Merkel cell carcinoma after chronic lymphocytic leukemia: case report and literature review

Increasing evidence supports an association of Merkel cell carcinoma (MCC) with immunodeficiency and neoplasia, and the management and outcome of these patients requires study. This report describes a 72-year-old man with newly diagnosed chronic lymphocytic leukemia (CLL) who developed MCC of his right upper extremity and died of bone marrow metastases at 8 months. In the five previously reported cases of MCC after CLL, a shorter time interval between the diagnosis of CLL and the onset of MCC was associated with a better prognosis. In contrast, in this case the near simultaneous onset of CLL and MCC was followed by a rapid, lethal outcome.     

Immunoglobulin gene rearrangements in hairy cell leukemia and other chronic B cell lymphoproliferative disorders

Immunoglobulin gene rearrangements have been investigated in 11 patients with hairy cell leukemia (HCL), 11 with prolymphocytic Leukemia (PLL), and 34 with chronic lymphocytic leukemia (CLL). Heavy and Light Ig chain gene probes have been used, and Ig genes were found in a rearranged configuration in all cases. Production of kappa and lambda light chains correlated with the respective gene rearrangements. With respect to the heavy chain locus, we found that in 6 of 21 cases of kappa-producing CLL only one allele was rearranged, whereas both alleles were rearranged in nearly all cases of lambda-producing CLL and either kappa- or lambda-producing HCL and PLL. Our data confirm the B cell nature of HCL and lead us to suggest that HCL derives from the clonal expansion of a cell at a later developmental stage than in CLL and PLL.     

Merkel cell carcinoma in a patient with B-cell chronic lymphocytic leukemia treated with cladribine and rituximab.

Merkel cell carcinoma (MCC) is an uncommon, neuroendocrine skin tumor with an aggressive clinical course. The etiology of the disease is unknown, although sun exposure and immunosuppression may play a role in its development. Coexistence of MCC with chronic lymphocytic leukemia (CLL) is extremely rare and to our knowledge it has been previously described in only 8 patients. We report a 51-year-old woman who presented with a red lump on the right cheek diagnosed as MCC. She had been diagnosed as having CLL 3 years earlier and was treated with 4 courses of cladribine (2-CdA) and subsequently with 4 courses of 2-CdA combined with rituximab. MCC was diagnosed on the basis of histological and immunohistochemical evaluation 2 months after the last course of 2-CdA and rituximab. Surgical excision with tumor-free margins was performed and local adjuvant radiotherapy was applied. Histopathological and immunohistochemical evaluation of the cervical lymph node specimens showed monotonous and diffuse infiltrate of small CD5+, CD20+, CD23+ lymphocytes and no MCC cells were present. To our knowledge, this is the first reported case of MCC occurring in CLL patients soon after treatment with 2-CdA and/or rituximab. The development of MCC in our patient may suggest that this complication rarely observed in CLL patients may have a link with strongly immunosuppressive therapy with 2-CdA and rituximab.     

Treatment of relapsed chronic lymphocytic leukemia: old and new therapies

There are several initial therapies available for chronic lymphocytic leukemia (CLL) that offer extended disease-free or treatment-free survival time. However, once patients relapse, particularly after fludarabine-based therapy, treatment choices have remained limited. Newer therapies have now become available, including alemtuzumab, fludarabine-based combinations, rituximab, methylprednisolone, alternative nucleoside analogs, flavopirodol, lenalidomide, signal transduction inhibitors/small molecules, and new monoclonal antibodies. We discuss selection of therapy for the relapsed patient using risk stratification and the role of clinical research in continuing to pursue therapeutic advances against CLL.     

A case repot of Merkel cell carcinoma on chronic lymphocytic leukemia: differential diagnosis of coexisting lymphadenopathy and indications for early aggressive treatment

Background  

Chronic lymphocytic leukemia (CLL) is a monoclonal disorder, characterized by a progressive proliferation of functionally incompetent B lymphocytes. There is increased evidence of association between CLL and skin cancers, including the uncommon Merkel cell carcinoma (MCC).     

Lineage relationship of chronic lymphocytic leukemia and hairy cell leukemia: studies with TPA

The tumor promoting agent TPA (phorbol ester; 1.6 X 10(-8)M) was used to induce the differentiation in vitro of B-chronic lymphocytic leukemia (B-CLL) cells from 14 untreated patients. The uninduced phenotype was SIg+, Mrbc+, RFT-1+, RFA-4-, FMC7-. After 72 h incubation with TPA, B-CLL cells became RFA-4+, FMC7+ and lost the capability of Mrbc rosetting. Large proportions of the "induced" cells also showed morphological and ultrastructural changes, such as undulating membranes and bleblike protusions and became strongly positive for tartrate resistant acid phosphatase (TRAP+) and also contained cytoplasmic immunoglobulins. These features are very similar to the features of hairy cell leukemia (HCL). These observations confirm previous clinical findings that B-CLL and HCL are related disorders of the B lineage. The development of "hairy" features in induced B-CLL and in HCL seems to be a malignancy-associated feature because the Mrbc+ normal B cells (B-CLL-equivalent cells) isolated from tonsil also develop TRAP positivity but no membrane aberrations.     

Pentostatin and cyclophosphamide: an effective new regimen in previously treated patients with chronic lymphocytic leukemia.

PURPOSE: Purine analogs and alkylators are important agents in the treatment of chronic lymphocytic leukemia (CLL). Previously, combinations of fludarabine and chlorambucil were abandoned because of increased toxicity from overlapping myelosuppression and immunosuppression. Of the purine analogs active in CLL, pentostatin may be least myelosuppressive. We hypothesized that combining pentostatin with cyclophosphamide would have less myelotoxicity than combinations using other purine analogs. PATIENTS AND METHODS: We studied 23 patients with previously treated CLL. All patients received pentostatin 4 mg/m(2). Seventeen patients received cyclophosphamide 600 mg/m(2), and six patients received cyclophosphamide 900 mg/m(2). Both drugs were administered on day 1 of each cycle, and cycles were repeated every 3 weeks for six treatments. Filgrastim, sulfamethoxazole/trimethoprim, and acyclovir were administered prophylactically. The median number of prior treatment regimens was three (range, one to five) with 13 patients (57%) refractory to prior fludarabine therapy. RESULTS: The cyclophosphamide 900 mg/m(2) dose level was associated with moderate to severe nausea, and we chose cyclophosphamide 600 mg/m(2) as the dose for further study. There were 17 responses (74%; 95% confidence interval, 63% to 85%), including four complete responses. The response rate was 77% in fludarabine-refractory patients. Myelosuppression was acceptable with grade 3/4 neutropenia and thrombocytopenia, seen in 35% and 30% of patients, respectively. The relative sparing of thrombopoiesis can be seen in that only one patient (5%) with an initial platelet count of more than 20,000 required platelet transfusions while receiving therapy. CONCLUSION: Pentostatin 4 mg/m(2) with cyclophosphamide 600 mg/m(2) is safe and effective in previously treated patients with CLL. On the basis of these results, we are currently studying pentostatin, cyclophosphamide, and rituximab (PCR) therapy in patients with CLL.     

Epstein-Barr virus infection and chronic lymphocytic leukemia: a possible progression factor?

Epstein-Barr virus is pathogenically associated with a well defined group of lymphoid and epithelial tumors in which the virus directly drives transformation of infected cells. Recent evidence however indicates that this virus may infect a subpopulation of tumor cells in patients with chronic lymphocytic leukemia (CLL) and EBV infection has been also associated with Richter transformation in a fraction of cases. We herein review available data suggesting a possible role of EBV as a direct or micro-environmental progression factor in a subset of CLL.     

Myeloid progenitor cells in the peripheral blood of patients with hairy cell leukemia and other "leukemic" lymphoproliferative disorders

We assayed granulocyte-macrophage committed progenitor cells (CFU-GM), erythroid committed progenitor cells (BFU-E) and pluripotent hemopoietic progenitor cells (CFU-MIX) in the peripheral blood of patients with hairy cell leukemia (HCL), acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL). In 8 HCL patients retaining their spleens, the number of circulating CFU-GM, BFU-E and CFU-MIX were under the lower limits of normal controls in 6, 6 and 5 cases, respectively, and were in the lower normal ranges in the remaining cases. Six splenectomized HCL patients had generally more circulating progenitor cells than their nonsplenectomized counterparts. In the peripheral blood of 2 patients with ALL and 3 patients with CLL, progenitor cells of all types were markedly increased compared to their respective values in the blood of control subjects. Hairy cells from 2 HCL patients failed to inhibit CFU-GM, BFU-E and CFU-MIX derived colony growth from control peripheral blood mononuclear cells. In 3 HCL patients previously low circulating progenitor cells did not rise 5-7 months after RC-alpha 2-IFN treatment despite normalization of peripheral blood counts. Our results suggest that a reduction of the committed and pluripotent progenitor cell compartment might be at least in part responsible for the pancytopenia in the majority of patients with HCL.     

Merkel cell carcinoma: a population-based study on mortality and the association with other cancers

Background  

Few population-based epidemiological data are available on Merkel cell carcinoma (MCC), a rare lethal non-melanoma skin cancer. We analysed multiple-cause-of-death records to describe MCC mortality and trends and the association with other primary cancers.     

Simultaneous diagnosis of hairy cell leukemia and chronic lymphocytic leukemia/small lymphocytic lymphoma: a frequent association?

The association of hairy cell leukemia (HCL) with other neoplasms, mainly non-Hodgkin's lymphomas, is well known. However, the simultaneous diagnosis of HCL and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is rare, with only few cases of such an association having been reported. We describe three patients with a well-characterized HCL in whom a CLL/SLL population was detected. Of note, these cases represent a significant proportion (11.5%; 95% CI: 0% to 24%) of the total number of HCL cases diagnosed in our institution during the same period of time. All three patients were treated with deoxycoformycin. They achieved a complete response of the HCL, whereas the CLL/SLL population persisted in all cases. The immunoglobulin gene rearrangement analysis, in two informative cases, suggested that the HCL and CLL/SLL populations arose from different B cell clones. This study indicates that the association of HCL and CLL/SLL might be much more frequent than previously recognized. Therefore, a large panel of monoclonal antibodies, including those necessary to detect CLL/SLL, should be employed when studying patients with HCL.     

Interleukins, TNF-alpha and beta-2M in patients with B cell chronic lymphocytic leukemia

In order to investigate the possible existence of a prognostic factor for B cell chronic lymphocytic leukemia (B-CLL), we determined the serum levels of TNF-alpha, IL-1a, IL-1b, IL-2, sIL-2R, IL-6, IL-10 and beta-2M in 20 patients. We observed significant changes in sIL-2R and beta-2M levels, whereas in all stages of disease, TNF-alpha and other interleukins exhibited only mild changes. An excellent correlation between sIL-2R and beta-2M levels and disease activity wes reported. Patients with aggressive disease (Rai stages III and IV and Richter's syndrome) had increased levels. Patients who responded to therapy and with improved clinical status had decreased sIL-2R and beta-2M levels. However, patients with progressive disease and no response to therapy were associated with increased levels of sIL-2R and beta-2M. In conclusions, as serum levels of sIL-2R and beta-2M are increased in the aggressive stages of B-CLL, they may be used as reliable markers for monitoring B-CLL activity, showing response to treatment and early relapse and/or disease progression.     

Trisomy 12 in a Case of Multiple Cutaneous Squamous Cell Carcinoma in Association with Chronic Lymphocytic Leukemia

Chronic lymphocytic leukaemia （CLL）, which shares clinical and morphological overlap with small lymphocytic lyjmphoma （SLL）, is a low-grade clonal B-cell lymphoproliferative disorder that accounts for 25% of all cases of leukaemia in Western countries, while it is considered rare in Oriental patients and is thought to constitute only 2% of all leukemias in these patients. CLL is associated with an increased incidence of secondary malignant neoplasms, such as brain tumors, melanomas, and gastrointestinal-tract carcinomas. However, the simulataneous occurrence of CLL and cutaneous squamous cell carcinoma （SCC） is rarely reported. We present here a case of CLL with multiple SCC on the face. Subsequent studies demonstrated the patient to have a trisomy 12 identified in bone marrow specimen.     

Investigation of an NQO1 polymorphism as a possible risk and prognostic factor for chronic lymphocytic leukemia

NAD(P)H:quinoneoxidoreductase 1 (NQO1) inhibits some cancers and increases p53 and apoptosis in cells. Due to an inactivating polymorphism, 10% of humans have no NQO1 activity. A case:control study suggested that chronic lymphocytic leukemia (CLL) patients may have an increased incidence of the NQO1 null genotype compared with controls. NQO1 genotype did not correlate with various CLL prognostic factors, but we observed a trend toward lower drug response in patients with the NQO1 null genotype. Inhibiting NQO1 activity decreased p53 levels and drug induced apoptosis in CLL cells. These results raise the possibility that the NQO1 polymorphism may be a risk factor for CLL and a predictor of response to chemotherapy.     

Chronic lymphocytic leukemia and other chronic lymphoid proliferations: surface marker phenotypes and clinical correlations

A diagnosis of chronic lymphocytic leukemia (CLL) was made in 81 patients referred for peripheral blood lymphocyte typing (PBL). A retrospective review was undertaken to see if correlations existed between surface marker phenotype-determined subclasses and clinical features. Surface markers utilized were surface immunoglobulin (sIg), sheep erythrocyte receptor (E), 65,000-dalton human T lymphocyte antigen (T65), Ia antigen, and for sIg+ cells, heavy and light chains. All patients were Ia+. Cells of 70% of patients were sIg+ E- T65+ Ia+, and the clinical heterogeneity was that of classical CLL. Eight of the nine patients with sIg+ E- T65- Ia+ cells had a paraprotein. The sIg- E+ T65+ Ia+ phenotype represented classical T cell CLL. Three of the five patients in the sEg- E- T65+ Ia+ group had significant albuminuria, and two had nephrotic-range proteinuria. Use of additional monoclonal antibodies to B cell surface antigens should further subclassify CLL and other lymphoproliferative disorders. Interesting clinical correlations with certain phenotypic subclasses do exist, and further subclassification and long-term follow-up may yield correlations between phenotypes and prognosis.     

Novel agents in chronic lymphocytic leukemia: efficacy and tolerability of new therapies

Alkylating agents and purine analogues have been the mainstays of therapy for chronic lymphocytic leukemia (CLL) for decades. The past decade witnessed the general clinical use of monoclonal antibodies such as rituximab and alemtuzumab, both as single agents and in combination regimens with cytotoxic drugs, for previously untreated and relapsed CLL. First-line chemoimmunotherapy regimens combining rituximab and purine analogues have greatly improved initial response rates and progression-free survival. Despite these advances in first-line therapy, patients with CLL invariably experience relapse and often acquire high-risk chromosomal abnormalities, such as del(11q22) and del(17p13), which result in resistance to current therapies. Patients who are refractory to fludarabine-based therapy have a median survival of <1 year. Therefore, new agents with novel mechanisms of action are needed for the treatment of patients with relapsed CLL, particularly for patients with high-risk genetic features. Recent clinical studies have examined the tolerability and efficacy of several novel agents in relapsed CLL: (1) the alkylator bendamustine, (2) the cyclin-dependent kinase inhibitor flavopiridol, (3) the immunomodulating drug lenalidomide, (4) the bcl-2 antisense oligonucleotide oblimersen, and (5) the Bcl-2 small-molecule inhibitor obatoclax. While these agents have demonstrated exciting clinical activity against genetically high-risk CLL, they have also induced toxicities that have not been commonly observed with previous CLL therapies. The most notable toxicities have been tumor lysis syndrome and tumor flare, which are potentially serious or even fatal complications of these new therapies. Thus, further studies are needed to define these agents' biologic mechanism(s) of action, clinical activity, and safety.