Search

"Midline granuloma syndrome" encompasses a number of specific clinicopathologic entities, such as "Wegener's granulomatosis, midline malignant reticulosis, lymphoma, nasal carcinoma and a broad spectrum of infectious diseases. In the course of studying a number of patients presenting with destructive lesions of the upper respiratory tract, 11 cases emerged as having unique clinicopathologic features. These are: 1) presence of locally destructive lesions which are always restricted to the upper respiratory tract. 2) Absence of systemic disease during a follow-up period of six months to 18 years (mean 7.3 years). On examination of repeated biopsy specimens the histopathologic picture consisted of acute and chronic inflammation with variable amounts of necrosis. Granulomata were seen in one case. Malignant or atypical cells were invariably absent. Frank vasculitis was not seen, although in five of the patients inflammatory cells in the wall of small vessels were conspicuous 4) Inability to demonstrate an infectious origin by culture or special stains. Radiation therapy has proven effective in patients with this entity, for which the term "Idiopathic Midline Destructive Disease" (IMDD) is proposed.

Seventeen patients with peripheral neuroepithelioma were treated with an intensive chemotherapy regimen of vincristine, Adriamycin (Adria Laboratories, Columbus, OH), and cyclophosphamide (VADRIAC) in combination with radiation therapy. Fifteen patients with stage III (seven) or stage IV (eight) at presentation were treated on a more intensive regimen including total body irradiation (TBI) (8 Gy). Two patients with stage I (one) or II (one) disease received a less intensive chemotherapy regimen of VADRIAC. Therapy was completed within 6 to 7 months in all patients. The disease arose in the chest wall in 12 patients, pelvis in three patients, and extremity in two patients. Sixteen of the 17 (94%) patients achieved a complete remission. With a median follow-up of 18 months, ten patients remain in complete remission with an actuarial survival of 68% and an actuarial relapse-free survival of 56% at 12 months. On the basis of our initial experience with this tumor, we believe that peripheral neuroepithelioma is a chemoresponsive and radioresponsive tumor.

Nine out of 70 patients with primary Sjögren's syndrome had vasculitis of small and/or medium-sized vessels. The small vessel vasculitis was of the hypersensitivity type: leukocytoclastic and lymphocytic. The medium vessel vasculitis was acute necrotizing and simulated polyarteritis nodosa histologically but lacked the characteristic aneurysmal formation. A healing stage of vasculitis, presenting as endarteritis obliterans, was seen in patients with Sjögren's syndrome and a long-standing history of vasculitis. The hypersensitivity vasculitis was localized mainly in the skin and provided mild clinical symptoms. The polyarteritis nodosa-like vasculitis was localized predominantly in internal organs and was associated with life-threatening symptoms. Endarteritis obliterans was mainly seen in acral sites of the extremities and presented with recurrent symptoms of obstruction. One patient died of vasculitis. The remaining patients are alive. The presence of anemia, cryoglobulinemia, and hypocomplementemia suggested an immune-complex origin of the vasculitic process.

Thirty-one previously untreated patients with Ewing's sarcoma were treated with an intensive chemotherapy program of vincristine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and cyclosphosphamide (VADRIAC) in combination with radiation therapy to the primary site (greater than 50 Gy) and bone metastases (45 to 50 Gy). An intensified regimen with one further cycle of chemotherapy (VADRIAC), total body irradiation (TBI), and autologous bone marrow transplantation was given to patients with primary tumors of the pelvis, humerus, femur, and chest wall without metastases and to all patients with metastases at diagnosis. Patients with primary tumors of the distal extremity and other sites without metastases at diagnosis were treated on a less intensive chemotherapy regimen of VADRIAC without the intensification. Therapy was completed within 6 to 7 months in all patients. Thirteen patients had metastatic disease at diagnosis; only two of these had the lung as the sole site of metastatic disease. Eighteen patients had no evidence of metastatic disease at diagnosis: ten of these patients had tumors that arose in central axis and proximal extremity sites, and eight had tumors that arose in distal extremity and other sites. Thirty of the 31 patients achieved a complete remission, although two patients underwent amputation: one before chemotherapy and radiation and one after chemotherapy and radiation because of persistent local disease. Seventeen remain in their first complete remission at a median time on study of 30 months and a median time after completion of therapy of 24 months. Fourteen patients have relapsed (13) or progressed (1): ten in metastatic sites and four in the primary site. One patient had persistent local disease after radiation requiring amputation. Nine of the 13 patients with metastatic disease at diagnosis have relapsed compared with five of the 18 patients without metastatic disease. For the entire group, the actuarial survival is 78% (65% to 87%) at 30 months, and the actuarial disease-free survival is 58% (46% to 69%) at 30 months.

Three malignant rhabdoid tumors of the kidney and two extrarenal rhabdoid tumors of soft tissues were studied by light and electron microscopy and by immunocytochemistry for the expression of keratin, vimentin, desmin, neurofilament triplet proteins, epithelial membrane antigen, myoglobin, and HNK-1 (Leu-7). Electron microscopy revealed the characteristic cytoplasmic whorled filamentous inclusions in all tumors. An epithelial phenotype (presence of cytoplasmic tonofilaments) was observed in two tumors (one renal and one extrarenal); and a focal primitive neural phenotype (cytoplasmic processes with neurosecretory granules), in a renal rhabdoid tumor. Strands of basal lamina were seen in two renal and one extrarenal rhabdoid tumors. Evaluation of basal lamina was more difficult in the third renal rhabdoid tumor, in which tissue preservation was not optimal. Primitive attachments were present in all rhabdoid tumors. Immunocytochemical staining supported a diverse phenotype, ranging from epithelial and/or mesenchymal to myogenous and/or neuroectodermal. Simultaneous expression of several of the studied antigenic determinants by the same tumor was noted. The findings suggest that both renal and extrarenal rhabdoid tumors express a diverse morphological and immunocytochemical phenotype.

Cells from the Y-79 human retinoblastoma line were successfully grown as long-term monolayer cultures in serum-supplemented or serum-free, defined medium after pretreatment of the substrate with poly-D-lysine and fibronectin. A significant proportion of the cells differentiated morphologically in serum-free, defined medium as well as in serum-containing medium after treatment with dibutyryl cyclic AMP (dbcAMP). In the defined medium, approximately 30% of the cells showed development of long, ramifying processes, consistent with putative neuronal differentiation. Addition of dbcAMP in the defined medium resulted in an increasing number of differentiating cells (up to 50%); scattered flat cells were observed as well. Treatment of serum-supported cultures with dbcAMP resulted in a larger proportion (10%) of flat cells. Attempts to differentiate the cells with retinoic acid were unsuccessful. These results show that Y-79 cells can grow in attachment culture and differentiate into at least two distinct morphological cell types as well as offering an interesting system for studying the factors controlling growth and differentiation in human tumor cells in vitro.

Immunocytochemical staining for neuron-specific enolase (NSE) was performed in 44 round-cell tumors from children by the improved immunoglobulin-enzyme bridge method with antiserum against NSE. The tumors studied consisted of 15 neuroblastomas showing various degrees of histologic differentiation, 13 Ewing's sarcomas, ten soft tissue sarcomas of diverse origin, and six lymphomas of bone and soft tissues. Neuron-specific enolase was detected in all neuroblastomas, irrespective of the degree of histologic differentiation. None of the other round-cell tumors was positive for NSE, except one embryonal rhabdomyosarcoma that contained differentiated myoblasts. The primitive cells of this tumor were negative as well. It is concluded that immunocytochemical staining with antibodies to NSE is a practical and reliable method for distinguishing neuroblastomas from other nonneural round-cell tumors in children. This is true even for the most primitive forms of neuroblastomas, in which morphologic techniques are less reliable. Neuron-specific enolase may also be useful in delineating the neural histogenesis of other ill-defined tumors.

One hundred twenty-four children and young adults with recurrent tumors, predominantly sarcomas, were treated with the combination of ifosfamide, etoposide, and the uroprotector, mesna (2-mercaptoethane sulphonate), in a phase II trial. The treatment regimen consisted of 12 cycles of therapy administered every 3 weeks. After evaluation of the tumor response to chemotherapy alone, radiation or surgery was used to eradicate residual sites of metastatic disease where possible. At the present time, 77 patients are evaluable for response to the chemotherapy; 43 of the patients have experienced a significant reduction in the tumor size in response to the chemotherapy alone (39 partial responses [PR] and four complete responses [CR]). Sixteen of 17 patients with Ewing's sarcoma, nine of 13 with rhabdomyosarcoma, four of eight with peripheral neuroepithelioma, three of eight with osteosarcoma, and 11 of 31 with other tumors have responded with a PR or CR. The toxicity of the regimen was acceptable. Moderate or severe toxicity evaluated on a per cycle basis included: neutropenia, 97%; thrombocytopenia, 32%; nephrotoxicity, less than 1%; mucositis, 1%; neurologic toxicity, 2%; nausea and vomiting, 13%; hemorrhagic cystitis, less than 1%. Fever was present after 33% of cycles and sepsis following 7%. One patient died due to sepsis and pancytopenia. At the present time, only seven of the 43 patients who responded to the chemotherapy regimen have relapsed, with a median follow-up of 10 weeks after the response. This drug combination is highly active in the treatment of recurrent sarcomas and other tumors in children and young adults.

The differential diagnoses of childhood and adolescent tumors composed of small round cells include a distinctive clinicopathological entity called malignant small cell tumor (MSCT) of the thoracopulmonary region in childhood. In the present study, 15 such tumors that fulfilled the criteria by Askin et al. were examined for features of possible neural differentiation by light and electron microscopy (EM). With hematoxylin-eosin stain (H&E) the tumors were made up of small undifferentiated cells; rosette formation was noticed in four cases. By immunohistochemistry all 15 tumors were positive for neuron/specific enolase (NSE), which is a specific marker for neural elements and their tumors including neuroblastomas. Ten of 15 MSCT had positive PAS staining. Ultrastructurally dense core (neurosecretory) granules and cell processes indicative of neuronal differentiation could be recognized in 10 of 14 tumors. The dense core granules were often atypical. Filamentous cytoskeleton, never observed in Ewing's sarcoma, was often present. Based on the current results, MSCT of the thoracopulmonary region can be considered a peripheral neuroectodermal tumor with the possible origin in intercostal nerves. MSCTs are generally misdiagnosed as Ewing's sarcoma due to their primitive appearance in H&E sections and their periodic acid-Schiff positivity. NSE immunostaining, preferably augmented by electron microscopy, is necessary for their correct diagnosis.

The histogenesis of retinoblastoma, the most common intraocular tumor of childhood, has been recently attributed to a primitive retinal cell which is capable of differentiation into both neuronal and glial elements. By manipulating the culture medium constituents and using differentiating agents, such as dibutyryl-cyclic AMP and butyrate, we have now been able to differentiate a population of Y-79 human retinoblastoma cells into cells of pigment epithelial character, as well as into cells of neuronal or glial nature. These studies additionally implicate the outer layer of the optic vesicle in retinoblastoma etiology, and introduce a new system for studying the biologic properties of primitive neural tumors as well as the embryonic development of the retina and central nervous system.