Bone marrow biopsy in monoclonal gammopathies: correlations between pathological findings and clinical data. The Cooperative Group for Study and Treatment of Multiple Myeloma.

Between January 1987 and October 1989, 561 consecutive untreated patients with monoclonal gammopathy of undetermined clinical importance (MGUS) (n = 295) or with multiple myeloma (n = 266) were evaluated in a multicentre trial. Both bone marrow biopsy and aspiration (performed at different anatomical sites) were required at presentation. Bone marrow biopsy data indicated that changes in bone marrow composition from MGUS to early multiple myeloma and to advanced multiple myeloma followed a precise pattern, including an increased percentage of bone marrow plasma cells (BMPC%), a shift from plasmocytic to plasmoblastic cytology, an increase in bone marrow cellularity and fibrosis, a change in bone marrow infiltration (becoming diffuse rather than interstitial), a decrease in residual haemopoiesis and an increase in osteoclasts. In multiple myeloma the BMPC% of biopsy specimens and aspirate were closely related, although in 5% of cases the difference between the two values was greater than 20%. Some histological features were remarkably associated with each other. For example, BMPC% was higher in cases with plasmoblastic cytology, heavy fibrosis, or reduced residual haemopoiesis. Anaemia was the clinical characteristic most influenced by bone marrow histology. The BMPC% was the only histological variable which affected the greatest number of clinical and laboratory characteristics, including, besides haemoglobin concentration, erythrocyte sedimentation rate, radiographic skeletal bone disease, and serum concentrations of monoclonal component, calcium, beta 2-microglobulin and thymidine kinase activity. These data indicate that comparative bone marrow histology in monoclonal gammopathies has clinical importance.

Experimental model in vivo for quantitative assessment of bone resorption inhibition.

Quantitative assessment of bone resorption inhibition in vivo is not easily accomplished; methods relying on a count of osteoclasts are questionable, and histomorphometric evaluation of the bone mass presents several technical problems as well. The authors developed a simple method to measure the inhibition of bone resorption by study of the proximal tibial metaphysis of growing rats: the height of the perichondrial bone ring was taken as an index of the balance between osteoblastic and osteoclastic activity because any agent that inhibits osteoclasts (without interference with osteoblasts) produces an increase in the height of this anatomical structure. Since the ring is well demarcated by surrounding tissues, its height can be measured with accuracy and used for quantitative assessment of bone resorption inhibition. This model was tested with salmon calcitonin, and it provides evidence in vivo that this hormone inhibits osteoclastic bone resorption.

Fine needle aspiration of thoracic splenosis. A case report.

BACKGROUND: Thoracic splenosis is a rare event, and fine needle aspiration (FNA) of a pleural implant of splenic tissue can be a pitfall when previous anamnestic data are ignored. CASE: A 53-year-old male underwent FNA of a left thoracic subpleural nodule highly suggestive of a metastatic lesion. The presence of a population of small and medium-sized lymphocytes suggested the possibility of lymphoproliferative disease; frozen sections confirmed this possibility. The final diagnosis was normal splenic tissue. Twenty-five years earlier the patient sustained a gunshot wound in the left side of the upper abdomen followed by splenectomy and drainage of the left pleural cavity because of mild, concomitant hemothorax. CONCLUSION: A left pleural thoracic nodule in subjects with a previous history of traumatic rupture of the spleen must be considered highly suggestive of thoracic splenosis. Scintigraphy with Tc 99 m and magnetic resonance imaging are diagnostic, while FNA, especially in the absence of anamnestic data, can create a pitfall that can induce inappropriate removal of ectopic, normally functioning splenic tissue.

Paraneoplastic marrow alterations in patients with cancer.

BACKGROUND: Bone marrow abnormalities may be found in patients with cancers even without marrow metastases. We have seen that patients with non-hematologic neoplasias may show bone remodelling, stromal modifications, reactive changes and myelodysplastic alterations of erythro-, granulo- and megakaryocytic series comparable to those found in myelodysplastic syndromes (MDSs). METHODS AND RESULTS: At the beginning of the study 58 bone marrow biopsies (BMBs), performed in 40 patients with previously diagnosed cancer from different primary sites but without marrow metastasis (group A), were evaluated. Osseous and stromal modifications, marked reactive changes, quantitative and qualitative alterations of erythro-, granulo- and megakaryopoiesis were observed. Afterwards, 30 BMBs from 20 patients without a previous diagnosis of neoplasia (group B) were found to have features similar to those discovered in group A. Further investigations detected malignant tumors in all these cases. The findings of the two groups were compared with our former observations on myelodysplastic syndromes. The main differences between groups A-B and MDSs regarded bone remodelling, stromal modifications and reactive changes. CONCLUSION: These marrow alterations linked to a neoplasia may be considered paraneoplastic. They may cause problems for a differential diagnosis with some proliferative diseases and, above all, with primary MDSs. The reported features should prompt the pathologist to suggest a search for possible occult cancer.

[Fibrous hamartoma in childhood]. / Amartoma fibroso dell'infanzia.

Is a rare soft tissue benign tumor usually appearing during the first two years of life, often occurring in axillary or upper arm region subcutaneous tissue. Surgery is the treatment of choice. The lesion histologically consists of three different tissue elements: dense mature fibrocollagenous, loose immature myxoid mesenchymal and mature adipose tissue. A case of fibrous hamartoma of infancy with the usual clinical characteristics, but with particular microscopic features due to the abundance in fibrocollagenous and scarcity of myxoid tissue, is described. The results of the immunohistochemical and ultrastructural study on the same patient are reported. The differential diagnostic problems are discussed.

Bone changes of mucolipidosis II at different ages. Postmortem study of three cases.

Bone changes are a constant feature of mucolipidosis II, with striking differences between newborns and older children. Intracellular, membrane-bound vacuoles were found in the chondrocytes, osteoblasts, osteocytes, and stromal fibroblasts of three affected children. Osteoclasts and marrow cells were unaffected. Ricketslike lesions were present at birth in the two younger cases, whereas signs of high bone turnover and defective calcification were no longer present in the older child. Severe abnormalities of the metaphyseal plate with the loss of normal cartilage architecture and the absence of endochondral ossification were the major changes in this age group.

[The role of carrier ATPases and neuromediators in neurological disorders]. / Rol' transportnykh ATFaz i neiromediatorov v nevrologicheskikh rasstroistvakh.

Physiological and biochemical processes which take place in the nervous system at stroke and neurotrauma are reviewed, and the experience of using low doses of steroid derivatives with piridamole in the treatment of central nervous system (CNS) disorders is summarized. ATPases (including Na,K-ATPase) are reported to play an important role in CNS functioning, the correlation between Na,K-ATPase activity and the extent of CNS injury is revealed. The use of NMR-spectroscopy method for investigation of brain and spinal cord condition in vivo is suggested.

Study of the bone pathology in early mucolipidosis II (I-cell disease).

Histological examination of the bones obtained on autopsy of a 5-month-old child with mucolipidosis II (I-cell disease) revealed inhibition of the growth plate calcification with defective vascular invasion and signs of hyperparathyroidism. These findings are the chondro-osseous basis of the early radiological ricket-like appearance of bones in the neonatal period or soon thereafter. Whether the early skeletal abnormalities of mucolipidosis II result from a primary enzymatic defect of cartilage and bone cells or from factors controlling bone metabolism deserves further study.

Myelodysplastic syndromes: a multiparametric study of prognostic factors and a proposed scoring system.

In 72 consecutive patients with previously untreated myelodysplastic syndromes (MDS) having a median follow-up of 44.9 (range: 6-198) months, a multiple regression analysis was conducted of the prognosis significance of 26 clinical and laboratory parameters, including bone marrow (BM) biopsy characteristics. Parameters which had independent prognostic meaning served to construct a scoring system for survival prediction. Only 7 parameters were significant: hemoglobin, BM cellularity, BM blast percentage, abnormal location of immature precursors (ALIP), fibrosis, dysmegakaryopoiesis and the erythro/myeloid ratio. They enabled us to predict 42% of all MDS patient survival (p less than 0.03) and 84% (p less than 0.02) of survival of patients who lived over 20 months. Based on the value of these parameters in individual cases, the patient population had a score ranging from 0 to 13, with a median value of 5. Median survival of patients with a score less than or equal to 5 was 117, while that of patients with a score greater than 6 was 33 mos. This scoring system, which has been draw from a wide panel of clinical and laboratory parameters, will be verified on prospective studies.

Inhibitory effect of salmon calcitonin on bone resorption: morphological study of the tibial growth plate in rats.

Salmon calcitonin (sCT) at doses of 100 and 50 UI given subcutaneously to growing rats produced in vivo evidence of osteoclastic activity inhibition. Histological assessment was carried out by measuring the perichondrial ring of Lacroix height, and a dose-correlated effect was found. These aspects were coupled with an increase in the osteoclast number and suggested that in studies with bone resorption inhibitors, morphological evaluation based on osteoclasts count is not reliable. The changes of the metaphysis suggested also that sCT affects the activity of hypertrophic chondrocytes of the growth plate. Plasma calcium levels did not differ significantly between treated rats and controls; an increased phosphatemia was observed in sCT-treated animals.

[Microcystic adenoma of the pancreas. Immunohistochemical and ultrastructural study of 7 cases]. / L'adenoma microcistico del pancreas. Studio immunoistochimico e ultrastrutturale di 7 casi.

Microcystic cystadenoma of pancreas is a rare benign neoplasm with peculiar pathologic characteristics. It is more frequent in women and in elderly age. Macroscopically it is composed of a spongy, microcystic mass with a starry central fibrous core. Histologically serous cysts are lined by cuboidal or flattened epithelium without nuclear atypias and with PAS positive cytoplasms. A surgical conservative approach is the treatment of choice. Seven cases of microcystic cystoadenomas of the pancreas observed within ten years at Osp. San Carlo Borromeo-Milano and Osp. Santa Maria degli Angeli-Pordenone from 6 women and 1 man aged 54-87 years are described. The preoperative and intraoperative investigations that have been necessary for reaching its diagnosis are discussed.

Malignant small cell tumor of the thoracopulmonary region in childhood: a case report.

A case of malignant small cell tumor of the thoracopulmonary region in a 3-year-old boy is presented. The rarity of this tumor in children justifies the presentation of a new case. Differential diagnosis with other childhood neoplasms is discussed.

Myelofibrosis in chronic granulocytic leukaemia: clinicopathologic correlations and prognostic significance.

We performed 221 marrow trephine biopsies in 139 patients with Ph1-positive (Ph1+) chronic granulocytic leukaemia (CGL) in order to assess the incidence, degree and prognostic significance of marrow fibrosis (MF) at various stages of the disease. We also attempted to elucidate the relationship between development of MF and the various clinical and haematological features of CGL. A significant correlation was found between the amount of fibrosis (graded from 0 to 3) and the stage of CGL, indicating that major fibrotic changes are associated with accelerated or blastic disease. Survival studies performed to assess the prognostic significance of the various degrees of MF, showed a progressively worse life-expectancy from grade 0 to grade 3 fibrosis. Multivariate regression analysis indicated Hb level, age, number of marrow megakaryocytes (MKs), time from diagnosis as the features most significantly correlated with the degree of MF. This study demonstrates that the natural history of CGL involves a progressive increase in reticulin deposition towards severe MF, although the rate of this progression varies widely. Monitoring changes of fibrosis with sequential biopsies could give a measure of the rate of progression of the disease and help in prognostic assessment of CGL patients. Our findings also confirm that among marrow features the number of MKs is the cytological variable most significantly correlated with MF.

Refractory cytopenias: clinical course according to bone marrow cytology and cellularity.

One hundred and one patients with refractory cytopenia were reviewed for morphological classification (using bone marrow, BM, imprints for cytology and Jamshidi biopsies for BM cellularity) and clinical course. Final diagnoses were: moderate aplastic anemia (MAA), myelodysplastic syndromes (MDS) and hypoplastic acute leukemia (HAL). Ninety-two patients received high dose testosterone enanthate (TE) as first treatment (starting dose = 7-10 mg/week i.m. for at least three months). Median survival was significantly longer in MAA than in MDS and in HAL. Among MDS patients, those with primary acquired sideroblastic (AISA) and refractory (RA) anemia had median survival similar to those with MAA, but distinctly longer (p = 0.01) than patients with RA with an excess of blasts (RAEB), RAEB in transformation (RAEBtr) and chronic myelomonocytic leukemia (CMMoL). Acute leukemia (AL) developed more rarely (p less than 0.02) in MAA, AISA and RA than in RAEB, RAEBtr and CMMoL. Response to TE was seen in about two thirds of MAA and in a half of MDS and HAL patients. Among MDS patients, those with hypocellular BM developed leukemia less frequently, responded to androgens more often and survived longer than those with normocellular and, especially, with hypercellular BM. These data indicate that the cytohistological classification of refractory cytopenias identifies essentially two groups with different clinical behaviour, one (MAA, AISA and RA) having long life expectancy and a low probability of developing AL and the other (RAEB, RAEBtr, CMMoL) with a short survival and relatively frequent leukemic complication. Bone marrow hypocellularity seems to be a favourable prognostic factor in MDS. Patients with refractory cytopenias, especially those with a hypocellular BM, can be advantageously treated with androgens.

Risk assessment in myelodysplastic syndromes: value of clinical, hematologic and bone marrow histologic findings at presentation.

We analyzed the prognostic value of clinical, hematologic and bone marrow (BM) histologic findings at presentation in 94 patients with myelodysplastic syndromes (MDS) (28 RA; 2 RARS; 34 RAEB; 6 CMML; 24 RAEB-t). With survival as the dependent variable, stepwise multivariate analysis indicated as the prognostically most important factors among the MDS taken as a whole: latency from the first symptoms to diagnosis, age, and percentage of BM blasts. In each main MDS group the most unfavorable initial characteristics were: 1) low Hb, no macro-megaloblastosis, male sex for RA/RARS; 2) low Hb and low platelet levels for RAEB/CMML; 3) granuloblastic hyperplasia and high BM blastosis for RAEB-t. Of the BM histologic parameters, only the percentage of blasts had significant prognostic value. Histologic assessment of BM blastosis, however, did not differ statistically from that based on cytologic examination of BM smears, so that marrow histology seemed not essential for initial prognostic assessment in MDS patients. The finding of abnormal localization of immature precursors (ALIP) in BM biopsies was associated with a negative trend without reaching statistical significance. Using four objective parameters of proven significance (age, Hb, platelets, and BM blasts) we devised a staging system of immediate clinical utility for prognostic stratification and risk-adapted therapeutic choices.

Bone marrow and blood involvement by non-Hodgkin's lymphoma: a study of clinicopathologic correlations and prognostic significance in relationship to the Working Formulation.

In a series of 172 patients with non-Hodgkin's lymphoma (NHL) classified according to the Working Formulation (WF) the overall incidence of bone marrow infiltration (BM+) at diagnosis was 39%: 59% for low-grade (LGML), 30% for intermediate-grade (IGML), and 25% for high-grade malignant lymphomas (HGML). The features most significantly correlated with the presence of BM+ were a low grade of histological malignancy, the degree of splenomegaly and high values of LDH, while those correlated with the extent of BM+ were a non-focal pattern of BM disease, the presence of blood involvement at diagnosis, and the degree of BM fibrosis. Blood involvement was detected at diagnosis in 13% of patients, and a further 16% developed a leukemic phase during the course of the disease. Blood involvement correlated significantly with splenomegaly, bulky disease, advanced clinical stage, and extent of BM+. The presence of BM infiltration 'per se' at diagnosis did not significantly affect prognosis. However, the extent of BM disease was correlated with a poorer outcome in IGML and HGML patients. Regarding peripheral blood involvement, in LGML patients only late leukemic conversions were significantly associated with a worse prognosis. In patients with IGML and HGML, either initial or subsequent blood involvement was correlated with significantly poorer outcome.