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PURPOSE: To investigate the pathologic substrates of sudden death in young competitive athletes. PATIENTS AND METHODS: Twenty-two cases of sudden death in young competitive athletes occurring in the Veneto region (northern Italy) in the period January 1979 to December 1989 were studied by postmortem examination. The athletes included 19 males and three females, ranging in age from 11 to 35 years (mean, 23 years). RESULTS: In 18 cases, sudden death occurred during (16 cases) or immediately after (two cases) a competitive sport activity. In 10 subjects, sudden death was apparently the first sign of disease. Postmortem examination disclosed that this fatality was due to arrhythmic cardiac arrest in 17 cases; among these, right ventricular cardiomyopathy, also known as 'right ventricular dysplasia,' was the most frequently encountered cardiovascular disease (six cases), followed by atherosclerotic coronary artery disease (four cases), conduction system pathology (three cases), anomalous origin of right coronary artery from the wrong aortic sinus (two cases), and mitral valve prolapse (two cases). In two athletes, the abrupt lethal complication was 'mechanical' and consisted of pulmonary embolism and rupture of the aorta; in three athletes, death was due to a cerebral cause. All athletes with right ventricular cardiomyopathy died during effort, and most had a history of palpitations and/or syncope. Whenever available, electrocardiographic (ECG) tracings showed inverted T waves in precordial leads and/or left bundle branch block ventricular arrhythmias. CONCLUSIONS: Clinicopathologic correlations indicate that in the Veneto region of Italy, right ventricular cardiomyopathy is not so rare among the cardiovascular diseases associated with the risk of arrhythmic cardiac arrest, and seems to account for the majority of cases of sudden death in young athletes; this disorder can be suspected during life on the basis of prodromal symptoms and ECG signs., The pathologic conditions leading to sudden death in young athletes were assessed by reviewing 22 cases. The deaths in occurred in 19 males and 3 females between January 1979 and December 1989. The ages of the athletes ranged from 11 to 35 years old. Sudden death occurred during an athletic activity in 16 cases, after the sports activity in two cases, and was the first sign of disease in 10 cases. Death resulted from cardiac arrest due to arrhythmia in 17 cases. These included six cases of right ventricular dysplasia, a heart condition characterized by abnormalities of the right heart ventricle; four cases of atherosclerotic coronary artery disease, characterized by fatty degeneration and thickening of the walls of the coronary arteries; three cases of abnormal conduction in the heart; two cases of defects in the physical structure of the right coronary artery; and two cases of mitral valve prolapse. The development of a blood clot in the lungs and rupture of the aorta occurred in two cases. Death was due to disorders affecting the brain in three athletes. All athletes with heart disease involving the right ventricle died during physical exertion and had a history of palpitations and/or fainting. These findings show that disease of the right ventricle is a common cause of sudden death among young athletes. This heart disorder is characterized by abnormalities in heart electrical activity and early symptoms, such as palpitations and fainting. (Consumer Summary produced by Reliance Medical Information, Inc.)

Interdigitating dendritic cell sarcoma is an extremely rare tumor. The diagnosis is difficult and is based on clinical, pathological and immunohistochemical evaluation. Differential diagnosis includes melanoma, mesenchymal and hematological malignancies. The mainstay of treatment is surgery for limited disease and different chemotherapy combinations have been tested for advanced disease. No evidence from prospective trials is currently available. We report the case of a 59 year-old male patient who experienced axillary lymphadenopathy with initial diagnosis of large-cell lung cancer on tumor biopsy. He underwent surgical resection with radical intent. Pathological diagnosis of interdigitating dendritic cell sarcoma was obtained on surgical samples. Nine months after radical surgery, he experienced systemic recurrence of disease and underwent chemotherapy with epirubicin and ifosfamide for 4 courses. During chemotherapy, he developed brain disease progression and underwent whole-brain radiotherapy. Systemic progression was then observed and molecular characterization was performed. B-RAFevaluation resulted positive for V600E mutation and the patient was treated with Vemurafenib according to molecular findings. He thus obtained initial clinical benefit but eventually died of brain hemorrhage. In conclusion, we report a case of B-RAFmutation detected in an interdigitating dendritic cell sarcoma patient treated with targeted therapy. B-RAF pathway could have a role in pathogenesis and evolution of this rare disease and could open new perspectives of treatment.

Follicular dendritic cell tumor (FDT) is a rare neoplasm usually occurring in the laterocervical lymph nodes, but presentations elsewhere are also well documented. We report a case of FDT in a 48-year-old man with myasthenia gravis, in whom a slow-growing mediastinal mass that had been surgically excised manifested after 3 years with a local recurrence in the same site. The lesion was aspirated and cytology showed a tumor composed of groups of oval or elongated cells intermingled with several mature small lymphocytes. On histology, the tumor was highly cellular with abundant perivascular lymphocytic infiltration; large cells with pale, eosinophilic cytoplasm and round nuclei, arranged in fascicles often showed a storiform pattern. Occasional binucleated cells were also present. A panel of antibodies showed positivity only for CD21 and CD35, and a weak response to S-100. Electron microscopy showed that the layer cells had convoluted nuclei and elongated interdigitating processes with desmosome-like junctions. The definitive diagnosis of FDT can be concluded only with positive immunostaining for CD21 and CD35. However, in the presence of a mixed population of lymphocytes and larger eosinophilic cells the hypothesis of FDT should always be considered. Ann Diagn Pathol 5:361-367, 2001.

Aims Evaluation of the impact of the extent of primary surgery and reintervention on the outcome of patients with medullary thyroid carcinoma.Methods Seventy-two patients with medullary thyroid carcinoma (MTC) were surgically treated between 1967 and 1992.Results Fifty-five cases were sporadic, 5 patients had MEN 2A, 4 MEN 2B syndrome and 8 familial non-MEN MTC; 1 patient had stage I disease, 30 patients stage II, 36 stage III and 5 stage IV. Sixty-four had their initial treatment at our center, and 8 came for subsequent treatment. At first treatment, 8 patients were subjected to partial thyroidectomy, 10 to total thyroidectomy, 53 to total thyroidectomy with neck dissection, and 1 to only radical neck dissection; postoperative serum calcitonin (Ct) levels returned to normal in 3, 6 and 27 patients, respectively. In the patient with only radical neck dissection, Ct levels remained elevated. No patient with Ct normalization after surgery became responsive to pentagastrin in the follow-up. Thirteen patients had a reoperation due to nodal relapse. At a mean follow-up of 5.7 years (6-252 months), the 10-year survival rate was 84.5% with a significant difference between patients under and over 40 years of age (96.4 vs 57%), between stage I-II (100%) and stage III, IV (83.8%, 0% respectively). At the last follow-up, 36 (50%) patients were alive and disease free and 26 were alive with disease (15 with distant metastases). Of the 10 deaths, 7 were due to tumor recurrence, 3 to 120 months after surgery.Conclusions Data suggest that an earlier diagnosis rather than more extensive surgery could improve survival and reduce recurrences. However, the least treatment required is total thyroidectomy plus central neck and upper mediastinum clearance and in addition, according to the extent of nodal involvement, mono- or bilateral neck dissection. To avoid ineffective reoperation due to distant (mainly liver) micro-metastases, persistent residual microscopic disease requires a more aggressive restaging.

Ultrastructural findings in an unusual case of chondromyxoid fibroma are reported. The tumor was located in the iliac bone of a 42-year-old woman with left hip pain of 5 years duration.

Two cases of androgen secreting adrenocortical carcinoma have been described by light and electron microscopy. The histological and ultrastructural features of the tumour cells were similar to those of compact cells of zona reticularis and to those described in virilizing adenomas. They possess numerous mitochondria with lamellar and tubular cristae, abundant smooth endoplasmic reticulum, lipofuscin bodies and scanty lipid. Irregularly shaped, crenated mitochondria, with outpouchings of the outer limiting membrane have also been observed. The clusters of neoplastic cells were surrounded by basement membrane which demonstrated a focal discontinuity, probably reflecting malignancy of the tumours. Hyperplasia of smooth endoplasmic reticulum and the presence of outpouchings of the mitochondrial outer limiting membrane might be the morphological manifestation of endocrine activity of the tumours.

Various growth phases of Moloney murine sarcoma virus (M-MSV) induced tumors in suckling and young adult BALB/c mice have been studied by light and electron microscopy. In the early phase (3-6 days following M-MSV), observations at the injection site of the thigh muscles consisted of endo- and perimysial edema, «activated» muscle satellite cells, endothelial cells and fibroblasts, scattered type C virus particles within the muscle fibers, muscle fibers and endomysial cells undergoing necrosis and macrophage and granulocyte infiltration. During the overt tumor phase (6-12 days following M-MSV), observation of neoplastic tissue disclosed proliferation of several cell types (endothelial, periosteal, fibroblasts, etc.), poorly differentiated myoblasts along with atypical rhabdo-myoblast-like cells and sarcolytes, type C virus budding from muscle fiber and myoblast plasma membrane, and intense degenerative and regenerative changes in the muscle fibers together with more profuse granulocyte infiltration. The regressive phase (13-21 days following M-MSV) presented reduced cellularity of the neoplastic tissue, a decrease in blast cells, diminishing granulocyte infiltration with contemporaneous appearance of prominent lymphocyte foci and gradual disappearance of virus particles. Although many cell types of mesenchymal origin proliferate following M-MSV infection, the above morphological findings indicate that striated muscle is a preferential site for virus replication and transformation. Furthermore, the peculiar virus cell relationships leading to cell lysis and continuous recruitment of newly infected cells have been widely documented. In the light of these findings it is suggested that, besides the host immune control of virus spread and tumor cell multiplication, the non clonal growth pattern of M-MSV induced tumors is a crucial factor in determining the spontaneous regression which occurs with high frequency in this experimental system.

A 68-year-old man underwent reoperation because of severe incompetence of a mitral valve xenograft, 96 months following implantation. Gross examination of the device showed yellow spots on the cusps, suggesting lipid infiltration, and a torn commissure. Plasmatic cholesterol and lipiprotein levels were normal. X-ray examination of the explants showed no calcific deposits. Histologic and electron microscopic studies disclosed massive accumulation of lipid clefts and droplets, predominantly at the level of the tear; focal loss and detachment of the endothelial lining and scanty porcine fibroblasts and collagen bundles with preserved periodicity were also noted. Primary disruption of porcine valvular bioprostheses without significant calcifications or collagen breakdown is uncommon. In the present case, lipid accumulation was the main determinant of tissue failure.

The age-standardized incidence rates of non-Hodgkin's lymphoma in the province of Padova during the period 1970-1974 were 3.19/105/year for males and 1.60/105/year for females. These rates are similar to those found in other industrialized countries and slightly higher than in the province of Torino. An increasing trend with age is described, beginning in the age group 35-44, while low rates were found in younger ages in both sexes. No relevant' pattern was shown in the geographical distribution of cases, and no observed/expected ratio was significant in any of the administrative districts considered. The influence of environmental factors and the limitations due to uncertain diagnostic criteria and the small size of the population considered are discussed.

Anatomico-clinical, histologic and ultrastructural data of a case of neurofibromatosis of the bladder are reported. The principal cells of the neurofibroma appear isolated in the intercellular substance and have thin cytoplasmic processes, vacuoles, microfibrils, dense osmiophilic bodies and occasional ergastoplasmic tubules. Moreover, the presence of intracytoplasmic axons, a basement lamina of thickened amorphous periplasmalemmatic material and cilia support the theory of the Schwann cell origin of these cells. On the basis of these observations, the hypothesis that neurofibroma, in contrast to neurinoma, arises from the Schwann cells of unmyelinated nerve is advanced.

Spontaneous lymphoma developed in 57 % female SJL/J mice, with a mean latent period of 58 weeks and in 33 % male SJL/J mice with a mean latent period of 72 weeks. In (CBA x SJL) F1and F2, the incidence in females was 79 % and 67 % at a mean age of 107 and 100 weeks respectively while in males it was 53 % and 41 % at 111 and 106 weeks. In reciprocal F1and F2hybrids, an incidence of 62 % and 37 % was observed in females at 118 and 109 weeks of age, while in males it was 33 % and 43 % at the mean ages of 72 and 90 weeks. Gross lesions were usually restricted to mesenteric, cervical, axillary and inguinal lymph nodes, Peyer's patches and spleen. Less frequently, lungs, liver, kidney and thymus were also involved. Histological examination of nodes in the pre-neoplastic stage revealed follicular hyperplasia with prominent germinal centers, sinus hystiocytosis, precence of pyroninophilic cells within the paracortical area and medulla, medullary plasmocytosis and epithelioid sarcoid-like noduli. Nodes, spleen and other affected organs examined during overt disease showed a pleomorphic pattern characteristic of type B reticulum cell neoplasm according to Dunn and contained predominantly plasma cells, giant cells or reticulum cells. At the electron microscope, these different cell types were detected within the neoplastic tissue. In addition, cells resembling immunoblasts were frequently observed, which suggests that they might represent proliferating tumor cells capable of differentiating into plasma cells. Type C-immature and A intracisternal particles were repeatedly observed, but no type C-mature particles were seen. Attempts to transplant neoplastic tissue in syngeneic hosts were successful. Cell-free extracts from primary SJL/J lymphomas were injected in newborn RFM and CBA mice. 4 out of 9 RFM mice developed SJL/J-like lymphoma at 64–70 weeks of age, while no lymphomas were found in 8 CBA mice over 70 weeks of age. Freund adjuvant injected intraperitoneally in (CBA x SJL/J) F1mice did not modify the incidence or the latency of the lymphomas when compared with control animals.

Extramedullary plasmocytoma is a tumor chiefly located in the upper air passages and oral cavity, usually characterized by a slow rate of growth and lack of the biochemical data distinctive of multiple myeloma. Eight cases of extramedullar plasmocytoma are reported, six located in the nasal cavity, one in the maxillary sinus and one in the oropharynx, and the relevant histological features are described: the pyronin affinity of cells, more evident at pH 4.8, was constantly positive; the Russell bodies and the Mott cells, similar to those seen in plasmacell granulomas, were seldom present; the argyrophylic reticulum was rather regular and generally with alveolar pattern; the stainability with the amyloid technique was positive in three cases. Such results are discussed in comparison with reports of other authors. The pertinent literature concerning clinical and pathological data is briefly reviewed. On the basis of the most recent studies on plasmacells, the histogenesis of extramedullary plasmocytoma is discussed, particularly in respect to plasmacell granulomas and multiple myeloma; the possibility that the basic cells constituting such tumors could be related to proplasmocyte is then suggested.

The ultrastructure of a dog mastocytoma examined with the electron microscope after fixation in glutaraldehyde, post-fixation in osmiumtetroxide and butyl-methyl methacrylate embedding is described. The ultrastructural characteristics with particular regard to the submicroscopic morphology of specific granules were studied in details, also with the aid of comparative observations on thick sections stained by Giemsa and toluidine blue. On the basis of their observations, the authors describe the following characteristics of neoplastic mastcells: microvilli, a well-developed Golgi region, centrioles, mithocondria, ribosomes, endoplasmic reticulum and 4 different types of granules. Other mastcells, with various degree of regressive phoenomena, had almost no microvilli, multiple interruptions of plasma membrane, mithocondrial swelling as well as vacuolar and fibrillar aspect of the cytoplasm. The morphology of different types of intracytoplasmic granules is discussed also in the light of parallel observations made by other authors. Expulsions of granules were not observed. The hypothesis of the phospholipidic nature of the lamellar component of granules is suggested.

Bone marrow from C57BL mice with myeloid leukemia induced by Graffi virus has been studied with the electron microscope by ultrathin section and negative stain techniques. Virus particles were usually found in different types of bone marrow cells as well as in extracellular spaces. However, the highest number of particles in various stages of maturation was observed in the cytoplasm of megakaryocytes. Two main types of virus particle were found: the immature Al particle and the mature C particle. They were morphologically indistinguishable from other murine leukemogenic viruses. In partially purified preparations studied by negative staining, some of the particles which were not penetrated by PTA, frequently showed a tail-like structure of variable length. In ultrathin sections, particles were found to originate by budding from the cell membranes. Budding of particles was particularly evident in megakaryocytes and especially within the granules and cytoplasmic vesicles or in connection with the platelet demarcating membranes. The findings of a high number of virus particles in all stages of maturation in megakaryocytes together with a certain degree of megakaryocytosis observed in the bone marrow suggest that this type of cell is possibly one of the main source of production of the virus. A few particles resembling morphologically mycoplasma were detected within the cytoplasm of some immature bone marrow cells.

Experiments have been performed to investigate the effects of polyinosinic-polycytidylic acid (Poly I:C) on humoral and cellular immunity in RFM/Un mice. Poly I:C, 0.1 mg i.p., administered 48 and 24 hours before 4 x 108SRBC produced a marked reduction in direct PFC/106cells and /spleen, and in the hemoagglutinin titre on the 3rd, 4th and 5th days after antigen inoculation. On the other hand, an increase in PFC and hemoagglutinin titre was observed on the 7th and 8th days. Histological examination revealed absence of germinal centers in the spleen on the 4th day. Poly I:C administered 24 and 48 hours after antigen produced an increase in direct PFC and hemoagglutinin titre on the 4th, 5th and 6th day. Histological examination disclosed evident germinal centers in the spleen on the 4th day after antigen. Poly I:C administered 5 to 1 days before antigen produced a markedly depressed direct PFC response in the groups injected 1 and 2 days before antigen. Recovery of the immune response was progressive and complete in groups injected 4 days before antigen. To study the effect of Poly I:C on secondary response to SRBC, two groups of animals injected with Poly I:C before or after antigen were reinjected with 2 x 108SRBC. Secondary response evaluated by hemoagglutinin titre at varying intervals after the immunization disclosed in both groups a much higher antibody titre than that seen in controls receiving SRBC only. Mice injected with Poly I:C 48 or 24 hours before reimmunization with 2 x 108SRBC were no different from controls on 3rd and 4th days in regard to number of indirect PFC as well as hemoagglutinin titre. Finally, mice immunized with two SRBC injections and then treated with Poly I:C on alternating days for 30 days had a much higher titre of hemoagglutinins than controls. In order to study the effect of Poly I:C on the cellular immune response, spleen cells from animals receiving Poly I:C 6–5 days before sacrifice were cultured in vitro with phytohemoagglutinin. DNA synthesis subsequent to PHA stimulation was evaluated by increase in 3HTdR incorporation. Cells from animals which had received Poly I:C demonstrated a remarkably higher 3HTdR uptake than cells from control animals. On the other hand, 5 x 106spleen cells obtained from RFM/Un mice injected with Poly I:C as above were inoculated in 1–4 day old (RFM/Un x CBA/H)F1hybrids. These were then sacrificed on day 8 and spleen indices calculated. Experimental animals disclosed GVH activity similar to that of controls (spleen index 2.3). From the results it is clear that if Poly I:C is injected before antigen the primary immune response is deppressed, whereas it is enhanced when Poly I:C is administered after antigen. On the other hand, the secondary response is generally enhanced regardless of the time of Poly I:C administration. Moreover, in Poly I:C –- treated animals there is an enhancement of PHA –- responsive cells while the GVH reactions is unchanged. As Poly I:C is capable of enhancing immune reactivity, the possibility of its use in antineoplastic chemotherapeutic protocols is suggested.

A case of malignant megakaryocytosis presenting a blood picture of acute leukemia (50%) blasts), marked hepato-splenomegaly and intense megakaryocytosis and myeloblastosis in the bone marrow, liver and spleen, is described. The authors accept megakaryocytosis as a well-defined disease entity, at least from the viewpoint of pathologic anatomy. The fairly rapid clinical course, the constant hepato-splenomegaly and the characteristic histological picture of the bone marrow, liver and spleen are the essential features necessary for a differential diagnosis from other myeloproliferative syndromes involving the megakaryocytic series.

WE have tried to elucidate the possible influence of immunological mechanisms in virus leukaemogenesis of mice. We used Graffi virus, which has been proved to be most leukaemogenic in many strains of mice when injected at birth1,2. In a preliminary investigation (C3Hf/Gs × CBA-T6T6)Flmice (hereafter called CCH) were inoculated subcutaneously, when 1, 15 and 20 days old, with 0.05 ml. of 20 per cent w/v cell-free extract containing Graffi virus. The mice were observed for development of leukaemia. The extracts which were obtained from C57BL mice with generalized leukaemia induced by the same virus were prepared as described before1. As shown in Table 1, a remarkable decrease in the incidence of leukaemia was observed in inverse relationship to the age at inoculation—from almost 100 per cent incidence in mice injected at birth to 12 per cent in animals injected when 15–20 days old. These results confirm that neonatal age is important in determining the neoplastic response of CCH mice to leukaemogenesis by Graffi virus.