Alberto G. Ayala

The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder

In October 1997, Dr. F.K. Mostofi assembled a group of individuals interested in bladder neoplasia at a meeting in Washington DC. The participants included urologic pathologists, urologists, urologic oncologists, and basic scientists with an interest in bladder neoplasia. The purpose of this meeting was to discuss bladder terminology and make recommendations to the World Health Organization (WHO) Committee on urothelial tumors. Following this meeting, a group of the urologic pathologists who attended the Washington meeting decided to broaden the representation of the group and arranged a meeting primarily of the members of the International Society of Urologic Pathologists (ISUP) at the 1998 United States and Canadian Academy of Pathology Meeting held in Boston. Massachusetts. At this meeting. issues regarding terminology of bladder lesions, primarily neoplastic and putative preneoplastic lesions, were discussed, resulting in a consensus statement. The WHO/ ISUP consensus classification arises from this consensus conference committees recommendations to the WHO planning committee and their agreement with virtually all of the proposals presented herein. 29 The effort involved in reaching such a consensus was often considerable. Many of those involved in this process have compromised to arrive at a consensus. The aim was to develop a universally acceptable classification system for bladder neoplasia that could be used effectively by pathologists, urologists, and oncologists.

A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors.

To evaluate the relative efficacy of cisplatin, cyclophosphamide, and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) (CISCA) versus methotrexate, vinblastine, Adriamycin, and cisplatin (MVAC), a prospective randomized trial was performed in patients with advanced metastatic urothelial tumors. Patients were stratified by histologic disease type and degree of tumor dissemination. Equal distribution of the clinical characteristics was achieved. One hundred ten patients with metastatic disease of the urinary tract (86 bladder, 16 renal pelvis, seven ureter, one prostatic urethra) met eligibility criteria and were enrolled on study. These represented 82% of the total patients seen during the study period in the Section of Genitourinary Oncology who met the eligibility criteria. The combined complete and partial response rate was significantly higher for patients treated with MVAC than for those treated with CISCA (65% v 46%; P less than .05). The survival duration of MVAC-treated patients was significantly longer than that of CISCA-treated patients (mean, 62.6 weeks; median, 48.3; range, 5.0+ to 162.3+ v mean, 40.4 weeks; median, 36.1; range, 7+ to 147.1+). We conclude that MVAC chemotherapy is superior to CISCA chemotherapy, achieving a higher response rate and a longer survival for equivalent patients with metastatic urothelial tumors.

Micropapillary component in lung adenocarcinoma: A distinctive histologic feature with possible prognostic significance

Micropapillary carcinoma or a micropapillary carcinoma component has been reported in the ovary, breast, and urinary bladder and is generally thought to have prognostic significance. However, little has been written on micropapillary differentiation in lung carcinoma. We studied 35 cases of primary lung adenocarcinoma with a micropapillary component seen at the M.D. Anderson Cancer Center. The micropapillary component in these tumors ranged from focal to prominent and was seen at both primary and metastatic sites. This component was not associated with any particular histologic subtype of lung adenocarcinoma. Of the 15 cases with available material, 14 (93%) stained positive for cytokeratin 7, whereas only two of the 15 cases (13%) stained positive for cytokeratin 20. Thyroid transcription factor-1 immunostaining of tumor nuclei was seen in 12 of the 15 cases (80%). Immunostaining was seen in areas both with and without micropapillary differentiation. Thirty-three of 35 patients (94%) developed metastases, which occurred most commonly in the lymph nodes (n = 26), and also in the lung (n = 17), brain (n = 9 cases), bone (n = 9 cases), and other sites. Most metastases had a prominent micropapillary component, irrespective of the extent of the micropapillary carcinoma component in the primary lung tumor. Adequate clinical follow-up information was available for 29 patients. The mean follow-up was 25 months. At their last follow-up, 16 of 29 patients (55%) were still alive with disease, 5 (17%) were dead of disease, and 8 (28%) were alive with no evidence of disease. We believe that a micropapillary component occurring in lung adenocarcinoma should be reported, as this component may be more likely to metastasize. The presence of this component should alert the clinician to search more carefully for metastases and have a closer follow-up on these patients. It is also important to recognize this component in evaluating a metastasis from an unknown primary site, as it should alert the pathologist to a possible primary in the lung in addition to breast, urinary bladder, and ovary.

Small cell carcinoma of the prostate part I a clinicopathologic study of 20 cases

Clinical information and histological slides of 20 cases of small cell carcinoma of the prostate seen at The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston over a 23‐year period were reviewed. Patients ages ranged from 30 to 89 years (median, 67 years). In nine cases, pure adenocarcinoma of the prostate preceeded recognition of the small cell component by 7 months to 8 years (median, 18 months); five of these were initially at Stage A. There was a small cell component at presentation in 11 cases (10, Stage D). Small cell carcinoma was merging with the adenocarcinoma in 11 cases and represented 30% to 90% of total tumor volume. Eleven of 20 patients died of their disease. Those presenting initially with a pure adenocarcinoma survived between 7 months and 9 years (median, 24 months). After the recognition of the small cell carcinoma component, regardless of a prior history of adenocarcinoma, death followed within 1.5 years (median, 5 months). This study suggests a biologic difference in behavior in prostatic carcinoma containing a small cell carcinoma component. The small cell component may manifest early or late in the disease.

Presurgical Chemotherapy Compared With Immediate Surgery and Adjuvant Chemotherapy for Nonmetastatic Osteosarcoma: Pediatric Oncology Group Study POG-8651

PURPOSE Successful therapeutic interventions to prevent disease progression in patients with nonmetastatic osteosarcoma have included surgery with adjuvant chemotherapy. Presurgical chemotherapy has been advocated for these patients because of putative improvement in event-free survival (EFS). The advantages of presurgical chemotherapy include early administration of systemic chemotherapy, shrinkage of primary tumor, and pathologic identification of risk groups. The theoretic disadvantage is that it exposes a large tumor burden to marginally effective chemotherapy. The contribution of chemotherapy and surgery timing has not been tested rigorously. PATIENTS AND METHODS Between 1986 and 1993, we conducted a prospective trial in patients with nonmetastatic osteosarcoma who were assigned randomly to immediate surgery or presurgical chemotherapy. Except for the timing of surgery (week 0 or 10), patients received 44 weeks of identical combination chemotherapy that included high-dose methotrexate with leucovorin rescue, doxorubicin, cisplatin, bleomycin, cyclophosphamide, and dactinomycin. RESULTS One hundred six patients were enrolled onto this study. Six were excluded from analysis. Of the remaining 100 patients, 45 were randomly assigned to immediate chemotherapy, and 55 were randomly assigned to immediate surgery. Sixty-seven patients remain disease-free. At 5 years, the projected EFS +/- SE is 65% +/- 6% (69% +/- 8% for immediate surgery and 61% +/- 8% for presurgical chemotherapy; P =.8). The treatment arms had similar incidence of limb salvage (55% for immediate surgery and 50% for presurgical chemotherapy). CONCLUSION Chemotherapy was effective in both treatment groups. There was no advantage in EFS for patients given presurgical chemotherapy.

TUMOR STAGE, VASCULAR INVASION AND THE PERCENTAGE OF POORLY DIFFERENTIATED CANCER: INDEPENDENT PROGNOSTICATORS FOR INGUINAL LYMPH NODE METASTASIS IN PENILE SQUAMOUS CANCER

PURPOSE We determine if histopathological factors of the primary penile tumor can stratify the risk of the development of inguinal lymph node metastases. MATERIALS AND METHODS Clinical records of 48 consecutive patients with squamous cell carcinoma of the penis who underwent resection of the primary lesion and either inguinal lymph node dissection or were observed for signs of recurrence (median followup 59 months) were reviewed. Parameters examined included pathological tumor stage, quantified depth of invasion and tumor thickness, histological and nuclear grade, percentage of poorly differentiated cancer in the primary tumor, number of mitoses and presence or absence of vascular invasion. Variables were compared in 18 lymph node positive and 30 lymph node negative cases. RESULTS Pathological tumor stage, vascular invasion and presence of greater than 50% poorly differentiated cancer were the strongest predictors of nodal metastasis on univariate and multivariate regression analyses. None of 15 pT1 tumors exhibited vascular invasion or lymph node metastases. Of 33 patients with pT2 or greater tumors 21 (64%) had vascular invasion and 18 (55%) had metastases. Only 4 of 25 patients (15%) with 50% or less poorly differentiated cancer in the penile tumor had metastases compared with 14 of 23 patients (61%) with greater than 50% poorly differentiated cancer (p = 0.001). No other variables tested were significantly different among the patient cohorts. CONCLUSIONS Pathological stage of the penile tumor, vascular invasion and greater than 50% poorly differentiated cancer were independent prognostic factors for inguinal lymph node metastasis. Prophylactic lymphadenectomy in compliant patients with pT1 lesions without vascular invasion and 50% or less poorly differentiated cancer does not appear warranted.

Primary adenocarcinoma of the urinary bladder. A clinicopathologic analysis of 72 cases.

Adenocarcinomas account for approximately 2% of primary epithelial malignancies of the urinary bladder. The clinicopathologic features of 72 cases treated at one institution are reported; 22 cases were evaluated immunohistochemically. Twenty‐four tumors were urachal and 48 nonurachal. The cases were analyzed according to their stage at presentation, histologic type, and mucin staining; they were tested immunohistochemically to determine their reaction to carcinoembryonic antigen, Leu‐M1, prostate‐specific antigen, and prostatic acid phosphatase. Tumor stage was a highly significant predictor of outcome (P = 0.001). Nonurachal tumors tended to have a worse outcome than urachal, but the difference was not statistically significant (P = 0.07). Histologic type was not a significant predictor of outcome (P = 0.10). For adenocarcinoma of the urinary bladder, stage was the most significant predictive factor; separating urachal from nonurachal tumors was important, but mucin histochemistry and immunohistochemistry did not help in this distinction. On occasion, a few tumors may react with some polyclonal antibodies to prostate‐specific antigen; thus these results must be interpreted with caution. In these instances, the possibility of using highly sensitive and specific monoclonal antibodies such as the one employed in this study should be considered.

Extraskeletal osteosarcoma : a clinicopathologic review of 26 cases

The clinical records and histopathologic features in 26 cases of extraskeletal osteosarcoma (ESOS) diagnosed at M. D. Anderson Cancer Center (Houston) between 1950 and 1987 were reviewed. Presentation was usually that of an enlarging soft tissue mass. The thigh (11 cases), upper extremity/shoulder girdle (three cases), and retroperitoneum (three cases) were the most common anatomic sites. Tumor size ranged from 2.5 to 30 cm. The predominant histologic pattern was osteoblastic in four cases, chondroblastic in two, fibroblastic or pleomorphic malignant fibrous histiocytoma (MFH)‐like in four, giant cell type MFH‐like in one, and small cell in one. Various mixtures of these patterns were seen in the remaining 14 tumors. The telangiectatic pattern was not seen as the predominant component in any primary tumor but was observed as a minor component. Thirteen tumors recurred locally and 16 metastasized; five patients had distant metastases at presentation. The lungs, bone, and soft tissue were the most frequent metastatic sites. Sixteen patients died of disease at 2 to 54 months, one patient died of unrelated causes at 61 months, seven patients were alive with no evidence of disease (NED) at 30 to 122 months, and two patients were alive with disease at 28 and 54 months, respectively. Tumor size (< 5 cm versus < 5 cm) was the main prognostic factor; all patients alive with NED for whom accurate tumor measurements were available (six of seven) had neoplasms measuring < 5 cm that were amenable to complete surgical excision. Histologic pattern and other clinicopathologic features did not significantly affect outcome.

The prostatic capsule: does it exist? Its importance in the staging and treatment of prostatic carcinoma

Pathologic evaluation of tumor extent in a radical prostatectomy specimen for prostatic adenocarcinoma is extremely important in staging and planning further therapy. We studied whole-organ sections of 50 prostate glands, obtained at either radical prostatectomy for adenocarcinoma or cystoprostatectomy for bladder cancer, to evaluate the so-called capsule of the prostate, the prostatic apex, and the surgical margins. The outer surface of the prostatic portion of the specimen was totally inked with different colors for the anterior, posterior, left, and right areas. Cross sections were processed for histologic examination, and the apex (distal 1.5 cm) was amputated and radially sectioned (like a cervical cone). We found that the “capsule” is made up of a band of concentrically placed fibromuscular tissue that is an inseparable component of the prostatic stroma. The outer surface of this tissue gives rise to a few bundles of fibromuscular stroma that penetrate and disappear into the periprostatic connective tissue stroma. The apex is sparse in glandular elements, particularly in the anterior portion, and the outer fibromuscular layer is no longer present. Thus we conclude that the prostate does not have a true capsule, but only an outer fibromuscular band.

Adjuvant chemotherapy of high-grade osteosarcoma of the extremity : updated results of the multi-institutional osteosarcoma study

The Multi-Institutional Osteosarcoma Study (MIOS) was designed to determine whether intensive multiagent adjuvant chemotherapy improves the outcome of patients with nonmetastatic high-grade osteosarcoma of the extremity as compared with concurrent controls. After definitive surgery of the primary tumor, patients were randomly assigned to immediate adjuvant chemotherapy or to observation without adjuvant treatment. Updated results of this trial indicate that the projected six-year event-free survival for the control group is 11% compared to 61% for the chemotherapy group (p less than 0.001). Similar results were observed in patients who declined randomization but who were followed according to the treatment arms of the protocol. When randomized and nonrandomized patients are pooled according to assigned treatment, a survival advantage favoring those patients treated with immediate adjuvant chemotherapy is apparent. An analysis of prognostic factors among patients receiving immediate adjuvant chemotherapy reveals that elevation of the serum lactic dehydrogenase at diagnosis is the factor most predictive of adverse outcome. Location of the primary site in the tibia confers a favorable prognosis. The authors conclude that the natural history of high-grade osteosarcoma of the extremity has not changed over the past two decades. The administration of immediate adjuvant chemotherapy has a significant favorable impact on event-free survival and should be recommended for all such patients.