"Stromatogenesis" and tumor progression

"Stromatogenesis" is the formation of new stroma occurring, in parallel with the neoplastic process, at sites of active tumor invasion, i.e., at the free surface of a developing exophytic tumor, at the invading tumor front of an advancing endophytic tumor, and at sites of tumor metastasis, wherein the newly formed stroma disrupts the continuity of normal structures, cleaving paths for the invading tumor cells. Stroma is also present at the heart of the tumor, but only as a secondary event following tumor advancement and subsequent incorporation of its periphery into inner tumor areas. The new stroma, composed of stromal cells and extracellular matrix (ECM), is loose and edematous at the expanding tumor fronts, and rather dense in central tumor areas and sites of tumor metastasis. The stromal cells facing tumor invasion are intensely proliferating (high MIB-1 index) spindle-shaped cells, alpha-smooth muscle actin positive, and loaded with thymidine phosphorylase (TP) and SPARC (secreted protein acidic and rich in cysteine). The associated ECM is rich in collagen III, SPARC, and new blood vessels (CD31) but is depleted of collagen I and fibronectin. These constitutional changes render stromatogenesis amenable to tumor cell invasion and are, in cases of incipient neoplasia, a prospective criterion of early stromal invasion. Other stromal cell or ECM constituents, such as the lactate dehydrogenase-5 (LDH-5), the acidic fibroblast growth factor (aFGF), the basic FGF (bFGF), and the collagens II and IV, remain unchanged, and others are negative: myosin, desmin, S-100 protein and epidermal growth factor receptor (EGFR). The mechanism of stromatogenesis is obscure but is probably stimulated by specific stromatogenic growth factors, released by neoplastic and inflammatory cells. It appears that the process is neither neoplastic nor reactive, but rather is a, hereto unexplained, phenomenon of host's complicity in tumor progression.     

Natural selection of tumor variants in the generation of "tumor escape" phenotypes

The idea that tumors must "escape" from immune recognition contains the implicit assumption that tumors can be destroyed by immune responses either spontaneously or as the result of immunotherapeutic intervention. Simply put, there is no need for tumor escape without immunological pressure. Here, we review evidence supporting the immune escape hypothesis and critically explore the mechanisms that may allow such escape to occur. We discuss the idea that the central engine for generating immunoresistant tumor cell variants is the genomic instability and dysregulation that is characteristic of the transformed genome. "Natural selection" of heterogeneous tumor cells results in the survival and proliferation of variants that happen to possess genetic and epigenetic traits that facilitate their growth and immune evasion. Tumor escape variants are likely to emerge after treatment with increasingly effective immunotherapies.     

Primary malignant giant cell tumor of bone: "dedifferentiated" giant cell tumor

Well documented examples of primary malignant giant cell tumor of bone (giant cell tumor and concurrent sarcoma arising de novo) are exceedingly rare in the literature. We report a case arising in the left ischium of a 44-yr-old man. He had no previous history of radiation therapy or multiple resections. Histologically, the tumor was a typical giant cell tumor of bone juxtaposed to a malignant fibrous histiocytoma (MFH). The juxtaposition of a high grade sarcoma (MFH) and a locally aggressive nonmalignant neoplasm such as giant cell tumor is analogous to several other tumors of bone and soft tissue in which a low grade malignant or locally aggressive tumor can be associated with MFH or fibrosarcoma de novo, namely chondrosarcoma, chordoma, liposarcoma, and well differentiated intraosseous and parosteal osteosarcoma. The presence of a high grade malignant component in each of the aforementioned neoplasms generally portends a more ominous prognosis, although this is not invariably true. Recognition of the phenomenon of "dedifferentiation" (or tumor progression) in some bone tumors and sarcomas is important to ensure appropriate treatment. Distinction from secondary malignant giant cell tumors which are usually radiation induced is also important, since the latter have a much worse prognosis than those with dedifferentiation occurring de novo.     

A "sugar" tumor of the lungs]

Histological structure of a rare benign tumor ("sugar" tumor of the lung) is described.     

"Brunneroma": hamartoma or tumor?

Clinically relevant "tumors" of duodenal glands (Brunner's glands) are uncommon. We present a patient suffering from an exceptionally large tumor of the pars descendens of the duodenum. The tumor remained undetected at endoscopy and is of interest because of its localization, size and its presumable production of urogastrone (human epidermal growth factor). "Brunneromas" are probably hamartomas rather than true neoplasias.     

"Somatostatinoma": a somatostatin-containing tumor of the endocrine pancreas.

We studied the pancreatic and enteric hormone profile of a 46-year-old woman who had hyperglycemia and a pancreatic tumor. Before operation, there was no evidence of overproduction of glucagon or insulin. The tumor's ultrastructure had a distinctive endocrine morphology, resembling D cells. Prompted by the recent demonstration of somatostatin in D cells of pancreatic islets, we analyzed the tumor and found a large quantity of immunoreactive somatostatin (301 ng per milligram of tissue). Insulin, glucagon, gastrin, vasoactive intestinal polypeptide and human pancreatic polypeptide were present in only trace quantities. The tumor cells were cultured in monolayers, which remained viable up to 51 days and released somatostatin into the culture medium. In seven insulinomas and two glucagonomas, we found the somatostatin content either much lower (less than 0.6 ng per milligram of tissue) or undetectable. After complete resection of the tumor, our patient became euglycemic and has remained so for the past 20 months.     

Malignant tumor of humerus with features of "adamantinoma" and Ewing's sarcoma

This female patient was born in 1935 and died in 1976 with a malignant bone tumor involving the proximal humerus following multiple local recurrences, axillary lymph node metastases, and pulmonary metastases. Histologically, over the course of time, there was an increase in features of an atypical Ewing's sarcoma, at the expense of findings of a typical, extra-cranial so-called adamantinoma. In contrast to another report, our case showed neither epithelial nor endothelial features on fine structural examination, but rather primitive mesenchymal cells, as is described for Ewing's sarcomas.     

Cytogenetic heterogeneity of genetically marked and metastatically competent "dominant" tumor cell clones

Examination of tumors usually shows them to consist of phenotypically and clonally heterogeneous cell subpopulations. On the other hand, previous studies from our laboratory have provided compelling evidence for the rapid evolution, or overgrowth, of single "dominant" clones during the course of primary tumor growth. Thus in one such study, syngeneic CBA mice were injected with a mixture of 50-100 different genetically tagged clones of a mouse mammary carcinoma called SP1. The vast majority of these clones were non-metastatic. The different clones were tagged by random integrations of foreign DNA using calcium phosphate-mediated transfection of the plasmid pSV2neo, the resultant primary tumors were found to consist of a single dominant clone, called B5, which was also shown to be metastatically competent. The detection of single dominant clones such as B5 in primary tumors can be reconciled with the concept of tumor cell heterogeneity if it could be shown that the dominant clone was in fact heterogeneous for other genetic or phenotypic markers, i.e., was homogeneous only for the plasmid-based genetic marker used for its detection. To study this question, we examined the karyotypes of several sublines of B5, two derived from a primary advanced tumor and one from a spontaneous lung metastasis. We indeed found evidence to support the existence of marked cellular heterogeneity within and between the three sublines examined. Thus, while all three retained common cytogenetic markers, each also expressed unique markers. Moreover, karyotypic heterogeneity within a given subline was observed. Thus the concept of clonal dominance of primary tumors by metastatically competent cell subpopulations is not incompatible with the concept of the cellular heterogeneity of tumors. The implications of the results are discussed.     

A histological and immunoenzymatic study on the histogenesis of "giant cell tumor of bones"

We carried out a prospective histologic and immunoenzymatic study, using lysozyme and AI-antichymotrypsin, of 15 well documented cases of giant cell tumors of bones. The histologic appearance of the majority of the tumors was characterized by great pleomorphism. The predominant histologic patterns could be classified as either fibroblastic or histiocytic. Mitoses were seen exclusively on stromal mononuclear cells. All tumors showed positive marking with both lysozyme and AI-antichymotrypsin. The enzymatic activity was more pronounced in areas of conventional histology and appeared as coarse orange-brown granules in the cytoplasm of many mononuclear and multinucleated giant cells. Enzyme-positive cells were less frequently found in fibroblastic areas of the tumor and especially in areas with minimal differentiation. The results indicate that giant cell tumor of bones may result from the neoplastic proliferation of mononuclear cells which in many areas of the tumor differentiate to either fibroblasts or histiocytes. Thus, giant cell tumor of bones may be analogous to fibrohistiocytic tumors of soft tissues.     

Rare lung tumors ("sclerosing hemangioma" and "intravascular sclerosing bronchioloalveolar tumor")

4 observations of rare lung tumours are described: one case of "sclerosing haemangioma" (SH), two cases of "intravascular sclerosing bronchioloalveolar tumour" (ISBT) and one case of asymptomatic disseminated lung lesion considered as angiosarcomatous variant of ISBT with a stroma amyloidosis (it differed from classical ISBT in former observations). Although the necessity of differential diagnosis of SH and ISBT is indicated in the literature, the comparative study of these tumours shows them to be completely different morphologically.