Acantholytic ectodermal dysplasia: clinicopathological study of a new desmosomal disorder.

We describe two boys with curly hair, palmoplantar keratoderma and skin fragility who presented clinical and histological features similar, but not identical, to those exhibited by patients with ectodermal dysplasia-skin fragility syndrome (McGrath syndrome) and other genetic desmosomal defects such as Carvajal syndrome and Naxos disease. Clinical features included trauma-induced blisters and erosions, palmoplantar keratoderma and hyperkeratotic, fissured plaques with perioral involvement. The patients had abundant curly scalp hair, and normal eyebrows and eyelashes. Sweating was normal. Nails were normal at birth but subsequently showed secondary dystrophy. Histopathological analysis of the skin demonstrated acantholysis and intercellular widening of the spinous and granular layers in involved regions. No involvement of scalp skin was seen. Desmosomes were markedly reduced in number and poorly developed with no clear insertions of the keratin filaments. The latter were clumped around the nuclei. Immunostaining of patient skin with antibodies raised against key desmosomal proteins demonstrated disrupted expression of desmoplakin, plakoglobin and desmoglein 1. Additional studies of the family history and of the desmoplakin, plakoglobin and desmoglein 1 genotype for both patients may help further elucidate the molecular cause of this variation on ectodermal dysplasia-skin fragility syndrome.

Microscopic benign and invasive malignant neoplasms and a cancer-prone phenotype in prophylactic oophorectomies.

BACKGROUND: The occurrence of approximately 5% of common epithelial malignant tumors of the ovary can be traced to inheritance of risk. One prophylactic strategy to decrease the probability of development of disease in individuals within families where this mendelian-dominant pattern of occurrence is apparent is to remove the ovaries of individuals at risk for ovarian cancer. The procedure, when done for this purpose, is recommended soon after completion of childbearing. PURPOSE: Our goal was to compare the histologic features of the ovaries of women at increased risk for ovarian cancer to those at no known increased risk for the disease. METHODS: Ovaries removed for prophylaxis from 20 women considered to be at increased risk for developing ovarian cancer were examined histologically. During the course of this work, it seemed apparent that these ovaries contained numerous atypical features compared with the expected appearance of normal ovaries. Hence, we expanded the study to include a control group whose ovaries were removed for reasons unrelated to cancer. The study, therefore, was not blinded. The increased risk in the cancer-prone individuals was determined by family history, specifically the presence of at least one first-degree relative and one second-degree relative with ovarian and/or breast cancer and positive linkage or mutational analysis of BRCA1 in some. The difference in mean ages of patients in the control and high-risk groups was not statistically significant. The difference among both groups with respect to the number of atypical features as well as the intensity of those features was ascertained by computing probabilities using Fisher's exact test (two-sided) for rows x columns contingency tables. RESULTS: Two unanticipated microscopic or near-microscopic malignant neoplasms and other benign and borderline tumors were discovered in the ovaries of the high-risk individuals. Of substantial interest was the finding that among the ovaries of high-risk women, 85% presented two or more and 75% presented three or more of the following histologic features: surface epithelial pseudostratification; surface papillomatosis; deep cortical invaginations of the surface epithelium, frequently with multiple papillary projections within small cystic spaces (microscopic papillary cystadenomas); epithelial inclusion cysts, frequently with epithelial hyperplasia and papillary formations; cortical stromal hyperplasia and hyperthecosis; increased follicular activity; corpus luteum hyperplasia; or hilar cell hyperplasia. Two or more or three or more such changes were observed in a lesser percentage (30% or 10%, respectively) of ovaries obtained from the control individuals, with a statistically significant difference (P = .001 or P = .00007, respectively), particularly considering that a detailed determination of a family history of cancer in the control group was not possible. CONCLUSIONS: The frequency of these changes in the high-risk ovaries compared with control ovaries suggests a characteristic histologic preneoplastic phenotype defined by an increased frequency and intensity of the above-described histologic features in the high-risk ovaries. Limited access to numerous small (stage I) ovarian cancers or cancer-prone ovaries by any one pathologist may explain the failure to identify the phenotype in the past. IMPLICATIONS: We suggest that the ovaries removed from ovarian cancer-prone individuals as a preventative measure should be thoroughly examined histologically to identify or rule out microscopic or near-microscopic invasive neoplasms.

Characterization of chromosome 9 in human ovarian neoplasia identifies frequent genetic imbalance on 9q and rare alterations involving 9p, including CDKN2.

We have examined 41 forms of ovarian cancer for genetic alterations on chromosome 9 using a combination of five RFLP DNA probes and 15 simple tandem repeat polymorphisms. Genetic imbalance (i.e., loss of heterozygosity, microsatellite instability, amplification) for 1 or more informative markers on chromosome 9 was observed in 66% (27 of 41) of our tumor panel. Genetic imbalance was observed on 9q in 59% (24 of 41) of tumors informative for at least one locus. In contrast, only 13% (5 of 40) of informative tumors demonstrated a genetic alteration involving 9p. Furthermore, allelic loss on 9q was more common in late stage tumors (63%, 17 of 27) and poorly differentiated tumors (75%, 15 of 20) as compared to benign and early stage tumors (30%, 3 of 10). Evaluation of 15 tumors showing limited regions of genetic imbalance has identified 2 candidate tumor suppressor regions on 9q and 1 on 9p. Interestingly, the regions defined to 9p21-p24, 9q31, and 9q32-q34 all overlap with several known disease loci. In this aspect, the potential role of the CDKN2 gene at 9p21-p22 in ovarian carcinogenesis was assessed in an extended panel of ovarian tumors, 11 human ovarian carcinoma cell lines, and 1 cervical tumor cell line. With the use of comparative multiplex PCR, homozygous deletions were detected in 16 of 115 (14%) fresh tumors and 3 of 12 cancer cell lines. For those tumors demonstrating allelic loss for markers on 9p no somatic mutations were observed in the retained allele of CDKN2, as determined by single-strand conformation polymorphism analysis, but a mutation was observed in an additional cell line. Furthermore, CDKN2 mRNA levels were similar in the 9 cancer cell lines that retain CDKN2, as compared to normal human ovarian surface epithelial cell lines. Overall, our results suggest the potential involvement of a gene or genes on chromosome 9q and de-emphasize a significant role for the CDKN2 gene on 9p in the initiation and progression of ovarian cancer.

Phase I trial of multiple cycles of high-dose chemotherapy supported by autologous peripheral-blood stem cells.

PURPOSE: To determine the safety and feasibility of delivering multiple cycles of front-line high-dose carboplatin and paclitaxel with hematopoietic peripheral-blood stem cell (PBSC) support. PATIENTS AND METHODS: Patients were required to have a malignant solid tumor for which they had received no prior chemotherapy. Mobilization of PBSC was achieved with cyclophosphamide, etoposide, and granulocyte-macrophage colony-stimulating factor (GM-CSF). After one cycle of conventional-dose carboplatin and cyclophosphamide with GM-CSF, patients received multiple cycles of high-dose carboplatin (area under the concentration-time curve [AUC], 12 to 20) and paclitaxel (250 mg/m(2)) with PBSC and GM-CSF repeated every 28 days. RESULTS: Twenty-four of 28 patients were assessable for toxicity and clinical outcome. Dose-limiting toxicities were dehydration, diarrhea, and electrolyte imbalances. The maximum-tolerated dose of carboplatin was AUC 16 (equivalent to a median of 1,189 mg/m(2)). The relationship of target AUC to measured AUC was linear (r(2) =. 29; P =.0011). The overall response rate was 96%, with a complete clinical response rate of 67%. The median time to progression from the first PBSC reinfusion was 49.5 weeks (range, 8 to 156+ weeks). CONCLUSION: Multiple cycles of high-dose carboplatin (AUC 16) and paclitaxel (250 mg/m(2)) can be safely administered with GM-CSF and PBSC support. Although this regimen is safe, feasible, and active, the use of multiple cycles of high-dose chemotherapy as front-line treatment remains experimental and should only be used in the context of a clinical trial.

Phase I trial of multiple cycles of high-dose carboplatin, paclitaxel, and topotecan with peripheral-blood stem-cell support as front-line therapy.

PURPOSE: To determine the safety and feasibility of delivering multiple cycles of front-line high-dose carboplatin, paclitaxel, and topotecan with peripheral-blood stem-cell (PBSC) support. PATIENTS AND METHODS: Patients were required to have a malignant solid tumor for which they had received no prior chemotherapy. Mobilization of PBSC was achieved with either filgrastim alone or in combination with cyclophosphamide and paclitaxel. Patients then received three or four cycles of high-dose carboplatin (area under the concentration-time curve [AUC] 16), paclitaxel (250 mg/m(2)), and topotecan (10-15 mg/m(2)), with the latter two agents administered as 24-hour infusions and supported with PBSC and filgrastim. Cycles were repeated every 28 days. RESULTS: Twenty patients were enrolled onto the trial and were assessable for toxicity and clinical outcome. Dose-limiting toxicities were stomatitis and prolonged hematopoietic recovery. The maximum-tolerated dose of topotecan was 12.5 mg/m(2) when given with high-dose carboplatin and paclitaxel for three cycles. Four cycles were able to be given with a dose of topotecan of 10 mg/m(2). The pharmacokinetics of each compound were not affected by the other agents. Eleven (85%) of 13 patients with assessable disease responded. CONCLUSION: Multiple cycles of high-dose carboplatin, paclitaxel, and topotecan can be safely administered with filgrastim and PBSC support. The recommended doses for phase II study are carboplatin AUC 16, paclitaxel 250 mg/m(2), and topotecan 10 mg/m(2). Trials are currently being conducted with this regimen as front-line treatment in patients with advanced ovarian cancer and extensive small-cell carcinoma. This approach remains experimental and should be used only in the context of a clinical trial.

The role of surgery in the management of ovarian cancer: primary and interval cytoreductive surgery.

Ovarian cancer remains the number one cause of mortality in gynecologic malignancies and the fifth most common cause of death among all malignancies in women. Unfortunately, recent data confirm that only approximately 90% of "apparent" early ovarian cancer are inadequately staged, and only approximately 80% of patients with advanced-stage disease are adequately staged. Interval debulking surgery, a newer treatment modality, appears to have a promising role for patients who cannot be adequately debulked at their initial surgery. Second-look laparotomy continues to be the most accurate way to document responses to chemotherapy in protocol settings, but additional clinical trials with newer second-line chemotherapy will be necessary before definitive statements can be made with regard to survival advantages in patients who undergo second-look laparotomy.

Improved outcome in patients treated with postoperative radiation therapy for pathologic stage I/II endometrial cancer.

PURPOSE: To evaluate prognostic factors and treatment outcome for high risk pathological Stage I and II endometrial cancer patients treated with consistent postoperative radiation therapy (RT) in a single institution and to compare these results to series where RT was variably applied. METHODS AND MATERIAL: Between 1986 and 1993, 98 pathologic Stage I and II endometrial cancer patients received postoperative RT at the Fox Chase Cancer Center. Papillary serous and clear cell histologies were excluded. Fifty-five patients underwent lymph node evaluation. In 17 patients, RT consisted of intracavitary brachytherapy alone to a median dose of 21 Gy, and in 81 patients, RT consisted of external beam RT to a median dose of 45 Gy followed by intracavitary brachytherapy to a median dose of 12 Gy. Intracavitary brachytherapy generally consisted of three high dose rate implants with the dose prescribed to a depth of 0.5 cm. Median follow up was 47 months. RESULTS: The 5-year overall survival (OS), disease free survival (DFS), and freedom from pelvic recurrence (FPR) rates were 83, 85, and 89%, respectively. Pelvic recurrence either as the sole pattern of failure or combined with distant metastases was seen in 2 and 7% of patients, respectively. Distant metastases alone occurred in 4% of the patients. Univariate analysis of prognostic factors including age, grade, capillary lymphatic space invasion, depth of myometrial invasion, type of lymph node evaluation, pathologic stage, the use of brachytherapy and the number of risk factors was performed for OS, DFS, FPR, and FDM. Capillary lymphatic space invasion was the only statistically significant predictor for reduced DFS. Absence of lymph node dissection as well as a higher number of risk factors showed a trend toward poorer DFS (p = 0.06 for both). Multivariate analysis revealed older age to be the only factor significant for reduced DFS, with the presence of capillary lymphatic space invasion and the absence of a lymph node dissection showing a trend toward poorer outcome (p = 0.07). CONCLUSIONS: The results of this study suggest a continued role for the use of postoperative RT in the treatment of patients with high risk endometrial cancer and will be compared to other series with similar high-risk factors.

Current status of staging laparotomy in colorectal and ovarian cancer.

Colon and rectal carcinomas. Accurate staging of colon and rectal carcinomas (CRCs) is vital to insure appropriate surgical and adjuvant therapy, and appropriate enrollment in and interpretation of adjuvant or neoadjuvant trials. Historically, CRC staging has relied on pathologic examination of surgical speciments. These newer techniques of endoscopic and intraoperative ultrasound, laparoscopy, and radioimmunoguided surgery may permit increased accuracy of staging by the surgeon. Cautious interpretation of investigations of these modalities is warranted, as studies include small numbers of patients and some of the work is preliminary. Despite this, we remain optimistic that as surgeons become more familiar with these techniques and as these modalities become more widely available, more accurate staging will facilitate optimal patient management in terms of complete resection of occult disease and appropriate adjuvant therapy. Ovarian carcinoma. The survival of patients with ovarian cancer has not appreciably changed in the past several decades. There are several reasons for this, some of which are related to the surgical procedures used to diagnose and treat these cancers. First, despite a great deal of literature that suggests an elevated CA-125 level in a postmenopausal woman with a pelvic mass is virtually diagnostic of ovarian carcinoma, an unexceptably large number of patients are still explored in community hospitals by a surgeon or obstetrician-gynecologist who is not prepared or adequately trained to perform the aggressive cytoreductive surgery that the patients require. Similarly, a large percentage of patients with "apparent" early ovarian cancer are not fully surgically staged at their initial surgery and often require reoperation to accurately define the extent of their disease, which will then determine the need for adjuvant therapy. Despite ongoing health care reforms, these patients should be referred to centers where the appropriate surgical procedure can be performed by an experienced gynecologic oncologist. Second-look laparotomy (SLL) has become more and more controversial, mainly because of a lack of effective second-line therapy, and should not be performed unless the patient fully understands its limitations and is willing preoperatively to participate in a subsequent trial based on the operative findings. Laparoscopy, both in the initial staging surgery and at reassessment laparotomy (SLL), is being re-evaluated but should be considered experimental until definitive trials determine its role.

The management of early ovarian cancer.

Approximately one third of patients with epithelial ovarian cancer present with localized or early-stage disease. Prognostic features identify certain subsets of patients with good risk characteristics who do not require adjuvant treatment after comprehensive surgical staging and cytoreduction. Only a minority of patients undergo such a complete procedure, which often results in understaging of these patients. In the United States, patients with poor prognostic features, such as stage IC to II disease, poorly differentiated histologic grade, clear cell histology, dense adhesions, and large volume ascites, have received adjuvant chemotherapy. Single-agent or combination chemotherapy, whole abdominal irradiation, and intraperitoneal phosphorus 32 have been evaluated, although no modality has been shown to improve overall survival. Randomized trials investigating the optimal therapy or whether any therapy is truly effective are in progress. Until the completion of these trials, the most common postoperative adjuvant therapy in these patients in this country remains combination chemotherapy.

Early ovarian cancer: a review of its genetic and biologic factors, detection, and treatment.

Early-stage ovarian carcinoma requires comprehensive surgical staging; reexploration for patients who had suboptimal initial surgery would indicate an apparent early ovarian carcinoma. After proper surgery, patients can be subdivided into a high- or low-risk group, and treatment options then can be discussed with the patient. Patients in the low-risk category can be followed up expectantly without any form of adjuvant therapy. Patients in the high-risk category, however, should be encouraged to participate in randomized clinical trials, because it is unclear at the current time which combination of chemotherapy and how many treatments should be used. A platinum-based paclitaxel regimen probably should be used, although the relative merits of carboplatin and cisplatin and the appropriate schedule for taxol (1 hour vs. 3 hours vs. 24 hours vs. 96 hours) are yet unknown. It is hoped that clinicians will continue to encourage patients to participate in randomized clinical trials so that optimal therapy for early ovarian cancer can be established.

IFAP syndrome "plus" seizures, mental retardation, and callosal hypoplasia.

Ichthyosis follicularis, congenital alopecia, and photophobia are typical features of a rare X-linked recessive disorder termed ichthyosis follicularis with atrichia and photophobia syndrome. A 3-year-old male with these findings and severe growth failure, mental retardation, generalized seizures, vascularizing keratitis, nail anomalies, inguinal hernia, and a normal chromosome constitution is presented. Two maternal male relatives were affected by the same condition. Magnetic resonance imaging revealed corpus callosum hypoplasia not described at present. Syndromes with alopecia, seizures, and mental retardation are analyzed on the basis of genetic and clinical results.

Cerebriform plantar hyperplasia: ultrastructural study of two cases.

In the present work we report the histopathological features of the cerebriform plantar hyperplasia observed in two patients with a mild form of the Proteus syndrome. Light microscopy revealed increased fibro-adipose tissue and adnexal structures in the dermis. Ultrastructurally, densely packed collagen fibrils variable in diameter and configuration, described as composite fibrils and unraveled fibrils, as well as a few fragmented elastic fibrils presenting an altered ratio between the elastin and the microfibrillar components were the major features observed. We consider that these histopathological findings will contribute to further delineate cerebriform plantar hyperplasia and also to establish clues for the early diagnosis of the Proteus syndrome.

Atrichia, ichthyosis, follicular hyperkeratosis, chronic candidiasis, keratitis, seizures, mental retardation and inguinal hernia: a severe manifestation of IFAP syndrome?

A boy with congenital atrichia, ichthyosis follicular, keratitis, cutaneous infections and a huge inguinal hernia, but without deafness is reported. We believe it represents a new case of a rare X-linked recessive syndrome known as ichthyosis follicularis, alopecia, photophobia syndrome (IFAP). The differential diagnosis from keratitis ichthyosis deafness is discussed. The cutaneous infections seen in our case suggest the possibility of considering a genetic link between these syndromes.

Costello syndrome: report of a new case with choanal atresia and fatal outcome.

We describe a girl with motor and mental retardation, macrocephaly, a "coarse" face, choanal atresia, postnatal feeding difficulty, redundant skin with deep palmar and plantar creases, and histopathological evidence of altered elastic fibers, who died at the age of 11 months. We believe this represents another case of Costello syndrome. Lacking papillomata, she had choanal atresia and underwent a fatal outcome at an early age. The differential diagnosis of cutis laxa in association with postnatal growth retardation and developmental delay and with cardio-facio-cutaneous and Noonan syndromes is discussed.

Phacomatosis pigmentokeratotica: another epidermal nevus syndrome and a distinctive type of twin spotting.

The name epidermal nevus syndrome could be applied to a group of clinically and histopathologically different entities as has been pointed out by Happle. Phacomatosis pigmentokeratotica is a further type of epidermal nevus syndrome distinguished by the presence of a sebaceous nevus and a contralateral speckled lentiginous nevus of the papular type, associated with skeletal or neurological abnormalities. Three new cases of this recently delineated syndrome are presented. A common origin may account for the temporal and spatial relationship between the epidermal and the speckled lentiginous nevus. The concept of melanocytic-epidermal twin spotting similar to the interpretation of vascular twin spotting could explain the pathogenesis of this entity.

Gynecologic cancers.

In conclusion, significant advances have been made in ovarian cancer. Specifically, these relate to the success of paclitaxel and platinum-based regimens. The appropriate scheduling, dosing, and the selection of carboplatin vs cisplatin remains controversial. The role of interval debulking surgery is still investigational and we remain cautiously optimistic as to its long-term benefit. The progress in the delivery of chemotherapy to patients with cervical carcinoma, endometrial carcinoma, vaginal carcinoma, and vulvar carcinoma has been slowed by the paucity of prospective-randomized trials. Although numerous single institution non-randomized trials show promising regimens, they lack significant power and appropriate study design to prove meaningful. Our goals in the future should be to try to enter most of these patients into national collaborative studies where significant conclusions can be made because of appropriate study design and adequate patient numbers.

[Linear Darier disease in two siblings. An example of loss of heterozygosity]. / Maladie de Darier linéaire dans une fratrie. Un exemple de perte d'hétérogénéité.

BACKGROUND: Darier's disease or keratosis follicularis is an autosomal dominant acantholytic disorder that frequently arises as a result of spontaneous mutation. It is either a generalized or localized condition due to a mutation in the SERCA2 12q23-q24,1 resulting in a faulty organization of the tonofilaments. We present two siblings affected with the linear form of this disorder and discuss these cases as an example of the genetic mechanism of loss of heterozygosity. CASE REPORTS: A 7 year-old girl was referred for evaluation of linear lesions present since the first year of age. Examination disclosed red, 1 to 2 mm papules that coalesced to form linear plaques on the left side of the vulvar and perianal areas, and on the left hand and foot. Her older brother had similar lesions in a linear arrangement on the left side of the face neck and homolateral foot. No lesions were found in their parents. Biopsies of both affected children revealed an intraepidermal suprabasal cleft. Dyskeratotic cells were present in the spinous layer, and corps ronds and grains near the granular layer. DISCUSSION: The linear form of Darier's disease could result from genetic mosaicism for this autosomal dominant disorder. As these children have a more pronounced involvement than the usual Darier's disease lesions, disposed in a linear arrangement, they probably represent a type 2 segmental manifestation of the disorder. Likewise, the presence of the same linear disorder in two siblings could be explained by loss of heterozygosity for the Darier's disease gene.