Pulmonary aspergillosis in acquired immune deficiency syndrome: autopsy study of an emerging pulmonary complication of human immunodeficiency virus infection.

Pulmonary aspergillosis has recently been described as an emerging infection in patients with acquired immune deficiency syndrome (AIDS), but the pathological changes have not been well documented. In this autopsy study, 17 cases of AIDS-related pulmonary aspergillosis were identified from the files of two institutions. With the exception of hypersensitivity reactions, the entire spectrum of pulmonary aspergillosis was represented. Thirteen patients exhibited acute invasive aspergillosis, and seven patients had evidence of subacute or chronic invasive infection, four of whom also had areas of acute invasion. One patient had necrotizing bronchial aspergillosis as well as acute invasive infection, and one individual had saprophytic colonization of a cavity caused by previous Pneumocystis carinii pneumonia (PCP) without evidence of invasive aspergillosis. The same conditions known to predispose immunocompromised individuals without human immunodeficiency virus (HIV) infection to invasive pulmonary aspergillosis were also identified in these patients with AIDS and included neutropenia, steroid therapy, and underlying lung disease. Additional pulmonary conditions were identified in all but one case and consisted mainly of infection or some form of chronic lung disease. In particular, half of the cases were associated with pulmonary fibrosis related to prior PCP. All cases occurred in or after 1990, confirming the perception of the recent emergence of aspergillosis in AIDS. As suggested by this study, one reason for this may be that patients with AIDS are now living long enough to develop one or more of the predisposing conditions for pulmonary aspergillosis.

Quantitative differences in the production and toxicity of CF2=BrCl versus CH2F-O-C(=CF2)(CF3) (compound A): the safety of halothane does not indicate the safety of sevoflurane.

UNLABELLED: Carbon dioxide absorbents degrade both halothane and sevoflurane to toxic unsaturated compounds (CF2=CBrCl and CH2F-O-C[=CF2][CF3] [i.e., Compound A], respectively). Given the long history of safe administration of halothane, comparable toxicities of these degradation products would imply a similar safety of sevoflurane. We therefore examined CF2=CBrCl in the context of four issues relevant to previous studies of the toxicity of Compound A: 1) reactivity of the degradation product in vitro; 2) rate of its production in vitro; 3) its in vivo toxicity; 4) importance of the beta-lyase pathway to the toxicity in vivo. We found the following. 1) CF2=CBrCl is less reactive than Compound A, degrading in human serum albumin at one-fifth the rate of Compound A. 2) Over a 3-h period of "anesthesia," a standard circle system containing Baralyme (Allied Healthcare Products, Inc., St. Louis, MO) produces 30 times as much Compound A from a minimum alveolar anesthetic concentration (MAC) concentration of sevoflurane as CF2=CBrCl from a MAC concentration of halothane; with soda lime, the difference is 60-fold. Correcting for differences in uptake of halothane versus sevoflurane decreases the differences to 20-40 times. 3) For a 3-h administration to rats, the partial pressure of Compound A causing minimal renal injury or necrosis of half the affected tubule cells exceeds the partial pressure of CF2=CBrCl causing minimal injury or necrosis of half the affected tubule cells by a factor of approximately 4-6. Thus, the ratio of production (Item 2 above) to the partial pressure causing injury with CF2=CBrCl is approximately a quarter of that ratio for Compound A. 4) Compounds that block the beta-lyase pathway either do not change (acivicin) or decrease (aminooxyacetic acid; AOAA) renal injury from CF2=CBrCl in rats, whereas these compounds increase (acivicin) or do not change (AOAA) injury from Compound A. We conclude that the safety of halothane cannot be used to support the safety of sevoflurane. IMPLICATIONS: Carbon dioxide absorbents degrade halothane and sevoflurane to unsaturated compounds nephrotoxic to rats. Relative to sevoflurane's degradation product, halothane's degradation product has less toxicity relative to production, less reactivity, and a different mechanism of injury. The clinical absence of halothane nephrotoxicity does not necessarily indicate a similar absence for sevoflurane.

Cutaneous squamous cell carcinoma in human immunodeficiency virus-infected patients. A study of epidemiologic risk factors, human papillomavirus, and p53 expression.

OBJECTIVE: To examine risk factors for the development of cutaneous squamous cell carcinoma (SCC) in a group of human immunodeficiency virus (HIV)-infected patients, including evaluation and detection of epidemiologic risk factors of human papillomavirus (HPV) and p53 expression. DESIGN: Case-control study during a 3-year period. SETTING: Dermatologic referral center. PATIENTS: Thirty-three HIV-infected patients who had 97 SCCs were compared with 24 HIV-infected patients who had 70 basal cell carcinomas (BCCs). MAIN OUTCOME MEASURES: Age, skin type, amount of sun exposure, actinic damage, family history of skin cancer and history of smoking and warts. Specimens of SCC and BCC were examined for HPV using polymerase chain reaction. Presence of p53 was examined using immunohistochemical analysis. Specimens from tumor-free, non-sun-exposed areas from these same patients were used as controls. RESULTS: Risk factors for the development of both types of carcinoma included fair skin type and excessive sun exposure (> 6 h/d during the previous 10 years). The HIV-infected patients with SCCs tended to have outdoor occupations. The location of SCCs favored the head and neck; BCCs were located on the trunk. Patients with SCCs had later-stage HIV disease than did patients with BCCs. Half of the patients with SCC had a history of genital or nongenital warts. Seventy-one percent (17/24) had a smoking history. No statistical difference existed between patients with SCCs and BCCs for history of smoking or warts. Human papillomavirus was not found in most of our SCC, BCC, or control specimens. However, 92% (22/24) of the SCC specimens and 90% (18/20) of the BCC specimens stained for p53. Control specimens from non-sun-exposed skin of HIV-infected patients did not stain for p53. Epidermal staining was present in 95% (17/20) of tissue adjacent to SCCs and 47% (7/15) of tissue adjacent to BCCs. A significantly positive correlation existed between the amount of sun exposure and the amount of p53 staining seen in adjacent epidermal tissue (r = 0.07; P = .01). CONCLUSIONS: Risk factors for the development of SCCs and BCCs in HIV-infected patients are similar: fair skin type and excessive sun exposure. Our study does not support that HPV is an oncogenic factor in the development of these cutaneous tumors but provides evidence that p53 overexpression may play a role.

Acetaminophen predisposes to renal and hepatic injury from compound A in the fasting rat.

Results of previous studies of Compound A, a degradation product of sevoflurane, suggested that decreases in glutathione stores may increase potential Compound A nephrotoxicity. By depleting these stores, fasting and various drugs may augment such nephrotoxicity. To test this possibility, we pretreated fasted Fisher rats with intraperitoneal 0 (vehicle only), 250, 500, or 1000 mg/kg of acetaminophen, a commonly used drug that depletes glutathione stores. After pretreatment, we administered Compound A for 3 h at concentrations ranging from 0 to 200 ppm. The larger doses of acetaminophen predisposed to greater renal and hepatic injury. For example, at 100 ppm Compound A, no rats had renal cortical injury when given vehicle only or 250 mg/kg acetaminophen, but 90% (9 of 10 rats) had injury at 500 mg/kg and 100% (13 of 13) at 1000 mg/kg. Similarly, at 100 ppm Compound A, hepatic injury was not evident with vehicle only or 250 mg/kg, but occurred in 30% of rats at 500 mg/kg, and in 69% at 1000 mg/kg. Given the considerable differences between humans and rats, and given the large doses of acetaminophen required, the clinical relevance of these findings is unclear. If clinically relevant, circumstances producing glutathione depletion (e.g., ingestion of drugs such as acetaminophen, or nutritional deficiencies) may predispose to renal or hepatic injury from Compound A in patients given sevoflurane at low fresh gas flow rates.

Lack of p53 protein immunoreactivity in bilateral diffuse uveal melanocytic proliferation.

BACKGROUND: Bilateral diffuse uveal melanocytic proliferation is a poorly understood disorder characterized by the progressive proliferation of uveal melanocytes associated with a systemic nonocular malignancy. Overexpression of p53 protein plays a role in the loss of regulatory control of normal cell proliferation, and p53 is the most commonly identified oncogenic protein in human malignancies. We tested the hypothesis that the aberrant cellular activity in bilateral diffuse uveal melanocytic proliferation involves the overexpression of p53 protein. METHODS: Eight eyes from four patients with bilateral diffuse uveal melanocytic proliferation were tested for p53 protein using an immunoperoxidase technique with an anti-p53 protein monoclonal antibody sensitive for normal and mutant p53 protein. RESULTS: The p53 protein could not be detected in any of the eight eyes. CONCLUSIONS: The proliferation of uveal melanocytes in bilateral diffuse uveal melanocytic proliferation does not depend on the overexpression of p53 protein. The loss of cellular regulatory control in bilateral diffuse uveal melanocytic proliferation is probably mediated through another mechanism.

Studies of the mechanism of nephrotoxicity of compound A in rats.

CO2 absorbents acting on sevoflurane produce compound A [CF2=C(CF3)OCH2F]. Rats breathing 25-50 ppm of compound A for 3-12 h demonstrate corticomedullary renal injury. Several halogenated alkenes also produce a well described corticomedullary lesion by conversion of glutathione conjugates of these alkenes to cysteine s-conjugates and subsequent metabolism by renal cysteine conjugate ß-lyase to nephrotoxic halothionoacetyl halides. We tested whether a similar mechanism explained the nephrotoxicity of compound A or whether an oxidative metabolism of compound A by cytochrome P-450 was required for the induction of nephrotoxicity. A closed rebreathing system was used and male Wistar rats were exposed for 1 h to: (1) oxygen alone; (2) 800 ppm compound A; (3) 800 ppm compound A after pretreatment with intraperitoneal aminooxyacetic acid (AOAA), 0.5 mmoles/kg, an inhibitor of renal cysteine conjugate ß-lyase; (4) 600 ppm compound A; (5) 600 ppm compound A after pretreatment with intraperitoneal AOAA, 0.50 mmoles/kg plus acivicin (AT-125), 0.25 mmoles/kg, an inhibitor of gamma glutamyl transpeptidase; (6) 600 ppm compound A after pretreatment with 1600 mg/kg piperonyl butoxide (PB) subcutaneously, and (7) 600 ppm compound A after pretreatment with 100 mg/kg 1-aminobenzotriazole (ABT) by intraperitoneal injection (both PB and ABT inhibit cytochrome P-450s). All rats were killed 24 h following exposure to compound A or oxygen, or to pretreatments without compound A, and the kidneys were collected for histological analysis. Pretreatments given without compound A did not cause renal injury. Necrosis was found in 20.9±16.7% (mean±SD) of corticomedullary tubule cells following exposure of Wistar rats to 600 ppm compound A. Pretreatment with AOAA plus AT-125 increased necrosis to 57.9±32.6%, (P<0.005). PB or ABT given prior to compound A increased corticomedullary injury to 39.0±31.4% (P<0.02) and 51.2±31.8% (P<0.025), respectively. In rats exposed to 800 ppm compound A, pretreatment with AOAA increased necrosis from 63.8±30.1% to 81.2±27.7% (P<0.1). Unlike many other halogenated alkenes, compound A does not appear to produce renal injury by conversion of a cysteine S-conjugate to a toxic thiol, nor does injury require metabolism mediaited by cytochrome P-450. Injury may result from direct toxicity of compound A or by an undetermined metabolic pathway.

High resolution radiography of cadaveric kidneys: unraveling the mystery of Randall's plaque formation.

PURPOSE: We used high resolution radiography to identify and characterize Randall's plaques in cadaveric kidneys. MATERIALS AND METHODS: A total of 50 consecutive sets of cadaveric kidneys was fixed, bivalved and imaged with micro-focal spot magnification radiography. Papillary calcifications were identified, localized and processed for light microscopy. Special immunohistochemical stains were implemented to aid localization of ectopic calcifications. Patient medical records and autopsy results were retrospectively evaluated and correlated with radiographic papillary calcifications. RESULTS: Of the 92 renal units with complete data 52 (57%) had radiographic evidence of renal medullary calcifications consistent with Randall's plaques. Unlike the original description of this condition, calcifications extended deep into the papilla. A history of hypertension was the only clinical parameter correlating with papillary calcifications. Calcium deposition was localized to the basement membrane of collecting tubules and vasa recta, and papillary interstitium. CONCLUSIONS: Randall's plaques are not merely subepithelial deposits. Rather, they appear to extend deep within the papilla, and are intimately associated with collecting tubules and vasa recta. An association between papillary calcifications and urinary stone formation has yet to be proved but is under investigation.

Metabolism of compound A by renal cysteine-S-conjugate beta-lyase is not the mechanism of compound A-induced renal injury in the rat.

Compound A [CF2 = C(CF3)OCH2F], a vinyl ether produced by CO2 absorbents acting on sevoflurane, can produce corticomedullary junction necrosis (injury to the outer stripe of the outer medullary layer, i.e., corticomedullary junction) in rats. Several halogenated alkenes produce a histologically similar corticomedullary necrosis by converting glutathione conjugates of these alkenes to halothionoacetyl halides. To test whether this mechanism explained the nephrotoxicity of Compound A, we blocked three metabolic steps which would lead to formation of a halothionoacetyl halide: 1) we depleted glutathione by administering dl-buthionine-S, R-sulfoximine (BSO); 2) we blocked cysteine S-conjugate formation by administering acivicin (AT-125); and 3) we inhibited subsequent metabolism by renal cysteine conjugate beta-lyase to the nephrotoxic halothionoacetyl halides by administering aminooxyacetic acid (AOAA). These treatments were given alone or in combination to separate groups of 10 or 20 Wistar rats before their exposure to Compound A. We hypothesized that blocking these metabolic steps should decrease the injury produced by breathing 150 ppm of Compound A for 3 h. However, we found either no change or an increase in renal injury, suggesting that this pathway mediates detoxification rather than toxicity. Our findings suggest that the cysteine-S-conjugate-mediated pathway is not the mechanism of Compound A nephrotoxicity and, therefore, observed interspecies differences in the activity of this activating pathway may not be relevant in the prediction of the nephrotoxic potential of Compound A in clinical practice.

Eccrine or apocrine poroma? Six poromas with divergent adnexal differentiation.

We describe six cases of benign eccrine poroma-like neoplasms with divergent adnexal differentiation. Four cases exhibited sebaceous differentiation in the form of individual or clustered sebocytes with or without sebaceous ducts. One case showed both sebaceous and hair follicle differentiation, and one case showed sebaceous and possible apocrine secretory differentiation. Clinically, most were skin-colored, red, or purple papules or nodules. One patient had a preoperative diagnosis of Bowen's disease, with an erythematous plaque. None recurred following biopsy. Previous reports of similar lesions have suggested a possible role for human papilloma virus (HPV) in their pathogenesis; however, immunohistochemical staining for HPV structural antigens was negative in all six of these cases. Similarities to previously reported cases of eccrine poroma-like neoplasms with sebaceous differentiation are discussed. Given the evidence of sebaceous and follicular differentiation seen in this study and the common embryologic origin of follicular, sebaceous, and apocrine structures, it follows that at least some benign neoplastic proliferations with histopathologic features of "eccrine" poroma could be of apocrine origin.

Cutaneous presentations of lymphoma in human immunodeficiency virus disease. Predominance of T cell lineage.

BACKGROUND AND DESIGN: Most non-Hodgkin's lymphomas in patients with human immunodeficiency virus infection are of B-cell lineage. Cutaneous lymphoma in the human immunodeficiency virus disease has not been systematically reviewed. We studied 25 patients with both human immunodeficiency virus infection and cutaneous presentations of lymphoma, using immunohistochemistry and in situ hybridization for Epstein-Barr virus. RESULTS: Two groups of patients were discerned: (1) those with conditions similar to mycosis fungoides or Sézary syndrome with an indolent course (n = 8) and (2) those with nodules or papules, greater immunosuppression, a rapid clinical course, and large cell lymphoma seen on biopsy specimens (n = 17). The epidermotropic lymphomas were T-cell lineage and CD30-. Thirteen of the large cell lymphomas were also of the T-cell type, and 71% were CD30+. Epstein-Barr virus was absent in the epidermotropic lymphomas, but it was present in 73% of the nonepidermotropic cases. CONCLUSIONS: Two forms of human immunodeficiency virus-associated cutaneous lymphoma were found: indolent disease resembling mycosis fungoides or Sézary syndrome and large cell lymphomas with a poor prognosis, whose cells often had a CD30+ T-cell phenotype and harbored the Epstein-Barr virus.

Nephrotoxicity in rats undergoing a one-hour exposure to compound A.

We previously demonstrated that rats experienced renal injury when exposed for 3-12 h to 50 ppm or more of a vinyl ether called Compound A [CF2 = C(CF3)OCH2F], a compound produced by CO2 absorbents acting on sevoflurane. These durations of exposure exceed the average duration of clinical anesthesia. We now report the effect of a 1-h exposure to 0, 100, 150, 200, 400, 600, or 800 ppm of Compound A in oxygen in 145 Wistar rats. Twenty-four hours after exposure, we obtained kidney and liver specimens for microscopic examination, applying hematoxylin and eosin, and (separately) an immunochemical marker (PCNA) for cell proliferation (regeneration). Compared with results from control rats (those breathing oxygen for 1 h), renal injury (defined as necrosis of the outer strip of the outer medullary layer or "corticomedullary junction necrosis") occurred at and above 200 ppm. Exposure to 150 ppm produced cell regeneration (i.e., stimulated cell proliferation). We conclude that the threshold concentrations for nephrotoxicity (i.e., minimal toxicity) for a 1-h exposure to Compound A exceed the maximum concentrations (particularly those at low inflow rates) reported in clinical practice by a factor of 2-3. If these threshold effects in rats apply to humans, one 1-h exposure to sevoflurane probably would not alter usual measures of renal function.

Tumor angiogenesis correlates with lymph node metastases in invasive bladder cancer.

Neovascularization of tumor tissue (tumor angiogenesis) is considered essential for tumor growth, proliferation and eventually metastasis. Microvessel density or count, a measure of tumor angiogenesis, correlates with clinical outcome in skin, breast, lung and prostate carcinomas. To determine whether an association of tumor angiogenesis and nodal metastasis exists in invasive bladder cancer, microvessel counts in 41 primary invasive stages (T2 to 4,NX,M0) bladder cancers were assessed. Microvessels were identified by immunostaining of endothelial cells for factor VIII-related antigen. Microvessels were scored in selected areas showing active neovascularization, either counting a 200 x field (0.74 mm.2) or by using a 10 x 10 square ocular grid (0.16 mm.2). The microvessel count correlated with the presence of occult lymph node metastases (p < 0.0001) by both techniques. The mean microvessel count in 27 patients without lymph node metastases was 56.2 microvessels per 200 x field (standard deviation [SD] 29.5, range 7 to 130) or 28.6 microvessels per grid (SD 14.4, range 4 to 65). The 14 patients with histologically proved lymph node metastases showed mean 138.1 microvessels per 200 x fields (SD 37.9, range 82 to 202) or 74.7 microvessels per grid (SD 14.4, range 43 to 115). Good correlation was noted between area and grid counting (r = 0.97). Tumor T stage, grade and the presence of vascular or lymphatic invasion did not correlate with the presence of lymph node metastases (p = 0.41, 0.59 and 0.26, respectively). Microvessel count may provide important information regarding the risk of occult metastasis in patients with invasive bladder carcinomas.

The pathological manifestations of pulmonary toxoplasmosis in the acquired immunodeficiency syndrome.

Pulmonary toxoplasmosis, once considered a rare complication of human immunodeficiency virus infection, recently has been reported with increasing frequency in patients with the acquired immunodeficiency syndrome (AIDS). However, published descriptions of the pathologic changes have been scanty, involve mainly single cases, and appear to conflict. Four cases of pulmonary toxoplasmosis observed at autopsy in patients with AIDS were reviewed. Two of the patients presented with Toxoplasma pneumonia and in one the diagnosis was made antemortem by open lung biopsy. Two patterns of pulmonary lesions associated with Toxoplasma gondii pneumonia were identified and appeared to be related to the stage and intensity of the infection. A pattern of interstitial pneumonitis/diffuse alveolar damage with a fibrinous alveolar exudate appeared to antecede a necrotizing pneumonia characterized by large areas of parenchymal necrosis. In the former pattern T gondii tachyzoites were found in small numbers and were mainly intracellular, whereas in necrotic areas tachyzoites were numerous and were extracellular as well as intracellular. Histopathologic diagnosis of the infection required careful search for the organisms even when they were plentiful Immunohistochemistry identified far more organisms than could be appreciated with routine stains and confirmed the diagnosis.

Parental origin of chromosome 9q22.3-q31 lost in basal cell carcinomas from basal cell nevus syndrome patients.

The basal cell nevus syndrome is an autosomal dominant disease, one of the most prominent phenotypic features of which is a large number of cutaneous basal cell carcinomas. The gene whose mutation underlies this disease has been mapped to chromosome 9q22.3-q31, and basal cell carcinomas frequently have allelic losses including this site. We report here that the chromosome 9q22.3-q31 lost in 24 basal cell carcinomas from basal cell nevus syndrome patients was the one predicted by linkage to contain the wild-type gene. Hence these data are compatible with the exception that the product of the basal cell nevus syndrome gene acts as a tumor suppressor.

Toxicity of compound A in rats. Effect of increasing duration of administration.

BACKGROUND: An olefin called compound A (CF2 = C(CF3)OCH2F) results from the action of soda lime or Baralyme on sevoflurane. We have demonstrated that rats exposed to the olefin for 3 h died at or were injured by olefin concentrations lower than those previously reported to produce these effects. The present report examines the impact of duration of exposure to the olefin on such effects. METHODS: Twenty-three groups of ten Wistar rats breathed 0, 12.5, 25, 50, 75, 100, 125, 150, 175, 200, 225, and 250 ppm of the olefin in oxygen for 6 or 12 h. Rats that survived were killed on day 1 or day 4 after breathing the olefin, and specimens of brain, kidney, lung, liver, and small intestine were obtained from all rats for examination by microscopy using hematoxylin and eosin stain and a stain (proliferating cell nuclear antigen) for cell growth (regeneration). RESULTS: The lethal concentrations in 50% of rats equaled 203 +/- 4 ppm (mean +/- SE) for a 6-h exposure period and 127 +/- 9 ppm for a 12-h exposure period, and both values were less than the previously determined value of 331 +/- 7 ppm for a 3-h exposure period. Compared with results from control rats (those breathing oxygen for 6 h or 12 h), only renal and pulmonary injury were found. Pulmonary injury only occurred at near-lethal concentrations. Renal injury (defined as necrosis of the outer stripe of the outer medullary layer or corticomedullary junction necrosis) occurred at and above 25-50 ppm for 6-h and 12-h exposures, respectively, a result similar to that previously obtained with a 3-h exposure. Exposure to 25-50 ppm stimulated cell regeneration in a dose-related manner. CONCLUSIONS: In rats, lethal concentrations of the olefin and concentrations producing severe renal injury are inversely related to the duration of exposure to the olefin, exceeding by two- to fourfold peak concentrations that can be obtained in clinical practice. The threshold concentrations for nephrotoxicity (i.e., minimal toxicity) equal concentrations that can be produced in clinical practice. However, even if these threshold effects in rats apply to humans, they probably would not alter renal function. Although dose-related, neither the lethal nor the toxic effects are simply a function of cumulative dose (concentration-time).

Toxicity of compound A in rats. Effect of a 3-hour administration.

BACKGROUND: Soda lime converts sevoflurane to CF2 = C(CF3)OCH2F, an olefin called compound A, whose toxicity raises concerns regarding the safe administration of sevoflurane via rebreathing circuits. The present report extends the findings of a previous investigation by others of the toxicity of this olefin, and establishes concentration-response relationships for such toxicity. METHODS: Eighteen groups of ten Wistar rats breathed 0, 25, 50, 100, 200, 300, 350, and 400 ppm of the olefin in oxygen for 3 h. The olefin concentrations were developed in a square-wave manner by injection of saturated vapor followed by a continuous delivery of dilute vapor. The lethal concentration in 50% (LC50) of animals was estimated by logistic regression. Rats were killed on day 1 or day 4 after breathing the olefin, and specimens of brain, kidney, lung, liver, and small intestine were obtained from all rats for examination using light microscopy. RESULTS: The LC50 equaled 331 ppm (95% confidence limits +/- 13 ppm). No injury resulted to lung or small intestine in either the experimental or the control group (those breathing only oxygen for 3 h). Renal injury (necrosis of the outer strip of the outer medulla, defined in this report as corticomedullary tubular necrosis) occurred at 50 ppm and greater; hepatic injury at 350 ppm and greater; and cerebral injury only at 400 ppm. CONCLUSIONS: The lethal concentration and the threshold for toxicity of the olefin are less than previously reported. The threshold for nephrotoxicity reaches the range of values for the olefin that have been attained in clinical practice. Further studies are required to determine whether these results in rats can be extrapolated to patients.

p53 oncoprotein expression and proliferation index in keratoacanthoma and squamous cell carcinoma.

BACKGROUND AND DESIGN: Whether solitary keratoacanthoma (KA) is a malignant neoplasm despite its self-limited clinical behavior, and the distinction between KA and squamous cell carcinoma (SCC) are related aspects of a long-standing debate among dermatopathologists. Recent advances toward understanding the molecular basis of malignant transformation may allow this issue to be resolved. Mutant p53 tumor-suppressor protein has been shown to accumulate in cutaneous SCC and other tumors, and may be a relatively specific marker of malignancy. We studied 20SCCs, 20KAs, and an additional 10 regressing KAs (rKA) by immunohistochemistry for the expression of p53 protein. Since p53 is believed to play a pivotal role in the regulation of cell division, we also quantitated proliferation in the tumors by examining Ki-67 antigen expression. RESULTS: Sixteen (80%) of the KAs showed nuclear staining with anti-p53 antibody, distributed along the outermost layers of the aggregates of neoplastic cells, while 12 (60%) of the SCCs were p53 positive. Eight (80%) of the rKAs also showed p53 positivity. Mean Ki-67 proliferation fraction was higher for KA than for SCC (55% vs 46%), but this difference was not statistically significant. p53 Expression did not correlate with the grade of SCC. CONCLUSIONS: A majority of KA, rKA, and SCC contain stainable quantities of p53 protein, supporting the view that KA is a type of regressing SCC.