Calcitonin negative medullary thyroid cancer in ectopic thyroid tissue: a rare diagnosis in an unusual location.

Medullary thyroid cancer is an aggressive form of thyroid cancer arising from parafollicular C cells. Calcitonin (CT) is a specific and sensitive biochemical marker which typically aids primary diagnosis and disease surveillance following treatment. There are rare cases of calcitonin negative medullary thyroid cancer (CNMTC) documented in the literature; however, to our knowledge, this case is the first report of CNMTC arising in ectopic thyroid tissue. We report a case of a 45-year-old man who attended his primary care physician with painless anterior neck swelling. In the absence of CT secreting disease, we have demonstrated the investigative process and the importance of immunohistochemical analysis to achieve a diagnosis. We also consider the challenges of monitoring disease recurrence in the absence of reliable biochemical markers.

Impact on colorectal cancer pathology reporting practice of migration from TNM 5 to TNM 8.

AIMS: The introduction of TNM 8 into UK pathology practice in January 2018 considers tumour deposits in colorectal cancer staging for the first time. The impact of this new classification on pathology reporting practices has yet to be evaluated. METHODS AND RESULTS: A clinical audit was conducted, comparing consecutive colorectal cancer resection specimens reported under TNM 5 classification guidelines in 2017 (n = 177) and TNM 8 guidelines in 2018 (n = 234). Tumour features (venous invasion, perineural invasion, lymph node metastatic disease, tumour deposits) and changes in reporting practices were evaluated among four specialist gastrointestinal pathologists working within a large pathology department. Adoption of TNM 8 practice led to an approximate doubling in the use of ancillary stains (41.0% of TNM 8 versus 22.0% of TNM 5 cases, P < 0.001) to help evaluate tumours. A narrowing of the range between pathologists was observed in reporting cases as having one or more form of regional, extramural, discontinuous tumour (TNM 5 range = 50.0-79.0%, TNM 8 range = 57.8-65.7%), with no change in the overall proportion of cases reported as such (62.7% versus 62.4%, P = 0.95). However, significant interobserver variation in reporting rates for individual parameters remained. CONCLUSION: TNM 8 colorectal cancer staging offers potentially greater reproducibility in pathology reporting of regional, extramural, discontinuous disease with similar proportions of patients reported as having one or more of these forms of tumour spread compared with TNM 5. Further guidance in defining individual features is required to reduce interobserver variation in pathology assessments and to help elucidate the clinical significance of each parameter.

Progress in the development of protein biomarkers of oesophageal and gastric cancers.

Upper gastrointestinal cancers originating in the oesophagus and stomach often present late and have a very poor prognosis. Treatment options include surgery for localised disease but, increasingly, neoadjuvant chemotherapy and radiotherapy are being employed to improve outcome. There is often a variable response to neoadjuvant treatment between individual patients and side effects are relatively common. There is an urgent need for novel biomarkers of upper gastrointestinal cancer, not only to improve screening and early diagnosis of the oesophageal and gastric cancers when treatment options are potentially more effective, but also to accurately guide therapy in more advanced disease. The development of predictive biomarkers will also help to more effectively identify those patients that will benefit from targeted therapies. Although many promising results have been derived from these studies there remains a lack of validated clinically applicable biomarkers available for translation into routine clinical use. This review will provide an overview of the recent proteomic research on upper gastrointestinal cancer protein biomarker identification and validation. The challenges faced in the development of validated, clinically acceptable and accurate protein biomarkers will also be discussed, along with possible areas of future progress.

Biomarkers of colorectal cancer: recent advances and future challenges.

Colorectal cancer (CRC) is a common malignancy and it contributes significantly to cancer mortality. Outcomes in colorectal cancer vary between patients and this is due to the complexity of colorectal carcinogenesis. Interactions between tumor cells and their microenvironment, genetic alterations, and changes in intracellular signalling networks are just some of the abnormal pathways involved in colorectal cancer development. Recent research has targeted components of all of these systems in order to develop biomarkers to aid in the early diagnosis of CRC and to assist in prognostic stratification. Proteomic analysis of tissue or blood-derived samples from CRC patients has proven to be a valuable technique for the identification of potentially informative biomarkers. Such biomarkers may prove to be clinically applicable and could offer greater patient acceptability when compared to conventional methods such as fecal-based testing. In this article we review the recent advances in the development of protein biomarkers of CRC with an emphasis on biomarkers available in the patient's serum and from tissue-based samples. Future challenges in terms of the development of accurate diagnostic, prognostic, and predictive biomarkers of CRC and the importance of validation and patient acceptability are also discussed.

The role of gene regulatory networks in promoting cancer progression and metastasis.

The majority of deaths owing to cancer are ultimately caused by metastatic disease. However, most research, to date, has focused on the molecular features of cancers at their primary sites rather than on understanding disseminated malignancy in its systemic form. The dynamic nature of metastatic malignancy and its behavior as a co-ordinated systemic disease require a cancer progression paradigm that is integrative and can incorporate both the proximate causes of cancer and the broader ultimate causes in an evolutionary and developmental context. The study of robust cellular attractor states that arise directly from the architectural patterns contained within gene regulatory networks is proposed as a conceptual framework through which many of the other disparate models of cancer metastasis can be more clearly viewed and, ultimately, unified, thus providing a new conceptual framework in which to understand cancer progression and metastasis.

Progress in the identification of plasma biomarkers of colorectal cancer.

Proteomic analysis of human tissue and plasma samples has been a useful tool in recent years for the identification of potential biomarkers to aid in the early diagnosis of colorectal cancer. However, biomarkers relating to the crucial transition between adenomatous lesions and invasive colorectal malignancy have not previously been described. The work of Choi et al. (Proteomics 2013, 13, 2361-2374) attempts to address this issue. Using plasma samples from age-matched patients with colorectal adenomas or invasive disease this group identified a range of plasma proteins and cytokines that were differentially expressed. This information not only provides insights into the biology of the adenoma to carcinoma progression sequence but it also represents a step towards the goal of achieving diagnostically accurate and clinically acceptable biomarkers in early colorectal cancer.

Current and emerging concepts in tumour metastasis.

Disseminated cancer accounts for most deaths due to malignancy. Despite this, research has focused predominantly on tumour development and progression at the primary site. Recently, attention has shifted towards the field of tumour metastasis. Several new and exciting concepts that have emerged in the past few years may shed light on this complex area. The established canonical theory of tumour metastasis, as a process emerging from a stepwise accumulation of genetic events fuelled by clonal evolution, has been challenged. New evidence suggests that malignant cells can disseminate at a much earlier stage than previously recognized in tumourigenesis. These findings have direct relevance to clinical practice and shed new light on tumour biology. Gene-profiling studies support this theory, suggesting that metastatic ability may be an innate property shared by the bulk of cells present early in a developing tumour mass. There is a growing recognition of the importance of host factors outside the primary site in the development of metastatic disease. The role of the 'pre-metastatic niche' is being defined and with this comes a new understanding of the function of bone marrow-derived progenitor cells in directing the dissemination of malignant cells to distant sites. Current research has highlighted the crucial roles played by non-neoplastic host cells within the tumour microenvironment in regulating metastasis. These new concepts have wide-ranging implications for our overall understanding of tumour metastasis and for the development of cancer therapeutics.

Quantitative analysis of tumor in bronchial biopsy specimens.

BACKGROUND: Diagnostic bronchial biopsy samples from lung cancer patients may be used for molecular biologic analyses to help select therapy and provide prognostic information. Some have suggested that direct molecular analysis of bronchial biopsy fragments may be feasible, bypassing histologic examination. We analyzed a series of 100 bronchial biopsy specimens in lung cancer patients to assess the frequency and quantity of tumor present in biopsy samples. METHODS: The proportion of tumor in bronchial biopsy specimens was assessed by measuring the tumor area in histologic sections using computer-aided morphometry. RESULTS: In only 48% of cases did all the biopsy fragments contain some tumor. The median number of fragments obtained at bronchoscopy was 4; median number actually containing tumor was 3. The mean total surface area of tumor (as a percentage of the total sample area) in biopsy fragments was, for all cases, 33.4%; median area 28%. Biopsies with small cell carcinoma had more tumor (mean area 46.5%, median 49%; p = 0.0006) than all other non-small cell carcinoma cases. CONCLUSION: Malignant bronchial biopsy samples frequently contain limited amounts of primary carcinoma. Often, one or more of the biopsy fragments will not contain tumor. This has important implications for the storage and use of bronchial biopsy samples for genetic analysis.

Mycobacterium microti infection associated with spindle cell pseudotumour and hypercalcaemia: a possible link with an infected alpaca.

A 44-year-old woman who had recently been on immunosuppressive therapy presented with malaise, cough, fever, weight loss, lymphadenopathy, severe hypercalcaemia and a paratracheal mass on imaging. The initial impression was of disseminated malignancy, and lymphoma was suspected. A mediastinal biopsy showed a mycobacterial spindle cell pseudotumour containing acid and alcohol fast bacilli (AAFB). Sputum microscopy demonstrated AAFBs, confirmed as Mycobacterium tuberculosis complex by PCR. Prolonged culture grew Mycobacterium microti, an organism often associated with disease in small rodents and llamas. M microti isolates from postmortem samples of an alpaca at a nearby farm were genetically indistinguishable. Although the patient had not visited the farm, concurrent illness in her adopted stray cat suggested a possible zoonotic connection. The patient responded to antituberculous therapy, and rehydration and pamidronate for hypercalcaemia. We believe the hypercalcaemia was caused by a similar mechanism to raised calcium levels sometimes seen in tuberculosis.