Myeloid/natural killer cell precursor acute leukemia with multiple subcutaneous nodules as the initial presentation: a case report and literature review

Myeloid/natural killer (NK) cell precursor acute leukemia is a rare neoplasm, which is characterized by high incidence of extramedullary infiltration, especially in the mediastinum and lymph nodes, an aggressive course and poor prognosis. As coexpressing myeloid and NK-cell antigens, myeloid/NK-cell precursor acute leukemia (MNKL) may pose diagnostic difficulty. Because the developmental pathway of normal NK cells is not well understood, neoplams of NK-cell origin are not clearly identified. To our knowledge, there have been only about 30 cases with this disease published previously. In the current paper, we present a case of a 21-year-old male patient whose initial presentation showed numerous subcutaneous nodules without bone marrow involvement. A diagnosis of MNKL was finally made by skin biopsy, bone marrow immunohistochemistry and immunophenotypic analysis. Although bone marrow achieved complete remission using DA chemotherapeutic regimen, the skin nodules did not regress. However, FLAG chemotherapeutic regimen, including fludarabine, cytarabine and G-CSF, was effective for both bone marrow and skin involvement. To the best of our knowledge, this study is the first to describe the effect of FLAG regimen for the treatment of this disease, indicating that it may be effective against the skin involvement of MNKL.     

Relapse of acute monocytic leukemia present with skin and tracheal involvement

A 34 year-old female was admitted because of anemia and leukopenia. Her bone marrow contained abundant blastic cells, which were histochemically positive for peroxidase and alpha-naphthyl butyrate esterase, but negative for ASD chloroacetate esterase. She was diagnosed as acute monocytic leukemia (FAB, M5a). Complete remission was achieved after the administration of BHAC, daunorubicin, 6MP and prednisolone, and she was discharged after consolidation therapies. But shortly later, she noticed hoarseness and erythematous nodules on her breast and abdomen. Though the examinations of peripheral blood and bone marrow did not show any abnormality, hoarseness rapidly worsened and she complained of dyspnea. X-ray and CT scan demonstrated narrowing of the trachea under the cricoid cartilage, and trans-tracheal biopsy revealed leukemic involvement. In addition, erythematous skin lesion showed the infiltration of leukemic cells by biopsy. Although radiation and chemotherapy was initiated, she died of pneumonia. We tried to discuss the laryngo-tracheal and skin involvement of acute monocytic leukemia as early symptoms of relapse.     

Primary and isolated adult T-cell leukemia/lymphoma of the bone marrow

The distribution of adult T-cell leukemia/lymphoma (ATLL) is typically systemic. In addition to peripheral blood (PB) and lymph nodes, extranodal sites such as the skin, lung, liver, gastrointestinal tract, and central nervous system are frequently involved. We report a unique case of ATLL in which the patient presented with prolonged fever. A 65-year-old man had high-grade fever lasting for 2 weeks. He showed no lymphadenopathy, hepatosplenomegaly, skin lesions, or PB involvement. Bone marrow examination showed widespread infiltration of ATLL cells. (18)F-fluorodeoxy glucose positron emission tomography (FDG-PET) revealed that the disease was confined to the bone marrow.     

Bone marrow vs extramedullary relapse of acute leukemia after allogeneic hematopoietic cell transplantation: risk factors and clinical course

A total of 118 consecutive adult patients with acute leukemia (78 AML, 36 ALL, and four acute mixed lineage leukemia) underwent allogeneic hematopoietic cell transplantation (HCT) after conditioning with BuCy (n=113) or a nonmyeloablative regimen of busulfan-fludarabine (n=5). After a median follow-up of 35.8 months (range, 6.4-91.0), 34 patients experienced at least one episode of leukemia relapse. Of 34 initial episodes, 14 (41%) occurred in extramedullary sites, with (n=8) or without (n=6) concomitant bone marrow involvement. The median time to relapse in the extramedullary sites was longer than that of relapse in bone marrow only (13.5 vs 6.1 months, P=0.046). Acute leukemia subtype and disease status at HCT showed an independent predictive value for overall relapse, as well as for extramedullary relapse with or without bone marrow involvement (Philadelphia chromosome positive acute leukemia vs low-risk AML, relative risk 22.68 (95% CI, 2.18-235.64); other than first CR vs first CR, relative risk 5.61 (95% CI, 1.80-17.51)), but not for bone marrow relapse. Our study suggests that there may be different pathogenetic mechanisms for bone marrow vs extramedullary relapse of acute leukemia after allogeneic HCT. The mode of relapse needs to be investigated in future reports of acute leukemia treated with allogeneic HCT.     

Bone lesions in hairy cell leukemia: Diagnosis and treatment

Skeletal involvement is a rare complication of hairy cell leukemia (HCL) with an incidence of approximately 3%. Bone lesions are commonly lytic, and the most common sites of involvement are the femoral head and neck. Skeletal involvement is typically associated with high tumor burden and bone marrow infiltration. However, isolated cases of skeletal disease without splenomegaly or bone marrow involvement are occasionally reported. This review focuses on skeletal lesions in HCL, particularly the pathogenesis, clinical symptoms, diagnostic methods, and treatment approach. A literature review of the MEDLINE database for articles in English concerning hairy cell leukemia, skeletal symptoms, bone involvement was conducted via PubMed. Publications from January 1970 to May 2020 were scrutinized. Additional relevant publications were obtained by reviewing the references from the chosen articles.     

Results of bone marrow examination in 275 patients with histological features that suggest an indolent type of cutaneous B-cell lymphoma

Whether or not bone marrow biopsies should be performed routinely in patients with skin lesions that show histological features consistent with an indolent B-cell lymphoma [marginal zone lymphoma (MZL) or follicle centre lymphoma (FCL)] has been debated. As no studies have addressed this question for this group of lymphomas, we evaluated the results of bone marrow biopsy examination in 275 patients with histological features consistent with MZL ( n  = 82) or FCL ( n  = 193) first presenting in the skin. In the MZL group, two of 82 patients (2%) showed bone marrow involvement, which was the only extracutaneous localization in one of these patients. In the FCL group, 22 of 193 patients (11%) had bone marrow involvement and was the only extracutaneous localization in nine of them. FCL patients with skin lesions and a positive bone marrow had a significantly worse prognosis when compared with patients with only skin lesions (5-year disease-specific survival 63% vs. 95%; P  = 0·001). These results indicate that bone marrow investigation is essential for staging patients with a FCL first presenting in the skin. Bone marrow examination appears to have limited value in patients with MZL presenting in the skin.     

The human T-cell leukemia/lymphoma virus associated with American adult T-cell leukemia/lymphoma

The human T-cell leukemia/lymphoma virus (HTLV) is a novel type-C retrovirus isolated from patients with T-lymphoproliferative malignancies. Thirteen cases of HTLV-associated malignancy from US centers were studied in detail. Ten of these cases share common clinical features and define a typical virus-associated adult T-cell leukemia/lymphoma (ATL). All ten patients presented with Ann Arbor stage IV lymphoma because of skin involvement, bone marrow involvement, or lymphomatous leptomeningitis. Lymphadenopathy occurred in 7 of 10 patients at presentation, and the malignant cells were cytologically pleomorphic. Leukemia occurred in 60% of the patients at presentation. Hypercalcemia was found initially in two-thirds of the patients, with lytic bone lesions or positive bone scans in 7 of 10. Complete remission occurred in 40%, but all have relapsed. These cases closely resemble those virus-positive cases of adult T-cell leukemia/lymphoma (ATL) reported from Japan and the Caribbean. Three additional virus- positive patients had atypical presentations and diagnoses (acute lymphocytic leukemia, Sezary's syndrome, leukemic reticuloendotheliosis), usually with less aggressive clinical courses and atypical demographic and laboratory features. Presence of HTLV serum antibodies in cases of ATL (with hypercalcemia and circulating malignant cells) appears to define a distinct clinicopathologic entity that may occur in geographic clusters.     

Bulky lymphadenopathy in acute myeloid leukemia

 Two cases of acute myeloid leukemia (AML) presenting with bulky adenopathy are reported. Both patients were febrile at admission and showed massive and diffuse lymph node involvement, hepatomegaly, and splenomegaly. Erythematopapular leukemic skin lesions were present in one case at the onset and developed in the other at the time of relapse. Anemia, thrombocytopenia, and moderate leukocytosis were present in both. The presence of immature cells in peripheral blood and bone marrow allowed a rapid diagnosis of AML, FAB M1, in one patient. In the other case, owing to the paucity of immature cells in peripheral blood and bone marrow, lymph node biopsy with histology, imprint cytology, and immunocytochemistry were essential for the diagnosis (AML, FAB M2, with trilineage dysplasia and basophilic involvement). Both patients achieved complete remission (CR), followed by an early relapse 3 months later. They underwent allogeneic bone marrow transplantation (BMT) from HLA identical siblings. One patient is actually alive and in CR at 6 months after BMT; the other patient showed a leukemic regrowth after transplantation and died 4 months later. Received: December 8, 1997 / Accepted: April 29, 1998     

Secondary biliary cirrhosis as a consequence of graft-versus-host disease

A 9-yr-old white girl with acute monoblastic leukemia received an HLA-identical, mixed lymphocyte culture-nonreactive bone marrow transplant from her sister. Twelve days after the transplant, a diffuse, pruritic, maculopapular rash involving the entire body surface (including the palms and soles) developed. Subsequent skin biopsy was consistent with cutaneous graft-versus-host disease, and biopsy-proven hepatic involvement manifested by severe, unremitting cholestatic jaundice soon followed. The patient's biliary status as monitored by serial liver biopsies demonstrated progression from chronic graft-versus-host disease to cirrhosis, culminating in death secondary to liver failure 25 mo after transplant.     

Modification of the clonogenic capacity of bone marrow cells from normal individuals by the tyrosine kinase inhibitor STI571

STI571 shows clinical activity in the treatment of chronic myelogenous leukemia, Philadelphia positive acute lymphoblastic leukemia and gastrointestinal stromal tumors. Resistance of normal progenitor cells to STI571 is essential when determining the optimal therapeutic window for patients with cancer without bone marrow involvement, and for patients with chronic myeloid leukemia who achieved complete cytogenetic remission. The effect of graded concentrations of STI571 on the clonogenic potential of normal fresh bone marrow hematopoetic progenitor cells from 13 normal individuals was analyzed. It was shown that lower concentrations of STI571 (0.1 and 0.5 microM/l) may increase colony numbers, whereas higher concentrations (>1 microM/l) may reduce normal colony formation.     

Coronary artery disease following bone marrow transplantation

A 19-year-old woman died suddenly 30 months after allogeneic bone marrow transplantation for refractory leukemia. On postmortem examination severe coronary artery disease and acute myocardial infarction were found. The patient had previously been given chemotherapy including daunorubicin for treatment of her leukemia. She received high dose cyclophosphamide and total body irradiation (1260 cGy) for her transplant. Diffuse chronic graft-versus-host disease, mainly affecting skin, subsequently developed, and was resistant to various therapies. The possible association of coronary artery disease and allogeneic bone marrow transplantation is discussed.     

All-trans-retinoic acid (ATRA) responsive skin relapses of acute promyelocytic leukaemia followed by ATRA-induced pseudotumour cerebri

A 30-year-old woman with acute promyelocytic leukaemia (APL) went into complete remission following idarubicin and cytarabine chemotherapy; 18 months later she developed repeated skin relapse, with no bone marrow involvement. DNA and RNA analysis of skin lesions revealed the presence of the PML/RARα hybrid gene, which was not detected at the same time in bone marrow. The skin relapses were successfully treated by all- trans -retinoic acid (ATRA) as single agent over 2 years. However, prolonged administration of ATRA caused pseudotumour cerebri, which disappeared upon drug withdrawal. The absence of the hybrid gene in the bone marrow by RT-PCR analysis led to the patient being autografted.     

Blastic plasmacytoid dendritic cell neoplasm should be treated with acute leukemia type induction chemotherapy and allogeneic stem cell transplantation in first remission

Blastic plasmacytoid dendritic cell (BPDC) neoplasm is a rare but clinically aggressive tumor known to be derived from the precursors of plasmacytoid dendritic cells (CD123+) with a high frequency of cutaneous and bone marrow involvement. Though majority of the patients initially respond to multi-agent chemotherapy, most would relapse within a year. We hereby report a patient with disseminated cutaneous BPDC with marrow involvement diagnosed by typical histo-pathological and flow-cytometric findings. He was subsequently treated with leukemia type induction regimen followed by allogeneic stem cell transplantation in first complete remission. He is now 18 months posttransplantation with continued remission with full donor chimerism. We recognize that BPDC with marrow involvement behaves like acute myeloid leukemia and aggressive treatment followed by stem cell transplantation may lead to long-term remission in selected cases.     

Recurrent spontaneous regression of aleukemic leukemia cutis in a girl with acute monocytic leukemia

Aleukemic leukemia cutis is a rare form of leukemia manifestation, defined as a skin infiltration of leukemic cells with no evidence of leukemia in the bone marrow. A 4-month-old girl was referred to our hospital because of exanthema that appeared and regressed repeatedly. Histological examination revealed partial infiltration of histiocytic cells in the skin lesion. However, the diagnosis could not be made at that time. At 9 and at 13 months old, appearances of exanthema similar to the previous time were combined with systemic fever, abnormal coagulation tests, and the marked increases of atypical lymphocytes in peripheral blood: however, these symptoms resolved spontaneously. At 14 months old, deterioration of the exanthema and an increase in the peripheral leukocyte counts were observed. Bone marrow aspiration revealed the predominance of monocytic blasts (76.4%), and the patient was diagnosed as having acute monocytic leukemia (M5b) with leukemia cutis. Complete remission was obtained with standard chemotherapy. Six months after the therapy was completed, an extramedullary relapse occurred in the inguinal lymph nodes, which was successfully treated with allogeneic bone marrow transplantation from an HLA-matched unrelated donor, and the patient has been free of disease for two years after the transplantation.     

Leukemic reticuloendotheliosis. A clinicopathologic study with review of the literature

The salient clinical and pathologic features of leukemic reticuloendotheliosis are evaluated in our 13 patients and in 98 patients described in the literature. Leukemic reticuloendotheliosis affects mainly male adults whose chief clinical manifestations are related to pancytopenia and splenomegaly. Splenomegaly is nearly constant and frequently massive, whereas lymphadenopathy is infrequent and skin involvement rare. Characteristic pathologic changes are present in the bone marrow, spleen and liver. Splenectomy often leads to remission; chemotherapy is not beneficial in most cases and is probably to be discouraged. The entity deserves recognition because the optimal clinical management is different from that of other forms of leukemia and lymphoma.     

All-trans-retinoic acid (ATRA) responsive skin relapses of acute promyelocytic leukaemia followed by ATRA-induced pseudotumour cerebri

A 30-year-old woman with acute promyelocytic leukaemia (APL) went into complete remission following idarubicin and cytarabine chemotherapy; 18 months later she developed repeated skin relapse, with no bone marrow involvement. DNA and RNA analysis of skin lesions revealed the presence of the PML/RARα hybrid gene, which was not detected at the same time in bone marrow. The skin relapses were successfully treated by all-trans-retinoic acid (ATRA) as single agent over 2 years. However, prolonged administration of ATRA caused pseudotumour cerebri, which disappeared upon drug withdrawal. The absence of the hybrid gene in the bone marrow by RT-PCR analysis led to the patient being autografted.     

Testicular infiltration in acute myeloid leukemia with complex karyotype including t(8;21)

Testicular infiltration is a well-known complication in acute lymphoblastic leukemia. In acute myeloid leukemia (AML), it has rarely been described and preferably occurred in cases with myelomonocytic or monoblastic differentiation. We report on a patient with AML with complex karyotype including translocation t(8;21) who presented with testicular infiltration at the time of his third bone marrow relapse. Cytological analysis of the specimen showed infiltration with blasts displaying the typical morphology of AML with translocation t(8;21) and comparable to those detected in the bone marrow. Fine needle aspiration cytology might suffice in these cases and should be performed if testicular involvement is suspected.     

Successful graft-versus-leukemia effect of second bone marrow transplantation on relapsed leukemia cutis that was refractory to intensive chemotherapy and donor lymphocyte transfusions in a patient with acute monocytic leukemia

We report a patient with acute monocytic leukemia (AMoL; M5) who received a second bone marrow transplantation (BMT) with graft-versus-leukemia (GVL) effect on relapsed leukemia cutis, which had been refractory to intensive chemotherapy and donor lymphocyte transfusions (DLTs). A 21-year-old woman was diagnosed with AMoL and achieved complete remission after intensive chemotherapy. The patient received a nonmanipulated allogeneic BMT from her HLA-identical father. Skin tumors developed in her upper extremities, chest, and thigh 11 months after BMT. Leukemia cutis was confirmed by skin biopsy. There was no evidence of relapse in bone marrow. The patient received several courses of chemotherapy and DLTs for the skin relapse, but the skin tumors persisted. The patient then received a second BMT from the same donor. On day 80, grade II acute graft-versus-host disease developed, and the remaining skin tumors were eradicated on day 98, most probably because of GVL effect.     

Isolated central nervous system relapse during cytologic and molecular hematologic remission in two patients with acute promyelocytic leukemia

Extramedullary involvement in the absence of bone marrow disease is rare in patients with acute promyelocytic leukemia (APL). We report two patients with APL who had central nervous system (CNS) relapse without evidence of cytologic and molecular disease of bone marrow after all-trans-retinoic acid (ATRA) treatment. Both of the patients were treated successfully with combination of intrathecal chemotherapy and radiotherapy with or without systemic chemotherapy. Although increasing number of cases with extramedullary involvement of APL after ATRA including therapy have been reported, further studies with a large series of patients are necessary to determine whether ATRA increases the risk of development of extramedullary involvement of disease in patients with APL.     

Two cases of B cell lymphoma associated with hemophagocytic syndrome

B cell lymphoma-associated hemophagocytic syndrome (B-LAHS) is clinically characterized by hepatosplenomegaly and bone marrow invasion without lymphadenopathy and skin lesions. Several cases of B-LAHS have been reported to demonstrate histopathologic findings of intravascular lymphomatosis (IVL), which in Western countries is characterized by a high rate of skin involvement and, rarely, bone marrow involvement and hemophagocytosis. Here we describe two interesting cases of B-LAHS. One patient was a 52-year-old woman whose bone marrow showed proliferation of large CD20-positive cells and hemophagocytosis at presentation. Combination chemotherapy was not effective, and the patient died of progressive disease. At autopsy, the lymphoma cells showed extravascular proliferation in many organs such as the bone marrow and liver, whereas in the adrenal glands, the lymphoma cells showed intravascular proliferation. The other patient was a 50-year-old man who had swellings of the bilateral kidneys and adrenal glands at presentation. Skin involvement by large lymphoma cells, a rare complication of B-LAHS, was observed. At autopsy, there was no evidence of IVL. Both of these patients showed high fever and cytopenia, and the disease took an aggressive clinical course, as in other reported cases of B-LAHS.