In 1976, Lane and Fenoglio used the terms "intraepithelial (mucosal) carcinoma," "carcinoma in situ" and "intraepithelial neoplasia" instead of dysplasia (Morson, 1974). [20] Using some photomicrographs, they attempted to define precursor lesions in the colon. They showed adenoma and carcinoma in situ as two morphologically different lesions and regarded the former to be the precursor of the latter. For them, both lesions were recognizable by conventional microscopy. They defined a precursor lesion such as this: "The term precursor tissue is synonymous with precancerous or preneoplastic lesion or tissue. This term implies that cancer will develop in such an abnormal focus with far greater frequency than seemingly morphologically normal adjacent tissue. Furthermore, it is apparent that the detection and removal of such a precursor tissue will reduce the incidence of colorectal carcinoma." [20]

One year later, Fenoglio and associates said the following about a precursor lesion: "In order to define the precursor tissue of ordinary large bowel carcinoma, particular attention will be given to the terminology. We have attempted to use simple accurate terms, with the help of diagrams and illustrations, so that internists, surgeons, radiologists, and pathologists will have the same mental image of what we are dealing with, in order to facilitate the communication that is so necessary for proper diagnosis and treatment in this field." [21] The authors showed some photomicrographs to demonstrate adenomatous tissue as a precursor lesion. In these pictures they marked the areas of so-called intramucosal carcinoma or carcinoma in situ that for them contrasted with adjacent adenomatous tissue at scanning magnification. It is worthwhile to note that in the previous article published by them, all changes in the same photomicrographs were considered as "intraepithelial neoplasia" (equivalent to precancer or dysplasia by Morson). Based on cytopathologic attributes of the cells, what they showed as precursor adenoma for us is carcinoma in situ. (Figs. 1, 2)

In 1981, at a symposium about colonic "dysplasia" in ulcerative colitis, [3] Fenoglio, Pascal, Haggitt, Hamilton, Lumb, and Riddell as members of a panel shared their thoughts and ideas to assess definitions and histopathological criteria for diagnosis of atypia, dysplasia, premalignant changes, precancer, and carcinoma in situ in ulcerative colitis. Criteria for diagnosis used by them were very different from one another; no agreement was reached in regard to a unifying terminology. [3] All members of the panel acknowledged, however, that there is no consistent system to define these lesions and Riddle emphasized that with these words: "The sections on dysplasia in ulcerative colitis still appear to indicate that there is considerable divergence of opinion especially with regard to terminology. This is rather unfortunate since several of the authors in this symposium have met at intervals to discuss this problem and even to look at slides together . . . The reader should therefore not leave the symposium with the idea that dysplasia in ulcerative colitis is in the same mess that it has been for the last decade ago or so. Dysplasia of the uterine cervix went through the same birth pangs. Inevitable discrepancy occurs when a subjective grading system is used to examine a spectrum of changes." [3]

At the same symposium, Fenoglio and Pascal suggested to use the term "colorectal intramucosal neoplasia (CRIN)" for defining so-called adenomatous changes in ulcerative colitis. They also suggested grading these lesions from I to III, which for them encompassed and covered all transitional forms such as "mild atypia," "severe dysplasia," "carcinoma in situ," "precancer," and "premalignant lesions." They believed the term CRIN to be understandable among pathologists, gastroenterologists, and surgeons. [3] In fact, they adopted the term as well as the system for classification from a similar system suggested by Richard in 1973 that he used for classification of so-called precancerous lesions of cervical mucosa and for which he suggested the unifying term "cervical intraepithelial neoplasia" (CIN). [22]

It was clear, however, that reproducibility of diagnosis of "colorectal intramucosal neoplasia (CRIN)" as conceived of by Fenoglio is low and this was actually confessed by him already in these words: "Since these changes represent a continuous spectrum of disease, even with a system of nomenclature as described above, there will be some lesions which will not fit precisely into one category or another. The degree of cellular pleomorphism which places a given lesion into a Grade II or a Grade III category will reflect the pathologist's judgments. In addition, among the early Grade I lesions there are bound to be a "gray zone," where it will be difficult, if not impossible, to distinguish neoplastic epithelium from regenerative epithelium." [3]

Fenoglio and Pascal always emphasized that there is no need to grade dysplasia because they regarded that separation to be artificial. They used the term "colorectal intraepithelial neoplasia" (CRIN), but although this term is more understandable than dysplasia, it also lacks precision and is not a specific diagnosis. The term encompassed a variety of lesions from reactive regenerative proliferation to cellular changes of overt carcinoma. Fenoglio and Pascal viewed it as follows: "One can easily compare this situation with the evolution of meaningful knowledge in the field of uterine cervical cancer. It was proved that cervical dysplasia of increasing grades and carcinoma in situ is a continuous spectrum in the development of cancer. If the artificial distinction between dysplasia and carcinoma in situ had been preserved and only the latter been recognized as a lesion requiring therapy, the incidence of cervical cancer would probably not have been reduced. The use of the term "cervical intraepithelial neoplasia" abolished that distinction and allowed us to think more rationally about the approach to such preinvasive lesions. It now seems that three major categories are clinically important: nonneoplastic, intraepithelial neoplasia, and invasive carcinoma."[3]

In another article published by Fenoglio and Pascal in 1982, they described and illustrated different stages of the development of an invasive carcinoma from a benign adenoma morphologically, but they did not mention the criteria morphologically by which they were able to separate these stages of development. [23] Although the integrity of an adenoma-carcinoma sequence and the precancerous nature of an adenoma was emphasized in their article, they never used "dysplasia" to describe these transitional stages, as Morson did before. Figure 3 shows the diagram used by Fenoglio and Pascal in the article published in 1982 for defining transitional stages. This picture had been used by them in 1977and 1981, too. This is what the authors had to say about the sequence as it was perceived by them: "As in the cervix, there is a histologic spectrum of degrees of neoplasia of the colonic crypt epithelium. The first neoplastic alteration is the formation of an adenomatous cell population (g). Cytologically, these cells are benign. Next in the morphologic continuum is an intraepithelial carcinoma (h) in which the epithelial cells have all the cytologic characteristics of a malignant cell population, but they are confined to the original crypt of Lirberkuhn and do not invade the surrounding lamina propria. This is followed by intramucosal carcinoma (i) in which the cytologically malignant cells are present in the glands as well as invading the intervening lamina propria . . . Once a tumor transgresses the muscularis mucosa (b) it is said to be invasive (j) and at this point, becomes a clinically important lesion which is capable of metastasis. For the purpose of this study, any malignant cell population found in adenoma and confined to the mucosa was classified as A0 (intraepithelial) & A1 (intramucosal)." [24] For us, these stages show a growth of a single process, a continuous spectrum of one disease, namely, progression, not transformation, of in situ carcinoma to invasive carcinoma.