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Background: Patients with hamartomatous polyposis syndromes have increased risk for colorectal cancer (CRC). Although progression of polyps to carcinoma is observed, pathogenic mechanisms remain unknown. The authors examined whether familial hamartomatous polyps harbor defects in DNA mismatch repair (MMR), and assayed for somatic mutation of PTEN, a gene inactivated in the germline of some hamartomatous polyposis syndrome patients., Methods: Ten hamartomatous polyposis syndrome patients were genotyped for germline mutations. Epithelial and nonepithelial polyp DNA were assayed for microsatellite instability (MSI) and PTEN frameshift mutation. DNA MMR and PTEN protein expression were assessed in all polyps by immunohistochemistry. In addition, 99 MSI-high sporadic CRCs and 50 each of hMLH1(-/-) and hMSH3(-/-) cell clones were examined for PTEN frameshifts., Results: Twenty-five (58%) of 43 hamartomatous polyposis syndrome polyps demonstrated dinucleotide or greater MSI in polyp epithelium, consistent with hMSH3 deficiency. MSI domains lost hMSH3 expression, and PTEN expression was lost in polyps from germline PTEN patients; sporadic hamartomatous polyps did not show any of these findings. PTEN analysis revealed wild type exon 7 and 8 sequences suggestive of nonexistent or rare events for PTEN frameshifts; however, MSI-high sporadic CRC showed 11 (11%) of 99 frameshifts within PTEN, with 4 tumors having complete loss of PTEN expression. Subcloning hMLH1(-/-) and hMSH3(-/-) cells revealed somatic PTEN frameshifts in 4% and 12% of clones, respectively., Conclusions: Nondysplastic epithelium from hamartomatous polyposis syndrome polyps harbors hMSH3 defects, which may prime neoplastic transformation. Polyps from PTEN(+/-) patients lose PTEN expression, but loss is not a universal early feature of all hamartomatous polyposis syndrome. However, PTEN frameshifts can occur in hMSH3-deficient cells, suggesting that hMSH3 deficiency could drive hamartomatous polyposis syndrome tumorigenesis., (Copyright © 2010 American Cancer Society.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

Background: Approximately 30 patients with malignant mesothelioma following radiotherapy have been described. Population-based studies of this occurrence have not been reported., Methods: 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., Results: 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)., Conclusions: 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.

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).

A unique case of carcinosarcoma of the colon is reported. The tumor invaded the bowel wall deeply, metastasized widely, resisted multi-agent chemotherapy, and caused the patient's death 4 years later. The tumor was composed of adenosquamous carcinoma admixed with sarcoma showing osseous, cartilaginous, and nonspecific spindle-cell differentiation. Although carcinoembryonic antigen appeared limited to carcinoma cells, cytokeratin immunoreactivity was observed in both carcinoma and sarcoma cells. Like carcinosarcomas at other body sites, the finding of cytokeratin in sarcoma cells supports partial epithelial differentiation in this component, likely retained from carcinoma precursor cells.

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.

Two patients developed extremely bizarre (pseudomalignant) granulation-tissue reactions in the larynx and facial sinuses, following radiation therapy for carcinoma. Containing pleomorphic spindle cells and numerous (sometimes atypical) mitotic figures, both tumefactive lesions simulated high grade malignancies. While the pleomorphic cells contained vimentin immunoreactivity, they were nonreactive for low or high molecular weight keratin. Flowcytometric study of paraffin-embedded tissues revealed DNA indexes of 0.75 and 1.0. Neither recurred locally nor spread distantly after therapy. Their granulation-tissue growth pattern, and the presence of stromal and endothelial cells showing similar degrees of cytologic atypia were central to their recognition as benign. These findings show that severely atypical, sometimes aneuploid, granulation-tissue reactions can occur following radiation exposure. Care should be taken not to misinterpret these lesions as malignant.

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.

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.

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.

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).

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.