High Ki-67 proliferative index predicts disease specific survival in patients with high-risk soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas (STSs) are heterogeneous neoplasms that have variable clinical outcome. Several clinical parameters and few molecular markers, including Ki-67 proliferative index, have been shown to correlate with patient prognosis. To the authors' knowledge, no definitive report exists to identify one molecular marker that can be analyzed easily in a clinical setting and that predicts survival in a cohort of patients with high-risk STS of identical clinical characteristics but variable outcome. METHODS: The influence of clinical prognostic factors was eliminated by selecting two patient groups with identical high-risk characteristics: large (> 10 cm), high-grade, deep, completely resected primary extremity STS (n = 47). Patients in the first group remained disease free (no evidence of disease [NED]) after primary tumor treatment (n = 19), whereas patients in the second group subsequently died of disease (DOD; n = 28). Triplicate 0.6-mm core biopsies from defined morphologic areas of paraffin embedded primary tumors were assembled on a tissue microarray and analyzed by immunohistochemistry with the MIB-1 antibody, and Ki-67 proliferative indices were correlated with patient outcome. RESULTS: High Ki-67 proliferative index, defined as greater than 30% tumor cells showing nuclear immunoreactivity, was significantly more frequent in the DOD group than in the NED group and was associated with tumor-related mortality (P = 0.02). This marker identifies an especially aggressive malignant phenotype within a cohort of high-risk tumors that is based on well established clinical and pathologic parameters alone and is easy to use in a clinical setting. CONCLUSIONS: On the basis of these data and previous reports, high Ki-67 proliferative index is suggested as a significant factor for predicting the prognosis of patients with high-risk STS and should be evaluated prospectively based on clinical trials.

Immune responses in tuberculosis: antibodies and CD4-CD8 lymphocytes with vascular adhesion molecules and cytokines (chemokines) cause a rapid antigen-specific cell infiltration at sites of bacillus Calmette-Guérin reinfection.

Rabbit primary dermal bacillus Calmette-Guérin (BCG) lesions were compared with reinfection BCG lesions in order to gain insight into how immune responses protect against clinical tuberculosis. As early as 3 hr, a marked infiltration of macrophages and lymphocytes occurred in the reinfection group, while very little cell infiltration occurred in the primary group. It seems that only an antigen-antibody reaction could produce such an immediate pronounced antigen-specific chemotactic effect, because very few lymphocytes are normally present in the skin. Therefore, antibodies hasten the accumulation of an expanded antigen-specific T-lymphocyte population (memory cells) at sites of bacillary lodgement. By 1-2 days, the primary and reinfection BCG lesions differed 400- to 500-fold in size. By 4-5 days, the size of the reinfection lesions had declined, while the size of the primary lesions had increased, so that, grossly, both types of lesion were similar. At 8 days in reinfection lesions and at 12 days in primary lesions, small secondary peaks in size occurred, which were probably caused by cell-mediated immune responses. In rabbits with primary BCG lesions, skin tests with Old Tuberculin were positive at 9 days, accompanied by a rise in the levels of antibodies to the secreted antigen, phosphate-specific transport protein 1, but the levels of antibodies to the constitutive antigens, purified protein derivative and heat-shock protein 65, did not increase appreciably until some time after 23 days. In tissue sections of reinfection BCG lesions, the percentage of mononuclear cells labelled, by in situ hybridization techniques, for the mRNA of monocyte chemoattractant protein 1 (MCP-1), a chemokine, peaked at 3 hr and then was down-regulated, whereas in primary lesions, this percentage was down-regulated only after 2 days. [The percentage in the tissue sections for the mRNAs of interleukins 1beta and 8, as well as the proteins of MCP-1 and tumor necrosis factor alpha (TNF-alpha), followed a somewhat similar time-course to that of MCP-1 mRNA.] A high percentage of mononuclear cells containing the MCP-1 mRNA 'factory' would favour enlargement of the lesions and a low percentage would favour their regression. At 5 days, the percentage of CD4 and CD8 lymphocytes, stained by immunohistochemical techniques, and the amount of microvasculature stained similarly for vascular cell adhesion molecule 1 were higher in the reinfection group, indicating that prior immunization caused a more rapid (antigen-dependent) up-regulation of these factors. Tuberculin reactions resembled early reinfection BCG lesions in almost every factor evaluated herein. In brief, the production of chemokines began soon after BCG reinfection, peaked within a few hours and was markedly down-regulated by 24 hr, a time at which the lesions of reinfection were of maximal size. Therefore, the amount of cell infiltration was tightly controlled, probably by the variety of mechanisms listed herein.

Hürthle cell carcinoma: a critical histopathologic appraisal.

PURPOSE: Controversy exists over the ability of morphology to predict the biologic behavior of Hürthle cell carcinoma. The aim of this study was to conduct a critical histopathologic review of Hürthle cell carcinoma and to correlate morphologic parameters with clinical outcome. PATIENTS AND METHODS: Patients with histologically confirmed Hürthle cell carcinoma treated between 1940 and 2000 form the basis of this study. Adenomas were excluded. Tumors of unknown malignant behavior ([UMB] n = 17) had solid growth pattern, incomplete capsular invasion (Ci), or both but no vascular invasion (Vi). Minimally invasive carcinomas ([MIC] n = 23) had one focus of intra- or extracapsular Vi, one focus of complete Ci, or both. Widely invasive carcinomas ([WIC] n = 33) demonstrated more than one focus of Vi, more than one focus of Ci, or both. The primary end points were relapse-free survival (RFS) and disease-specific survival (DSS). Rates of recurrence/death were estimated by Kaplan-Meier method. The univariate influence of prognostic factors on end points was analyzed by log-rank test, and multivariate analysis was performed by Cox regression. RESULTS: Median follow-up was 8 years. No patients with UMB or MIC relapsed or died of disease. Of WIC, 73% relapsed and 55% died of disease. Age, size, and extent of resection did not influence outcome. Adverse predictors of RFS and DSS among WIC were extrathyroidal extension, nodal metastasis, positive margin, and solid growth pattern (P <.05). Both Ci and Vi were associated with worse DSS (P <.05). On multivariate analysis, extrathyroidal extension and nodal metastases were independent predictors of outcome (P <.05). CONCLUSION: Patients with Hürthle cell carcinoma have a prognosis that is predicted by well-defined histomorphologic characteristics. Unlike differentiated thyroid cancer, nodal metastases predict a worse outcome in widely invasive Hürthle cell carcinoma, as does extrathyroidal extension.

Validation of tissue microarrays for immunohistochemical profiling of cancer specimens using the example of human fibroblastic tumors.

Tissue microarrays allow high-throughput molecular profiling of cancer specimens by immunohistochemistry. Phenotype information of sections from arrayed biopsies on a multitissue block needs to be representative of full sections, as protein expression varies throughout the entire tumor specimen. To validate the use of tissue microarrays for immunophenotyping, we studied a group of 59 fibroblastic tumors with variable protein expression patterns by immunohistochemistry for Ki-67, p53, and the retinoblastoma protein (pRB). Data on full tissue sections were compared to the results of one, two, and three 0.6-mm core biopsies per tumor on a tissue array. Ki-67 and p53 staining was read as two categories (positive or negative). Concordance for this staining between tissue arrays with triplicate cores per tumor and full sections were 96 and 98%, respectively. For pRB staining was read as three categories (high, moderate, or negative), where concordance was 91%. The use of three cores per tumor resulted in lower numbers of lost cases and lower nonconcordance with standard full sections as compared to one or two cores per tumor. Correlations between phenotypes and clinical outcome were not significantly different between full section and array-based analysis. Triplicate 0.6-mm core biopsies sampled on tissue arrays provide a reliable system for high-throughput expression profiling by immunohistochemistry when compared to standard full sections. Triplicate cores offer a higher rate of assessable cases and a lower rate of nonconcordant readings than one or two cores. Concordance of triplicate cores is high (96 to 98%) for two category distinction and decreases with the complexity of the phenotypes being analyzed (91%).

Clinicopathologic analysis of patients with adult rhabdomyosarcoma.

BACKGROUND: Rhabdomyosarcoma (RMS) in adults (age > or = 16 years) is rare, accounting for less than 3% of adult soft tissue sarcomas. There is little information describing the disease biology or clinicopathologic factors that influence survival in adults with RMS. The objective of this study was to define the factors in patients with adult RMS that predict outcome, disease progression, and survival. METHODS: Eighty-four adult patients with a pathologic diagnosis of RMS that was confirmed by immunohistochemistry were identified by a prospective inpatient data base during the period 1982--1999 and were analyzed for disease specific survival and metastasis free survival using the Kaplan-Meier actuarial method. Statistical significance was evaluated using the log-rank test for univariate influence and a Cox regression model for multivariate influence. RESULTS: The median disease specific survival was 22 months. Patient age, extent of disease, tumor size at the time of diagnosis, and margin status after resection were significant predictors of disease specific survival. Patients who underwent a complete resection had a significantly longer median survival (105 months) compared with any other subgroup of patients. The histologic subtype did not predict patient survival but did vary with patient age. Most notably, the proportion of the pleomorphic subtype increased with advancing age, accounting for 42% of RMS in patients over the age of 40 years. CONCLUSIONS: The most important predictors of outcome in patients with adult RMS are patient age, tumor size, extent of disease, and margin status after resection. In contrast to patients with pediatric RMS, no association was noted between survival and histologic subtype in this group of patients with adult RMS. All histologic subtypes of RMS are aggressive malignancies with poor disease specific survival despite aggressive multimodality management.

Desmoid tumors of the head and neck--a clinical study of a rare entity.

BACKGROUND: Desmoid tumors are are, nonmalignant neoplasms that show locally aggressive growth but lack the potential to metastasize. Common anatomic sites include the extremity, abdominal wall, and mesentery. Little is reported about clinical features and outcome of desmoid tumors of the head and neck. METHODS: Twenty-one patients with desmoid tumors of the head and neck treated at MSKCC between July 1982 and June 1999 were identified from our inpatient tumor database. All patients underwent surgical resection and were prospectively followed. Clinicopathologic features and treatment modalities were evaluated. RESULTS: Patient age at diagnosis was 22 to 76 years, with a female-male ratio of 16:5. Most tumors were located in the supraclavicular fossa or the muscles of the neck (n = 19). Patients most commonly had a painless mass (n = 13) or neurologic symptoms including pain or neurologic deficit (n = 8). Extent of resection was limited to the tumor in nine patients. In the other 12, structures including the accessory or phrenic nerve, parts of the brachial plexus, or bony structures were resected. Persistent neurologic or functional deficits after surgery were noted in 12 patients. Five of 21 patients had recurrences (24%). Eleven patients received radiation therapy. In this small population, no obvious benefit for patients receiving radiation vs patients who were not irradiated, regardless of their surgical margin status, was seen. Treatment for recurrence was re-resection or re-resection plus radiation. Eighteen patients remained free of disease after treatment, two patient have stable disease and one died of other causes. No patients died of their disease. CONCLUSIONS: Desmoid tumors of the head and neck are rare, fibrous neoplasms with a good prognosis but significant morbidity. Function-preserving surgery should be a primary goal to minimize morbidity. In this small group of patients, the benefits of radiation therapy in patients with positive margins could not be clearly demonstrated and should be balanced against radiation-related morbidity.

Müller's muscle-conjunctival resection ptosis procedure.

The Müller's muscle-conjunctival resection procedure is a relatively simple means of relieving ptosis in patients whose upper eyelids elevate to a normal level with phenylephrine instillation. The Müller's muscle-conjunctival resection procedure has advantages over the Fasanella operation because tarsus is preserved, and over the levator aponeurosis advancement and tuck operation because the results are more predictable.

Clinical observations in 101 consecutive patients with Duane's retraction syndrome.

We retrospectively studied 101 consecutive patients with Duane's retraction syndrome. Eighty-five percent were unilaterally affected and 15% were bilaterally affected. More patients had straight eyes in primary position than esotropia or exotropia. On lateral version reflex testing the amount of underaction of the lateral and medial rectus muscles could be determined, and could be used to predict whether the patients' eyes were esotropic, exotropic, or straight in primary position. Almost all the patients showed an esotropia when looking to one side and either an exotropia or no deviation to the other side. The degree of the exotropia and the esotropia on opposite sides determined whether a head turn would be present and in what direction. On adduction, the palpebral fissure in the affected eye narrowed in one half the patients because of motion of both upper and lower eyelids, and in 40% because of motion of only one eyelid. When the lower eyelid elevated, it usually assumed a straight horizontal contour with peaking of the punctum lacrimalis (appearing as a small pyramid). The statistical predominance of females and left eyes was more significant among patients whose eyes were straight in primary position. All patients tested demonstrated stereopsis. Most of the amblyopic patients had anisometropia.

Reconstruction of the upper eyelid crease and fold.

For good cosmesis the upper eyelid creases and folds must be symmetric. The lid creases must be the same height above the upper lid margins. The skin below the crease must be smooth and firmly attached to the tarsus, or, in cases with a short tarsus, adherent to the short tarsus and levator muscle up to the crease. The skin above the crease must be loosely attached so that it forms symmetric folds over the crease. We have developed surgical procedures aimed at the following: (1) equalizing the upper lid creases and folds where they are asymmetric, (2) creating lid creases and folds where absent, as in Orientals, (3) removing excess unsightly skin folds, as in dermatochalasis, and (4) forming a lid fold by skin grafting where there is insufficient skin above the crease.

Upper eyelid retraction after blowout fractures.

Two patients developed upper eyelid retraction secondary to a blowout fracture of the orbital floor. Posttraumatic overaction of Muller muscle is a possible cause of the eyelid retraction.

Anterior segment ischemia and sector iris atrophy: after strabismus surgery in a patient with chronic lymphocytic leukemia.

A 69-year-old woman with chronic lymphocytic leukemia developed segmental iris atrophy and iridocyclitis after routine surgery for exotropia. Both the clinical picture and fluorescein angiogram indicated anterior segment ischemia. It is postulated that this was related to hyperviscosity of the blood caused by a high white blood cell count (114,000/cu mm). The possibility of anterior segment ischemia should be kept in mind when contemplating strabismus or retinal detachment surgery in the presence of hematologic disorders likely to increase blood viscosity. In these cases a minimal amount of surgery should be done with proper supportive therapy. Strabismus surgery should be done in stages allowing for hemodynamic compensation between procedures.

Müller muscle-conjunctiva resection. Technique for treatment of blepharoptosis.

A new technique for resecting the Müller muscle and the conjunctiva for correction of blepharoptosis has been developed. The operation is performed on all patients in whom a 10% phenylephrine hydrochloride solution instilled in the conjunctival cul-de-sac will elevate the blepharoptotic eyelid to a cosmetically acceptable level. The results of the surgery have been satisfactory in 27 of 28 operated eyelids.

Corneal dellen in the limbal approach to rectus muscle surgery.

A retrospective study of 170 cases of horizontal rectus muscle surgery performed during the years 1969 and 1970 at the University of Illinois Eye and Ear Infirmary revealed a 6-5 per cent incidence of dellen with the limbal approach to the muscle and a 2-2 per cent of incidence of dellen with the nonlimbal or direct approach to the muscle. This was significant to the 5 per cent level of confidence by the chi2 test. We feel that this finding of an increased incidence of dellen with the limbal approach complements the current theory of desiccation as the cause of corneal dellen. We do not recommend abandonment of the limbal approach to rectus muscle surgery because of this finding, but suggest that surgeons scrutinize more carefully their postoperative patients for dellen. If dellen do not occur careful trimming of the conjunctiva to avoid bunching and thickening may perhaps eliminate them.

Lateral rectus muscle paralysis associated with closed-head trauma.

We examined 21 patients with closed-head trauma and resulting paralysis of the lateral rectus muscle. Clinical findings included laterally directed gaze palsy, some unconsciousness, and pseudo-duane's phenomenon suggesting a supranuclear lesion at the level of the upper pontine tegmentum, and pontine paramedial reticular formation. The surgical procedure of choice was a "midline operation," that is, the appropriate number of millimeters of recession and resection to achieve 0 to 5 degrees of exotropia in the primary position of gaze. Frequently, the medial rectus muscle must be recessed 10 nm or more and the lateral rectus muscle resected 10 nm or more to achieve this result. None of the 21 patients had diplopia after the midline procedure.

Upper eyelid retraction after glaucoma filtering procedures.

After glaucoma filtration surgery, 2 patients developed overaction of Müller's muscle with resultant upper eyelid retraction. We theorize that stimulation of Müller's muscle is caused by a sympathomimetic chemical in the aqueous that travels from the bleb, under the bulbar and palpebral conjunctiva, to Muüller's muscle. In one case excision of Muüller's muscle relieved the retraction. In the other case, preventing aqueous from reaching Müller's muscle reduced the retraction.

Treatment of enophthalmic narrow palpebral fissure after blow-out fracture.

Surgery for a narrow palpebral fissure caused by enophthalmos after a blow-out orbital fracture was performed in three patients from seven months to three years after injury. The surgery was directed not to the cause of the enophthalmos, but to the narrowed palpebral fissure which was the noticeable cosmetic defect. The surgical procedure used to widen the palpebral fissure was the Müller's muscle-conjunctival resection blepharoptosis operation, and a phenylephrine test was used preoperatively to select candidates for this operation. After widening of the palpebral fissure, which created the illusion of exophthalmos, the cosmetic result was acceptable.

Surgical treatment of exotropia after surgically produced pseudoparalysis of the medial rectus muscle.

The characteristic clinical findings of pseudoparalysis of the medial rectus muscle include exotropia in primary position, widened medial fissure on the affected side, limitation of adduction on the affected side, an A-pattern exotropia, and a paradoxical forced-traction test. We have devised a surgical technique to restore good movement of the eye in adduction. The priniciple behind the technique is that all adhesions between Tenon's capsule covering the muscle and conjunctiva, and between muscle and sclera must be found and cut posterior to the fornix. This will allow the muscle to be brought forward easily so that it can be resected and advanced for restoration of function.