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Background We recently published 2-year results of the prospective, randomized IMRT-MC2 trial, showing non-inferior local control and cosmesis in breast cancer patients after conventionally fractionated intensity-modulated radiotherapy with simultaneously integrated boost (IMRT-SIB), compared to 3D-conformal radiotherapy with sequential boost (3D-CRT-seqB). Here, we report on 2-year quality of life results. Patients and Methods 502 patients were enrolled and randomized to IMRT-SIB (50.4 Gy in 1.8 Gy fractions with a 64.4 Gy SIB to the tumor bed) or to 3D-CRT-seqB (50.4 Gy in 1.8 Gy fractions, followed by a sequential boost of 16 Gy in 2 Gy fractions). For quality of life (QoL) assessment, patients completed the QLQ-C30 and QLQ-BR23 questionnaires at baseline, 6 weeks and 2 years after radiotherapy. Results Significant differences between treatment arms were seen 6 weeks after radiotherapy for pain (22.3 points for IMRT vs. 27.0 points for 3D-CRT-seqB; p = 0.033) and arm symptoms (18.1 points for IMRT vs. 23.6 points for 3D-CRT-seqB; p = 0.013), both favoring IMRT-SIB. Compared to baseline values, both arms showed significant improvement in global score (IMRT: p = 0.009; 3D-CRT: p = 0.001) after 2 years, with slight deterioration on the role (IMRT: p = 0.008; 3-D-CRT: p = 0.001) and social functioning (IMRT: p = 0.013, 3D-CRT: p = 0.001) as well as the future perspectives scale (IMRT: p = 0.003; 3D-CRT: p = 0.0034). Conclusion This is the first randomized phase III trial demonstrating that IMRT-SIB was associated with slightly superior QoL compared to 3-D-CRT-seqB. These findings further support the clinical implementation of SIB in adjuvant breast cancer treatment.

Purpose Hypofractionated radiotherapy is the standard of care for adjuvant whole breast radiotherapy (RT). However, adoption has been slow. The indication for regional nodal irradiation has been expanded to include patients with 0–3 involved lymph nodes. We investigated the impact of the publication of the updated German S3 guidelines in 2017 on adoption of hypofractionation and enrollment of patients with lymph node involvement within a randomized controlled phase III trial. Methods In the experimental arm of the HYPOSIB trial (NCT02474641), hypofractionated RT with simultaneous integrated boost (SIB) was used. In the standard arm, RT could be given as hypofractionated RT with sequential boost (HFseq), normofractionated RT with sequential boost (NFseq), or normofractionated RT with SIB (NFSIB). The cutoff date for the updated German S3 guidelines was December 17, 2017. Temporal trends were analyzed by generalized linear regression models. Multiple logistic regression models were used to investigate the influence of time (prior to/after guideline) and setting (university hospital/other institutions) on the fractionation patterns. Results Enrollment of patients with involved lymph nodes was low throughout the trial. Adoption of HFseq increased over time and when using the guideline publication date as cutoff. Results of the multiple logistic regressions showed an interaction between time and setting. Furthermore, the use of HFseq was significantly more common in university hospitals. Conclusion The use of HFseq in the standard arm increased over the course of the HYPOSIB trial and after publication of the S3 guideline update. This was primarily driven by patients treated in university hospitals. Enrolment of patients with lymph node involvement was low throughout the trial.

Purpose In the modern era, improvements in radiation therapy techniques have paved the way for simultaneous integrated boost irradiation in adjuvant breast radiation therapy after breast conservation surgery. Nevertheless, randomized trials supporting the noninferiority of this treatment to historical standards of care approach are lacking. Methods A prospective, multicenter, randomized phase 3 trial (NCT01322854) was performed to analyze noninferiority of conventional fractionated intensity modulated radiation therapy with simultaneous integrated boost (IMRT-SIB) to 3-D conformal radiation therapy with sequential boost (3-D-CRT-seqB) for breast cancer patients. Primary outcomes were local control (LC) rates at 2 and 5 years (noninferiority margin at hazard ratio [HR] of 3.5) as well as cosmetic results 6 weeks and 2 years after radiation therapy (evaluated via photo documentation calculating the relative breast retraction assessment [pBRA] score [noninferiority margin of 1.25]). Results A total of 502 patients were randomly assigned from 2011 to 2015. After a median follow-up of 5.1 years, the 2-year LC for the IMRT-SIB arm was noninferior to the 3-D-CRT-seqB arm (99.6% vs 99.6%, respectively; HR, 0.602; 95% CI, 0.123-2.452; P = .487). In addition, noninferiority was also shown for cosmesis after IMRT-SIB and 3-D-CRT-seqB at both 6 weeks (median pBRA, 9.1% vs 9.1%) and 2 years (median pBRA, 10.4% vs 9.8%) after radiation therapy (95% CI, –0.317 to 0.107 %; P = .332). Cosmetic assessment according to the Harvard scale by both the patient and the treating physician as well as late-toxicity evaluation with the late effects normal tissues- subjective, objective, management, analytic criteria, a score for the evaluation of long-term adverse effects in normal tissue, revealed no significant differences between treatment arms. In addition, there was no difference in overall survival rates (99.6% vs 99.6%; HR, 3.281; 95% CI: –0.748 to 22.585; P = .148) for IMRT-SIB and 3-D-CRT-seqB, respectively. Conclusions To our knowledge, this is the first prospective trial reporting the noninferiority of IMRT-SIB versus 3-D-CRT-seqB with respect to cosmesis and LC at 2 years of follow-up. This treatment regimen considerably shortens adjuvant radiation therapy times without compromising clinical outcomes.

Background: 10-year results from several studies showed improved disease-free survival and distant metastasis-free survival, reduced breast cancer-related mortality, and variable effects on overall survival with the addition of partial or comprehensive regional lymph node irradiation after surgery in patients with breast cancer. We present the scheduled 15-year analysis of the European Organisation for Research and Treatment of Cancer (EORTC) 22922/10925 trial, which aims to investigate the impact on overall survival of elective internal mammary and medial supraclavicular (IM-MS) irradiation. Methods: EORTC 22922/10925, a randomised, phase 3 trial done across 46 radiation oncology departments from 13 countries, included women up to 75 years of age with unilateral, histologically confirmed, stage I–III breast adenocarcinoma with involved axillary nodes or a central or medially located primary tumour. Surgery consisted of mastectomy or breast-conserving surgery and axillary staging. Patients were randomly assigned (1:1) centrally using minimisation to receive IM-MS irradiation at 50 Gy in 25 fractions (IM-MS irradiation group) or no IM-MS irradiation (control group). Stratification was done for institution, menopausal status, site of the primary tumour within the breast, type of breast and axillary surgery, and pathological T and N stage. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival analysed according to the intention-to-treat principle. Secondary endpoints were disease-free survival, distant metastasis-free survival, breast cancer mortality, any breast cancer recurrence, and cause of death. Follow-up is ongoing for 20 years after randomisation. This study is registered with ClinicalTrials.gov, NCT00002851. Findings: Between Aug 5, 1996, and Jan 13, 2004, we enrolled 4004 patients, of whom 2002 were randomly assigned to the IM-MS irradiation group and 2002 to the no IM-MS irradiation group. At a median follow-up of 15·7 years (IQR 14·0–17·6), 554 (27·7%) patients in the IM-MS irradiation group and 569 (28·4%) patients in the control group had died. Overall survival was 73·1% (95% CI 71·0–75·2) in the IM-MS irradiation group and 70·9% (68·6–72·9) in the control group (HR 0·95 [95% CI 0·84–1·06], p=0·36). Any breast cancer recurrence (24·5% [95% CI 22·5–26·6] vs 27·1% [25·1–29·2]; HR 0·87 [95% CI 0·77–0·98], p=0·024) and breast cancer mortality (16·0% [14·3–17·7] vs 19·8% [18·0–21·7]; 0·81 [0·70–0·94], p=0·0055) were lower in the IM-MS irradiation group than in the control group. No significant differences in the IM-MS irradiation group versus the control group were seen for disease-free survival (60·8% [95% CI 58·4–63·2] vs 59·9% [57·5–62·2]; HR 0·93 [95% CI 0·84–1·03], p=0·18), or distant metastasis-free survival (70·0% [67·7–72·2] vs 68·2% [65·9–70·3]; 0·93 [0·83–1·04], p=0·18). Causes of death between groups were similar. Interpretation: The 15-year results show a significant reduction of breast cancer mortality and any breast cancer recurrence by IM-MS irradiation in stage I–III breast cancer. However, this is not converted to improved overall survival. Funding: US National Cancer Institute, Ligue Nationale contre le Cancer, and KWF Kankerbestrijding.

Background and purpose Outcome of patients with genitourinary rhabdomyosarcoma has been improved in the past, but organ preservation rates are too low. Conservative surgery with LDR-brachytherapy has been advocated, but LDR-brachytherapy is often not available. We wanted to establish a novel treatment modality combining HDR-brachytherapy and conservative surgery. Material and Methods We performed an organ preserving tumor resection with intraoperative placement of brachytherapy tubes. Suitable patients were selected following assessment of response to neoadjuvant chemotherapy where organ preserving surgical resection was deemed feasible. In bladder-prostate rhabdomyosarcoma, only tumors located below the bladder neck could be treated by brachytherapy. After surgery, high dose rate brachytherapy was carried out for 30–36Gy total dose. Results A total of 11 patients were treated up to now (embryonal histology n =10, alveolar histology n =1) with a median follow-up of 18months [4–80]. All patients were IRS group III. There were no significant side effects. One patient had local relapse and was successfully treated with re-excision. All other patients are in the first complete remission. One patient developed a neurogenic bladder and required creation of a Mitrofanoff stoma. Conclusion Combined conservative surgery and high dose rate brachytherapy is a treatment option for selected rhabdomyosarcoma patients. The paper highlights the essential technical challenges and clearly shows limitations of this treatment approach.

To prospectively investigate the role of re-irradiation (re-RT) combined with hyperthermia (HT) in a contemporary cohort of patients affected by recurrent breast cancer (RBC). Within the prospective registry HT03, patients with resected RBC and previous irradiation were included. Re-RT was applied to the recurrence region with doses of 50–50.4 Gy, with a boost up to 60–60.4 Gy to the microscopically or macroscopically positive resection margins (R1/R2) region. Concurrent HT was performed at 40–42 ℃. Primary endpoint was LC. Acute and late toxicity, overall survival, cancer-specific survival (CSS), and progression-free survival (PFS) were also evaluated. 20 patients and 21 RBC were analyzed. Median re-RT dose was 50.4 Gy and a median of 11 HT fractions were applied. Re-RT+HT was well tolerated, with three patients who experienced a grade (G) 3 acute skin toxicity and no cases of ≥G3 late toxicity. With a median follow up of 24.7 months, two local relapses occurred. Ten patients experienced regional and/or distant disease progression. Five patients died, four of them from breast cancer. PFS was favorable in patients treated with re-RT+HT for the first recurrence with doses of 60 Gy. A trend towards better CSS was found in patients with negative or close margins and after doses of 60 Gy. Full-dose re-RT+HT for RBC is well tolerated, provides good LC, and seems to be more effective when applied at the time of the first relapse and after doses of 60 Gy. The registry will be continued for validation in a larger cohort and with longer follow-up.

Background Low blood 25-hydroxyvitamin D (25(OH)D) concentrations have been associated with cancer in dogs. Little research has examined what other factors may affect 25(OH)D concentrations. Objectives (1) To determine whether the presence of cancer (lymphoma, osteosarcoma, or mast cell tumor [MCT]) in dogs is associated with plasma 25(OH)D concentrations and (2) identify other factors related to plasma 25(OH)D concentrations in dogs. Animals Dogs newly diagnosed with osteosarcoma (n = 21), lymphoma (n = 27), and MCT (n = 21) presented to a tertiary referral oncology center, and healthy, client-owned dogs (n = 23). Methods An observational study design was used. Dietary vitamin D intake, sex, age, body condition score (BCS), muscle condition score (MCS), and plasma concentrations of 25(OH)D, 24,25-dihydroxyvitamin D (24,25(OH)2D) (a marker of CYP24A1 activity), as well as ionized calcium (ICa), parathyroid hormone, and parathyroid hormone-related protein concentrations were measured. An analysis of covariance was used to model plasma 25(OH)D concentrations. Results Cancer type (P = 0.004), plasma 24,25(OH)2D concentrations (P < 0.001), and plasma ICa concentrations (P = 0.047) had significant effects on plasma 25(OH)D concentrations. Effects of age, sex, body weight, BCS, MCS, and plasma PTH concentrations were not identified. A significant interaction between ICa and cancer was found (P = 0.005). Plasma 25(OH)D concentrations increased as ICa concentrations increased in dogs with cancer, whereas plasma 25(OH)D concentrations decreased as ICa concentrations increased in healthy dogs. Conclusions and Clinical Importance Results support a relationship between cancer and altered vitamin D metabolism in dogs, mediated by plasma ICa concentrations. The CYP24A1 activity and plasma ICa should be measured in studies examining plasma 25(OH)D concentrations in dogs.

The aim of this retrospective study was to analyze the outcome of patients with locally advanced cervical carcinoma treated by adjuvant radiochemotherapy and to determine risk factors for local and distant relapse. Furthermore, acute and late effects of treatment were recorded. A total of 72 patients with FIGO stages I–III cervical carcinoma were treated by radical hysterectomy, pelvic lymphadenectomy, and postoperative radiochemotherapy. Only patients with positive pelvic lymph nodes, parametrial involvement, positive margins, or tumor bulk were eligible. Patients were irradiated with a standard pelvic field (50.4 Gy in 28 fractions). The majority of patients received platinum-based chemotherapy. After a median follow-up of 37 months, estimated 1-, 2-, and 4-year disease-free survival (DFS) and overall survival (OS) rates were 89%, 80%, 68% and 95%, 88%, 76%, respectively. Nine of the 72 patients had pelvic recurrences including only 1 isolated local failure; 23 of the 72 patients presented with distant relapse. The majority of relapses occurred within the first 3 years after adjuvant treatment. The number of positive pelvic lymph nodes (> 1) was the strongest prognostic factor for DFS. Treatment was well tolerated with transient acute hematologic (~30%) and gastrointestinal (~30%) grade 3 toxicity. Small bowel obstruction (~6%) was the only important late sequelae. Adjuvant radiochemotherapy in patients with advanced cervical cancer and several risk factors is highly effective to prevent local relapse. Future efforts to improve outcome should be placed on improvement of systemic control especially in subgroups with high-risk features for distant relapse. Combined treatment was well tolerated with moderate acute and late toxicity.

The mammographic and histologic findings were reviewed in 41 consecutive cases of isolated lobular carcinoma in situ (LCIS) unassociated with any malignant diagnosis. Thirty-one needle-directed breast biopsies were performed to evaluate clustered microcalcifications. In 24 of the 31 cases, the calcifications were found in areas of benign breast disease, with LCIS representing a separate process. In the few cases in which microcalcifications were seen in association with LCIS, a greater number of similar calcifications were present in adjacent benign disease. Soft-tissue abnormalities necessitating the performance of a biopsy represented benign foci, except in one patient with LCIS in and adjacent to a fibroadenoma. The authors conclude that LCIS has no characteristic mammographic features. LCIS is detected as an incidental finding at breast biopsy, with the mammographic abnormality predominantly reflecting a benign process.

Although many of the vasculitides within the classification of the American College of Rheumatology can have a component of granulomatous inflammation with giant cells, two (ie, giant-cell [temporal] arteritis and Takayasu arteritis) are characterized by infiltrates that are dominated by granulomatous and/or giant-cell-containing inflammation. Furthermore, granulomatous and/or giant-cell dominant infiltrates can characterize disseminated giant-cell arteritis, granulomatous vasculitis of the central nervous system, localized giant-cell arteritis, mesenteric inflammatory veno-occlusive disease, primary cutaneous phlebitis, and giant-cell phlebitis of mesenteric veins and/or omentum. Like the other systemic vasculitides, there is considerable clinicopathologic overlap between these giant-cell vasculitides. Indeed, they are likely closely related, but how they specifically relate to each other is not clear. Their accurate diagnosis is important; because serious morbidity and even death may occur, if proper treatment is delayed or if excessive immunotherapy is given.

Mediastinal germ-cell tumors (GCTs) usually occur within the anterior mediastinum, accounting for about 15% of all mediastinal cysts and tumors. They are associated with the thymus, presumably arising from extragonadal germ cells or thymic cells with germ-cell potential. Mediastinal seminoma develops primarily in young males with rare cases reported in females; likewise, embryonal carcinoma, endodermal sinus tumor or yolk-sac tumor, choriocarcinoma, and malignant mixed or combined GCTs also overwhelmingly affect males. Mature cystic teratoma affects males and females equally. The prognosis for mediastinal mature cystic teratoma and seminoma is very good. Nonseminomatous malignant GCTs of the mediastinum often present with advanced disease and do not respond as well to chemotherapy as their gonadal counterparts. Nonetheless, it is important to separate mediastinal GCTs from other undifferentiated malignant tumors, especially thymic carcinoma, which has a poor prognosis. Clearly, some patients with mediastinal GCTs respond very well to modern therapies.

The proliferative rate of a tumor has been considered predictive of its clinical course. We evaluated the expression of the proliferative marker Ki-67 and its relationship to survival, disease-free survival and other clinicopathologic variables in both stage I and stage II non-small cell lung cancer (NSCLC). A total of 260 patients with surgically resected stage I (n = 193), and II (n = 67) NSCLC with at least 5 years follow-up were identified. The median survival for patients with low expression of Ki-67 (or = 25%) was 54 months, while for those with high expression (25%), it was 45 months (P = 0.1). The disease-free survival in patients with low expression of Ki-67 was 59 months while it was only 32 months for patients with high Ki-67 (P = 0.1). Out of 136 patients, 84 (62%) had both increased S-phase (8%) and high Ki-67 (P = 0.001). A total of 28 of 30 patients who had loss of antigen A had high expression of Ki-67 (93.3%) (P = 0.03). Ki-67 expression was also higher in squamous cell (54/63, 85.7%) compared to nonsquamous cell cancer (70/108, 64%) (P = 0.03). We also analyzed for the presence of symptoms with survival. The presence of symptoms was not found to be statistically significant, for overall survival (P = 0.33) or disease-free survival (P = 0.72). When individual symptoms were analyzed, the presence of cough was statistically significant for both overall and disease-free survival. The median survival was 39 months for patients with cough, and 57 months for patients without cough (P = 0.04). Multivariate analysis showed higher N and T stages, presence of cough and loss of antigen A, predicted for poorer overall survival. Higher N and T stages, loss of antigen A, presence of mucin and cough and increased expression of Ki-67 predicted decreased disease-free survival. Although we did not find a statistically significant difference between low and high Ki-67, there was a trend for a poorer overall and disease-free survival in patients with high Ki-67 expression. Larger studies may be needed to prove a statistically significant effect of Ki-67 on survival. Future studies should assess the potential prognostic significance of the presence of symptoms (particularly cough) in addition to clinical-pathologic variables (such as T and N stage) and biological markers in patients with early stage NSCLC.

We investigated the expression of BDNF and its high affinity receptor trkB in fetal dopaminergic grafts in a rat model of Parkinson's disease. Grafts were allowed to differentiate for 7, 14, 28, or 56 days, respectively and were analyzed immunocytochemically thereafter with antibodies directed against tyrosine hydroxylase, BDNF and trkB. At all time points investigated, grafts contained tyrosine hydroxylase immunoreactive neurons. Immature grafts (7 days) displayed no immunoreactivity for BDNF which was restricted to glial cells at the graft-host interface. After longer differentiation periods BDNF-immunoreactivity was detectable in neurons and astrocytes within the grafts. No trkB immunoreactivity was found in immature grafts but a strong signal for trkB emerged in grafted neurons older than 14 days whereas glial cells remained unlabeled at all time points investigated. Expression of BDNF and trkB in grafted neurons and of BDNF in sourrounding glial cells suggests an autocrine or paracrine action of BDNF on dopaminergic neurons possibly mediated by activated glia.

Schwann cells naturally support axonal regeneration after injury in the peripheral nervous system, and have also shown a significant, albeit limited, ability to support axonal growth and remyelination after grafting to the central nervous system (CNS). It is possible that Schwann cell-induced axonal growth in the CNS could be substantially increased by genetic manipulation to secrete augmented amounts of neurotrophic factors. To test this hypothesis, cultured primary adult rat Schwann cells were genetically modified using retroviral vectors to produce and secrete high levels of human nerve growth factor (NGF). These cells were then grafted to the midthoracic spinal cords of adult rats. Findings were compared to animals that received grafts of nontransduced Schwann cells. Spinal cord lesions were not placed prior to grafting because the primary aim of this study was to examine features of grafted Schwann cell survival, growth, and effects on host axons. In vitro prior to grafting, Schwann cells secreted 1.5 + 0.1 ng human NGF/ml/106cells/day. Schwann cell transplants readily survived for 2 wk to 1 yr after in vivo placement. Some NGF-transduced grafts slowly increased in size over time compared to nontransduced grafts; the latter remained stable in size. NGF-transduced transplants were densely penetrated by primary sensory nociceptive axons originating from the dorsolateral fasciculus of the spinal cord, whereas control grafts showed significantly fewer penetrating sensory axons. Over time, Schwann cell grafts also became penetrated by TH- and DBH-labeled axons of putative coerulospinal origin, unlike control cell grafts. Ultrastructurally, axons in both graft types were extensively myelinated by Schwann cells. Grafted animals showed no changes in gross locomotor function. In vivo expression of the human NGF transgene was demonstrated for periods of at least 6 m. These findings demonstrate that primary adult Schwann cells 1) can be transduced to secrete augmented levels of neurotrophic factors, 2) survive grafting to the CNS for prolonged time periods, 3) elicit robust growth of host neurotrophin-responsive axons, 4) myelinate CNS axons, and 5) express the transgene for prolonged time periods in vivo. Some grafts slowly enlarge over time, a feature that may be attributable to the propensity of Schwann cells to immortalize after multiple passages. Transduced Schwann cells merit further study as tools for promoting CNS regeneration.

Current technologies can identify subsets of patients who are at greater risk for developing recurrent carcinoma. This article presents conventional and generally accepted pathologic features of breast carcinoma that allow breast carcinoma patients to be placed into low-risk or high-risk categories for recurrence-free or overall survival. Also, the role of flow cytometry, estrogen-progesterone receptor measurement, tumor angiogenesis, and selection oncoprotein expression, such as c-erbB2, are reviewed.

This study was conducted to determine the prognostic significance of tumor angiogenesis, c-erbB2, epidermal growth factor receptor, Ki-67, and p53 for patients with nasopharyngeal carcinoma.In this retrospective study, the authors retrieved clinical data and made immunohistochemical preparations on archival tissue specimens from 30 patients with nasopharyngeal carcinoma treated with radiation therapy at the University of California at San Francisco between 1956 and 1990. The pretreatment clinical and immunohistochemical data were correlated with cervical lymph node metastasis at diagnosis, and endpoints including development of locoregional failure, distant metastasis, disease free survival, and overall survival.Intense tumor angiogenesis, defined as microvessel counts for 60 or more microvessels per 200 x field correlated with the development of distant metastasis (P = 0.03), shorter overall survival (P = 0.02), and disease free survival (P = 0.05). Strong c-erbB2 expression correlated with a shorter overall survival (P = 0.02) and disease free survival (P = 0.02). Stage IV disease (P = 0.04) and the presence of cervical lymph node metastasis (P = 0.05) correlated with a shorter overall survival. A duration of symptoms of fewer than 6 months correlated with a shorter disease free survival (P = 0.05). No association was observed between any of the biologic prognostic factors and lymph node involvement or locoregional failure.The results of this study show that the tumor angiogenesis and c-erbB2 expression are significant prognostic indicators for patients with nasopharyngeal carcinoma. The presence of cervical lymph node metastasis, Stage IV disease, and a duration of symptoms fewer than 6 months also indicate a poor prognosis. The authors did not find any prognostic significance for epidermal growth factor receptor, Ki-67, or p53. These results suggest that tumor microvessel counts and c-erbB2 may be useful in identifying patients who may benefit from systemic chemotherapy or other novel treatment strategies.

Approximately 30 patients with malignant mesothelioma following radiotherapy have been described. Population-based studies of this occurrence have not been reported.Patients with malignant mesothelioma of the pleura were collected. All of the patients had a prior cancer and had received radiotherapy to the region in which the malignant mesothelioma developed. Data from the National Cancer Institute's Surveillance, Epidemiology and End Results Program and the Connecticut Tumor Registry were evaluated for cases of malignant mesothelioma of the pleura occurring in patients with a previous cancer. The literature on post-irradiation malignant mesotheliomas was reviewed.Eight patients (4 men, 4 women) with malignant mesothelioma occurring in sites of radiotherapy for a prior tumor were identified. The mean age at diagnosis of mesothelioma was 45 years (range: 22-78 years), and the average interval between radiotherapy and the mesothelioma was 21 years (range: 11-29 years). Three of the patients had also received chemotherapy. Histologically, the mesotheliomas were epithelial in five cases, biphasic in one, and sarcomatous in one. One hundred forty-two patients were identified in the epidemiologic survey. The majority were men (89%), with a mean age for all patients of 68.5 years (range: 35-86 years) and a median latency between first cancer and mesothelioma of 4.3 years (range: 2 months-29.9 years).Mesotheliomas rarely develop as second malignant neoplasms. Within a large, population-based survey of patients with cancer, temporal patterns and demographic features of most second primary mesotheliomas were similar to asbestos-related tumors, although the late effects of cancer treatment might have contributed to the occurrence of cancer in some patients.

To determine the relationship between capillary density, a recognized surrogate of tumor angiogenesis, and magnetic resonance (MR) imaging-derived estimates of plasma volume (PV) and microvascular permeability in two mammary carcinoma models.Dynamic spin-echo imaging was performed by using albumin-(gadolinium-diethylenetriaminepentaacetic acid)34, a prototype blood-pool contrast medium, in 14 rats with a subcutaneously implanted slow- or fast-growing subtype of R3230 mammary carcinoma. Data were fitted to an established two-compartment kinetic model to estimate PV and permeability.MR imaging-derived tumor PVs and permeabilities increased exponentially with increasing capillary density. MR imaging-derived microvascular characteristics correlated strongly with histologic capillary density, with an r2 of .85.Contrast medium-enhanced MR imaging may prove useful in estimating angiogenic activity in carcinomas. MR imaging may be superior to histologic assay because it is noninvasive, can be used to "sample" the entire tumor, and reflects both anatomic and physiologic characteristics.

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 (p0.0001) 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.

It has been estimated that approximately 1 in 9 women (living to age 85 years) in the United States will develop breast cancer at some time in their lives; hence the interpretation of breast biopsies has become a large and important component of the surgical pathologist's practice. Indeed, there is great pressure on surgical pathologists to make accurate diagnoses of breast lesions because of their high incidence, the increased public awareness of breast disease, the greater use of screening mammography to detect early carcinomas, the development of multiple therapeutic options (which is often determined by tumor pathology), and the harsh medical-legal climate. The focus of this article will be to define the clinicopathologic features of two malignant breast lesions that are particularly prone to simulate benign lesions, and thus pose important diagnostic problems to surgical pathologists. The two lesions include spindle-cell carcinoma and low-grade duct carcinoma in situ.

A more accurate method of detecting nodal disease in squamous cell carcinoma of the tongue is needed so that treatment of the neck with its associated morbidity can safely be reserved for patients who actually have metastatic disease. Tumor angiogenesis and the expression of the p53 antigen--which have each been shown to be predictive of metastasis in breast and colon cancer, respectively--are examined for their ability to predict neck metastasis in tongue cancer. Fifty-seven patients with T1 and T2 squamous cell carcinoma of the oral tongue, whose neck disease was examined by dissection or by 2-year follow-up, were studied. Twenty-eight patients (49%) were node positive and 29 patients (51%) were node negative. The primary tumors were immunohistochemically stained for the p53 antigen and for factor VIII, which allowed the blood vessels within the tumor to be quantitated. The mean vessel counts per x200 high-power field were 59.8 and 61.5 for node-positive and node-negative patients, respectively (p = 0.8). Node-positive patients showed overexpression of p53 43% of the time, vs. 61% for node-negative patients (p = 0.17). Multivariate analysis confirmed that no difference in tumor angiogenesis or the expression of the p53 antigen was found between tumors that had metastasized and those that had not. Therefore neither tumor angiogenesis nor the p53 tumor marker is clinically useful in determining lymph node metastasis in these patients.

Ewing's sarcoma (ES) and peripheral neuroepithelioma (PN) are closely related tumors, and it can be difficult to distinguish them from other small-round-cell tumors (SRCTs). The glycoprotein p30/32MIC2 is highly, but not exclusively, expressed in both ES and PN. Although the monoclonal antibody (Mab) HBA71, which reacts with P30/32MIC2, has been reported to be relatively specific and highly sensitive for both neoplasms, it is not readily available. Yet, Mab O13 is commercially available, and it purportedly displays the same immunostaining characteristics as HBA71. Because O13 has not been studied extensively, we immunostained 21 ES/PNs and 147 other tumors or lesions that might show SRCT-like features with O13. The results were similar to those reported for HBA71. We found O13 to be 100% sensitive for ES/PN; and, no immunostaining was noted on the SRCTs often included in the differential diagnosis of ES/PN (i.e., conventional neuroblastoma, rhabdomyosarcoma, and non-lymphoblastic lymphomas). But, O13 immunoreacted with lymphoblastic lymphomas and some other tumors and normal tissues. Nonetheless, this nonspecific reactivity should not cause diagnostic problems, if an antibody panel containing anti-desmin and anti-leukocyte common antigen is used in conjunction with O13. We conclude that, within the proper diagnostic context, strong immunoreactivity of a SRCT tumor for O13 should be considered good evidence that the tumor is ES/PN.

Cervical dysplasia, or cervical intraepithelial neoplasia (CIN), is a premalignant precursor to cervical cancer. This study was designed to determine whether dysplastic lesions are angiogenic. Tissue sections from 23 surgical specimens were immunohistochemically stained for factor VIII antigen, a marker for endothelial cells. The results demonstrate that a region of neovascularization develops along the basement membrane subtending dysplastic epithelium when compared to adjacent normal epithelium. Comparison of microvessel counts underlying low grade lesions (condyloma and CIN I) with microvessel counts of CIN III lesions shows a statistically significant increase in the more advanced lesions. In a subset of the high grade lesions, large vascular structures are also noted in the upper layers of the epithelium, suggesting that a second stage of neovascularization consists of extension of stromal vascular papillae into the dysplastic lesions toward the surface of the epithelium. There is no statistical correlation between the amount of inflammation and the angiogenic ratio for each lesion, implying that angiogenesis is not secondary to the inflammatory response evoked by the lesion. The human papillomavirus type present in four CIN III lesions was determined by in situ hybridization; the amount of angiogenesis appears to be independent of the human papillomavirus type.

A 66-year-old woman presented with a superior-anterior mediastinal mass that contained considerable calcification by computed tomography. Initial biopsy interpretation was inconclusive but suggested a giant cell sarcoma of soft parts because the tumor contained atypical epithelioid cells and osteoclastlike giant cells. After radiation and chemotherapy, the tumor was removed. It contained large epithelioid cells, pale chondroid areas, metaplastic bone, and osteoclastlike giant cells. Immunohistochemical and electron microscopic studies revealed the epithelioid cells to be factor VIII positive and to contain abundant intermediate filaments, micropinocytotic vesicles, Weibel-Palade bodies, basal lamina, and primitive cell-cell junctions. These epithelioid cells also stained for muscle-specific actin (HHF-35), yet were negative for desmin and cytokeratins (CAM 5.2 and AE1/3). The findings were most consistent with those reported to occur in epithelioid hemangioendothelioma.

A 62-year-old woman presented with an asymptomatic anterior mediastinal mass. Clinically considered to be a thymoma, the tumor was solid, firm, and composed of hypocellular dense collagen and cytologically bland, spindled fibroblastlike cells growing in a patternless pattern. There was no apparent connection to pleura or pericardium, yet the clinicopathologic features clearly fit with solitary fibrous tumor (SFT) of mediastinum. SFTs occur most commonly in pleura but have been reported in other locations, including the mediastinum, where aggressive behavior has been more common when these tumors are compared to those occurring in pleura. Although it is difficult to predict behavior for all cases of SFT occurring in the mediastinum by cytologic features alone, morphologic criteria for benign and malignant forms have been described. Roughly half the malignant forms will progress, yet the single most important indicator of clinical outcome is whether the tumor can be initially totally excised.

Nuclear matrix proteins (NMP) are nonhistone proteins found in the nucleus of many eukaryotic cells. Furthermore certain NMPs are reported to be cell-type specific and expressed differentially by malignant cells. To study the specificity of NM-200.4 (an antibody reactive to NMPs extracted from cultured breast carcinoma cells of the T-47D line), cancers and benign tissues from multiple body sites were surveyed. All 17 breast carcinomas showed strong reactivity to tumor cell nuclei. Also nuclei from one of two lung carcinomas, a papillary thyroid carcinoma, an ovarian fibroma, and a lymphoma were strongly reactive. One leiomyosarcoma and a dermoid cyst were negative. Although 1 benign breast with duct hyperplasia showed moderate reactivity, only 1 of 10 benign breast biopsies without hyperplasia showed reactivity. Three of 4 skin biopsies, 2 liver biopsies, 6 of 9 kidney biopsies, and 5 of 10 gastrointestinal mucosal biopsies showed reactivity in benign nuclei. It is concluded that, although breast carcinoma nuclei showed the most consistent reactivity for NM-200.4, both benign and malignant nuclei from other body sites also show reactivity.

The ultrastructural features of 502 mast cells, including 34,187 granules, were studied from seven human tissue sites (lung, skin, colon, stomach, small bowel, breast parenchyma, and axillary lymph nodes). Granule areas and substructure were detailed according to the microenvironment (lung alveoli, lung bronchi, bowel mucosa, bowel submucosa, breast skin, breast parenchyma, and axillary lymph nodes). Although completely closed, discrete scrolls were present in some mast cell granules at all tissue locations, they were present more frequently in granules from bowel mucosa and lung (scroll-rich morphology). In contrast, most of the mast cell granules from skin, breast parenchyma, axillary lymph nodes, and bowel submucosa were rimmed by incomplete scrolls forming parallel lamellae; centrally, amorphous granular material and/or grating/lattice-like structures occurred (scroll-poor morphology). In breast, the latter granules had a mean granule area almost twice that of all other sites. Individual mast cells having granules with both scroll-rich and scroll-poor features were common in all tissue sites and microenvironments. In fact, 7.8% of mast cells had granules showing at least one completely closed, discrete scroll and grating/lattice-like structures, sometimes within the same granule. These observations indicate that mixed forms occur and that there is considerable morphologic diversity between the predominant mast cell found in mucosa and lung (scroll-rich morphology) and the predominant mast cell found in skin, breast parenchyma, axillary lymph nodes, and bowel submucosa (scroll-poor morphology).

Biopsies of lesional and nonlesional skin from 14 patients with localized cutaneous or associated systemic mastocytosis were examined by ultrastructural and immunohistochemical techniques. Mast cells within lesions of the dermis were highly variable between patients with regard to cell number and extent of degranulation, although lesional sites consistently contained more mast cells than did nonlesional sites. Two mast cell patterns were identified based upon granule morphology. In biopsies from 8 patients, the majority of granules contained electron-dense amorphous zones; crystalline lattices; and indistinct, incomplete solid scrolls forming parallel lamellae. In biopsies from 6 patients, in addition to these granules, there were also granules composed of electron-dense amorphous zones, reticulated matrices, and/or distinct scrolls with lucent cores interrupted by dense spheres. The granule morphology for the first group (N = 8) was identical with that seen in the preponderant type of skin mast cell of 6 normal control subjects, whereas the granule morphology of the second group (N = 6) displayed an abnormal ultrastructural phenotype for skin that included granule types normally found not only in skin but also in intestinal lamina propria and lung. For individual patients, the patterns of granule ultrastructure were consistent between clinically nonlesional and lesional skin. A minority of cells in both patient groups appeared primitive ultrastructurally, exhibiting rudimentary, Golgi-associated progranules; monocyte-like morphologic characteristics; and mitotic activity. Moreover, when mast cells in lesional skin were screened for a limited panel of surface antigens, they displayed common patterns of reactivity (M718+, HLA-DR/DQ+, CD4+), and in a selected case, immunoelectron microscopy confirmed the presence of these antigens on mast cell plasma membranes. Dermal mast cells from normal donors (N = 6) lack these epitopes. These observations suggest that infiltrates in cutaneous mastocytosis may exhibit phenotypic characteristics not only of cutaneous mast cells, but in some patients also of mucosal mast cells. In either circumstance, the mast cells may display antigenic determinants common to monocyte/macrophages. Concordance of granule phenotype between lesional and clinically uninvolved skin of individual patients furthers the notion that even localized mastocytosis reflects covertly defective systemic mast cell homeostasis.

Interpretation of breast biopsies has assumed a large and important component of the surgical pathologist's practice. Currently, about 10% of women will develop breast carcinoma during their lifetime. This high incidence, coupled with increased public awareness of breast disease, greater use of screening mammography to detect early carcinomas, development of multiple therapeutic options (the latter often influenced by the pathology of the tumor), and a harsh medicolegal climate have placed greater demands on surgical pathologists for accurate interpretation of breast tissues. The focus of this report is to define the clinicopathologic features of five benign breast lesions that mimic malignant breast disease, and thus pose important diagnostic considerations to surgical pathologists.

Reported are two cases of oncogenic osteomalacia, each caused by a small mesenchymal tumor, with detailed assessment of the tumors by light microscopy, electron microscopy, and immunohistochemistry. One tumor was a primitive mesenchymal tumor with prominent giant cell and vascular components, and the second resembled the giant cell variant of soft parts chondroma. Osteoclast-like, multinucleated giant cells and vascularity were prominent features in both tumors. Although the literature documents a histologically heterogeneous group of tumors as causing this syndrome, most have multinucleated giant cells and/or extensive vascularity. The high incidence of these two histologic features in this group of tumors suggests that either or both may be related to the pathogenesis and/or metabolic consequences of oncogenic osteomalacia/rickets.

Giant cell tumors of synovium (pigmented villonodular synovitis) involving the vertebral column recently have been seen in two women: the third and fourth cases to be reported in the English-language literature. Unlike the previously reported cases, both these tumors grew outside the dura and produced symptoms of spinal cord compression. The first case involved lumbar vertebrae 5 and 6; the second, lumbar vertebrae 2 and 3. Even though initial resection of both tumors was incomplete, the patients improved postoperatively. One tumor was known to be unresectable at the time of surgery. In the other patient, a recurrence of symptoms required second and third resections 4 and 8 months after the first, respectively. Although synovial giant cell tumors rarely metastasize, the rate of local recurrence is high, especially if excision is incomplete. For this reason, close follow-up of patients with lesions in the spinal column is indicated. Increased physician awareness that synovial giant cell tumors can occur in the spine will help to ensure that these tumors are not misdiagnosed in this location.

A patient is described with chronic colitis, watery diarrhea, and colonic mucosal subepithelial collagen deposition that resolved while being treated with sulfasalazine. The clinicopathologic features were consistent with collagenous colitis. Theoretically, the thickened collagen layer impairs water and electrolyte absorption, producing watery diarrhea. Such increased collagen is rarely observed in other inflammatory colon diseases and may represent a distinct morphologic reaction to various, yet undefined, injuries. Although the clinical course is benign, appropriate therapy for the debilitating symptoms is poorly understood. This report suggests that sulfasalazine may be helpful in some cases.

Summary Two patients presented with hypophosphataemic osteomalacia and were subsequently found to have small tumours unusual histopathology and location causing the osteomalacia. Each tumour was found after an intensive search for occult masses. Studies of vitamin D metabolism and renal tubular function before and after surgery yielded further insight into the pathophysiology of oncogenic osteomalacia. These cases demonstrate that microscopic quantities of tumour are capable of causing the syndrome and further illustrate the high index of suspicion often necessary to locate causative tumours in patients with hypophosphataemic osteomalacia.

Recent development of an antibody to the M subunit of lactic dehydrogenase (LDH) allows the rapid isolation and measurement of LDH-1 levels. I and my colleagues studied 101 consecutive patients admitted to the hospital for possible acute myocardial infarct (AMI). The LDH-1 level was 100 IU/L or more, and the ratio of LDH-1 to total LDH (LDH-1/LDH-T ratio) was 0.40 or higher, during the course of illness in 93% of the patients with AMI. The specificity was 95% and the positive predictive value, 86%. These two criteria were met eight to 24 hours after the appearance of symptoms, and often persisted seven to 14 days. Measurement of LDH-1 level and LDH-1/LDH-T ratio is a useful adjunct in the laboratory diagnosis of AMI.

A serial radiographic-pathologic correlation based on specimen radiography was performed on 27 consecutive, clinically occult, noncalcified breast cancers to determine the frequency of and correlation between appearances at mammography, pathologic diagnoses, and the features of the histologic margins. Twenty (74%) of the lesions were infiltrating ductal cancers, five (19%) were intraductal cancers, and two (7%) were medullary cancers. Forty-one percent of these malignancies contained microscopic calcifications. Lesions demonstrated at mammography in these 27 cases consisted of a well-defined round mass (n = 1); well-defined lobulated masses (n = 2); indistinct round, oval, or lobulated masses (n = 7); irregular or mixed lesions (n = 7); spiculated masses (n = 9); and architectural distortion (n = 1). Histologic margins of infiltrating and intraductal cancers, created by several types of tumor-fat interfaces and surrounding reactive fibrosis, correlated with these radiographic appearances. Serial specimen radiographic-pathologic correlation can improve our understanding of the appearance of early breast cancer at mammography.

Reported are the pathologic features of atypical cysts and/or renal cell carcinomas found in the kidneys of four patients having either tuberous sclerosis or Hippel-Lindau disease. In addition, cellular DNA contents of the cells lining the atypical cysts and comprising the carcinomas were quantitated using both static and flow cytometric techniques. These studies showed that cysts lined by atypical epithelial cells are frequently present in renal parenchyma adjacent to the renal carcinomas, and that the cytologic features of atypical cells lining the cysts were essentially the same as the cytologic features found in the adjacent well-differentiated, renal cell carcinomas. DNA quantitative studies revealed that both the renal cell carcinomas and the atypical cyst lining cells had the same DNA indices and were essentially DNA euploid. In this patient group these findings are consistent with the hypothesis that the atypical cyst lining cells evolve into the renal cell carcinomas; however, they do not prove this proposed but likely sequence.

Pseudoangiomatous hyperplasia of mammary stroma (PHMS) is a benign proliferation of keloid-like fibrosis, containing slit-like pseudovascular spaces. Its main importance is its distinction from angiosarcoma; however, the clinicopathologic spectrum of PHMS remains incompletely described. We report two new cases and describe our findings in 200 consecutive breast specimens evaluated for the presence of PHMS. The first patient presented with peau-de-orange change in the overlying breast skin, thus mimicking inflammatory breast carcinoma. Furthermore, this patient's PHMS lesion had been diagnosed and treated inappropriately as a low-grade angiosarcoma. The second case showed the more typical, fibroadenoma-like presentation of PHMS. In addition, PHMS changes occur commonly in routine breast biopsy specimens. In fact, our review of 200 consecutive breast specimens showed PHMS in at least one microscopic focus in 23% of cases. The PHMS changes occurred in younger patients than the control population and were associated with fibrocystic changes, in fibroadenomas, in gynecomastia, in normal breast tissue, and in sclerosing lobular hyperplasia. Ultrastructural and immunohistochemical studies of one case showed that the capillary-like spaces were either acellular or lined by fibroblasts. Pseudoangiomatous hyperplasia of mammary stroma represents a clinicopathologic spectrum, extending from focal, insignificant microscopic changes to cases where PHMS produces a breast mass. Increased awareness of PHMS and its clinicopathologic spectrum will allow its differentiation from other vascular tumors of the breast, especially low-grade angiosarcoma.

We report two cases of unexplained, isolated, persistently increased aspartate aminotransferase activity in serum. In the first patient, this lasted for 10 years and prompted multiple hospitalizations and medical/surgical consultations. For patient two, the abnormal enzyme activity resulted in hospitalization for further evaluation of possible heart disease. In spite of extensive investigation to determine the possible reason for the abnormality, no clear clinical cause was ever discovered in either patient. Electrophoretic and immunologic evidence indicates that the enzyme was complexed to IgG in the serum of both individuals. Recognition that this complex is probably benign may obviate other patients having to undergo unnecessary hospitalization, anxiety, and expense.

Reported are the pathologic features of 17 mesenchymal tumors documented as causing osteomalacia or rickets. Although these tumors were histologically polymorphous, they were classifiable into four morphological groups. In the first group there were ten unique tumors showing mixed connective tissue features and containing variably prominent vascular and/or osteoclast-like giant-cell components. Tumors of this group also displayed focal microcystic changes, osseous metaplasia, and/or poorly developed cartilaginous areas. The cartilaginous areas sometimes showed considerable dystrophic calcification. With one exception, all tumors of this group occurred in soft tissue and demonstrated benign clinical behavior. The single malignant tumor originated in bone, recurred locally, and metastasized to lung. The tumors comprising the remaining three groups (six tumors) occurred in bone, demonstrated benign clinical behavior, and were grouped according to their close resemblance to tumors known to occur in bone, that is osteoblastoma-like (four tumors), nonossifying fibroma-like (two tumors), and ossifying fibroma-like (one tumor).

The clinical and pathologic findings of two patients with malignant ectomesenchymomas of soft tissue are reported. Malignant ectomesenchymomas are a composite of ganglion cells or neuroblasts and one or more malignant mesenchymal elements, usually rhabdomyosarcoma. Our first case was composed of ganglioneurosarcoma plus rhabdomyosarcoma, the second composed of neuroblastoma plus rhabdomyosarcoma. The name is derived from the suggestion that they arise from pluripotential ectomesenchyme. An English language literature search revealed 11 other cases that arose in soft tissue and had adequate clinicopathologic data. Of the 13 cases, 10 occurred in infants, three occurred in adults, and nine were males. Six patients were alive and free of disease at last follow-up (range, 0.6-12 years; mean, 3.4 years), four patients had died of tumor (within 0.5-3.3 years; mean, 1.3 years), one case had died of Adriamycin (doxorubicin) toxicity, and two cases had been lost to follow-up. Complete surgical resection is the mainstay of treatment and chemotherapy appears to be important.

Two patients developed nodular, well-circumscribed tumors of the breast, discovered by mammography. They were fibroadenoma-like by gross examination and biphasic by light microscopy, containing both tubular glands and spindled myoid cells. Immunocytochemical studies revealed cytokeratin and S-100 immunoreactivity in both the spindled myoid cells and in the tubuloglandular cells (S-100 was focal in the latter). In addition, the spindled myoid cells were immunoreactive for vimentin but negative for desmin. Ultrastructural studies showed the tubular glands to be composed of luminal epithelial cells focally surrounded by myoepithelial cells, but the stroma contained spindled myoepithelial cells admixed with occasional fibroblasts. The diagnostic term, "adenomyoepithelioma," is appropriate for biphasic tumors having both glandular and myoepitheliomatous differentiation. Although additional experience is necessary to be conclusive regarding the biologic behavior of these unusual lesions, the authors believe the adenomyoepitheliomas described here are benign. They were well circumscribed without invasion of adjacent breast, contained neither mitotic figures nor cytologic atypia, and have not recurred or metastasized (6 and 10 months after removal).