Blastic plasmacytoid dendritic cell neoplasm (BPDC) is a rare and aggressive entity with poor prognosis; since the first case report, this neoplasm has had a number of different names such as hematodermic neoplasm, plasmacytoid dendritic cell tumor, NK-cell lymphoma. Until recently this entity was recognized as a distinct disease derived from precursors of plasmacytoid dendritic cells, thanks to the advances on the immunological classification of hematologic malignancies. We present the clinical cases of two patients of advance age with this disease, with particular attention to the dismal results of the different chemotherapy regimens employed for their treatment.Keywords:
Rare Non Hodgkin’s Lymphoma; Cutaneous Neoplasm; Blastic Plasmacytoid Dendritic NeoplasmCase 1.
A 71 year-old-male presented in august 2010 with a 4-month history of skin lesions characterized by 1-3 cm, erythematous nodules and papules on the anterior and posterior walls of the chest, as well as in the neck and submandibular region (Figure 1). He complained about the presence of fever, up to 380C without hourly predominance, weight loss of 8 Kg in the last month, bone pain and asthenia. Initially it was diagnosed for his primary physician as leprosy and began treatment with rifampin, dapsone and minocycline. Laboratory test showed: Hemoglobin 9.9 g/dl, leukocytes 17.3 x103
/L, platelets 89 x103
/L; a leucoerythroblastic pattern was showed in the blood smear. Glucose 131 mg/dl, creatinin 1.0 mg/dl, uric acid 5.5 mg/dl, ALT 15 UI/L, AST 15 UI/L, alkaline phosphatase 1562 UI/L (Normal value 40-117 UI/L), lactyc dehydrogenase 699 UI/L (Normal value 101-218 UI/L), direct and indirect bilirubin 0.4 and 0.5 mg/dl, total protein 6.6 g/dl, albumin 3.9 g/dl, globulin 2.7 g/dl, and ultrasensitive C-reactive protein 18.20 mg/dl.
Because of the abnormalities found on the blood cytology he was sent for evaluation. An aspiration and biopsy of the bone marrow (BM), and also a biopsy of the cutaneous lesions were done immediately. The BM showed megaloblastic and dispoyetic changes in all cellular lines. Immunophenotipyc changes were detected in the bone marrow with 14% of immature cells showing myeloid and monocytic antigens. The abnormal cells expressed MPO, CD11c, CD13, CD33, CD34, CD64, CD117, HLADR. The cytogenetic analysis showed a normal 46, XY karyotype. The PET-CT scan showed increased and diffuse captation in the BM, cardiomegaly, minimum bilateral pleural effusion and a 14x9 cm spleen. The skin biopsy showed a neoplastic population positive for CD123, CD4 and CD56 (Figure 2a ,2b).The diagnosis of hematodermic tumor was made.
Figure 1. Case 1 cutaneous lesions.
Figure 2a. Neoplastic cells of small and medium size with granular chromatin in the nucleus and large eosinophlic cytoplasm localized in superficial, medium an deep dermis are seen ( Hematoxilin and eosin stain).
Figure 2b. Immunohistochemistry of skin biopsy showing positivity for CD4, CD56 and CD123.
His initial treatment began with standard CHOEP . He had an early improvement of the skin lesions (Figure 3). But, after two courses of treatment there was disease progression with new cutaneous tumors in the thighs and abdomen, greater cytopenias and worsening of the general symptoms. In December 2010 he received the B phase of the HyperCVAD regimen  as a rescue treatment. Again there was transient improvement of skin lesions and general symptoms; however, the patient experienced tumor lysis syndrome characterized by acute renal failure, hydroelectrolyte abnormalities, severe mucositis and pancytopenia. Finally he developed infection by S. malthophilia, septic shock and death.
Figure 3. Case 1 skin lesions after first course of chemotherapy.
A 62-year-old man presented in august 2011 with a history of two and a half-months with erythematous nodular tumors, initially painful, localized at both parietals, cervical region and right axilla (Figure 4). Almost simultaneously, adenomegalies with progressive growth appeared in both yugular regions, right mastoid, right axilla and both inguinal regions. He complained about a mass of progressive growth in right hypochondrium. The initial test showed: Hemoglobin 11.1 g/ dl, leukocytes 4.6 x103/μl, platelets 65 x103/μl, a leucoerythroblastic pattern was found in blood smear. Glucose 79 mg/ dl, creatinine 0.7 mg/dl, ST 26 UI/L, ALT 17 UI/L, alkaline phosphatase 53 UI/L, lactic dehydrogenase 424 UI/L, total bilirubin 0.3 mg/dl, direct bilirubin 0.1 mg/dl, total protein 6.4 g/dl, albumin 3.6 g/dl, globulin 2.8 g/dl, uric acid 7.1 mg/dl. The bone marrow aspirate showed massive blastic cell infiltration. The flow cytometry in bone marrow showed an abnormal cell population wich compromised 77% of CD45-positive leukocytes. This abnormal population expressed CD4, CD2, CD56, HLA-DR with partial cytoplasmic CD3. The cytogenetic evaluation of bone marrow found a complex karyotype: 41-43, XY, add (5) (q35), +7, add (7) (p11.2)x2, -8, del (9) (p13), -10, -10, der (13) t (13;17) (p11.2;q21), del (13) (q12q14), -17, -22, -22, +mar [cp3] /46, XY .The histopathologic findings in the cutaneous lesions showed a blastic neoplasia positive for CD4, CD123, CD56 and Ki 67 index of 100% (Figure 5a, 5b). The PET-CT scan reported multiple tumoral adenomegalies in cervical region, axillas, mediastinum, retroperitoneum, iliac an inguinal regions. Both lungs showed multiple positive nodules. There was hypercaptation in the parietal lesions and splenomegaly.
Figure 4. Case 2 initial cutaneous lesions.
Figure 5a. Similar histologic findings to case 1. In this case the neoplastic cells were immerse in a myxoid substance positive for alcian blue stain ( Hematoxilin and eosin stain).
Figure 5b. Immunohistochemistry showing positivity for CD4, CD56 nd CD123. The patient received as front therapy the HyperCVAD regimen (2) with a remarkably improvement in tumoral lesions, adenomegalies and general symptoms since the first course of treatment (Figure 6). By March 2012 the patient completed 4 cycles of the regimen in both phases (A and B) for a total of 8 courses of chemotherapy. Complications associated to treatment were 3 episodes of neutropenic enterocolitis and complicated diverticular disease that required laparoscopic sigmoidectomy with colostomy. The PET-CT scan after treatment showed persistence of nodular lesions in both lungs, without visceral or ganglionar disease. Because of this, a biopsy of one of the pulmonary nodule was done with findings of fibrosis and reactive changes without neoplasia. Bone marrow evaluation reported normal immunophenotype, the cytogenetic assay showed 46, XY, add (7) (q36), del (13) (q12q14)  / 46, XY  as chromosomic abnormalities. Bone marrow biopsy was negative for neoplasia. There was complete disappearance of lymph nodes and cutaneous disease.
Figure 6. Clinical response after first cycle of chemotherapy, case 2.
By September 2012 the patient experienced cutaneous and hematologic relapse, with new skin lesions of the same characteristics as the initial skin plaques in thorax and leukocyte count of 130 x103/μl, Hemoglobin 7.9 g/dl and platelet count
of 70 x103/μl. The bone marrow study found 92% of abnormal cells by flow cytometry with the same pattern as initially. A very complex karyotype with multiple numerical and structural chromosome abnormalities was observed in 70% of analyzed metaphases, this study showed increase in the size of the abnormal clone compared with the first cytogenetic analysis. Biopsy of bone marrow informed massive infiltration by the same blastic cells.
He initiated a rescue treatment based on bortezomib, lenalidomide, doxorubicin and dexametasone previously used in lymphoid
and plasmacytoid neoplasm . After the first course of treatment the leukocyte count drop to 27 x103/μl, however, there was persistence of 47% blast cells, with new leukocyte count elevation shortly after. Then he received as a second line of rescue treatment, one course of clofarabine, etoposide and cyclophosphamide previously used in lymphoid tumors . With this therapy the patient developed severe pancytopenia, febrile neutropenia and hemorrhagic enterocolitis. Finally he presented severe hypotension, shock and fatal arrhythmia.
BDCP is a very uncommon neoplasia recently identified as a separate entity, from a broad spectrum of myelomonocytic and dendritic cell proliferations [5,6,9]. This neoplasm have been informed generally in adults older than 60 years, however there are cases as young as 6 years old  and it mainly affects men without racial predominance [5,8,10]. The clinical manifestations are characterized by an aggressive and rapid onset of cutaneous lesions, infiltration of bone marrow, lymph nodes and leukemic presentation as in our cases [5,-8,10-12]. However there are patients with solitary lesion in the skin at diagnosis, these patients seem to have better prognosis and excellent response to local radiation therapy . There is a case report without dermic compromise . Histopathologycally this neoplasm shows high expression of CD4, CD43, CD56, CD123, HLA-DR, TCL1, BDCA-2/CD303 and low levels of CD43 and CD68 similar to our clinical cases (5,9). Recently Sapienza et al. address some important issues about the cell origin and pathogenesis of BPDCN based on gene expression profiling. BPDCN is related to myeloid derived plasmacytoid dendritic cells in resting state. In this paper, they discovered and aberrant activation of the NF-kB pathway in the BPDCN cells, in fact, they used an anti-NF-kB-treatment in cell line CAL-1 in vitro achieving the molecular shutoff of the NF-kB pathway. This discovery opens the gate to drugs that inhibit the NF-kB pathway as Bortezomib . We used Bortezomib in one of our cases without good results.
Because of the low incidence, aggressivity and poor survival of this malignancy, the optimal treatment has not been established. It has been treated as an acute myeloid or lymphoblastic leukemia as well as a lymphoproliferative disorder [1-4, 10-12]. The median survival for this entity is 12 to 14 months irrespective to the initial clinical manifestations [5,6,8]. In the present cases the overall survival was 4 and 14 months respectively. There are reports using agents as lenalidomide with encouraging results in animal models  and more recently 5-azacitidine has been reported as an option treatment, however, also with low survival .
Because the above mentioned, the use of treatment options as stem cell transplantation is limited, however there are several reports that address this issue in this neoplasm reporting long survival [17-19]. Because the age and comorbidities in our first case and the negative in the second case to make the histocompatibility test, we did not have the opportunity to consider this treatment option. Our patients had a poor survival as reported in literature.
Finally, is important to consider the impact of a right initial diagnosis since this entity can mimic other diseases because the broad clinical manifestations, in one of our cases it was misdiagnosed as lepra. It has been reported that because the cutaneous signs sometimes can be confused with lupus erythematosus .