques, nodules, and/or large tumors. Generally, prognosis of patients with CLL with leukemia cutis is good; however, it is unclear how the combined effects of both having a concomitant melanoma and having a CD52 CLL will affect our patient’s overall prognosis. Given that both CLL and melanoma can be diagnosed concomitantly, and that these patients may have an overall worse prognosis, we present this case to emphasize the importance of being vigilant when assessing lymphoid infiltrates in patients with malignant melanoma. REFERENCES 1. Shanshal M, Haddad RY. Chronic lymphocytic leukemia. Dis Mon. 2012;58:153–167. 2. Royle JA, Baade PD, Joske D, et al. Second cancer incidence and cancer mortality among chronic lymphocytic leukaemia patients: a populationbased study. Br J Cancer. 2011;105:1076–1081. 3. Robak E, Robak T. Skin lesions in chronic lymphocytic leukemia. Leuk Lymphoma. 2007;48:855–865.
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| www.amjdermatopathology.com
Am J Dermatopathol Volume 36, Number 8, August 2014 4. Riou JP, Ariyan S, Brandow KR, et al. The association between melanoma, lymphoma, and other primary neoplasms. Arch Surg. 1995; 130:1056–1061. 5. Verwer N, Murali R, Winstanley J, et al. Lymphoma occurring in patients with cutaneous melanoma. J Clin Pathol. 2010;63:777–781. 6. Farma JM, Zager JS, Barnica-Elvir V, et al. A collision of diseases: chronic lymphocytic leukemia discovered during lymph node biopsy for melanoma. Ann Surg Oncol. 2013;20:1360–1364. 7. Riches JC, Gribben JG. Understanding the immunodeficiency in chronic lymphocytic leukemia: potential clinical implications. Hematol Oncol Clin North Am. 2013;27:207–235. 8. Gru AA, Lu D. Concurrent malignant melanoma and cutaneous involvement by classical hodgkin lymphoma (CHL) in a 63 year-old man. Diagn Pathol. 2013;8:135. 9. Brewer JD, Christenson LJ, Weenig RH, et al. Effects of chronic lymphocytic leukemia on the development and progression of malignant melanoma. Dermatol Surg. 2010;36:368–376. 10. Cartron G, Linassier C, Bremond JL, et al. CD5 negative B-cell chronic lymphocytic leukemia: clinical and biological features of 42 cases. Leuk Lymphoma. 1998;31:209–216. 11. Efstathiou S, Tsioulos D, Zacharos I, et al. The prognostic role of CD5 negativity in B-cell chronic lymphocytic leukaemia: a case-control study. Haematologia (Budap). 2002;32:209–218.
Ó 2014 Lippincott Williams & Wilkins
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