N-myc gene amplification/expression in localized stroma-rich neuroblastoma (ganglioneuroblastoma).

Using nucleic acid analysis and in situ hybridization we have demonstrated N-myc amplification and expression in two children with a localized (stages I and II) stroma-rich neuroblastoma (NB) (ganglioneuroblastoma). The phenomenon was observed in both undifferentiated and mature ganglion-like cells. The two children are alive and disease-free without any treatment after 16 and 17 months. These observations suggest that morphologic differentiation in NB in vivo is not necessarily followed by a decrease in N-myc expression. Moreover, N-myc amplification does not represent an adverse prognostic factor. In contrast with what happens in undifferentiated NB, N-myc amplification does not have an adverse effect on prognosis when occurring in localized (stages I and II), stroma-rich NB with a favorable histology.

Precancerous lesions of the biliary tree.

Malignant tumors may arise from any portion of the biliary tree. The term cholangiocarcinoma (CC) applies to both intra- and extrahepatic tumors. More than 95% of these tumors are adenocarcinomas. Differentiation between CC and metastatic adenocarcinoma represents a difficult task for the pathologist. The presence of an intratumoral mini-ductal plate, and in situ carcinoma in bile ducts near the tumor and modulation from the bile duct towards parenchymal liver cells represent the major criteria in assessing the identity of an adenocarcinoma as a primary CC. Primary sclerosing cholangitis and congenital bile duct cysts both put patients at risk of developing CC. Lithiasis, recurrent pyogenic cholangitis, and typhoid infection are suspected but not proven predisposing conditions. Fluke infestations (Clonorchis sinensis and Opisthorchis viverrini) play a role in Far Eastern countries. Bile duct adenoma and multiple biliary papillomatosis may carry a malignant transformation potential. Pseudopyloric metaplasia may be a precursor lesion of CC.

Metanephric adenoma.

In a recent survey of more than one hundred childhood renal tumors in our Laboratory files, we identified a unique case characterized by an unusual degree of differentiation and cell maturity. Histologically this case was notable for an orderly array of small and uniformly-packed tubules with a rosette-like configuration. The nuclei were oval, smooth and of a bland appearance. Mitoses were absent. Many glomerular figures were intermingled. This renal tumor picture is somewhat different from that known as tubular Wilms' tumor because of the well-differentiated adenomatous pattern and the absence of any blastema. The term metanephric adenoma is suggested for this tumor, which may represent the benign counterpart of Wilms' tumor.

Wilms' tumor after treatment.

Sixty-one Wilms' tumors (WTs) from 59 patients who received preoperative therapy were studied. Twenty-seven WTs from 26 patients who did not receive preoperative treatment were also reviewed as controls. Marked and diffuse morphological changes occurred in treated cases. Necrosis affected mostly undifferentiated and replicating elements and was extensive, up to 90% of tumor mass. Minimal residual tumor, permitting recognition as Wilms', was always spared. Epithelial and rhabdomyoblastic components were more resistant to treatment; moreover, they appeared to be susceptible to differentiation and maturation. Necrosis and muscle cell differentiation seemed to have prognostic implications. Cases with extensive necrosis (greater than 90%) had a better outcome, although the difference was not statistically significant. The rhabdomyoblast/tumor mass ratio, after treatment, appears to carry prognostic meaning. Chemotherapy had no apparent effect on anaplasia.

Histological diagnosis of hepatocellular carcinoma.

The classical morphological criteria in the diagnosis of hepatocellular carcinoma (HCC) include: a) the similarity of tumour cells to hepatic cord cells; b) the trabecular nature of the growth with capillary and canaliculi formation; and c) the intravascular growth of trabecular carcinoma. These criteria apply to the most common variants of HCC but they do not define all cases of HCC. That makes additional criteria and certain refinements necessary. A promising approach to the diagnosis of HCC is that based upon the consideration by the pathologist of some relevant aspects of the natural history of this tumour. A panel of tests exploring the various functions and properties of liver cells should be developed. This study provides a guideline to a dynamic approach in the diagnosis of HCC. The rationale is based on 5 points; among them, bile production, fibrinogen synthesis, Mallory body, fibrinogen G-G selection and HBV antigen expression can be considered at present as confident markers for the morphological diagnosis of HCC.

Fibrocartilaginous mesenchymoma of bone.

Two bone tumors in children were characterized by prevalent low-cellular fibrous stroma of mature appearance and lobules of hyaline cartilage or chondroid tissue. Endochondral ossification was an additional finding. Clinically the two cases presented with osteolytic lesions of considerable size and relapsing course thus enhancing the suspicion of malignancy. The pathological diagnosis was controversial but both patients are disease-free several years after diagnosis. Histopathologically, the process duplicated the consecutive steps of embryonal endochondral bone formation. In a review of the pertinent literature it was found that these two cases reflect to a large extent the bone lesion reported in 1984 by Dahlin et al. and designated fibrocartilaginous mesenchymoma of the bone.

Pleomorphic (anaplastic) neuroblastoma in nude mice.

Two pleomorphic (anaplastic) neuroblastomas, from two children aged 1 and 6 years, were transplanted into nude mice. Two noteworthy observations were made. In one case, the transplanted tumor gave rise to a soft-tissue sarcoma. Moreover, in both cases hepatic metastases were associated with a striking modification of murine hepatocytes, resulting in hyperchromatic and dysplastic nuclei. The latter finding was particularly evident in the hepatic areas surrounding all metastases of pleomorphic (anaplastic) neuroblastoma cells.

Non-familial hemophagocytic lymphohistiocytosis.

A case of non-familial hemophagocytic lymphohistiocytosis (HLH) is described. The patient had a chronic course being alive and doing relatively well 3 years since onset. The specific pathological features of this disorder are discussed with emphasis on the fact that a remarkable loss of lymph node structure is sustained by a mature lymphohistiocytic infiltrate. Erythrophagocytosis is assessed as an important but not specific finding. Lymphocyte depletion is an important feature of the lesion. The presence of overlapping features in HLH, infection-associated hemophagocytic syndrome (IAHS) and X-linked recessive lymphoproliferative syndrome (XLS) is emphasized.

The xanthogranulomatous process. Xanthogranulomatous inflammation.

The precise histopathological features of the xanthogranulomatous process (XP) have been defined in an extensive review of all cases from various organs available in our files. The result was that the XP has the following aspecific but characteristic findings: the presence of granular, eosinophilic, PAS positive histiocytes in the initial stages; the mixture of foamy macrophages and activated plasma cells; the presence of suppurative foci and hemorrhages. Abscess, necrosis and most of all hemorrhages play a a role in eliciting this inflammatory response. This is in accordance with the observations so far reported in the literature. A very interesting result of our study is that some unquestionable cases of XP in cutaneous soft tissue had a histopathological picture indistinguishable from xanthoma. Basing on our experience and on an extensive study of the literature we suggest that the XP mechanism may in some way play a role in several diseases where the inflammatory or reactive nature is more or less ascertained or suspected and the secondary significance of foam cell production is overtly manifest.

Pleomorphic (anaplastic) neuroblastoma.

Four very unusual cases of neuroblastoma in children are reported. Clinically, they had a similar presentation: advanced disease at onset, diffuse abdominal spread, poor treatment response, and rapid progression. Pathologically, the four cases were characterized by a striking degree of cellular and nuclear pleomorphism and anaplasia with bizarre and monstrous expressions. Although some authors have referred to the immature ganglion cells found in neuroblastoma as "bizarre ganglion cells," they usually mean the enlarged, maturing neuroblasts that are typical of ganglioneuroblastoma but far from the extreme anaplasia seen in our cases. A correlation between the clinical course and the histological picture could be hypothetically suggested, but additional evidence and confirmation is needed. These cellular aberrations might represent an unsuccessful and impaired attempt at maturation. Independent from prognosis, the definition of anaplastic neuroblastoma is a useful conceptual specification in the study of this tumor and of giant cell and pleomorphic malignant neoplasms of childhood.

Xanthogranulomatous osteomyelitis.

Two cases of osteomyelitic lesions, histologically characterized by prominent foam macrophages arranged in a mosaic pattern, had the following pathologic features: neutrophil infiltration, foam cell formation, numerous plasma cells, and fibrin precipitates. According to similar situations in other organs, the term xanthogranulomatous osteomyelitis was applied to these cases. This differential diagnosis can be applied to other bone lesions in which foam macrophages may play an important role.

Multiple endocrine neoplasia type 2b (MEN 2b). Report of 2 pediatric cases.

Two new sporadic cases of multiple endocrine neoplasia type 2b (MEN 2b) are described. Both patients were diagnosed in pediatric age and presented the characteristic features of the syndrome (facies "sui generis", Marfanoid habitus, mucosal neuromas, history of chronic gastrointestinal disturbances) and developed medullary thyroid carcinoma (MTC). In the former case, metastatic neck adenopathies were the first sign by which the disease was recognized. Antitumor treatment consisted of total thyroidectomy, cervical node dissection, administration of I131 and neck irradiation. This patient is alive and well 20 months from diagnosis, still having high serum levels of thyrocalcitonin (TC). In the latter case, the syndrome was diagnosed on clinical grounds before the development of a MTC. The patient was then strictly followed-up and thyroidectomy performed only when serum TC levels rose to abnormally high values: no tumor spread was documented at that time. She is alive and well 4 years from diagnosis.--Early recognition of MEN 2b syndrome is necessary in order to detect and properly treat MTC.

Renal dysplasia of the sacral region: metanephric dysplastic hamartoma of the sacral region.

We believe this to be the third reported case of an unusual congenital sacral tumor-like lesion characterized histologically by the presence of dysplastic and immature renal-like tissue with a predominant glomerular and tubular structure. This lesion appears important in the differential diagnosis of extrarenal nephroblastoma, and should be regarded as a dysplastic overgrowth. An origin from mesonephric or metanephric remnants is suggested.

Foamy degeneration of placenta.

A case of striking foamy transformation of placental and stromal decidual cells is reported. These findings are similar to those described in the placenta of infants affected by fetal storage disorders. However, in our case a very critical study allowed us to conclude that these changes were non-specific and regressive. They were presumed to be concomitant with fetal death or possibly secondary to oedema or anoxia. This case is reported to demonstrate how difficult the differential diagnosis of the appearance of the placenta in fetal storage disorders may be.

Giant cell granulomatosis of lymph nodes with a fatal course.

We report two examples of an unusual expression of fatal granulomatosis with primary lymph node location, characterized histologically by numerous giant cells of the Langhans' type, effacement of the nodal structure, mixed lymphohistiocytic infiltrate, and marked histiocyte cell maturity, all features which initially did not exclude the possibility of a granulomatous process of infectious origin. The clinical features of these cases include cellular or combined immunodeficiency, a possible family history and a rapidly fatal course. The present article emphasizes the great similarity which can exist between histiocytic and granulomatous disorders, the great variability of histiocytic diseases from the pathological view-point, the presence of borderline examples, and the several overlapping features of different entities. Specifically, the most remarkable finding of these two cases is the existence of numerous mature giant cells of the Langerhans' type within a massive obliteration of the nodal structure. Furthermore, these giant cells characterized by a strikingly orderly disposition of peripheral nuclei in a wreath-like pattern, frequently suggesting the structure of Touton's giant cells.

Effect of peptichemio in nonlocalized neuroblastoma.

PTC, a mixture of oligopeptides of m-L-sarcholysin, acting primarily as an alkylating agent, was utilized as initial therapy following diagnosis in 80 children with nonlocalized neuroblastoma. Of the 67 evaluable patients (21 Stage III, 41 Stage IV and five Stage IV-S), 51 had measurable lesions allowing to evaluate PTC activity; objective tumor responses to the drug were recorded in 45 of these 51 cases (88.2%); 5/5 Stage III, 37/41 Stage IV, 3/5 Stage IV-S. Complete responses were obtained in seven patients (13.7%), partial responses in 32 (62.7%), objective improvement in six (11.8%). Four patients (7.8%) had either no tumor change, or tumor progression. There have been two early drug-related deaths (3.9%). Stage III and IV patients responding to PTC were then treated by irradiation + VCR, followed by cycles of a combination of ADriamycin, vincristine, and cyclophosphamide. Stage IV-S patients received no further therapy. Thirteen of 21 Stage III (61.9%), five of 41 Stage IV (12.2%) and four of five Stage IV-S (80%) are presently alive from 19-48 months (median, 27 months). PTC is an effective agent in advanced neuroblastoma. However, the results of this report do not indicate that its addition to a "standard" treatment, at least in the schedule adopted in this protocol, has improved the final outcome of children with nonlocalized disease.

[Ewing's sarcoma. Results of treatment in 16 consecutive cases]. / Il sarcoma di Ewing. Risultati del trattamento in 16 casi consecutivi.

In the period January 1974-August 1981, 16 previously untreated cases of Ewing's Sarcoma have been diagnosed at the Giannina Gaslini Children's Hospital Genova. Eight were male, eight female. Median age at diagnosis was 11 years. Two patients presented with a unique metastatic lesion, in the right lung and in an illiac lymph node, respectively. Fourteen patients have been initially treated with local radiotherapy (dosages ranging form 4,800 to 6,600 rads) in association with antiblastic polichemotherapy utilizing 4 drugs (Adriamycin, Actinomycin D, Vincristine, Cyclophosphamide). The Rosen et al.'s T-2 protocol was adopted, modifying the initial phase in order to give more weight to Adriamycin and reduce the toxic effects related to radio-chemotherapy combination. Two patients bearing a costal primary were immediately treated with a more complex and aggressive chemotherapy (T-6 Protocol), followed by local irradiation (in one case preceded by surgical ablation) and then chemotherapy again (T-2 protocol, second phase) for 10 months. Treatment determined a fast subjective relief in the 13 symptomatic patients. All 16 cases achieved a status of complete remission. Four of them subsequently relapsed: locally in two, in distant sites in the remaining 2. All 4 died 12-27 months form diagnosis. Twelve patients are presently alive without evidence of disease at 3-92 months (median 37 months) following diagnosis. Treatment has caused early and delayed toxicity in all cases. However, the entity of these complications varied considerably from one patient to an other. Age at diagnosis and site of primary tumor were the factors most relevant in this respect.

Ectomesenchymoma. Report of two cases.

Two cases of ectomesenchymoma are reported. This tumor type is defined as a form including ectodermal components represented by neuroblasts or ganglion cells and differentiated mesenchymal structures of various types. Some authors classify this tumor with the peripheral nerve neoplasms but we consider it to be a distinct neoplasm. Clinically and pathologically the tumors have no features of peripheral nerve tumors and may occur with nerves or away from them.

Epithelioid granulomata in a nonossifying fibroma. The possible drug-induced mechanism.

A 13-year-old boy affected by bursitis of the R knee and nonossifying fibroma of the distal metaphysis of the R femur, was treated in the weeks prior to surgical intervention with water-soluble aspirin tablets to relieve local pain. Unexpected epithelioid cell granulomata were observed inside the neoplastic fibrous stroma of the nonossifying fibroma. The coincidental appearance of a slight blood eosinophilia (7%) and perioral fixed drug eruption are clues that suggest that the histological bone findings may represent an expression of the hypersensitivity response elicited by aspirin. It cannot be ruled out that this unusual finding may be related to documented previous trauma, resulting in interstitial hemorrhages and subsequent reactive resorptive processes.

Malignant monomorphic histiocytoma in children.

Four cases of malignant histiocytoma in children are reported. Malignant histiocytoma is defined as a histologic variant of fibrohistiocytoma, characterized by a histologic absence of a fibroblastic component, and a predominant proliferation of malignant histiocytes with an epithelial-like appearance. However, the ultrastructural study of one case also revealed the presence of fibroblasts. Thus, an authentically pure form of malignant histiocytoma does not exist. Nonetheless, it is important to emphasize the histologic distinctions between malignant histiocytoma and malignant fibrohistiocytoma and to emphasize the possible differences in their biologic behavior.