Personalized prediction of tumor response and cancer progression on prostate needle biopsy.

PURPOSE: To our knowledge in patients with prostate cancer there are no available tests except clinical variables to determine the likelihood of disease progression. We developed a patient specific, biology driven tool to predict outcome at diagnosis. We also investigated whether biopsy androgen receptor levels predict a durable response to therapy after secondary treatment. MATERIALS AND METHODS: We evaluated paraffin embedded prostate needle biopsy tissue from 1,027 patients with cT1c-T3 prostate cancer treated with surgery and followed a median of 8 years. Machine learning was done to integrate clinical data with biopsy quantitative biometric features. Multivariate models were constructed to predict disease progression with the C index to estimate performance. RESULTS: In a training set of 686 patients (total of 87 progression events) 3 clinical and 3 biopsy tissue characteristics were identified to predict clinical progression within 8 years after prostatectomy with 78% sensitivity, 69% specificity, a C index of 0.74 and a HR of 5.12. Validation in an independent cohort of 341 patients (total of 44 progression events) yielded 76% sensitivity, 64% specificity, a C index of 0.73 and a HR of 3.47. Increased androgen receptor in tumor cells in the biopsy highly significantly predicted resistance to therapy, ie androgen ablation with or without salvage radiotherapy, and clinical failure (p <0.0001). CONCLUSIONS: Morphometry reliably classifies Gleason pattern 3 tumors. When combined with biomarker data, it adds to the hematoxylin and eosin analysis, and prostate specific antigen values currently used to assess outcome at diagnosis. Biopsy androgen receptor levels predict the likelihood of a response to therapy after recurrence and may guide future treatment decisions.

Patterns of inguinal groin metastases in squamous cell carcinoma of the vulva.

OBJECTIVES: Assess the pattern of groin node metastases in squamous cell carcinoma (SCC) of the vulva in relation to the site of the primary lesion. Assess whether the identified pattern of lymphatic spread supports the current surgical practice of assessing contralateral nodes for lateral lesions with ipsilateral nodal involvement. METHODS: A retrospective study of surgically staged patients with primary SCC of the vulva between 1955 and 1990 was conducted. This cohort of patients was divided in 4 subgroups by location of primary lesion: unilateral, bilateral, midline, and patients with mediolateral lesions. All clinical and pathological data were reviewed and updated to the 1988 TNM vulvar classification. RESULTS: 320 patients met the inclusion criteria, and almost all of them (>95%) underwent bilateral groin assessment. Of the 108 patients with positive groin lymph-node (LN) involvement, 77 presented with unilateral and 24 with bilateral inguinofemoral involvement. Of the 163 patients presenting with only unilateral vulvar lesions, 48 had inguinofemoral node involvement: 37 with ipsilateral-only nodal metastases, 8 with bilateral LN invasion, and only 3 (1.8%) had isolated contralateral nodal metastases. None of these patients with unilateral vulvar lesion that was either < or = 2 cm in biggest diameter or with invasion < or = 5 mm had bilateral groin LN involvement at diagnosis. CONCLUSIONS: Ipsilateral lymphadenectomy is suitable for patients with unilateral lesions, distant from the midline, and either negative ipsilateral nodes, or with positive ipsilateral LN with lesions smaller than 2 cm.

Pathobiology of pituitary adenomas and carcinomas.

OBJECTIVE: To examine relationships between pituitary tumors and lesion size, invasiveness, resectability, deoxyribonucleic acid ploidy, cell cycle profile, mitotic activity, and immunoreactivity for MIB-1, proliferating cell nuclear antigen (PCNA), p27Kip1, and p53. PATIENTS AND METHODS: One hundred fifty-three adenomas of most pathological subtypes, including 20 medically treated and prolactin and growth hormone-containing tumors, as well as 10 premetastatic tumors and 13 pituitary carcinomas, were studied. RESULTS: Significant (P < 0.05) differences were noted between functional versus nonfunctional adenomas (percent aneuploidy, percent S phase, p27Kip1 labeling indices [LI], male sex, tumor size, and frequency of visual disturbance); Cushing's versus silent adrenocorticotropin adenomas (percent hypertetraploidy, p53 LI, tumor size, visual disturbance, and resectability); untreated versus medically treated prolactin cell adenomas (MIB-1 LI, p53 LI, and resectability); untreated versus medically treated growth hormone-containing adenomas (percent diploidy, percent S phase, MIB-1 LI, p53 LI, and p27 LI); untreated prolactin cell adenomas versus premetastatic tumors (percent hypertetraploidy, PCNA LI, p53 LI, invasiveness, and resectability); untreated growth hormone-containing adenomas versus premetastatic tumors (percent diploidy, percent S phase, PCNA LI, p53 LI, invasiveness, and resectability); Cushing's adenomas versus premetastatic tumors (percent diploidy, percent hypertetraploidy, percent S phase, MIB-1 LI, p53 LI, tumor size, invasiveness, visual disturbance, and resectability); Nelson's adenomas versus premetastatic tumors (p53 LI, tumor size, invasiveness, and resectability); silent adenomas as a whole versus nonfunctional adenomas (percent nondiploid, percent S phase, invasiveness, and respectability); silent adrenocorticotropin adenomas I and II versus silent adenoma Subtype III (invasiveness); silent adrenocorticotropin adenoma Subtypes I and II versus premetastatic tumors (MIB-1 LI and invasiveness); silent adenoma Subtype III versus premetastatic tumors (PCNA and p53 LI); and premetastatic tumors versus metastatic pituitary carcinomas (MIB-1 LI). CONCLUSION: Only trends toward differences were noted between Cushing's versus Nelson's adenomas and between prolactinomas of reproductive female patients versus those of menopausal female patients and male patients. Too few "atypical adenomas" were encountered to permit their comparison with premetastatic tumors, but our results suggest that most pituitary carcinomas arise by malignant transformation from adenomas.

HLA-DQ8 is a predisposing molecule for detergent enzyme subtilisin BPN'-induced hypersensitivity.

Several million individuals are exposed to agents in the workplace associated with atopy and asthma. Detergent enzymes have been implicated in occupationally induced hypersensitivity. However, the genetic susceptibility and T cell responses to detergent enzymes are undefined. We generated and used HLA-DQ6, -DQ8, -DR2, -DR3, and -DR4 transgenic mice to examine the immune and inflammatory components involved in the response to the detergent enzyme subtilisin BPN'. Based on in vitro and in vivo studies, for the first time, we present evidence that DQ8 is a strong susceptibility marker for BPN'-induced hypersensitivity. Only DQ8 mice showed consistent T cell responses to five immunodominant regions of BPN' comprising peptides #14 to 16, 36-37, 42-43, 62-63, and 80-81. The DQ8 mice also developed allergic eosinophilic inflammatory reactions in the airways following intranasal instillations of this enzyme. The DQ8 mice also responded to BPN' with a significant IgG1 and IgE production. We propose that the HLA Class II tg mice are useful for understanding allergenic responses to enzymes in humans, screening of allergenic and immunogenic properties of detergent enzymes, and for the development of modified enzymes to maintain efficient detergent qualities without allergic properties.

Long-term survival and disease recurrence in patients with primary squamous cell carcinoma of the vulva.

OBJECTIVES: To assess time to failure and sites of failure with extended follow-up of patients with squamous cell carcinoma (SCC) of the vulva. METHODS: A retrospective analysis of 330 patients with primary SCC of the vulva treated at Mayo Clinic between 1955 and 1990 was conducted. The main outcome measures were the rates of treatment failure. The Kaplan-Meier method and the log-rank test were used to estimate the rates of overall survival, disease-free survival, and recurrence. The Cox proportional hazards model was used to assess independent variables as prognostic factors for treatment failure. RESULTS: All 330 patients in the cohort underwent lymphadenectomy; 113 patients (34.2%) had involvement of the inguinofemoral nodes and 88 patients (26.7%) had treatment failure. Treatment failures occurred more frequently in patients who presented with inguinal metastasis at the primary surgery and during the first 2 years of follow-up. After 2 years, both groups, with or without positive inguinal nodes, had similar treatment failure rates. Most patients with disease recurrence in the groin died within the first 2 years of follow-up. Involvement of the inguinal nodes was the main independent predictive factor for survival, disease recurrence, and metastasis. CONCLUSIONS: Most treatment failures occurred during the 2 years after initial surgical management. However, in 35% of patients, disease reoccurred 5 years or more after diagnosis, which demonstrates the need for long-term follow-up. Complete ipsilateral or bilateral inguinofemoral lymph node dissection ensures a thorough evaluation and treatment of the groin.

Sarcomatoid variant of salivary duct carcinoma: clinicopathologic and immunohistochemical study of eight cases with review of the literature.

Salivary duct carcinoma (SDC) is an uncommon, high-grade tumor. We present 8 cases of sarcomatoid SDC, which has been defined recently as a rare variant of SDC. The 8 patients (5 men, 3 women) had a mean age of 63.6 years. Histologically, all tumors were characterized by a biphasic neoplasm composed of both SDC and sarcomatoid elements. In 3 cases, sarcomatoid components showed osteosarcomatous heterologous differentiation. A residual pleomorphic adenoma was detected in 5 tumors. The sarcomatoid component showed focal immunoreactivity for cytokeratin in 4 cases and epithelial membrane antigen in all 8 cases. Diffuse p53 immunostaining was detected in 3 cases, and it was coexpressed in both components. Our observations support the histogenetic theory of a common origin of the carcinomatous and sarcomatoid populations. Of the 13 patients, including our 8, reported to have sarcomatoid SDC arising in a major salivary gland and for whom long-term follow-up data were available, 7 have died of disease (mean survival, 15.6 months). These results indicate that sarcomatoid SDC is a highly aggressive tumor, similar to conventional SDC.

Small cell carcinoma of the major salivary glands: clinicopathologic study with emphasis on cytokeratin 20 immunoreactivity and clinical outcome.

Small cell carcinomas arising in salivary glands, extremely rare high-grade malignant tumors, are subclassified into neuroendocrine and ductal types. The neuroendocrine type may be segregated further into Merkel cell and pulmonary varieties according to cytokeratin 20 immunoreactivity. Whether subclassification of this tumor group has any biologic or clinical significance is not known. We examined 15 cases (11 men, 4 women; mean age, 66.5 years) of small cell carcinoma of major salivary glands from a single institution and analyzed their clinicopathologic profiles, including immunohistochemical features and prognostic factors. Three fourths of small cell carcinomas showed cytokeratin 20-positive immunostaining, often with a paranuclear dotlike pattern of reactivity. All tumors were immunoreactive for at least 2 of 6 neuroendocrine markers examined, and 6 tumors were also positive for neurofilament, with a paranuclear dotlike pattern. Postoperatively, 9 patients developed metastatic disease, and 10 patients died of disease 2 to 45 months (mean, 15.9 months) after diagnosis. By log-rank analysis, overall survival was reduced significantly for patients with a primary tumor larger than 3 cm in diameter (P = 0.032), negative immunostain reaction for cytokeratin 20 (P = 0.012), and decreased immunoreactivity for neuroendocrine markers (P = 0.034). These results indicate that small cell carcinoma of major salivary glands is a highly aggressive tumor, although the prognosis may be better than for extrasalivary neoplasms. Our data also suggest that most salivary gland small cell carcinomas exhibit neuroendocrine differentiation. Immunohistochemical expression of cytokeratin 20 can be used to classify salivary small cell carcinomas into Merkel cell and pulmonary types and may have prognostic significance.

Invasive micropapillary salivary duct carcinoma: a distinct histologic variant with biologic significance.

An invasive micropapillary component has been described in tumors of several organs and is nearly always associated with aggressive biologic behavior. We present 14 cases of salivary duct carcinoma (SDC) with an invasive micropapillary component (invasive micropapillary SDC) and compare the clinicopathologic findings of these cases with those of cases of conventional SDC. The mean age of the 14 patients (10 men, 4 women) was 65.8 years (range, 26-80 years). The mean size of the tumors was 2.4 cm (range, 1.3-5 cm). The parotid gland was involved in 12 patients and the submandibular gland in 2. Histologically, all tumors had an invasive micropapillary architecture admixed with features typical for SDC. Invasive micropapillary carcinoma was characterized by morula-like small cell clusters without fibrovascular cores, surrounded by a clear space. Tumor cells exhibited moderate- to high-grade nuclear features, conspicuous nucleoli, and eosinophilic cytoplasm. This component was distributed diffusely in 9 tumors and focally in 5. Angiolymphatic and perineural invasion was seen in all tumors. A residual pleomorphic adenoma was detected in four tumors. Of the 12 tumors examined, all were diffusely positive for cytokeratin 7 and epithelial membrane antigen (with a distinctive "inside-out" pattern) but negative for cytokeratin 20. Tumors were frequently immunoreactive for BRST-2 (gross cystic disease fluid protein-15) and androgen receptor protein. Aberrant expression of HER-2/neu or p53 was detected in seven tumors each. The mean Ki-67 labeling index was 33.1% (range, 6.3%-61.6%). All 14 patients with invasive micropapillary SDC had cervical or periglandular lymph node metastasis, and this value was significantly higher than for conventional SDCs. Local recurrence developed in 4 patients and distant metastatic disease in 9. Clinical follow-up (mean, 25.5 months) was available for 13 patients: 9 died of disease within 24 months after the diagnosis (mean, 17.6 months), 1 was alive with metastatic disease at 19 months, and 3 were free of disease. Overall survival of these patients with invasive micropapillary SDC was significantly shorter than that of patients with conventional SDC (n = 49) in our series (P = 0.031). Our results suggest that invasive micropapillary SDC is a distinct, aggressive variant of SDC, with a propensity for extensive lymph node metastasis and rapid disease progression.

Dedifferentiated adenoid cystic carcinoma: a clinicopathologic study of 6 cases.

Dedifferentiated adenoid cystic carcinomas are a recently defined, rare variant of adenoid cystic carcinomas characterized histologically by two components: conventional low-grade adenoid cystic carcinoma and high-grade "dedifferentiated" carcinoma. We examined six cases and analyzed their clinicopathologic profiles, including immunohistochemical features and p53 gene alterations. The 6 patients (3 men and 3 women) had a mean age of 46.8 years (range, 34-70 y). The mean size of the tumors was 3.5 cm (range, 1.7-6 cm). The submandibular gland, maxillary sinus, and nasal cavity were involved in 2 cases each. Postoperatively, 5 patients had local recurrence and 5 developed metastatic disease. Five patients died of disease at a mean of 33.7 months after diagnosis (range, 6-69 mo), and one other was alive with disease at 60 months. Histologically, the conventional low-grade adenoid cystic carcinoma component of the tumors consisted of a mixture of cribriform and tubular patterns with scant solid areas. The high-grade dedifferentiated carcinoma component was either a poorly differentiated adenocarcinoma (4 cases) or undifferentiated carcinoma (2 cases). Three tumors were studied immunohistochemically. Myoepithelial markers were expressed in low-grade adenoid cystic carcinoma but not in the dedifferentiated component. In 2 cases, diffusely positive p53 immunoreactivity together with HER-2/neu overexpression was restricted to the dedifferentiated component. Loss of pRb expression was demonstrated only in the dedifferentiated component of the 1 other case. The Ki-67-labeling index was higher in the dedifferentiated component than in the low-grade adenoid cystic carcinoma component. Furthermore, molecular analysis of 2 cases demonstrated the loss of heterozygosity at p53 microsatellite loci, accompanied by p53 gene point mutation, only in the dedifferentiated carcinoma component of 1 case, which was positive for p53 immunostaining. These results indicate that dedifferentiated adenoid cystic carcinoma is a highly aggressive tumor. Because of frequent recurrence and metastasis, the clinical course is short, similar to that of adenoid cystic carcinomas with a predominant solid growth pattern. Limited evidence suggests that p53 abnormalities in combination with HER-2/neu overexpression or loss of pRb expression may have a role in dedifferentiation of adenoid cystic carcinoma.

Dedifferentiation in low-grade mucoepidermoid carcinoma of the parotid gland.

Mucoepidermoid carcinoma (MEC), a common malignant salivary gland neoplasm, is generally divided into low-, intermediate-, and high-grade types according to the histologic features. To our knowledge, the present report describes the first case of dedifferentiation occurring in a low-grade MEC. A 55-year-old man presented with a biphasic neoplasm of the right parotid gland composed of low-grade MEC and dedifferentiated high-grade anaplastic undifferentiated carcinoma. Immunohistochemically, carcinoembryonic antigen expression was restricted to the low-grade MEC portion. The Ki-67-labeling index was higher in the dedifferentiated component than in the low-grade component. On image cytometric analysis, the low-grade MEC was diploid, whereas the dedifferentiated carcinoma was aneuploid. Although the patient was alive 10 years after the initial diagnosis, the tumor has recurred twice, at 3 months and 7 months after the initial resection. It is important to recognize that dedifferentiation can occur in a low-grade MEC, similar to other low-grade salivary gland carcinomas.

Features of airway remodeling and eosinophilic inflammation in chronic rhinosinusitis: is the histopathology similar to asthma?

BACKGROUND: Asthma and chronic rhinosinusitis (CRS) coexist clinically in >50% of patients with CRS. Although epithelial damage and basement membrane thickening are well-known features of airway remodeling in asthma, they have not been described in CRS. OBJECTIVE: In this study, we tested the hypothesis that histopathologic features of asthma, namely, the chronic eosinophilic inflammation, epithelial damage, and basement membrane thickening of the airway mucosa, are also present in sinonasal specimens from patients with CRS. METHODS: We examined histologic specimens from 22 randomly selected patients with refractory CRS undergoing endoscopic sinus surgery and 4 healthy control subjects. The shedding of the epithelium and basement membrane thickening were evaluated by 3 independent observers' scores of hematoxylin-and-eosin staining. Eosinophilic inflammation was monitored with immunohistochemistry for eosinophil major basic protein. A novel, computerized method objectively analyzed confocal microscopic images of major basic protein immunofluorescence to determine areas with the least and most inflammation per specimen. RESULTS: Specimens from all patients with CRS (22/22) revealed epithelial damage (shedding) and basement membrane thickening. Strikingly heterogeneous eosinophilic inflammation, which did not differ between allergic and nonallergic patients, was detected in all patients with CRS and was absent in all healthy control subjects. CONCLUSION: The histopathologic findings of asthma, namely, heterogeneous eosinophilic inflammation and features of airway remodeling, are also present in CRS. These findings, coupled with the common clinical coexistence of both diseases, suggest that the same pathologic disease process is manifest as CRS in the sinonasal tissue and as asthma in the lower airway.

Risk of occult inguinofemoral lymph node metastasis from squamous carcinoma of the vulva.

PURPOSE: This study was undertaken to correlate preoperative primary tumor size and American Joint Committee on Cancer and International Federation of Gynecology and Obstetrics categories with the risk of subclinical metastases from squamous carcinoma of the vulva to inguinofemoral nodes in patients with a palpably negative groin preoperatively. METHODS AND MATERIALS: Clinical notes, operative reports, and pathology reports from 1955 to 1990 were reviewed to assign retrospectively 1969 American Joint Committee on Cancer N(0) and N(1) and 1988 International Federation of Gynecology and Obstetrics T categories. RESULTS: Of 446 patients with primary carcinoma of the vulva, 226 had a groin without features indicative of lymph node metastasis. Occult groin node metastases were detected in 15.2%, 30.0%, 24.5%, and 0% of patients with T(1), T(2), T(3), and T(4) cancers, respectively. Subclinical node metastases were found in 7.0%, 22.2%, 26.9%, 34.1%, and 20.0% of patients with primary cancers measuring 1.0 cm or less, 1.1 to 2.0 cm, 2.1 to 3.0 cm, 3.1 to 5.0 cm, and larger than 5 cm, respectively. CONCLUSIONS: Efficacy assessment for elective groin node irradiation and quantitative description of the radiation dose-control relationship for subclinical disease should be based on estimates of the risk of subclinical disease within the target volume. This study may help to assess the effectiveness of current therapies.

Detection of fungal organisms in eosinophilic mucin using a fluorescein-labeled chitin-specific binding protein.

BACKGROUND: The ability to identify fungal hyphae in patients with chronic rhinosinusitis (CRS) has been inconsistent. A new fluorescein-labeled staining method targets chitin found in fungal cell walls. OBJECTIVE: We hypothesize that this method would be able to more consistently detect fungi within the mucin of CRS patients. METHODS: Fifty-four consecutive CRS surgical patients were evaluated. After ensuring sensitivity and specificity of this new method, all specimens were stained with either fluorescein-labeled chitinase or Grocott methanamine silver stain for comparison. RESULTS: All 54 specimens contained eosinophilic mucin on hematoxylin and eosin staining. One or more fungal hyphae could be visualized within the mucin of 54 (100%) of 54 specimens stained using the fluorescein-labeled chitinase. Only 41 (76%) of 54 of the specimens stained with the Grocott methanamine silver stain technique demonstrated fungi. CONCLUSION: The fluorescein-labeled chitinase-staining technique has greater sensitivity in detecting fungal organisms within eosinophilic mucin. Fungal organisms are present in the mucin of CRS patients.

Corticotroph carcinoma of the pituitary: a clinicopathological study. Report of four cases.

To understand the relationship between pituitary adenoma and carcinoma, four adrenocorticotropic hormone-producing pituitary adenomas and corresponding metastatic carcinomas were studied. All were functional macroadenomas (three cases of Nelson syndrome and one of Cushing disease) that initially invaded the sella turcica and occurred in women ranging in age from 17 to 66 years (mean 45 years). Metastases (two craniospinal and two systemic) occurred after latency periods of 6 to 13 years. Histological specimens were immunostained for pituitary hormones, Ki-67 antigen (MIB-1), p53 and p27 proteins, D-type cyclins, and glucocorticoid receptor messenger (m)RNA. The DNA content of the specimens was assessed using Feulgen stain. Reactivities were quantified by digital image analysis. Primary/recurrent lesions and metastatic tumors differed according to their respective mean mitotic indices (1.2/10 hpf compared with 4.3/10 hpf), MIB-1 labeling (1.7% compared with 8%), p53 staining (37.3% compared with 49.9%), and p27 labeling (48% compared with 25%). Cyclin D, immunoreactivity provided no prognostically significant information. Glucocorticoid receptor mRNA was detected in all cases. Results of a ploidy analysis were variable and nonprognostic. In keeping with the 2000 World Health Organization classification of endocrine neoplasms, our findings support the concept that primary tumors that exhibit mitotic activity, an increased (> 3%) MIB-1 labeling index, and/or p53 immunoreactivity should be termed "atypical adenomas" to denote their aggressive potential and the possibility of future malignant transformation.