Because most colorectal carcinomas appear to arise from adenomas, studies of different stages of colorectal neoplasia may shed light on the genetic alterations involved in tumor progression. We looked for four genetic alterations (ras-gene mutations and allelic deletions of chromosomes 5, 17, and 18) in 172 colorectal-tumor specimens representing various stages of neoplastic development. The specimens consisted of 40 predominantly early-stage adenomas from 7 patients with familial adenomatous polyposis, 40 adenomas (19 without associated foci of carcinoma and 21 with such foci) from 33 patients without familial polyposis, and 92 carcinomas resected from 89 patients. We found that ras-gene mutations occurred in 58 percent of adenomas larger than 1 cm and in 47 percent of carcinomas. However, ras mutations were found in only 9 percent of adenomas under 1 cm in size. Sequences on chromosome 5 that are linked to the gene for familial adenomatous polyposis were not lost in adenomas from the patients with polyposis but were lost in 29 to 35 percent of adenomas and carcinomas, respectively, from other patients. A specific region of chromosome 18 was deleted frequently in carcinomas (73 percent) and in advanced adenomas (47 percent) but only occasionally in earlier-stage adenomas (11 to 13 percent). Chromosome 17p sequences were usually lost only in carcinomas (75 percent). The four molecular alterations accumulated in a fashion that paralleled the clinical progression of tumors. These results are consistent with a model of colorectal tumorigenesis in which the steps required for the development of cancer often involve the mutational activation of an oncogene coupled with the loss of several genes that normally suppress tumorigenesis.

Genetic alterations during colorectal-tumor development.

Mutations in codon 12, 13, or 61 of one of the three ras genes, H-ras, K-ras, and N-ras, convert these genes into active oncogenes. Rapid assays for the detection of these point mutations have been developed recently and used to investigate the role mutated ras genes play in the pathogenesis of human tumors. It appeared that ras gene mutations can be found in a variety of tumor types, although the incidence varies greatly. The highest incidences are found in adenocarcinomas of the pancreas (90%), the colon (50%), and the lung (30%); in thyroid tumors (50%); and in myeloid leukemia (30%). For some tumor types a relationship may exist between the presence of a ras mutation and clinical or histopathological features of the tumor. There is some evidence that environmental agents may be involved in the induction of the mutations.

https://cancerres.aacrjournals.org/content/canres/49/17/4682.full.pdf

ras Oncogenes in Human Cancer: A Review

The urokinase-type plasminogen activator (u-PA) system consists of the serine proteinases plasmin and u-PA; the serpin inhibitors alpha2-anti-plasmin, PAI-1 and PAI-2; and the u-PA receptor (u-PAR). Two lines of evidence have strongly suggested an important and apparently causal role for the u-PA system in cancer metastasis: results from experimental model systems with animal tumor metastasis and the finding that high levels of u-PA, PAI-1 and u-PAR in many tumor types predict poor patient prognosis. We discuss here recent observations related to the molecular and cellular mechanisms underlying this role of the u-PA system. Many findings suggest that the system does not support tumor metastasis by the unrestricted enzyme activity of u-PA and plasmin. Rather, pericellular molecular and functional interactions between u-PA, u-PAR, PAI-1, extracellular matrix proteins, integrins, endocytosis receptors and growth factors appear to allow temporal and spatial re-organizations of the system during cell migration and a selective degradation of extracellular matrix proteins during invasion. Differential expression of components of the system by cancer and non-cancer cells, regulated by paracrine mechanisms, appear to determine the involvement of the system in cancer cell-directed tissue remodeling. A detailed knowledge of these processes is necessary for utilization of the therapeutic potential of interfering with the action of the system in cancers.

The urokinase-type plasminogen activator system in cancer metastasis: a review

RAS proteins are essential components of signalling pathways that emanate from cell surface receptors. Oncogenic activation of these proteins owing to missense mutations is frequently detected in several types of cancer. A wealth of biochemical and genetic studies indicates that RAS proteins control a complex molecular circuitry that consists of a wide array of interconnecting pathways. In this Review, we describe how RAS oncogenes exploit their extensive signalling reach to affect multiple cellular processes that drive tumorigenesis.

/pdf/ras-oncogenes-weaving-a-tumorigenic-web-3ae4v7jug2.pdf

RAS oncogenes: weaving a tumorigenic web

The text consists of two sections, one for those studying or practicing diagnostic radiology, nuclear medicine and radiation oncology; the other for those engaged in the study or clinical practice of radiation oncology--a new chapter, on radiologic terrorism, is specifically for those in the radiation sciences who would manage exposed individuals in the event of a terrorist event. The 17 chapters in Section I represent a general introduction to radiation biology and a complete, self-contained course especially for residents in diagnostic radiology and nuclear medicine that follows the Syllabus in Radiation Biology of the RSNA. The 11 chapters in Section II address more in-depth topics in radiation oncology, such as cancer biology, retreatment after radiotherapy, chemotherapeutic agents and hyperthermia.

Radiobiology for the Radiologist

Background: Differentiation of melanoma from melanocytic nevi is difficult even for skin cancer specialists. This motivates interest in computer-assisted analysis of lesion images. Objective: Our purpose was to offer fully automatic differentiation of melanoma from dysplastic and other melanocytic nevi through multispectral digital dermoscopy. Method: At 4 clinical centers, images were taken of pigmented lesions suspected of being melanoma before biopsy. Ten gray-level (MelaFind) images of each lesion were acquired, each in a different portion of the visible and near-infrared spectrum. The images of 63 melanomas (33 invasive, 30 in situ) and 183 melanocytic nevi (of which 111 were dysplastic) were processed automatically through a computer expert system to separate melanomas from nevi. The expert system used either a linear or a nonlinear classifier. The "gold standard" for training and testing these classifiers was concordant diagnosis by two dermatopathologists. Results: On resubstitution, 100% sensitivity was achieved at 85% specificity with a 13-parameter linear classifier and 100%/73% with a 12-parameter nonlinear classifier. Under leave-one-out cross-validation, the linear classifier gave 100%/84% (sensitivity/specificity), whereas the nonlinear classifier gave 95%/68%. Infrared image features were significant, as were features based on wavelet analysis. Conclusion: Automatic differentiation of invasive and in situ melanomas from melanocytic nevi is feasible, through multispectral digital dermoscopy. (J Am Acad Dermatol 2001;44:207-18.)

https://www.jaad.org/article/S0190-9622(01)03432-6/pdf

Automatic differentiation of melanoma from melanocytic nevi with multispectral digital dermoscopy: A feasibility study

Evidence suggests that the plasminogen activators (PAs), in particular urokinase-type PA (uPA), play a pivotal role in tumor invasion and metastasis. We studied the contribution of the PAs to the malignant phenotype through the chemical induction of melanocytic neoplasms in uPA-deficient mice. Primary tumors were induced and promoted concurrently in 35 uPA -/- deficient and 35 uPA +/+ wild-type mice using a single application of 7,12-dimethylbenz(a)anthracene followed by repetitive applications of croton oil. Animals were sacrificed at 60-day intervals for 1 year. At necropsy, the four largest pigmented lesions in each animal were excised, characterized histologically, and evaluated microscopically for evidence of invasion. The regional lymph nodes, lungs, and solid abdominal visceral organs were sectioned and examined microscopically for evidence of metastatic disease. Cellular blue nevi were induced in 100% of uPA -/- and uPA +/+ promoted animals. Although a reduction in the radial and vertical progression of these lesions was noted in the uPA-deficient mice compared with the wild-type group, more than 95% of cellular blue nevi induced in both groups of animals invaded the underlying tissues. These lesions did not metastasize to the regional lymph nodes. Malignant melanoma arose in 5 of 35 (14.3%) of promoted wildtype mice. These tumors were locally aggressive, produced tissue-type PA, but were not metastatic to the regional nodes, lungs, or abdominal viscera. These results indicate that the invasive capability of melanocytic lesions may depend more on tissue-type PA than uPA activity. No melanomas were induced in the uPA -/- mice. The resistance of the uPA -/- strain to melanoma induction suggests that uPA contributes to malignant progression. We propose that the absence of uPA negatively affects tumorigenesis by decreasing the liberation and availability of growth factors such as basic fibroblast growth factor.

https://cancerres.aacrjournals.org/content/canres/56/15/3597.full.pdf

Induction of Primary Cutaneous Melanocytic Neoplasms in Urokinase-Type Plasminogen Activator (uPA)-deficient and Wild-Type Mice: Cellular Blue Nevi Invade but Do Not Progress to Malignant Melanoma in uPA-deficient Animals

Dull pink globules were found within the epidermis in 65% of junctional, 75% of compound, and 25% of intradermal types of Spitz's nevi (the nevi of large spindle and/or epithelioid cells). These globules were PAS-positive, diastase-resistant and also were positive with the trichrome stain. Similar-appearing eosinophilic globules were noted in the epidermis in only 2% of malignant melanomas and in but 0.9% of ordinary melanocyte nevi. The globules in malignant melanomas and in ordinary melanocytic nevi were negative with PAS and trichrome stains. Therefore, the finding of PAS- and tri-chrome-positive eosinophilic globules within the epidermis is a helpful sign for histologic differentiation of Spitz's nevus from malignant melanoma.The histologic differentiation of Spitz's nevus (the nevus of large spindle and/or epithelioid cells) from malignant melanoma is of utmost importance in dermatopathology. Most authors agree that no single histologic finding enables absolute differentiation of the benign neoplasm from the malignant one. One of us (HK), while reviewing a large series of melanocytic lesions, observed distinctive eosinophilic globules within the epidermis and the dermis of many specimens of Spitz's nevus. The microscopic appearance of these globules and their significance is the subject of this paper.

Eosinophilic globules in Spitz's nevi: New findings and a diagnostic sign.

When dermatofibromas are composed predominantly of fibroblasts and extend into the subcutaneous tissue, it may be difficult to distinguish them from dermatofibrosarcoma protuberans. Because the patterns of extension of dermatofibroma have not been well characterized, we studied 185 cases of the fibrous variant of dermatofibroma with extension into the subcutaneous tissue and 40 cases of dermatofibrosarcoma protuberans. Dermatofibromas had two main patterns of extension into subcutaneous tissue. One pattern, seen in 133 of 185 cases (72%), consisted of irregular extension into the subcutaneous tissue in a vertical or radial fashion, predominantly along the septa, which appeared wedge-shaped. The other pattern, seen in 52 of 185 cases (28%), showed a smooth and well-demarcated deep margin that bulged into the subcutaneous tissue. Dermatofibrosarcoma protuberans also had two main patterns of extension into the subcutaneous tissue. In one pattern, seen in 12 of 40 cases (30%), slender spindle-shaped cells extended along septa and between fat cells in a classic honeycomb or lacelike pattern. The other pattern observed in 24 of 40 cases (60%) exhibited a distinct multilayered pattern in which the bundles of slender spindle-shaped cells showed a predominantly parallel orientation to the skin surface. In four cases (10%), a mixture of both patterns was present. We conclude that the patterns of extension of dermatofibroma into the subcutaneous tissue are different from the patterns of dermatofibrosarcoma protuberans.

Dermatofibroma extending into the subcutaneous tissue. Differential diagnosis from dermatofibrosarcoma protuberans

Background: Lichen planopilaris (LPP) is the prototype of scarring alopecias that mainly target the infundibuloisthmic (bulge) region of hair follicle. Hair follicle stem cells have been shown to reside in the bulge.

Methods:  We carried out this study to better define the possible pathogenetic role of the bulge in LPP. Thirty-five cases of LPP were studied. Multiple serial sections of biopsy specimens stained with hematoxylin and eosin, periodic acid Schiff-diastase, and Elastic van Gieson. The following immunostains were applied: CD3, CD4, CD8, CD1a, and Ki-67. Uninvolved follicles and normal scalp biopsy specimens served as normal controls.

Results:  All cases showed a lichenoid lymphocytic infiltrate at the bulge region. The bulb area was spared. CD8+ T cells were increased compared with CD4+ T-cell population. Langerhans' cells were decreased. Proliferating stem cells, highlighted by Ki-67, showed a marked decrease in the bulge compared with uninvolved follicles.

Conclusion:  Our study supports the finding that in LPP, the inflammatory infiltrate mainly involves the bulge region, where the stem cells reside. Once this area is damaged, the hair loses its potential of regrowth with resulting scarring alopecia. This is in contrast with inflammatory non-scarring alopecias such as alopecia areata, where the bulb region is targeted, sparing the stem cells.

Hideko Kamino

Papers

Automatic differentiation of melanoma from melanocytic nevi with multispectral digital dermoscopy: A feasibility study

Induction of Primary Cutaneous Melanocytic Neoplasms in Urokinase-Type Plasminogen Activator (uPA)-deficient and Wild-Type Mice: Cellular Blue Nevi Invade but Do Not Progress to Malignant Melanoma in uPA-deficient Animals

Eosinophilic globules in Spitz's nevi: New findings and a diagnostic sign.

Dermatofibroma extending into the subcutaneous tissue. Differential diagnosis from dermatofibrosarcoma protuberans

Possible role of the bulge region in the pathogenesis of inflammatory scarring alopecia: lichen planopilaris as the prototype