Microangiopathic hemolytic anemia and leukoerythroblastic blood film heralding bone marrow metastatic gastroesophageal adenocarcinoma.

Despite modern technological advancements in laboratory hematology, the blood film remains an important diagnostic aid. Herein, we report the case of a patient with a history of gastric cancer, who presented seven years following apparently successful surgery and adjuvant chemo-radio-therapy, with blood film findings of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and leukoerythroblastosis (LEB). Although mimicking features of thrombotic thrombocytopenic purpura (TTP), subsequent bone marrow examination instead revealed an association with occult recurrence of necrotic, metastatic gastric adenocarcinoma. This case report and literature review highlight these rare, but important, hematological manifestations of gastric cancer, and the importance of astute laboratory and bone marrow investigations in preventing delays in appropriate treatment of the underlying malignancy.

Lenalidomide therapy in myelofibrosis with myeloid metaplasia.

We present results of 2 similarly designed but separate phase 2 studies involving single-agent lenalidomide (CC-5013, Revlimid) in a total of 68 patients with symptomatic myelofibrosis with myeloid metaplasia (MMM). Protocol treatment consisted of oral lenalidomide at 10 mg/d (5 mg/d if baseline platelet count < 100 x 10(9)/L) for 3 to 4 months with a plan to continue treatment for either 3 or 24 additional months, in case of response. Overall response rates were 22% for anemia, 33% for splenomegaly, and 50% for thrombocytopenia. Response in anemia was deemed impressive in 8 patients whose hemoglobin level normalized from a baseline of either transfusion dependency or hemoglobin level lower than 100 g/L. Additional treatment effects in these patients included resolution of leukoerythroblastosis (4 patients), a decrease in medullary fibrosis and angiogenesis (2 patients), and del(5)(q13q33) cytogenetic remission accompanied by a reduction in JAK2(V617F) mutation burden (1 patient). Grade 3 or 4 adverse events included neutropenia (31%) and thrombocytopenia (19%). We conclude that lenalidomide engenders an intriguing treatment activity in a subset of patients with MMM that includes an unprecedented effect on peripheral blood and bone marrow abnormalities.

Clinical spectrum of myelophthisis in cancer patients.

Myelophthisis is a form of bone marrow failure due to replacement of hematopoietic tissue by abnormal tissue, most commonly metastatic carcinomas. This results in extramedullary hematopoiesis, typically in the spleen leading to premature release of hematopoietic cells into the circulation. Peripheral blood findings may include nucleated red blood cells, tear drop forms, giant platelets, and immature leukocytes. This is called a leukoerythroblastic picture. The first case demonstrates acute myelophthisis as a presentation of pancreatic cancer. The second case is of extramedullary hematopoiesis as a manifestation of widely metastatic melanoma. The presence of a leukoerythroblastic peripheral blood picture should serve as a valuable clue about a possible underlying malignancy. This late presentation of advanced cancer may now be rarely seen because of early diagnosis and more effective therapies.

Multiple diffuse fibrosarcoma of bone associated with extramedullary hematopoiesis.

We report a case of multiple diffuse fibrosarcoma of bone. The patient, a 38-year-old man, was referred to our hospital with knee pain, anemia and thrombocytopenia. No solid mass was seen on radiographic examination of the kneejoint, but magnetic resonance imaging showed hypointensity of the distal femur. Femoral biopsy revealed proliferation of long spindle-shaped fibrosarcoma cells, while a bone marrow biopsy of iliac bone (which appeared normal on radiographic examinations) showed replacement of hematopoietic cells by fibroblast-like spindle cells. A diagnosis of multiple diffuse fibrosarcoma of bone was therefore made. Autopsy revealed tumor invasion into multiple bones and several visceral organs and extramedullary hematopoiesis in the liver, spleen and lymph nodes. As this patient had leukoerythroblastic anemia with poikilocytosis, splenomegaly exhibiting extramedullary hematopoiesis, and apparent fibrotic change in his bone marrow, we suggest that this extremely rare disease should be considered in the differential diagnosis of myelofibrosis.

[Primary myelofibrosis transforming into multiple subcutaneous monoblastoma--a case report].

A 83-year-old man was diagnosed with primary myelofibrosis based on the presence of leukoerythroblastosis, splenomegaly, chromosome 46 XY, a dry tap bone marrow aspiration and fibrosis on bone marrow biopsy, when he was admitted for herpes zoster in June 1987. He was admitted for a second time with multiple subcutaneous tumors over his entire body in July, 1989. He had mild splenomegaly, but no hepatomegaly nor lymphadenopathy. Laboratory tests were as follows: RBC 214 x 10(4)/microliters, Hb 5.1 g/dl, Ht 17.7%, WBC 3,200/microliters with leukoerythroblastosis, platelets 11.6 x 10(4)/microliters, s-lysozyme 251 micrograms/ml, u-lysozyme 770 micrograms/ml, NAP ratio 98%, score 278. Bone marrow aspiration resulted in a dry tap. Bone marrow biopsy showed marked fibrosis. Histologic examination of subcutaneous tumor biopsy specimens revealed a diffuse infiltration of monocytes with flexuous nuclei. These cells were positive for alpha-naphtyl butyrate esterase stain, and negative for peroxidase, alpha-naphtol ASD chloroacetate esterase stain and platelet glycoprotein IIb/IIIa stain (APAAP). Ultrastructurally, these cells were mostly monocytes and promonocytes, while phenotypically, CD11b, CD13, CD14, CD33 and HLA-DR were positive. These date indicated that the subcutaneous tumors originated from monocytes.

Granulocytic fragments in sepsis.

We report here three patients with sepsis and one with acute pancreatitis and possible sepsis who developed granulocytic fragments on blood smears obtained prior to death. In case 1, these fragments were identified cytochemically. In case 3, granulocytic cytoplasmic projections and fragments were identified by electron microscopy of the buffy coat. All patients had leukerythroblastosis. The average corrected white blood count (WBC) was 46 X 10(9)/liter with 34 nucleated red blood cells (nRBC)/100 WBC. Patient 1 had thrombocytosis whereas patients 2, 3, and 4 were thrombocytopenic. Terminal complement levels were decreased in patients 3 and 4 as previously noted in sepsis (Sprung CL, Shultz DR, Marcial E, et al.: Complement activation in septic shock patients. Crit Care Med 14:525, 1986). A general correlation between nRBC and granulocytic fragments/100 hpf (high power field) was observed in patients 3 and 4. Granulocytic fragments were not identified on the blood smears of several patients with leukemoid reactions without erythroblastosis. Although the precise etiology of these fragments is unclear, we believe their recognition is important because all patients died within 32 hours after granulocytic fragments were identified. Furthermore, these fragments can falsely elevate the platelet count. Although myeloid fragments have previously been noted in leukemia and lymphoma, this is the first report of their association with conditions unrelated to hematologic neoplasms. These fragments can easily be recognized by careful examination of the blood smear and represent a newly recognized aspect of the septic shock syndrome.

The pathogenesis of splenic extramedullary hematopoiesis in metastatic carcinoma.

Splenic extramedullary hematopoiesis (EMH) is a characteristic finding in agnogenic myeloid metaplasia (AMM) and in the spent phase of polycythemia vera (PV). Evidence from our laboratory has suggested that splenic EMH in these conditions results from the filtration of circulating hematopoietic cells from the peripheral blood and does not arise de novo from splenic stem cells. To further test this hypothesis, 31 autopsy and 26 surgical cases of carcinoma metastatic to the bone marrow were studied. The presence of leukoerythroblastosis (LEB) correlated with intravascular hematopoiesis (IVH) in the bone marrows associated with reticulin fibrosis, and with splenic EMH in the autopsy cases. These studies provide evidence that stromal changes in the bone marrow with resulting IVH, LEB, and splenic EMH are not unique to AMM and PV but also occur in such unrelated conditions as metastatic carcinoma, and suggest that these phenomena are causally related.

Familial hypercholesterolemia with unusual foamy histiocytes. Report of a case with myelophthisic anemia and xanthoma of the maxillary sinus.

Accumulation of phagocytic histiocytes with a foam cell morphology has been described in a number of diseases. Familial hypercholesterolemia, one such disease, is characterized by foamy histiocytic accumulation in cutaneous or tendinous xanthomas and within atheromatous lesions. This report describes a patient with familial hypercholesterolemia who had two unusual manifestations of foamy histiocytic accumulation: a maxillary sinus xanthoma, which presented as an expansile mass, and diffuse bone marrow replacement with foamy histiocytes, which was associated with myelophthisic anemia. The accumulation of foamy cells in both locations resembled that seen in many of the storage diseases. The possibility of foamy histiocytic accumulation should be considered in the differential diagnosis of patients with these disease entities who present with space-occupying lesions.

Leukoerythroblastosis with blasts in a patient with alcoholic hepatitis.

Leukemoid reactions are common in alcoholic hepatitis. We report a case of biopsy-proven alcoholic hepatitis with leukoerythroblastosis and blasts on the peripheral smear. We take this to be the second case of blasts and the first case of leukoerythroblastosis reported in a patient with alcoholic hepatitis.

Giant basal cell carcinoma with metastases and myelophthisic anemia.

We report a 59-year-old, dark-complexioned black man with a giant basal cell carcinoma infiltrating virtually the entire scalp. Widespread metastatic bone marrow involvement produced a myelophthisic anemia. Basal cell carcinoma is rare in blacks, is rarely this large, and very rarely produces myelophthisic anemia from bone marrow metastases.

Metastatic oligodendroglioma presenting as a leukoerythroblastic anaemia.

The clinical course of a patient with oligodendroglioma, treated initially with surgery and radiotherapy, is described. The patient later presented with leukoerythroblastic anaemia due to metastasis to bone marrow. This behaviour had not been previously described in oligodendroglioma.

Leukoerythroblastosis and cancer frequency, prognosis, and physiopathologic significance.

This investigation was carried out on 100 bone marrow biopsies with metastases and 56 autopsies on patients with evidence of cancer. Leukoerythroblastosis was found in 44% of the patients with bone marrow mestastases and was more frequent in prostatic and gastric carcinoma. Moreover, the postmortem study of patients who died with cancer showed that leukoerythroblastosis was always the sign of bone marrow metastasis. A significant correlation was found between these blood changes and bone marrow fibrosis around the metastasis. Furthermore, leukoerythroblastosis seems caused by hepatosplenic extra medullary hematopoiesis.