One of the most familiar microscopic images in the repertoire of human tumors is that offered by cutaneous basal cell carcinoma of the skin. As a result of its high frequency and the distinctiveness of its low-power histologic appearance, it has become one of the prototypical examples of "instant pattern recognition" among surgical pathologists and dermatopathologists alike. Indeed, it is the standard against which similar tumors in other parts of the body are compared, in the sense that that if they are thought to recapitulate that pattern of growth they are descriptively designated as basaloid. The purpose of this presentation is to advance the hypothesis that the basaloid pattern seen in basal cell carcinoma and all its congeners represents the morphologic expression of a common histogenetic theme, i.e., the activation or derepression through neoplastic transformation of a mechanism by which the normal cells of the region differentiate in an attempt to form whatever adnexal structures are present at that particular site.

THE BASALOID TUMORS FAMILY
The major tumor types to which the terms basal cell or basaloid have been applied include:

1 - Basal cell carcinoma of skin
The term was first proposed by Krompecher because of his belief that this tumor arose from the basal cell layer of the skin, i.e., the layer of cells of the stratum malpighii also known as stratum basale or stratum germinativum, which borders on the dermis and which was viewed as the progenitor of the cells in the upper epidermal layers. This tumor type was contrasted with the previously described squamous cell carcinoma (squamous cell epithelioma; prickle cell carcinoma or epithelioma), a tumor thought to differentiate along the more superficially located prickle cell of the stratum malpighii. The very fact that Krompecher called the tumor "basal cell epithelioma" rather than "basal cell carcinoma" is further evidence of his belief that this tumor arose from surface rather than adnexal epithelium, being that at the time the term epithelioma was used for tumors of the surface epithelium, whereas that of carcinoma was employed for malignant tumors of the glands. The progressive replacement of "basal cell epithelioma" for "basal cell carcinoma" in the course of the years was not due to a change of opinion regarding its presumed histogenesis but rather the consequence of the tendency to designate all malignant epithelial tumors as carcinomas regardless of subtype. No significant changes in terminology have been made in the course of the past 50 years, to the point that one can safely say that the term "basal cell carcinoma" (with its implied origin from the epidermal basal layer) is one of the most entrenched in tumor pathology.

2 - Basaloid carcinoma of anal canal
The terminology used over the years for this tumor has been a great source of confusion. I am referring to the malignant neoplasm centered in the strip of non-keratinizing squamous mucosa lining the anal canal, bound by the perianal skin at one end and columnar mucosa at the other. Originally it was described as a squamous cell carcinoma with various degrees of keratinization, but subsequent observers noted the morphologic similarities with cutaneous basal cell carcinoma, urged to distinguish it from the latter because of its vastly more aggressive behavior, and suggested for it to be called basaloid carcinoma. An interesting semantics twist occurred when the "transitional" features of the epithelium lining the anal canal were noted, with the suggestion that they were the result of the common origin of this region of the digestive tract and the bladder from the embryologic cloaca, and the ensuing proposal to designate this tumor as cloacogenic carcinoma. However, ultrastructural and other observations have provided evidence against the validity of this concept, and the circle has been closed by returning to the original concept that carcinomas of the anal canal are basically squamous cell carcinomas. That may well be the case, but the fact that they usually have basaloid features cannot be denied.

3 - Basaloid carcinoma of upper aerodigestive tract
This tumor shares many morphologic and behavioral similarities with the tumor just described, in that it arises from non-keratinizing squamous epithelium, it exhibits basaloid features, and is characterized by aggressive behavior. It can occur anywhere in the region, although it seems to predilect the "digestive" rather than the "aerial" portion of the tract, in the sense that it is more common in the oral cavity, orohypopharynx and esophagus than in the nasal cavity, paranasal sinuses, nasopharynx, or larynx. As basaloid tumor of the anal canal, this neoplasm has been interpreted by some as "probably nothing more than another unusual histologic variant of squamous cell carcinoma". Also in analogy with the anal canal tumors, authors have warned pathologist not "to use the term basal cell carcinoma for such tumors" because "unwary are apt to be misled by the term". Interestingly, it has been stated that confusion with ameloblastoma should also be avoided, and that the presence of a focal squamous cell carcinoma component among the basaloid areas is the most important distinguishing feature. Regrettably, no mention of basaloid carcinoma was made in the most recent edition of the WHO Book on "Histologic typing of Oesophageal and Gastric Tumors".

4 - Basaloid proliferation of skin overlying dermatofibromas
The curious phenomenon, long known to dermatopathologists, has been thought to be the result of "stimulation" of the epidermal basal layer by the dermal lesion, with the resulting induction of abortive hair follicle structures. It is regarded as a benign and probably non-neoplastic event, to be distinguished from the "true" basal cell carcinoma that is rarely found overlying the same dermal lesion.

5 - Ameloblastoma
This tumor of the jaw, formerly known as adamantinoma, is universally regarded as originating from odontogenic epithelium and is thought to recapitulate embryonal structures of the tooth germ. In its conventional follicular pattern, the tumor islands consist of a central mass of polyhedral or angular cells resembling stellate reticulum, surrounded by a palisaded layer of cuboidal or columnar cells. When the basaloid pattern is particularly pronounced, the tumor has been sometimes confusingly referred to as basal cell ameloblastoma. It should also be mentioned that in some primary intraosseous carcinomas of the jaw there are basal-type cells forming alveoli or arranged in a plexiform pattern, with palisading of the peripheral cells.

6 - Adamantinoma of long bones
This mysterious primary bone neoplasm, to which the old term "adamantinoma" is still attached by virtue of its morphologic resemblance to the aforementioned ameloblastoma, is usually found within the shaft of the tibia. It varies considerably in morphologic appearance from case to case, but its most distinctive pattern (and the one that has given rise to most histogenetic speculations) is best described as basaloid, because of the columnar shape and palisaded distribution of the peripheral cells and the stellate arrangement of the central cells.

7 - Basaloid tumors at other sites, such as uterine cervix, prostate, and salivary glands.

THE UNIFYING EMBRYOLOGIC THEME
During embryologic development, the fact that an adnexal structure will be formed at a particular site along an epithelial lining is first manifested by an area of crowding of deeply basophilic cells in the basal layer of that epithelium, accompanied by an elongation of these cells perpendicularly to the basement membrane. Subsequently, the areas of crowding develop into buds that protrude into the underlying stroma, and a palisading of the columnar epithelial cells distributed at the periphery of these buds becomes prominent. The stroma surrounding these buds is thought to be the "inducer" of this development. In subsequent stages, the bud will develop into whatever adnexal structure it was programmed to become, i.e., pilosebaceous units in the skin, salivary gland-type glands in the upper aerodigestive tract, perianal glands in the anal canal, and teeth in the oral cavity. This formation is referred as hair germ in the skin and as tooth germ in the jaw. For the sake of discussion, this formation will be henceforth referred to as adnexal bud regardless of which adnexal structure is supposed to develop into.

THE ADNEXAL BUD COMPONENT OF BASALOID CARCINOMAS
1 - Basal cell carcinoma of skin
The fact that basal cell carcinoma of the skin is anything but an undifferentiated tumor of epidermal basal cells was apparent to some of the early students of this tumor. Mallory remarked on the morphologic similarities with the embryonal hair follicle and went as far as designating it "hair matrix carcinoma". Foot followed suit and proposed the term "adnexal carcinoma". Masson expressed "repugnance" at the term basal cell carcinoma on similar grounds. In the first edition of his book, Walter Lever placed basal cell carcinoma among the tumors of skin appendages. Curiously, this histogenetic connection between basal cell carcinoma and hair follicles became blurred in recent times, and it was flatly denied by some authors.

In our opinion, basal cell carcinoma is a skin neoplasm whose distinctive appearance derives from the formation of adnexal buds, and that these buds represent a primitive attempt of skin adnexal structures, primarily of hair follicle type. The evidence in favor of this hypothesis is considerable. Basal cell carcinoma of the skin occurs with a frequency that is directly related to the density of pilosebaceous units of the region, and is practically absent in region when such structures do not occur, such as palms and soles. In some cases, the differentiation toward follicular structures is even more obvious, a good example being the tumor known as basal cell carcinoma with follicular differentiation. I am not aware of any absolutely specific markers of immature hair follicle epithelium, but if they existed, I predict that cutaneous basal cell carcinoma would exhibit them.

2 - Basaloid carcinoma of anal canal
Here the adnexal bud differentiation is towards the glands of the region, which are usually simply referred to as anal or perianal glands. These have an elongated ductal portion and an acinar component of mucous type, which is deeply embedded within the muscle fibers of the region.

3 - Basaloid carcinoma of upper aerodigestive tract
The component of this region which the adnexal bud is attempting to recapitulate is that of the mucous glands usually referred to, somewhat inappropriately, as minor salivary glands. The morphologic signs pointing to this fact are many. In addition to the basic basaloid pattern, they include the presence of abundant deposition of basement membrane material at the interphase between tumor and stroma and in between the tumor cells, sometimes resulting in an adenoid cystic carcinoma-like appearance.

4 - Basaloid proliferation of skin overlying dermatofibromas
There is no controversy about the nature of the adnexal bud in this circumstance, i.e., that it represents an attempt of hair follicle structures as a response to the stimulus by the underlying dermatofibroma. The reason why there is no argument here while there is one with basal cell carcinoma is simply because the differentiation towards hair follicles has proceeded further and is therefore more easily recognized. In the few cases in which it does not, the diagnosis then made is that of basal cell carcinoma overlying a dermatofibroma.

5 - Ameloblastoma
Here again, the nature of the adnexal bud is well known, i.e., formation of tooth germ structures. Specifically, the peripheral cells in a palisaded arrangement are thought to represent the neoplastic equivalent of internal dental epithelium or preameloblasts, whereas the centrally located cells are viewed as tumoral counterparts of the stellate reticulum. For the purposes of this discussion, a particularly interesting aspect of this lesion is the fact that sometimes it is seen arising from gingival epithelium, in which case the basaloid character of the proliferation and the similarities with the other tumors here discussed becomes even more evident.

6 - Adamantinoma of long bones
The nature of the adnexal bud in this tumor has been a great source of speculation and it remains a mystery. The similarities with ameloblastoma of the jaw led to the fanciful suggestion that the tumor results from the fetus having bitten himself while inside the uterus, thus implanting odontogenic epithelium within the tibia. Subsequent writers have drawn an analogy with skin adnexal structures, using as supporting argument the close proximity of tibia to the skin, the occasional occurrence of identical tumors in the soft tissues overlying the tibia, and the marked morphologic, ultrastructural and immunohistochemical similarities of the tumor with skin adnexal (and particularly sweat gland) neoplasms. One would have been tempted to speculate that the osteofibrous lesion sometimes accompanying adamantinoma of the tibia is the mesenchymal inducing agent for an epithelial neoplastic proliferation with adnexal buds, where it not for the fact that the mesenchymal cells themselves are keratin-positive, suggesting that they have the capacity to evolve into epithelial-like structures. Thus, one can only conclude that the histogenesis of this tumor and the nature of its adnexal bud (which is unquestionably there) remains to be established.

CONCLUSIONS
The unifying theme of this proposal is that the basaloid appearance of tumors results from the formation of adnexal buds attempting to recapitulate the adnexal structures normally present at that particular site. The similarities among the various buds are the consequence of the initial common structure, and their difference derive from the type of adnexae that the buds are destine to become. It is interesting that – with the possible exception of basal cell tumor of salivary glands - the formation of adnexal buds and basaloid tumors is a feature of squamous epithelium, whether keratinizing (skin) on non-keratinizing (anal canal, upper aerodigestive tract, uterine cervix). To be noted is the fact that some of the basaloid tumors are low-grade and rarely metastasizing (basal cell carcinoma of skin, ameloblastoma of jaw, and to some extent adamantinoma of long bones) whereas others are high-grade and with a high metastatic ratio (basaloid carcinomas of anal canal and upper aerodigestice tract). This distinction acquires important diagnostic connotations at some sites, such as the perineal region. Here, a basaloid tumor of the perineal skin or vulva is likely to be differentiating along cutaneous hair follicles structures and therefore be low-grade, whereas a basaloid tumor higher up in the anal canal is likely to be differentiating along perianal glands and therefore be high-grade.