Structure and significance of the pits with their tumors in the nevoid basal cell carcinoma syndrome

Structure and significance of the pits with their tumors in the nevoid basal cell carcinoma syndrome

Structure and significance of the pits with their tumors in the nevoid basal cell carcinoma syndrome* J. B. Howell, M.D., and Robert G. Freeman , M .D...

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Structure and significance of the pits with their tumors in the nevoid basal cell carcinoma syndrome* J. B. Howell, M.D., and Robert G. Freeman , M .D. Dallas , TX Parallel histopathologic, histochemical, scanning, and transmission electron microscopic (EM) observations were made on palmar pits of one patient and on palmar pits, with an unprecedented number of basal cell carcinomas, of another patient. The first scanning view of tumor growing into the lumen of a pit from the genetically defective epidermis below is presented. The anatomy of the pit is demonstrated for the first time by scanning view of a transected pit. Our observation s confirmed those of Hashimoto et aP on the mechanisms involved in premature desquamation of the stratum corneum and on the true nature of the epithelium at the base of the pit. This epithelium resembled closely basal cell epithelioma and represented carcinoma in situ. The striking demarcation afforded by the azure B stain of normal and abnormal portions of the palmar epidermis with pit and the poor stainability of the pit with tumor was likewise confirmed. The tumors exhibit aggressive behavior infrequently. (J AM ACAD DERMATOL 2:224-238, 1980.)

Five major stigmatizing features characterize the nevoid basal cell carcinoma (NBCC) syndrome, a genetic entity with dominant inheritance. They are: (I) multiple and usually aggressive basal cell carcinomas presenting at an early age; (2) epithelium-lined jaw cysts with connective tissue stroma supporting many small , distinctive mural cysts, which commonly cause symptoms; (3) a variety of skeletal anomalies, especially of the ribs, skull, and spine; (4) ectopic calcification; and (5) pits of the hands and feet. I The pits are a useful cutaneous marker, and, based on our experience, we believe they are a pathognomonic sign of the syndrome.f From the Division of Dermatology, Department of Internal Medicine (Dr. Howell) and Department of Pathology (Dr . Freeman). University of Texas Health Science Center. Reprint requests to: Dr. J. B. Howell. 862 Wadley Tower. Baylor Medical Plaza , 3600 Gaston Ave.• Dallas. TX 75246. *Portions were used for the Presidential Address to the American Dermatological Association, April 7. 1979. Del Coronado . CA.

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The pits typically are asymptomatic , permanent ,? and occur in approximately two thirds of the adults with the syndrome ." They are shallow depressions (usually 1 to 3 mm in depth and diameter), nonpalpable, and flesh-colored, pink, or red.! They are found only on the hands and feet. Pits of the palms or soles occur in other disorders, including Darier's disease (Fig. 1, A), punctate keratosis of the palmar creases, and pitted keratolysis, but those pits differ clinically and microscopically from the NBCC syndrome pits (Fig. 1, B). The prominent follicular orifices of follicular atrophoderma on the backs of the hands in Bazex syndrome:' are sometimes improperly referred to as pits, but they should not be confused with the pits of the NBCC syndrome. Light microscopic studies of the pits have shown thinning of the stratum granulosum, vacuolization of the stratum malpighii, and irregular shape and size of the rete ridges at the base of the pit. 2. 5 Electron microscopic (EM) studies of the 0190-9622/80/030224+15$01.50/0 © 1980 Am Acad Dermatol

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Fig. 1. A, Scanning EM surface view of replica of pits of Darier's disease on summit and side of one dennatoglyphic ridge. Darier 's pits are pits of sweat pores. B , Scanning EM surface view of replica of pits of the NBCC syndrome. These pits are larger, involve more than one dermatoglyphic ridge, and are not related to sweat pore structure. (Courtesy Drs. J. D. Wilkinson, R. A. Marsden, and R. P. R. Dawber.)

pits have shown poorly developed tonofibrils, small keratohyaline granules, incompletely discharged cementsomes, and premature desquamation of the horny cells ." Microscopic studies of numerous pits from a

small series of patients revealed a dramatic discovery, that of a basal cell epithelioma arising from the genetically altered epidermis beneath the pit. Pinkus was the first to find an early basal cell epithelioma- in serial sections of several palmar

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Fig. 2. Patient 1. Numerous pits and pits with their tumors. These many clearly visible, elevated, palpable, palmar basal cell carcinomas are developing from the g-enetically altered epidermis beneath the pits. This is the largest number of spontaneously occurring nevoid basal cell carcinomas of the palms thus far discovered. A, Left palm. B, Right palm.

pits from a 17-year-old boy. Holubar et al" found a basal cell epithelioma beneath each of three palmar pits taken for biopsy from an 8-year-old girl; Bernhard's examination of black dots on the palms of a 13-year-old black girl showed them to be pigmented basal cell epitheliomas arising from the epidermis underneath her pits." This report describes a spectacular case of multiple nevoid basal cell carcinomas of the palms developing from the defective epidermis at the base of the pits (Fig. 2). The remarkable number of pits with tumors-more than we had ever seen or had seen reported-prompted us to make an extensive histologic study of the pits and the pits with tumors in this patient. The results of histopathologic, histochemical, and scanning and transmission EM studies are reported here and are

compared with parallel studies made of palmar pits without tumors from another patient with the NBCC syndrome. CASE REPORTS The spectacular example of basal cell carcinomas (Fig. 3), growing from the epidermis under the palmar pits in unprecedented number (Patient 1), became available for investigation through the courtesy of Dr. James Maberry of Fort Worth, TX. A patient with typical pits, without tumors (Patient 2), was a man we were treating for numerous basal cell carcinomas of the face. He allowed us to use specimens of skin with pits from his left palm for comparison with Patient 1.

Case 1 In contrast to all other patients with pits of the hands and feet, Patient 1, a 46-year-old white woman, sought

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Fig. 3. A, Closer view of the left palm shown in Fig. 2, A. B. Closer view of the right palm shown in Fig. 2, B. dermatologic help because of the discomfort and sen sitivity produced by numerous small tumors on her palms. More usually, patients have asymptomatic pits with or without tumors and become aware of the pits only after having them pointed out. The clinical appearance of Patient 1's hands was striking. The tumors, which upon examination were associated with pits, stood out easily and could be identified even from a distance. This made them the most prominent clinical feature of this case . The patient had also become aware of an increasing number of small, pearly nodules developing over her nose, inner canthi, and nasomalar folds. Up to the time of our examination, only a few of the facial lesions had grown rapidly and had become invasive, ulcerous, or destructive. Our microscopic examination of the tumors from the palm and face revealed them to be basal cell carcinomas. The patient's 17-year-old daughter and her father, sister, and one brother were found to have pits of the hands . Her father also had several basal cell carcinomas

on his face. Neither the patient nor the members of her family whom we saw gave any history of jaw cysts. The patient and her family declined to be examined for ectopic calcification and developmental abnormalities of the skeleton. We diagnosed the patient's condition to be the NBCC syndrome, based on the presence of pits of her hands , the basal cell carcinomas of her face, and the family history of pits of the hands and basal cell carcinomas.

Case 2 A 35-year-old white man came for treatment of numerous infiltrating, destructive basal cell carcinomas that had appeared relatively early in life . A total of thirteen basal cell carcinomas (which were IOto 20 mm wide by 12 to 25 mm long) were remo ved by the open excision technic of curettage and electrodesiccation. These tumors were on his scalp, forehead, right ear, face, neck , chest, and shoulders. Microscopic analysis of eight lesions confirmed a diagnosis of basal cell carcinoma.

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The patient gave no history that suggested previous cases of the NBCC syndrome in his family. This patient, too, declined to be examined for the presence of jaw cysts, skeletal anomalies, ectopic calcification, or other associated defects. His condition was diagnosed as the NBCC syndrome, based not only on the location and behavior of the tumors but also on the presence of the characteristic pits on his hands. The patient was unaware of these pits until they were demonstrated to him by the examining physician (J. B. H.).

INVESTIGATIVE TECHNICS Using 2% lidocaine (Xylocaine) as a local anesthetic, skin punch biopsy specimens (4 to 6 mm in diameter) were taken. From Patient I, the specimens from two sites on the left index finger contained pits, and the specimens from three sites on the right palm contained tumors. From Patient 2, the specimens from two areas of the left palm contained pits . Tissue for routine microscopy was fixed in 10% neutral buffered formalin, embedded in paraffin, and processed routinely. Tissue for histochemistry was wrapped in aluminum foil, frozen in liquid nitrogen, and transferred to the laboratory . It was then mounted, and sections were made with the use of a cryostat. The sections were treated for reactions of phosphorylase , acid phosphatase, succinic dehydrogenase, and sulfhydryl and disulfide groups . These histochemical preparations and appropriate known positive control tissue for each technic were examined and photographed, and the results were recorded . Tissue for scanning and transmission EM was fixed immediately in 5% glutaraldehyde in phosphate-buffered saline (PBS) buffer, pH 7.4. It was then refrigerated at 4 C. For scanning EM, the fixed tissue was rinsed for two lO-minute periods in PBS buffer. It was dehydrated in 30%, 50%, 95%, and three changes of 100% acetone for 10 minutes in each solution. Then it was transferred to fresh 100% acetone in the chamber of a critical-point drying apparatus. After critical-point drying, the tissue was mounted on a holding stub with silver paint and coated with gold-palladium in a vacuum evaporator for viewing on a JEOL Model JSM-35 scanning electron micro scope. For transmission EM, the fixed tissue was rinsed for two IO-minute periods in PBS buffer. It was postfixed in 1% OS04 in PBS buffer for 30 minutes at room temperature. Then it was dehydrated in 50%, 70%, 95%, and three changes of 100% ethyl alcohol for 10 minute s each and in two changes of 100% propylene oxide for 10 minutes each. The tissue was immersed in Spurr/propylene oxide (l: 1) solution overnight at 4 C.

The specimen was removed from that solution and allowed to return to room temperature. It was then immersed in Spurr/propylene oxide (3: I) solution for 2 to 4 hours, immersed in 100% Spurr solution in a labeled mold, and allowed to polymerize at 60 C for 48 hours . A Porter-Blum MT-2 ultramicrotome with a diamond knife was used to cut thin, pale gold sections. The sections were poststained for 3 minutes in a filtered, saturated solution of uranyl acetate in 50% ethanol, rinsed for I minute in distilled water, stained for 3 minutes in Reynolds' lead citrate solution, and rinsed for 1 minute in distilled water. They were viewed with a JEOL Model 100S transmission electron microscope. Thin sections were stained with azure B and examined by light microscopy.

RESULTS

Histochemical studies These studies were conducted on tissue of a pit from Patient 2 and a pit containing a tumor from Patient I, and they were similar. The phosphorylase reaction was moderately positive in the epidermis at the base of the pit and in normal epidermis on the same slide; there was no significant difference in staining reaction between the two sites. In both areas, the reaction was most intense in the basal epidermis, with intensity at higher levels . A strongly positive reaction was seen in sweat ducts within the underlying dermis and focally in the epidermis in areas that may represent acrosyringium. The acid phosphatase reaction in the basal epidermis was about as intense as in adjacent normal epidermis. In the superficial epidermis beneath the pit, it was somewhat more intense and more irregular than in the adjacent normal epidermis. The reaction was even stronger in the acrosyringium . Granules were also seen in the stratum corneum of both the palmar pit and the adjacent normal epidermis; these may represent false staining. No significant differences were noted in staining reactions for succinic dehydrogenase and for sulfhydryl and disulfide compounds.

Light microscopic studies Light microscopic study of palmar pits containing tumors showed that the lower surface of the epidermis underlying the base of the pit contained

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Fig. 4. Low-power scanning EM view of a pit with undulating margins and a deep furrow separating the floor of the pit from its rounded. sloping walls. (Original magnification, X20.)

Fig. 5. Closer view of pit, showing a protuberance in the floor and free margins of squames on the wall. (Original magnification, x36.)

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a proliferation of small basaloid cells. These were in solid masses and in irregular anastomosing cords, with moderately loose fibrovascular stroma that contained a few lympho cytes and histiocytes. In the tumor cells, the nuclei were small, uniform', and oval. Peripheral palisading was sometimes present. The cytoplasm was slightly more abundant than has been observed in typical basal cells, and it contained moderate amounts of glycogen. Intercellular bridges could occasionally be discerned. In a few instances, intraepidermal sweat ducts could be identified within the tumor and in the epidermis forming the base of the pit. Light microscopic study of palmar pits without tumors from Patient 2 revealed a thin, irregular keratin layer, with abrupt transition to a thicker, more uniform keratin layer at the border of the pit . The granular layer was irregular, thin, and incomplete. The prickle layer beneath the pit was often slightly acanthotic, the nuclei were uniform and in an orderly arrangement , and the cytoplasm was slightly irregular and pale-staining. It often showed an abrupt transition to normal staining at the pit margin.

Transmission EM studies Selected areas of the pit and adjacent normal epidermis were examined by transmission EM. The epidermal cells appeared normal, with normal nuclei, nuclear membranes, cell membranes, desmosomes, endoplasmic reticulum, and tonofibrils. The keratohyaline granules in the granular layer were irregularly shaped. In some areas, they were hard to find or were small. Walls of the stratum corneum at the base of the pit also showed a normal structure. The cell membrane, remnants of desmosomes, and the pattern of tonofibrils appeared to be intact and within normal limits; there was no evidence of degeneration or defective squame structure or production of tonofibrils. The rounded bodies presumably were cementsomes. A few keratinocytes showed cytoplasmic vacuolization. The basal lamina was intact; no fragmentation, duplication, or other alteration was observed. A few bacteria were sometimes seen between the superficial layers of the stratum corneum in the base of the pit.

Scanning EM studies The surface views of four pits were examined' by scanning EM (Fig. 4). The pits appeared as round or oval depressions, with irregularl y contoured walls. At the tops of the pits, the walls were rounded, gently sloping masses of keratin, continuations of the adjacent normal stratum corneum (Fig. 5). The steep slopes of the walls consisted of the exposed edges of stacked layers of keratin, which presented ' a "shingle" effect (Fig. 6). Flakes of keratin and individual squames on the surfaces of the walls were separated: As the walls descended, the rounded contours gave way to steep slopes that descended sharply to the bases of the pits. Here, annular furrows separated the walls from the bases (Fig. 7). The bases of the pits had irregular perimeters. On the floors were heaped masses of keratin, which were sometimes cracked and separated. In some instances, a small, rounded knob, which probably represented an acrosyringium, protruded from the floor of a pit (Fig. 8). Higher magnification showed a few individually separated squames and , occasionally, bacteria and erythrocytes scattered on the floors of the pits. In addition to the inspection of palmar pits from surface views, two pit specimens were sharply transected with a razor blade. Scanning views of the cross sections were made. In these views, the same general structure of the pits was observed (Figs . 9 and 10), with epidermis at the bases of the pits and lines of transition between the epidermis and the stratum corneum that presumably represented granular layers. The stratum corneum overlying the epithelium at the bases of the pits was thin , irregular, and contained large defects. Flakes of keratin and individual squames separated easily . from the floor surfaces. The stratum corneum at the margins of the pits was thicker, more compact, and more adherent. The keratin showed loosening and separation only near the surface of the stratum corneum . The contours of the pit walls were gently rounded at the tops. They descended more precipitously toward the bases of the pits to a point of sharp transition between pit epithelium and normal epithelium. A shingle-like effect of exposed layers of squames on the pit walls was noted from this view, too.

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Fig. 6. High-power scanning EM view of the free margins of squames on the wall. (Original magnification, X200.)

Fig. 7. Scanning EM close view of the floor of the pit in the foreground and a deep furrow separating it from the steeply sloping wall. (Original magnification, X 130.)

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Fig. 8. The protuberance on the floor of the pit shown in this scanning EM view is considered an acrosyringium. (Original magnification, x 180.)

Fig. 9. As shown in this scanning EM view, in a transected pit epidermis is seen at the base, the granular layer (arrows} is visible, keratin in the pit is loose , in contrast with a thick stratum compactum in the wall and only a superficial stratum disjunctum. (Original magnification, x24.)

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Fig. 10. Scanning EM closer view of the base from Fig. 9 reveals epidermis, granular layer (arrows), and loose keratin. (Original magnification, x60.)

The results of parallel studies of light microscopic, transmission EM, scanning EM, and histochemical investigation of Patient I with pits and tumors (Fig. II) and Patient 2 with pits (Fig. 12) without tumors were identical. The only exception was the basal cell carcinomas arising from the genetically altered epidermis underlying the pits. DISCUSSION

We have reported the most dramatic case of' multiple basal cell carcinomas of the palms arising from the genetically altered epidermis beneath the pits that we have ever seen. It provided an opportunity to study further this puzzling stigma of the NBCC syndrome (Fig . 2). The presentation of this feature in this patient was striking in appearance. In other reported cases of tumors associated with pits of the hands or feet (and in the case of our Patient 2), the patients were unaware of the tumors and , in fact, unaware of the pits themselves." The pits typically are asymptomatic and must be pointed out to the patient by the examining physician. In the rare instances in which basal cell epitheliomas were associated with

pits, the tumors had been discovered fortuitously" during microscopic examination of biopsy specimens of the pits . Careful examination of serial sections revealed a tumor developing from ' the base of a pit in two studies.v" In contrast, our Patient 1 was aware of an abnormal sensitivity of her palms due to the many small tumors that were prominent (Fig. 3) even from a distance. This was the most impressive clinical feature of the syndrome. On close inspection, the pits without tumors appeared typical of the asymptomatic pits seen in other cases, but the tumors stood out noticeably. Although microscopic analysis showed the tumors to be basal cell epitheliomas, they did not show rapid growth, ulceration, or evidence of locally malignant behavior, which is the rule for rodent ulcers in other sites in NBCC syndrome patients. A few of the lesions on this patient's face grew rapidly and became invasive , ulcerous, or destructi ve; these were diagnosed by microscopic examination as basal cell carcinomas . The nature of the pits themselves, and especially of the pits with tumors, has been a most enigmatic feature of the NBCC syndrome. What

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Fig. 11. Patient 1. Scanning EM view of a pit with a tumor, showing the tumor (T) , an incomplete furrow (arrows). and a position of the wall of the pit. (Original magnification , X 101.)

Fig. 12. Patient 2. Transmission EM view. Keratin from the floor of the pit shows intact squames, well-developed desmosomcs, and tonofibrils . Cementsomes are not shown . (Original magnification, X9,520.)

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Fig. 13. Patient 1. Transmission EM view. Parts of tumor cells are shown with welldeveloped desmosomes, tonofibrils, an oval nucleus, and one nucleolus . (Original magnification, X 6,500.)

Fig. 14. Patient 1. Photomicrograph of a tumor with nodular and anastomosing strands of basaloid tumor cells and keratotic foci. (Hematoxylin-eosin stain; X 100.)

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Fig. 15. Patient 1. Tumor with basaloid cells, peripheral palisading, and keratotic foci. (Hematoxylin-eosin stain; x400.)

produces the pits? What causes the epidermis underlying one pit, which looks no different from epidermis beneath another pit, to give rise to basal cell epithelioma? Why do the palmar tumors in this patient not behave aggressively as some of the tumors found on her face do? Because of these perplexing questions, we took the opportunity to gather, with microscopic and histochemical studies, as much information as possible about these lesions. The histochemical studies of pit and tumor tissue showed reactions that were, for the most part, not significantly different from the reactions of adjacent normal tissue. The only other battery of histochemical tests made on pit or tumor tissue was that of Holubar et aI. 6 The only test common to our two studies was the one for succinic dehydrogenase; they, too, found enzymatic activity to be the same in tumor and normal tissue. Our light microscopic studies confirmed the excellent and classic studies by Mehregan" and the ultrastructural level by Hashimoto et aI.5 We also found that the epithelium beneath the pits stained only weakly with azure B, which supports the

speculation by Hashimoto et aP that the poor stainability of the keratinocytes is likely a result of poor development of tonofibrils. Earlier studies of the pits with transmission and scanning EM have been reported," and transmission electron micrographs of pits with tumors have been published." Our study confirms those previous studies. It presents the first scanning electron micrographs of cross sections of pits (Figs. 9 and 10) and the first scanning electron micrographs of pits with tumors (Fig. 11). Our transmission electron micrographs of the pits showed small keratohyaline granules and incomplete discharges of cementsomes in the epithelium beneath the pits, confirming the earlier observations by Hashimoto et aI. 5 The premature desquamation of horny cells along the intercellular spaces is not due to degeneration of the horny cells. It may be due to an incomplete discharge of the cementsomes, perhaps because they have a shortened transit time, a hypothesis proposed by Hashimoto et aI. 5 Why these cornified cells undergo premature desquamation is another challenging question.

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Fig. 16. Patient 1. Tumor with overlying epidermis, a slightly protuberant sweat pore, and an underlying sweat duct, not a part of the tumor. (Hematoxylin-eosin stain; x400.)

The scanning electron micrographs of the pits viewed from the surface confirm the observations of UIlman et al.? We extended these observations with scanning electron micrographs of the pits viewed in cross section. The sharply demarcated defect in the cornified layer is even more evident from this view (Figs. 9 and 10). Presumably, the geneticaIly altered epidermis under the bases of the pits has a defective production of keratin. At the bases of the pits, there is a prompt transition from the granular layer into a stratum disjunctum; in contrast, the walls of the pits consist primarily of normal stratum compactum with stratum disjunctum only near the surfaces of the walls (Fig. 9) . Holubar et al" raised the possibility that these palmar tumors might come from sweat ducts. Fig. 8 shows a protuberance in the floor of the pit that we believe to be an acrosyringium, but we believe that the sweat ducts occasionally found in the tumors arc entrapped by the tumor tissue and arc not the source of the tumor. The status of the epidermis underlying the pits is a matter of import and concern. Is this epidermis a variant of basal cell epithelioma, or is it basal

cell epithelioma in situ? Our findings support the hypothesis proposed by Hashimoto et aP that this epidermis is basal cell epithelioma or basal cell epithelioma in situ. We, too, found with light microscopy a lack of keratinization of pit tissue and a proliferation of basaloid cells in irregular rete ridges, sometimes in a palisading pattern; both characteristics are highly suggestive that the tissue is indeed basal ceIl epithelioma. Previous experience indicates that growth of microscopically identifiable tumors beneath the pits is rare, and that clinically obvious multiple tumors underlying the pits are even rarer. The high incidence of tumor formation in the pits of our Patient I, however, lends support to the concept that this altered epidermis underlying the pits has several similarities to the cells of basal ceIl epithelioma. Alternatively, the tissue may be a tumor that is biologically different but histologically similar to basal cell carcinoma (Figs . I I and 13 to 16). An important but yet unsolved puzzle is the infrequency of rapid growth and invasiveness of the palmar and plantar tumors . This is in sharp con-

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trast to the behavior of the head and neck tumors of NBCC syndrome patients and of rodent ulcers due to other causes. Until this report, the tumors associated with pits had been discovered in young patients 8, 13, and 17 years of age. Whether the tumors in these patients will become numerous with time to become like those in our Patient 1 (Figs. 15 and 16), or exhibit aggressive behavior, we do not know at the moment. Rodent ulcers of the palm or sole are rare, but there are three reports of such tumors in patients with the NBCC syndrome. Taylor and Wilkins" removed a recurrent basal cell carcinoma, by Mohs '. chemosurgery, from the palm of a patient with the syndrome. Ward" published a photograph of his patient's heel with a lesion he considered clinically to be a growing basal cell carcinoma. Microscopic examination was not done. Bunting and Remensnyder'" recorded bilateral ulcerating basal cell carcinomas of the soles in a patient with the syndrome. Whether these tumors had originated from the epidermis beneath the pit was not documented, but this is highly probable. Exposure to carcinogens, such as radiation or chemicals, would be expected to have a synergistic and multiplicative effect on the incidence of cancer in syndrome patients. That the pits of the NBCC syndrome can give rise to numerous basal cell carcinomas is dramatically shown by our Patient 1. Radiotherapy for the treatment of childhood tumors, such as medulloblastoma, is followed promptly by large numbers of basal cell carcinomas of the skin with rapid growth and aggressive behavior."-" Radiation acts to multiply the spontaneous incidence of cancer. In the NBCC syndrome, roentgen rays may supply the subsequent mutation for tumor development.Pr'" Anyone with this syndrome, whose hands or feet have been treated with

or frequently exposed to roentgen rays, should be observed at frequent intervals for possible radiation-induced basal cell carcinomas developing from the epidermis underlying the pits or from the normal epidermis of the hands. Martha M. Tacker, Ph.D., helped with the writing and editing of this article.

REFERENCES 1. Howell JB, Anderson DE: The nevoid basal cell carcinoma syndrome, ill Andrade R, Gumport SL, Popkin GL, et aI, editors: Cancer of the skin: Biologydiagnosis-management. Philadelphia, 1976, W. B. Saunders Co., pp. 883-898. 2. Howell JB, Mehregan AH: Pursuit of the pits in the nevoid basal cell carcinoma syndrome. Arch Dennatol 102:586-597, 1970. 3. Dodd GD, Jing BS, Anderson DE: Nevoid basal cell carcinoma syndrome. Unpublished observations. 4. Bazex A, Dupre A, Christol B: Follicular atrophoderma, basal cell epithelioma and hypotrichosis. Ann Dennat et Syph 93:241-254, 1966. 5. Hashimoto K, Howell JB, et al: Electron microscopic studies of palmar and plantar pits of nevoid basal cell epithelioma. J Invest Dermatol 59:380-393, 1972. 6. Holubar K. Matras H, Smalik AV: Multiple palmar basal cell epitheliomas in basal cell nevus syndrome. Arch Dermatoll0l:679-682, 1970. 7. Ullman S, Sendergaard J, Kobayasi T: Ultrastructure of palmar and plantar pits in basal cell nevus syndrome. Acta Derm Venereol (Stockh) 52:329-336, 1972. 8. Taylor WB, Wilkins JW Jr: Nevoid basal cell carcinoma of the palm. Arch Dermatol 102:654-655, 1970. 9. Ward WH: Nevoid basal cell carcinoma associated with a dyskeratosis of the palms and soles: A new entity. Australas-Dermatol 5:204-208, 1960. 10. Bunting PD, Remensnyder JP: Basal cell nevus syndrome. Plast Reconstr Surg 60:895-901, 1977. 11. Strong LC: Genetic and environmental interactions. Cancer 40: 1861-1866, 1977. 12. Strong LC: Theories of pathogenesis: Mutation and cancer, ill Mulvihill JJ, Miller RW, Fraumeni JF Jr, editors: Genetics of human cancer. New York, 1977, Raven Press, pp. 401-415. 13. Wilkinson JD, Marsden RA, Dawber RPR: Review of Darier's disease in the Oxford region. Br J Dermatol 97:15-16, 1977.