Revisiting the transcriptional analysis of primary tumours and associated nodal metastases with enhanced biological and statistical controls: application to thyroid cancer.

BACKGROUND: Transcriptome profiling has helped characterise nodal spread. The interpretation of these data, however, is not without ambiguities. METHODS: We profiled the transcriptomes of papillary thyroid cancer nodal metastases, associated primary tumours and primary tumours from N0 patients. We also included patient-matched non-cancerous thyroid and lymph node samples as controls to address some limits of previous studies. RESULTS: The transcriptomes of patient-matched primary tumours and metastases were more similar than those of unrelated metastases/primary pairs, as previously reported in other organ systems. This similarity partly reflected patient background. Lymphoid tissues in the metastases confounded the comparison of patient-matched primary tumours and metastases. We circumvented this with an original data adjustment, revealing a differential expression of stroma-related gene signatures also regulated in other organs. The comparison of N0 vs N+ primary tumours uncovered a signal irreproducible across independent data sets. This signal was also detectable when comparing the non-cancerous thyroid tissues adjacent to N0 and N+ tumours, suggesting a cohort-specific bias also likely present in previous similarly sized studies. Classification of N0 vs N+ yielded an accuracy of 63%, but additional statistical controls absent in previous studies revealed that this is explainable by chance alone. We used large data sets from The Cancer Genome Atlas: N0 vs N+ classification was not better than random for most cancers. Yet, it was significant, but of limited accuracy (<70%) for thyroid, breast and head and neck cancers. CONCLUSIONS: The clinical potential of gene expression to predict nodal metastases seems limited for most cancers.

Parathyroidectomy in primary hyperparathyroidism: retrospective study of 167 patients, experience in Jules Bordet Institute.

The aim of this study is to compare our surgical results of parathyroidectomies in primary hyperparathyroidism with literature results. From 1985 until 2009, 167 patients were operated for primary hyperparathyroidism by bilateral central neck exploration. The sex ratio (women/men) is 4/1 and the middle age is 57 years old. We record clinical information, laboratory and radiological results of the preoperative period. We count 158 adenomas, 5 parathyroid hyperplasias, two carcinomas and two parathyroid glands reported as normal. The morbidity rate was low (0.6%) and there was no mortality. With a mean follow-up of 6 years, the majority of symptoms and clinical signs improved after surgery, the parathyroid hormone level (PTH) and the calcaemia normalized in all patients except 4/166 (2.41%). Among twenty-four patients who go for a Dual-Energy X-ray Absorptiometry test (DEXA), 16/24 (66.67%) demonstrated a lumbar spine bone mass increase and 15/24 (62.5%) a total hip bone mass increase. There was one recurrence of hyperparathyroidism due to a missed second adenoma in the mediastinum. In conclusion, the parathyroidectomy by bilateral neck exploration under general anesthesia in the treatment of primary hyperparathyroidism is a surgical technique associated with a high recovery rate and a low complications rate. A systematic study of the bone mass before and after parathyroidectomy should allow identification of the factors that are associated with the bone density increase of these patients.

Recurrent invasive thymoma with pleural dissemination : disease management and treatment possibilities.

Thymoma is the most common benign neoplasm of the anterior mediastinum presenting often an agressive behaviour typical for the malignants tumors. The rate of invasive thymoma recurrency is relatively high. We present the case of a 55-year old man with a recurrent invasive thymoma with a pleural dissemination, detected on CT-imaging 2 years following his primary surgery. Since the first pre-operative imaging studies showed no invasion of the adjacent organs and a thymoma was suspected, a surgical resection was decided as a first line treatment. Per-operatively a number of adjacent structures were invaded and despite a macroscopical RO resection, the margins were microscopically positive. An invasive thymoma, WHO classification B3, Masaoka stage IVb was diagnosed and the patient received adjuvant radiotherapy. We highlight the role of multimodality treatement and disscus the potential of surgical, radiotherapeutical and systemic therapy in stage IV thymoma as well as in recurrent disease.

Quality assurance in head and neck surgical oncology: EORTC 24954 trial on larynx preservation.

BACKGROUND: The Head and Neck Cancer Group (HNCG) of the EORTC conducted a quality assurance program in the EORTC 24954 trial on larynx preservation. In this multicentre study, patients with resectable advanced squamous cell carcinoma of the larynx or hypopharynx were randomly assigned for treatment with sequential or alternating chemoradiation. The need for a quality assurance program is the evaluation and prevention of differences in treatments between centres in this multidisciplinary study. METHOD: The surgical subcommittee of the HNCG prepared a questionnaire, and clinical records of all patients were verified during audits of independent teams. Data relating institutional practices were collected during a face to face interview with members of the local team. RESULTS: 271 clinical records from the nine main contributing centres were reviewed. The main difference between centres was the time interval between first consultation and treatment initiation, with a mean of 45 days. On the pathology report the nodal involvement was described by level in 36% of the cases according to the American Academy of Otolaryngology-Head and Neck Surgery classification. Extranodal spread was not always described in neck dissection specimens. CONCLUSION: The EORTC 24954 trial on larynx preservation was the first prospective trial with a quality assurance program in head and neck surgical oncology. The analysis shows similarities in practices, but also points out some important differences between centres. Operation reports were fairly complete, but uniformity in pathology reports should be improved.

Systems biology of cancer: entropy, disorder, and selection-driven evolution to independence, invasion and "swarm intelligence".

Our knowledge of the biology of solid cancer has greatly progressed during the last few years, and many excellent reviews dealing with the various aspects of this biology have appeared. In the present review, we attempt to bring together these subjects in a general systems biology narrative. It starts from the roles of what we term entropy of signaling and noise in the initial oncogenic events, to the first major transition of tumorigenesis: the independence of the tumor cell and the switch in its physiology, i.e., from subservience to the organism to its own independent Darwinian evolution. The development after independence involves a constant dynamic reprogramming of the cells and the emergence of a sort of collective intelligence leading to invasion and metastasis and seldom to the ultimate acquisition of immortality through inter-individual infection. At each step, the probability of success is minimal to infinitesimal, but the number of cells possibly involved and the time scale account for the relatively high occurrence of tumorigenesis and metastasis in multicellular organisms.

[Mastocytosis: revisited with new cytogenetic data]. / La mastocytose: une maladie revisitée a la lumière des nouvelles données génétiques.

Mastocytosis is a heterogenous disorder due to abnormal proliferation and infiltration of mast cells in different tissues, primarily the skin and the bone marrow. Cutaneous mastocytosis is often benign and regresses spontaneously. Systemic mastocytosis is a chronic disease in which some types are indolent but other types such as mast cell leukemia are very aggressive. Pathogenesis of systemic mastocytosis involves a somatic mutation of the gene coding for the c-kit receptor, the most frequent mutation being D816V. Diagnostic criteria have been established by the WHO using histopathological, molecular and biochemical parameters. Treatment of systemic mastocytosis remains a challenge for the clinician due to variability and complexity of the disease. There is, in addition, a lack of a standard and efficient treatment. New targeted therapies with tyrosine kinase inhibitors directed against the c-kit receptor are currently being studied, with the purpose to act specifically on the " primum movens "of the disease. The current review provides an overview of pathogenesis, clinical presentation, diagnosis and classification of cutaneous and systemic mastocytosis. We also discuss the prognosis and the different treatments currently available according to the sub-type of mastocytosis.

Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year results of EORTC trial 24891.

BACKGROUND: We report the 10-year results of the EORTC trial 24891 comparing a larynx-preservation approach to immediate surgery in hypopharynx and lateral epilarynx squamous cell carcinoma. MATERIAL AND METHODS: Two hundred and two patients were randomized to either the surgical approach (total laryngectomy with partial pharyngectomy and neck dissection, followed by irradiation) or to the chemotherapy arm up to three cycles of induction chemotherapy (cisplatin 100 mg/m(2) day 1 + 5-FU 1000 mg/m(2) day 1-5) followed for complete responders by irradiation and otherwise by conventional treatment. The end points were overall survival [OS, noninferiority: hazard ratio (preservation/surgery) ≤ 1.428, one-sided α = 0.05], progression-free survival (PFS) and survival with a functional larynx (SFL). RESULTS: At a median follow-up of 10.5 years on 194 eligible patients, disease evolution was seen in 54 and 49 patients in the surgery and chemotherapy arm, respectively, and 81 and 83 patients had died. The 10-year OS rate was 13.8% in the surgery arm and 13.1% in the chemotherapy arm. The 10-year PFS rates were 8.5% and 10.8%, respectively. In the chemotherapy arm, the 10-year SFL rate was 8.7%. CONCLUSION: This strategy did not compromise disease control or survival (that remained poor) and allowed more than half of the survivors to retain their larynx.

[Thyroid cancers]. / Les cancers thyroïdiens.

During the last two decades, the incidence of thyroid cancer has doubled, mainly do to the early detection of small papillary tumors. However, mortality stayed stable (0.05/100.000). Well differentiated cancers (papillary and follicular) demonstrated a excellent survival prognosis (95 % at 30 years for the majority of the patients), factors of prognosis: age, size of the initial tumor, presence (or not) of distant metastases, lymph node involvement (only in patients 45 year or older). Surgery is the main treatment and should be with curative intent, hence the importance of a thorough preoperative work-up: sonography, needle aspiration cytology and MRI of cervicomediastinum for large tumors and/or suspected lymph nodes. Total thyroidectomy is mandatory, excepted for well selected patients with small (pT1) unilateral tumors under the age of 45. Central compartment lymph node clearance is advocated (but not evidence based) with presentation of the recurrent laryngeal nerves and of the parathyroids. Ablation of residual thyroid tissue (Iode 131) should be advocated for patients at high (or intermediary) risk of recurrence, only after multidisciplinary concertation. Unlimited follow-up checking the thyroglobulin serum local after the total thyroidectomy and radioactive ablation, the availability of recombinant rhTSH avoids the withdrawal of thyroid hormones (hypothyroid period). Anaplastic carcinomas are very aggressive, no therapeutic solution, excepted in some selected case for when radical surgery is possible (flap reconstruction) followed by chemoradiation. Calcitoninenia to detect and to follow medullary thyroid cancer after total thyroidectomy and lymph node clearance.

Association of parathyroid adenoma and familial hypocalciuric hypercalcaemia in a teenager.

OBJECTIVE: Familial hypocalciuric hypercalcaemia (FHH) is clinically characterized by mild to moderate parathyroid hormone (PTH)-dependent hypercalcaemia, autosomal dominant pattern of inheritance, and normal to frankly reduced urinary calcium excretion in spite of a high serum calcium (clearance (Ca)/clearance (Cr)<0.01). FHH has a benign course and should be differentiated from primary hyperparathyroidism. It is usually caused by a heterozygous loss-of-function mutation in the calcium-sensing receptor gene (CASR). DESIGN: We report the case of a 16-year-old patient with hypercalcaemia and a mixed family history of parathyroid adenoma and mild hypercalcaemia. Serum calcium was 14 mg/dl with a serum iPTH of 253 pg/ml. RESULTS: A neck 99mTc-sesta MIBI tomoscintigraphy showed a definite hyperactivity in the left upper quadrant. A surgical four-gland exploration confirmed a single parathyroid adenoma. After surgical resection of a left superior parathyroid adenoma, the patient's hypercalcemia improved but did not normalize, returning to a level typical of FHH. An inactivating mutation in exon 4 of the CASR gene, predicting a p.Glu297Lys amino acid substitution was found. CONCLUSIONS: Thus, this 16-year old patient presented with the association of FHH and a single parathyroid adenoma. The young age of the patient and the association of parathyroid adenoma and FHH in his grandmother argue for a causal link between CASR mutation and parathyroid adenoma in this family. This case contributes to illustrate the expanding clinical spectrum of CASR loss-of-function mutations.

[Quality of life after radical surgery and radiotherapy for advanced or recurrent laryngeal and hypopharyngeal cancers]. / Evaluation de la qualité de vie après chirurgie radicale et radiothérapie dans le traitement de tumeurs avancées ou récidivantes du pharyngolarynx.

AIM: To determine the functional disabilities and overall quality of life of patients operated for advanced (Stages III-IV) or recurrent squamous cell carcinomas (SCCA) after radiation therapy of the (pharyngo)larynx. METHODS: From 1984 to 1997, 135 patients were consecutively treated for SCCA of the (pharyngo)larynx. There were 118 men and 17 women with a mean age of 60 years. The University of Washington QOL questionnaire (UW-QOL) (Deleyiannis et al) was administered to 19 long term survivors. Self-administered scale consisting of nine domains affected by treatment for head and neck cancer: pain, physical appareance, global activity, entertainement, employment, chewing, swallowing, speech and shoulder function. For each patient, a total score and weighted score were determined. Descriptive statistics were used. RESULTS: 9/19 patients reported that compared with one year prior to the diagnosis of cancer their general health was the same. Pain resolved in 78%; the physical appearance was juged not modified in 52% of the cases. Chewing and swallowing functions were respected in 94% of the cases. These functions were considered as very important in 53% and 68% respectively. Five patients are still at work; 11 patients retired. Work was considered as very important for 9/19 patients. Speech rehabilitation permitted a modified but well understandable communication in 63% of the cases. This function was considered by 88% of the patients as very important. Finally, 73% of the patients (14/19) reported having a good to excellent overall QOL. CONCLUSION: Though disabling, pharyngolaryngectomies do not necessarily translate into worse overall QOL; ultimate disabilities are widely variable. Many factors such family, friends, personal leisure, activities, employement, cultural habits were important and depending on each patient in enjoyement of life's estimation.

Combined ipsilateral treatment of cervical lymph nodes metastases from an unknown primary.

INTRODUCTION: The management of squamous cell carcinoma in undetermined primary tumours in the head and neck region (approximately 5.5% of patients) is controversial. MATERIAL AND METHODS: The present report examines the outcomes for 14 patients after an initial treatment strategy directed principally at the side of the neck that is clinically involved. The distribution of nodal status was as follows: 1 N1, 8 N2A, 4 N2B, and 1 N3. RESULTS: Initial treatment included a modified neck dissection in 12 cases and radical neck dissection in 2 cases, plus postoperative radiation in 10 cases. Radiotherapy was directed at the ipsilateral side of the neck alone. Concomitant radiochemotherapy was given in 2 cases. The rate of disease control on the ipsilateral side was 12/14. Two patients were treated by chemotherapy but died of their disease. The failure rate on the contralateral side was 2/14. These two patients were successfully salvaged. During follow-up, a primary tumour was detected in one case. At the end of the follow-up, 10 patients were alive. CONCLUSIONS: Modified radical neck dissection combined with postoperative radiation with or without chemotherapy could be considered in N1-N3 lymph node status. Despite generally advanced disease at presentation, patients presenting with cervical metastasis from an unknown primary carcinoma have a reasonable survival expectation and aggressive treatment is warranted. Careful follow-up is required for effective salvage treatment.

[Primary lymphoma of the thyroid gland]. / Lymphome primitif de la thyroïde: à propos de 5 cas.

Malignant primary lymphoma of the thyroid gland is a rare disease. The principal clinical sign is a rapidly growing goiter, leading to signs of compression, raising the question of differential diagnosis with anaplastic cancer. Multimodality therapy with surgery, radiotherapy, and chemotherapy appears to be of value. We retrospectively reviewed the management and outcomes of five consecutives patients with thyroid lymphoma.

Fistula and stenosis after 135 (pharyngo)laryngectomies.

BACKGROUND: Despite progress made with reconstruction, morbidity is still elevated after (pharyngo)laryngectomy. The present study was designed to determine the incidence and predisposing factors of the complications following (pharyngo)laryngectomy. METHODS: Primary surgical treatment was delivered in 60 patients. Seventy-five patients underwent surgical salvage following radiotherapy. Different factors were evaluated as potentially predisposing to fistula formation. RESULTS: Stenosis is rare: 5.1% in the present series. A pharyngocutaneous fistula developed in 48.8% of patients. After a multivariate analysis, the site of the tumour was defined as a significant risk factor for pharyngocutaneous fistula formation. CONCLUSIONS: Despite progress made with reconstruction, morbidity is still elevated after major resection of the phary golarynx. Stenosis, a frequent complication when partial pharyngectomy is needed, is rare: 5.1% in the present series. Fistulas are relatively frequent but the majority resolved either with local irrigation or with subsequent flaps. The site of the tumour was a significant risk factor for pharyngocutaneous fistula formation, as defined by a multivariate analysis.

Sentinel lymph node evaluation in squamous cell carcinoma of the head and neck cancer: preliminary results.

INTRODUCTION: Sentinel lymph node biopsy is a new technique in staging the clinically NO neck. Tumour spread to the neck is the most important prognostic factor in head and neck squamous cell carcinoma (HNSCC). MATERIAL AND METHODS: Patients with histologically confirmed HNSCC, with no clinical and no radiological (CT or MRI) evidence of cervical lymph node involvement were eligible for this prospective study. The lymph node mapping was performed by preoperative lymphoscintigraphy and intraoperative use of hand-held gamma probe. Four injections (with Tc 99m-labeled nanocolloids) were performed around the primary tumour. The SLN, as indicated by dynamic scintigraphy and the neck dissection specimen, were sent separately for histological analysis. The presence of occult metastasis in the SLN and in the neck dissection specimen were compared. RESULTS: Ten consecutive patients (8 males ; 2 females) with a mean age of 61 years (range 47 to 74 years) were prospectively entered into the study. The primary tumour was located on the oral tongue in 4 cases, in the floor of the mouth in 5 cases and in the oropharynx in 1 case. Primary tumours were staged T2 in nine cases, one tumour was staged T1 according to UICC 1997. All the tumours were clinically staged cN0 by palpation and computed tomography (or MRI). Lymphoscintigraphy was performed and revealed a SLN in all cases. The sentinel node biopsy technique permitted an upstaging of the clinically cN0 neck in 3/10 cases. The SLN technique was false negative in one patient with a skip metastasis. CONCLUSION: SLN evaluation in HNSCC is feasible and provides a highly accurate staging of NO necks in oral and oropharyngeal carcinomas.

Acrylamide, an in vivo thyroid carcinogenic agent, induces DNA damage in rat thyroid cell lines and primary cultures.

Chronic treatment of rats with acrylamide induces various tumors among which thyroid tumors are the most frequent. The aim of the present study was to develop an in vitro model of acrylamide action on thyroid cells to allow the investigation of the mechanism of this tumorigenic action. The first part of the study considered as targets, characteristics of thyroid metabolism, which could explain the thyroid specificity of acrylamide action: the cAMP mitogenic effect and the important H2O2 generation by thyroid cells. However, acrylamide did not modulate H2O2 or cAMP generation in the thyroid cell models studied. No effect on thyroid cell proliferation was observed in the rat thyroid cell line FRTL5. On the other hand, as shown by the comet assay, acrylamide induced DNA damage, as the positive control H2O2 in the PC Cl3 and FRTL5 rat thyroid cell lines, as well as in thyroid cell primary cultures. The absence of effect of acrylamide on H2AX histone phosphorylation suggests that this effect does not reflect the induction of DNA double strand breaks. DNA damage leads to the generation of mutations. It is proposed that such mutations could play a role in the carcinogenic effect of acrylamide. The mechanism of this effect can now be studied in this in vitro model.

Skin metastases from a head and neck carcinoma: a prognostic factor?

BACKGROUND: Distant metastases in head and neck cancer are often to the lung, and rarely to the skin sites. METHOD: To ascertain that a skin metastasis indicates a poor prognosis, a review was conducted of patients with head and neck cancer. RESULTS: Three out of seven patients had evidence of local recurrence at the time of development of the skin metastases, and three out of seven had evidence of distant metastases. The average survival time was 1 month after the development of skin metastases. CONCLUSION: Skin metastases may represent the first clinical evidence of impending recurrence or distant metastasis. The development of skin metastasis is associated with a poor prognosis. Current treatment options are limited in their efficacity.

Acute respiratory failure from tracheopathia osteoplastica.

Tracheopathia osteoplastica is a benign cartilaginous and osseous metaplasia of the laryngo-tracheobronchial tree diagnosed more commonly in adults over 50 years of age. We report here the case of a 54-year-old man who underwent thyroidectomy for multinodular goiter. Immediately after an uneventful surgery, he developed an acute respiratory failure with radiologic picture of Adult Respiratory Distress Syndrome. Mechanical ventilation was set up again, bronchoscopy with biopsy disclosed a massive tracheobronchial haemorrhage from a tracheopathia osteoplastica. Supportive treatment was successfully provided and the patient resumed to a normal life 14 days after the operation.

[Secondary malignant tumors of the parotid]. / Les tumeurs malignes secondaires de la parotide.

AIM OF THE STUDY: Secondary malignant tumors of the parotid gland are uncommon. They arise from primary tumors located in the head and neck or from distant primary tumors. The formers are dominated by squamous cell carcinomas and melanomas, the latters by renal and lung cancers. Distinction between malignant primary tumors and metastasis of other primary tumors to the parotid gland is very important to appreciate, because the result of this will change therapeutic procedure and the evaluation of prognosis. METHODS: A series of 23 patients with tumors metastatic to the parotid gland are reported. All clinical and pathological data were reviewed. The management of secondary tumors of the parotid gland and the results were analyzed in order to try to identify common features and implications for management. RESULTS: The most frequent histologic types were squamous cell carcinoma and melanoma. Most primary tumors occurred in the head and neck. Metastasis to the parotid gland presented with a median time of 18 months after diagnosis of the primary tumor. All the patients had a parotid mass. No patient had facial nerve weakness. Parotid metastases were treated by superficial parotidectomy with preservation of the facial nerve in all cases, associated in 14 cases with a homolateral selective neck dissection and in 6 cases with a homolateral radical neck dissection. Twenty-one patients were submitted to radiation therapy. Seven patients died after the treatment: in 3 cases, death was due to a local recurrence with cervical relapse; 4 patients presented cervical and metastatic lesions. CONCLUSION: This retrospective review confirmed that patients with involvement of cervical nodes and metastatic parotid tumors have a worse prognosis than those without involvement of cervical nodes. The addition of postoperative radiotherapy provides no additional benefit.