The genomic and evolutionary landscapes of anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. Finally, we unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas and emerge from a common malignant field through acquisition of characteristic clonal driver mutations.

Loss of heterozygosity (LOH) profiles--validated risk predictors for progression to oral cancer.

A major barrier to oral cancer prevention has been the lack of validated risk predictors for oral premalignant lesions (OPL). In 2000, we proposed a loss of heterozygosity (LOH) risk model in a retrospective study. This paper validated the previously reported LOH profiles as risk predictors and developed refined models via the largest longitudinal study to date of low-grade OPLs from a population-based patient group. Analysis involved a prospective cohort of 296 patients with primary mild/moderate oral dysplasia enrolled in the Oral Cancer Prediction Longitudinal Study. LOH status was determined in these OPLs. Patients were classified into high-risk or low-risk profiles to validate the 2000 model. Risk models were refined using recursive partitioning and Cox regression analyses. The prospective cohort validated that the high-risk lesions (3p and/or 9p LOH) had a 22.6-fold increase in risk (P = 0.002) compared with low-risk lesions (3p and 9p retention). Addition of another 2 markers (loci on 4q/17p) further improved the risk prediction, with five-year progression rates of 3.1%, 16.3%, and 63.1% for the low-, intermediate-, and high-risk lesions, respectively. Compared with the low-risk group, intermediate- and high-risk groups had 11.6-fold and 52.1-fold increase in risk (P < 0.001). LOH profiles as risk predictors in the refined model were validated in the retrospective cohort. Multicovariate analysis with clinical features showed LOH models to be the most significant predictors of progression. LOH profiles can reliably differentiate progression risk for OPLs. Potential uses include increasing surveillance for patients with elevated risk, improving target intervention for high-risk patients while sparing a large number of low-risk patients from needless screening and treatment.

Lethal neuroendocrine carcinoma in ulcerative colitis.

A 48-year old male with longstanding and extensive pancolitis developed a high grade and rapidly lethal malignant lesion in the ascending colon characterized by a neuroendocrine carcinoma. Prior biopsies obtained from multiple sites in the colon during endoscopic surveillance were reported to show only inflammatory changes without dysplasia. Although operator-dependent, repeated endoscopic studies may have limitations during surveillance programs because the biological behavior of some colonic neoplastic lesions may have a rapid and very aggressive clinical course.

Loss of desmoglein 1 expression associated with worse prognosis in head and neck squamous cell carcinoma patients.

AIMS: Mucosal squamous cell carcinomas are the most common head and neck malignancies. We hypothesised that over-expression of intracellular signalling proteins and decreased expression of desmoglein molecules would be associated with aggressive tumour behaviour in patients with head and neck squamous cell carcinoma. METHODS: Seventy-eight cases of head and neck squamous cell carcinoma were immunohistochemically stained for desmoglein 1, desmoglein 2, desmoglein 3, p53, bcl-2, vimentin, cyclin D1, p16, p21, p27, E-cadherin, and E2F-1 in paraffin-embedded tissue blocks in a microarray. RESULTS: The disease-specific survival was 56% at 5 years and 49% at 10 years. Expression of the desmoglein isotypes correlated positively with each other except for desmoglein 2 and desmoglein 3, which did not show a significant correlation. Desmoglein 1 and E-cadherin expression also correlated. On univariate analysis, only expression of desmoglein 1 correlated with patient outcome; lack of expression of desmoglein 1 was associated with a significantly worse disease-specific survival (p = 0.035). Hierarchical clustering analysis identified a subgroup of three patients with an immunophenotype distinct from the other tumours, characterised by co-expression of p16, p27, E2F-1 and bcl-2. Further statistical analysis of the prognostic significance of this small subgroup was not possible, but these three patients are alive and well. CONCLUSIONS: Decreased expression of desmoglein 1 is associated with a worse prognosis in head and neck squamous cell carcinoma patients. Examination of an extended panel of immunomarkers revealed a rare subtype of squamous cell carcinoma characterised by the expression of multiple proliferation-associated markers and the anti-apoptotic protein, bcl-2; determination of the prognostic significance of this subgroup will require study of a larger case series.

Evolution of collagenous colitis into severe and extensive ulcerative colitis.

Collagenous colitis is an inflammatory mucosal disorder of the colon with distinctive histopathological features, including a thickened subepithelial collagen layer. The clinical course is usually benign, but serious complications, including death, may occur. In the present report, a 69-year-old woman with watery diarrhea and collagenous colitis developed bloody diarrhea that was refractory to treatment medications, including corticosteroids and azathioprine. Endoscopic and histopathological studies showed a focal neutrophilic inflammatory process that progressed to a diffuse and extensive form of colitis, eventually requiring total proctocolectomy. Careful histological review of the resected colon showed no evidence of persistent collagenous colitis. These findings suggest an important need for continued long-term follow-up of patients with collagenous colitis because superimposed and serious colonic complications may occur, including a severe and extensive pancolitis refractory to medications and necessitating total proctocolectomy.

Fluorescence visualization detection of field alterations in tumor margins of oral cancer patients.

PURPOSE: Genetically altered cells could become widespread across the epithelium of patients with oral cancer, often in clinically and histologically normal tissue, and contribute to recurrent disease. Molecular approaches have begun to yield information on cancer/risk fields; tissue optics could further extend our understanding of alteration to phenotype as a result of molecular change. EXPERIMENTAL DESIGN: We used a simple hand-held device in the operating room to directly visualize subclinical field changes around oral cancers, documenting alteration to fluorescence. A total of 122 oral mucosa biopsies were obtained from 20 surgical specimens with each biopsy being assessed for location, fluorescence visualization (FV) status, histology, and loss of heterozygosity (LOH; 10 markers on three regions: 3p14, 9p21, and 17p13). RESULTS: All tumors showed FV loss (FVL). For 19 of the 20 tumors, the loss extended in at least one direction beyond the clinically visible tumor, with the extension varying from 4 to 25 mm. Thirty-two of 36 FVL biopsies showed histologic change (including 7 squamous cell carcinoma/carcinomas in situ, 10 severe dysplasias, and 15 mild/moderate dysplasias) compared with 1 of the 66 FV retained (FVR) biopsies. Molecular analysis on margins with low-grade or no dysplasia showed a significant association of LOH in FVL biopsies, with LOH at 3p and/or 9p (previously associated with local tumor recurrence) present in 12 of 19 FVL biopsies compared with 3 of 13 FVR biopsies (P=0.04). CONCLUSIONS: These data have, for the first time, shown that direct FV can identify subclinical high-risk fields with cancerous and precancerous changes in the operating room setting.

Resolution of paraneoplastic collagenous enterocolitis after resection of colon cancer.

A 52-year-old woman developed severe watery diarrhea, weight loss, anemia and hypoalbuminemia. A localized colon cancer was detected. Subsequently, extensive collagenous mucosal involvement of the small and large intestine was discovered. After resection of the colon cancer, her symptoms resolved. In addition, resolution of the inflammatory process occurred, including the subepithelial collagen deposits. Despite extensive small and large intestinal involvement, both clinical and histological resolution of collagenous inflammatory disease was evident. Collagenous enterocolitis is an inflammatory process that may represent a distinctive and reversible paraneoplastic phenomenon.

Toluidine blue staining identifies high-risk primary oral premalignant lesions with poor outcome.

There is a pressing need for the development of visual aids that will facilitate the detection of oral premalignant lesions (OPLs) with a high-risk of progression. Preliminary data suggest that toluidine blue stain may be preferentially retained by OPLs with high-risk molecular clones. In this study, we monitored OPLs from 100 patients without any history of oral cancer for an average of 44 months in order to evaluate the association of toluidine blue status with clinicopathologic risk factors, molecular patterns (microsatellite analysis on seven chromosome arms: 3p, 9p, 4q, 8p, 11q, 13q, and 17p) and outcome. Toluidine blue-positive staining correlated with clinicopathologic risk factors and high-risk molecular risk patterns. Significantly, a >6-fold elevation in cancer risk was observed for toluidine blue-positive lesions, with positive retention of the dye present in 12 of the 15 lesions that later progressed to cancer (P = 0.0008). This association of toluidine blue status with risk factors and outcome was evident even when the analysis was restricted to OPLs with low-grade or no dysplasia. Our results suggest the potential use of toluidine blue in identifying high-risk OPLs.

Raman spectroscopy for optical diagnosis in the larynx: preliminary findings.

BACKGROUND AND OBJECTIVES: Raman spectroscopy (RS) provides information about molecular structure and is a potential tool for non-invasive tissue diagnosis. To determine if Raman spectra could be obtained rapidly from laryngeal tissue in vitro, and compare Raman spectra from normal, benign, and cancerous laryngeal tissue. STUDY DESIGN/MATERIALS AND METHODS: Forty-seven laryngeal specimens were studied using RS with signal acquisition times (SAT) between 1 and 30 second(s). Multivariate analysis was used to determine the diagnostic ability of RS compared to standard histology (n = 18, 13, and 16 respectively for normal tissue, carcinoma, and squamous papilloma). RESULTS: Good quality spectra were obtained with 5-second SAT. Spectral peak analysis showed prediction sensitivities of 89%, 69%, and 88%, and specificities of 86%, 94%, and 94% for normal tissue, carcinoma, and papilloma. CONCLUSIONS: In the larynx, spectral differences appear to exist between normal tissue, carcinoma, and papilloma. The ability to obtain spectra rapidly supports potential for future in vivo studies.

Raman spectroscopy for optical diagnosis in normal and cancerous tissue of the nasopharynx-preliminary findings.

BACKGROUND AND OBJECTIVES: Raman spectroscopy (RS), which can detect molecular changes associated with cancer, was explored as a means of distinguishing normal and cancerous nasopharyngeal tissue. STUDY DESIGN/PATIENTS AND METHODS: Tissue from six patients with normal and cancerous biopsies was studied using a rapid acquisition Raman spectrometer. RESULTS: Spectra were obtainable within 5 seconds. Consistent differences were noted between normal and cancer tissue in three bands 1,290-1,320 cm(-1) (P = 0.005), 1,420-1,470 cm(-1) (P = 0.006), and 1,530-1,580 cm(-1) (P = 0.002). CONCLUSIONS: Spectral differences appear to exist between normal and cancerous nasopharyngeal tissue. The ability to obtain spectra rapidly supports the potential for future in vivo application.

Increased allelic loss in toluidine blue-positive oral premalignant lesions.

OBJECTIVE: Recent studies have shown that a loss of chromosome regions (loss of heterozygosity [LOH]) containing known or presumptive tumor suppressor genes is predictive of the cancer risk of oral premalignant lesions. This preliminary study investigated whether the dye toluidine blue (TB) preferentially stains oral premalignant lesions with LOH. This stain has been used by clinicians to delineate dysplasia/carcinoma in the oral cavity. STUDY DESIGN: The study included 32 patients with oral lesions who underwent biopsy after the assessment of TB dye retention. A total of 39 biopsy specimens were examined (14 hyperplastic, 25 dysplastic). Fourteen of the biopsy specimens were TB-negative. The specimens were analyzed for LOH at 10 microsatellite loci on 3 chromosome arms (3p, 9p, and 17p), and the LOH results of TB-positive samples were compared with those that were negative for the tissue staining. RESULTS: TB-positive samples had a higher frequency of loss than TB-negative cases for loci on 3p (P = .013) and 17p (P = .049). In addition, more TB-positive cases showed a loss of multiple arms (>2 arms, P = .015), a pattern that has been associated with markedly increased cancer risk. CONCLUSION: The study results suggest that TB staining may help identify oral premalignant lesions with increased LOH and increased cancer risk.