Currently the only effective treatment capable of modifying the natural course of respiratory allergy is specific allergen immunotherapy for a minimum of 3 consecutive years. In this patient the conventional treatment has not worked, so it is possible to escalate to specific allergen immunotherapy. It is true that it is not necessary to wait 10 years to start it since it is indicated and its use is allowed if there is clinical relevance in patients older than 5 years. Omalizumab is a biological treatment that would only be indicated in cases of severe moderate bronchial asthma secondary to respiratory allergy.

Currently the only effective treatment capable of modifying the natural course of respiratory allergy is specific allergen immunotherapy for a minimum of 3 consecutive years. In this patient the conventional treatment has not worked, so it is possible to escalate to specific allergen immunotherapy. [HIDDEN] It is true that it is not necessary to wait 10 years to start it since it is indicated and its use is allowed if there is clinical relevance in patients older than 5 years. Omalizumab is a biological treatment that would only be indicated in cases of severe moderate bronchial asthma secondary to respiratory allergy.

16-year-old woman diagnosed with allergic rhinoconjunctivitis due to sensitization to grass pollens since she was 10 years old, who does not fully control the symptomatology during the pollination season with oral antihistamines and nasal topical corticosteroids. Which etiologic therapeutic option would be indicated:

Specific immunotherapy by sublingual or subcutaneous route for a minimum period of 3 years.

Specific immunotherapy by sublingual or subcutaneous route for a maximum period of 1 year.

Omalizumab subcutaneously every 4 weeks for up to 1 year.

Omalizumab subcutaneously every 4 weeks for a minimum period of 6 months.

Comparison of the long-term efficacy of subcutaneous and sublingual immunotherapies in perennial rhinitis.

Both sublingual and subcutaneous immunotherapies have a documented clinical efficacy, but only a few comparative studies have been performed. To evaluate and compare the long-term efficacies of subcutaneous and sublingual immunotherapy. One hundred and ninety-three patients with house dust mite allergies, out of an original total of 230, were treated with subcutaneous and sublingual house dust mite-specific immunotherapies for 3 years and also observed for 3 years after discontinuation of the treatment. The patients were randomized into 2 groups: the sublingual group (97 patients) and the subcutaneous group (96 patients). The therapy's success was evaluated using the symptom score, skin prick test results, and the nasal allergen challenge score. The patients were evaluated at the beginning of the study, at the end of years 1, 2, and 3, and also at the end of the 1st and 3rd years after discontinuation of the specific immunotherapy treatment. Immunotherapy induced a significant improvement during the treatment and the follow-up period. We found a greater improvement in the subcutaneous group compared to the sublingual group when we looked at the comparative results of the total 6 years. We suggest subcutaneous immunotherapy for patients with perennial allergic rhinitis due to the better results that were obtained during our study period. Nevertheless, sublingual immunotherapy is now accepted by WHO as a valid alternative to the subcutaneous route and should be used in all patients who require immunotherapy and do not accept the subcutaneous route of allergen administration.

Compliance in subcutaneous and sublingual allergen immunotherapy: A nationwide study.

Allergic rhino-conjunctivitis is a highly prevalent condition. In moderate to severe cases, allergen immunotherapy (AIT) is a cost-effective therapeutic option. Previous data have reported a large difference in treatment compliance of subcutaneously (SCIT) and sublingually (SLIT) administered AIT. By use of the unique civil registration number assigned to all Danish citizens and the Danish National Health Service Prescription Database, compliance rates of all patients prescribed with grass pollen AIT from January 1998 until December 2016 were analysed annually during the three-year treatment period. The male/female ratio was close to 1:1 in SCIT, while SLIT was more frequently used by men. A large proportion of users was children or adolescents (32% and 45%, SCIT and SLIT, respectively). Compliance of both subcutaneous and sublingual treatment gradually fell each year; compliance in year 3 was 57% and 53% for subcutaneous and sublingual treatment, respectively. Compliance of grass pollen sublingual treatment was also analysed each year after registration on the Danish market. Compliance significantly increased following the introduction and stabilised on a relatively high level. Based on previous studies, we hypothesised that AIT compliance would be low, especially in SLIT. However, in Denmark, compliance in SCIT and SLIT was almost similar, and the majority of patients completed the three-year treatment period with a compliance in the last quintile.

Specific immunotherapy for allergic rhinitis to grass and tree pollens in daily medical practice-symptom load with sublingual immunotherapy compared to subcutaneous immunotherapy.

Abstract Background. Despite strong evidence for subcutaneous and sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis, comparative data are scarce. Objectives. We performed an individual patient data meta-analysis of four observational studies to compare the effectiveness of both application routes. Methods. After individual analysis, a subsequent analysis of the total data pool was performed. Descriptive and explorative data analysis methods were used. Results. Altogether 847 patients (382 male, 453 female) aged 3-78 years (mean age 28.3 years) were treated with specific immunotherapy: 665 (78.5%) patients sublingual and 182 (21.5%) subcutaneous. The majority of patients (61.6%) in both treatment groups started specific immunotherapy due to severe rhinitis symptoms which occurred frequently or very frequently. Most patients in both treatment groups had moderate to severe conjunctivitis symptom load which occurred frequently or very frequently. Median rhinitis and conjunctivitis symptom loads decreased during both treatments to the same extent. Similar improvements in the symptom loads were observed in patients stratified for age, disease duration, and presence or absence of mild to moderate asthma. Conclusion. The effectiveness of sublingual and subcutaneous immunotherapy with pollen extracts appeared virtually equal in daily medical routine. Due to the advantageous safety profile, the sublingual application may be favorable.

Long-term efficacy of the sublingual and subcutaneous routes in allergen immunotherapy.

Allergen immunotherapy is highly effective in selected patients with allergic rhinitis, allergic asthma, and Hymenoptera venom allergy. Unlike anti-allergic drugs, both subcutaneous and sublingual immunotherapies have been shown to modify the underlying cause of the disease, with proved long-term clinical benefits after treatment cessation. In this review, we analyzed 10 randomized, double-blind, placebo controlled clinical trials of allergen immunotherapy that included blinded follow-up for at least 1 year after treatment withdrawal. Three studies of pollen subcutaneous immunotherapy provided evidence that a sustained, tolerogenic effect of subcutaneous immunotherapy can be achieved after 3 years of treatment. Six trials of sublingual immunotherapy provided robust evidence for long-term clinical benefit and persistent immunologic changes after grass pollen, house-dust mite, or Japanese cedar immunotherapy, whereas a clinical trial of both sublingual and subcutaneous grass pollen immunotherapies showed that 2 years of immunotherapy were efficacious but insufficient to induce long-term tolerance. These studies strongly supported international guidelines that recommend at least 3 years of allergen immunotherapy of proven value to achieve disease modification and sustained clinical and immunologic tolerance.

Allergen immunotherapy

Sublingual Sublingual immunotherapy involves putting drops or a tablet of allergen extracts under the tongue, which are then absorbed through the lining of the mouth. Sublingual immunotherapy has been demonstrated to be effective against rhinoconjuctivitis and asthma symptoms. This effectiveness, however, varies depending on the type of allergen. The strongest evidence for the efficacy of sublingual immunotherapy comes from studies that used grass allergens or mite allergens to alleviate allergic rhinitis symptoms; the evidence shows modest improvement. Sublingual immunotherapy is used to treat allergic rhinitis, often from seasonal allergies, and is typically given in several doses over a 12-week period. It works best when given 12 weeks before the start of the pollen season. The first dose is given by a physician to monitor for any rare reactions or anaphylaxis. Subsequent doses can be taken at home which makes this a convenient alternative to subcutaneous immunotherapy.

[Oral immunotherapy in oculorhinitis from Gramineae].

We have evaluated the efficacy of oral immunotherapy in 34 patients affected by seasonal allergic rhinoconjunctivitis due to grass pollen. Diagnosis was performed on the basis of medical history, Skin Prick Test and Rast and the mean duration of the disease was 6 years. The treatment started in November and consisted of increasing daily doses of allergen; when the maximum dose was reached, it was continued twice a week till April. After two years of treatment we observed a statistically significant reduction in the severity of the symptoms considered and in the amount of oral antihistamines taken during the pollen season. The treatment was well tolerated and patients did not experienced any adverse effect. We therefore conclude that oral immunotherapy is a valid alternative to traditional subcutaneous immunotherapy in the treatment of seasonal allergic rhinoconjunctivitis due to grass pollen.

Duration of Allergen Immunotherapy for Long-Term Efficacy in Allergic Rhinoconjunctivitis.

Subcutaneous and sublingual immunotherapy are effective for allergic rhinitis. An important question is whether allergen immunotherapy provides a sustained clinical effect after treatment cessation. In view of potential side effects, cost and the necessary patient commitment, long-term benefit is an important consideration for the recommendation of immunotherapy over standard pharmacotherapy. In this review, we analyse the existing evidence for long-term effects of both routes of administration in the context of double-blind, placebo-controlled, randomised clinical trials that included a follow-up phase of at least 1 year after treatment cessation. Overall, evidence suggests that 3 years of either subcutaneous or sublingual immunotherapy result in clinical benefit and immunological changes consistent with allergen-specific tolerance sustained for at least 2-3 years after treatment cessation. The data presented here support recommendations in international guidelines that both routes of administration should be continued for a minimum of 3 years. Gaps in the evidence remain regarding the long-term efficacy of immunotherapy for perennial rhinitis and studies performed in children.

Effectiveness of Sublingual Immunotherapy in the Treatment of HDM-Induced Nasobronchial Allergies: A 3-Year Randomized Case-Control Study From Kashmir.

Allergen immunotherapy (AIT) is the only disease-modifying treatment for allergic disorders that induces immunological tolerance through administration of specific allergens. Studies on AIT for subcutaneous route are in abundance; however, the efficacy of AIT in tablet form through sublingual route has not been well elucidated. The present prospective, parallel-group, controlled study sought to compare the efficacy of sublingual immunotherapy (SLIT) tablets with pharmacotherapy (PT) in 332 house dust mite (HDM)-specific allergic asthma and/or rhinitis patients over a period of 3 years. Patients were followed up for a 6-month run-in period and then randomly stratified as those who would receive SLIT, SLIT in addition to PT (SLIT+PT), and PT alone. AIT was administered in the form of sublingual tablets. Symptom and medication scores were measured every 3 months. <iIn vitro</i evaluation of serum total and HDM specific immunoglobulin E (HDM sIgE) levels was carried out every 3 months, whereas <iin vivo</i skin prick test was performed annually for 3 years. Our study demonstrated sustained clinical improvement, reduction in inhaled corticosteroid (ICS) dose and duration as well as prevention from development of neosensitization to other aero allergens in HDM-allergic asthmatics and/or rhinitis patients treated with 3 years SLIT. Despite a remarkable clinical improvement with AIT, we observed that SLIT did not significantly change the skin reactivity to HDM at 3 years and there was no significant change in the ratio of serum total and HDM sIgE. Given the immune and disease modifying effects of AIT in allergic diseases, the present study supports the notion of its sublingual mode being an effective long-term immunomodulator in HDM-sensitized nasobronchial allergies.

Efficacy of Grass Pollen Allergen Sublingual Immunotherapy Tablets for Seasonal Allergic Rhinoconjunctivitis: A Systematic Review and Meta-analysis.

Randomized clinical trials (RCTs) and meta-analyses of sublingual immunotherapy (SLIT) for the treatment of seasonal allergic rhinoconjunctivitis (SARC) have shown a modest clinical benefit compared with placebo. Furthermore, indirect comparison by meta-analyses showed that subcutaneous immunotherapy is more effective than SLIT. Despite these data, SLIT has become the most prescribed treatment of SARC in Europe in recent years, and it was approved by the US Food and Drug Administration for the treatment of SARC to grass pollen in the United States on April 1, 2014. To assess the efficacy and safety of the grass pollen sublingual tablets licensed as drugs in the treatment of patients with SARC to grass pollen. Computerized bibliographic searches of MEDLINE, EMBASE, the Cochrane Library, and ClinicalTrials.gov (from inception to April 30, 2014) were supplemented with a manual search of reference lists. Randomized clinical trials were included if they compared the grass pollen SLIT tablets approved by regulatory authorities in the European Union and the United States for SARC with placebo. Data on populations, interventions, and outcomes were extracted from each RCT according to the intent-to-treat method by 2 independent observers and were combined using the method by DerSimonian and Laird. The primary end point was the difference in the symptom score and medication score between SLIT and placebo. We pooled data using random-effects meta-analysis, with standardized mean differences (SMDs) and 95% CIs reported. Data were available in 13 RCTs for the symptom score (4659 patients) and in 12 RCTs for the medication score (4558 patients). We found a small treatment benefit in the symptom score (SMD, -0.28; 95% CI, -0.37 to -0.19; P < .001) and in the medication score (SMD, -0.24; 95% CI, -0.31 to -0.17; P < .001). Adverse events were reported in 1384 of 2259 patients (61.3%) receiving SLIT and in 477 of 2279 patients (20.9%) receiving placebo. Seven patients in the SLIT group reported treatment-related adverse events requiring epinephrine. Findings show a small benefit of the grass pollen sublingual tablets in reducing symptoms and in decreasing the use of symptomatic medication (antihistamines and corticosteroids) in patients with SARC. Considering the low magnitude of the benefit, the convenience and easy administration do not seem to be sufficient reasons for the choice of SLIT.

Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis.

Allergen immunotherapy (desensitization) by injection is effective for seasonal allergic rhinitis and has been shown to induce long-term disease remission. The sublingual route also has potential, although definitive evidence from large randomized controlled trials has been lacking. The aim was to confirm the efficacy of a rapidly dissolving grass allergen tablet (GRAZAX, ALK-Abelló, Hørsholm, Denmark) compared with placebo in patients with seasonal rhinoconjunctivitis. A longitudinal, double-blind, placebo-controlled, parallel-group study that included 51 centers from 8 countries. Subjects were randomized (1:1) to receive a grass allergen tablet or placebo once daily. A total of 634 subjects with a history of grass pollen-induced rhinoconjunctivitis for at least 2 years and confirmation of IgE sensitivity (positive skin prick test and serum-specific IgE) were included in the study. Subjects commenced treatment at least 16 weeks before the grass pollen season, and treatment was continued throughout the entire season. The primary efficacy analysis showed a reduction of 30% in rhinoconjunctivitis symptom score (P < .0001) and a reduction of 38% in rhinoconjunctivitis medication score (P < .0001) compared with placebo. Side effects mainly comprised mild itching and swelling in the mouth that was in general well tolerated and led to treatment withdrawal in less than 4% of participants. There were no serious local side effects and no severe systemic adverse events. Sublingual immunotherapy with grass allergen tablets was effective in grass pollen-induced rhinoconjunctivitis. The tablet was well tolerated with minor local side effects. The grass allergen tablet represents a safe alternative to injection immunotherapy suitable for home use.

Double-blind, placebo-controlled study with sublingual immunotherapy in children with seasonal allergic rhinitis to grass pollen.

Sublingual immunotherapy (SLIT) has been recognized as a viable alternative to subcutaneous immunotherapy for respiratory allergies both in adults and children, but clinical documentation about safety and efficacy in children is still poor. The purpose of this study was to assess the efficacy and tolerance of SLIT in children who are sensitized to grass pollen. Children with a clinical history of intermittent rhinoconjunctivitis, with or without mild asthma and positive skin prick tests to grass pollen, were selected to participate in a 2-year double-blind, placebo-controlled study with SLIT, using a grass extract (ALK-Abellò). 22 children were analyzed at the end of the study. No relevant side effects occurred in the active group. A statistically significant difference (p = 0.05; Mann-Whitney test) in favor of the active group (n = 10) could be shown for drug consumption during the second year, as well as a significant improvement as compared to the first year of SLIT (p = 0.05; Wilcoxon test). Despite the small number of patients, our data suggest that SLIT with a grass pollen extract is well tolerated in children and is able to significantly reduce drug consumption during the second year of treatment. Studies in larger groups of children sensitized to both grass and tree pollens are needed to definitively assess the role of SLIT in intermittent, seasonal rhinitis and pollen asthma.

Allergic rhinitis

Allergen immunotherapy Allergen immunotherapy (AIT, also termed desensitization) treatment involves administering doses of allergens to accustom the body to substances that are generally harmless (pollen, house dust mites), thereby inducing specific long-term tolerance. Allergen immunotherapy is the only treatment that alters the disease mechanism. Immunotherapy can be administered orally (as sublingual tablets or sublingual drops), or by injections under the skin (subcutaneous). Subcutaneous immunotherapy is the most common form and has the largest body of evidence supporting its effectiveness.

[Comparison of injection-related and local immunotherapy].

Allergen-specific immunotherapy is a well-accepted method in the management of respiratory allergic diseases, applied since over 90 years. Traditional immunotherapy is the practice of subcutaneous administering to subjects with allergy, increasing amounts of modified allergen to achieve hyposensitisation. Recently other routes of allergen administration were proposed including bronchial, nasal, oral and sublingual routes. Controlled trials failed to demonstrate the clinical efficacy and the safety of oral and bronchial administration. Nasal immunotherapy is also declining due to limited efficacy and special administration technique. The sublingual route is safe and efficacious. Unfortunately, up to date no well-designed controlled study comparing subcutaneous with sublingual methods of immunotherapy is available. Still several points need to be elucidated, including long lasting efficacy, mechanism of action, optimal dose, adherence to this therapy and cost-effectiveness. However, sublingual immunotherapy is now accepted by WHO as a valid alternative to the subcutaneous route and should be used in all patients who require immunotherapy and do not accept subcutaneous route of allergen administration. One question is presently beyond discussion: it is better to administer sublingual immunotherapy in patients with allergic diseases than not to give immunotherapy at all.

Omalizumab

Chronic spontaneous urticaria Omalizumab is indicated for chronic spontaneous urticaria in adults and adolescents (>12 years old) poorly responsive to H1-antihistamine therapy. When administered subcutaneously once every four weeks, omalizumab has been shown to significantly decrease itch severity and hive count. Adverse effects The main adverse effect is anaphylaxis (a life-threatening systemic allergic reaction), with a rate of occurrence of 1 to 2 patients per 1,000.

Efficacy of subcutaneous and sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: a meta-analysis-based comparison.

Subcutaneous (SCIT) and sublingual (SLIT) immunotherapy are the 2 most prescribed routes for administering allergen-specific immunotherapy. They were shown to be effective in control of symptoms and in reducing rescue medication use in patients with allergic diseases, but their effectiveness has to be balanced against side effects. In recent years, SLIT has been increasingly prescribed, instead of SCIT, because of improved safety and easy administration. We assessed which route is the most effective in the treatment of patients with seasonal allergic rhinitis to grass pollen. An indirect meta-analysis-based comparison between SCIT and SLIT was performed. Treatment efficacy was determined as the standardized mean difference (SMD) in symptom and medication scores obtained with active treatment, SCIT or SLIT, compared with placebo. Studies were included if they were double-blind randomized controlled trials comparing SCIT or SLIT with placebo. Thirty-six randomized controlled trials (3014 patients; 2768 controls) were analyzed. The overall effect size of SCIT for symptom score (SMD, -0.92; 95%CI, -1.26 to -0.58) was significantly higher than SLIT, both administered via drops (SMD, -0.25; 95% CI, -0.45 to -0.05) and tablets (SMD, -0.40; 95%CI, -0.54 to -0.27). Similar results were reported for medication score (SCIT: SMD, -0.58; 95% CI, -0.86 to -0.30. SLIT drops: SMD, -0.37; 95% CI, -0.74 to -0.00. SLIT tablets SMD, -0.30; 95% CI, -0.44 to -0.16). Our results provide indirect but solid evidence that SCIT is more effective than SLIT in controlling symptoms and in reducing the use of antiallergic medications in seasonal allergic rhinoconjuntivitis to grass pollen.

Allergen immunotherapy

Side effects during sublingual immunotherapy treatment are usually local and mild and can often be eliminated by adjusting the dosage. Anaphylaxis during sublingual immunotherapy treatment has occurred on rare occasions. Potential side effects related to subcutaneous immunotherapy treatment for asthma and allergic rhinoconjunctivitis include mild or moderate skin or respiratory reactions. Severe side effects such as anaphylaxis during subcutaneous immunotherapy treatment are relatively uncommon. Discovered by Leonard Noon and John Freeman in 1911, allergen immunotherapy is the only medicine known to tackle not only the symptoms but also the causes of respiratory allergies. A detailed diagnosis is necessary to identify the allergens involved. Types

Pollen

Treatment Antihistamines are effective at treating mild cases of pollinosis; this type of non-prescribed drugs includes loratadine, cetirizine and chlorpheniramine. They do not prevent the discharge of histamine, but it has been proven that they do prevent a part of the chain reaction activated by this biogenic amine, which considerably lowers hay fever symptoms. Decongestants can be administered in different ways such as tablets and nasal sprays. Allergy immunotherapy (AIT) treatment involves administering doses of allergens to accustom the body to pollen, thereby inducing specific long-term tolerance. Allergy immunotherapy can be administered orally (as sublingual tablets or sublingual drops), or by injections under the skin (subcutaneous). Discovered by Leonard Noon and John Freeman in 1911, allergy immunotherapy represents the only causative treatment for respiratory allergies.

Allergen immunotherapy

Types Subcutaneous Subcutaneous immunotherapy (SCIT), also known as allergy shots, is the historical route of administration and consists of injections of allergen extract, which must be performed by a medical professional. Subcutaneous immunotherapy protocols generally involve weekly injections during a build-up phase, followed by monthly a maintenance phase that consists of injections for a period of 3–5 years. The build-up phase involves the patient being administered injections which contain increasing amounts of allergens about one to two times per week. The length of the build-up phase is dependent upon how often injections are administered, but normally ranges from three to six months. After the effective dose is reached, the maintenance phase is implemented, which varies depending upon an individual’s response to the build-up phase.

Both sublingual and supralingual routes of administration are effective in long-term allergen-specific immunotherapy.

The aim of this study was to confirm or refute the difference between efficacy of long-term specific immunotherapy (SIT) with standardized allergen vaccine consisting of six grass pollens (oat grass, orchard grass, fescue, rye grass, timothy grass, and rye) administered either by sublingual or by supralingual route. To investigate clinical and immunologic changes, 51 patients of a previous 1-year double-blind, placebo-controlled, randomized study were enrolled in an open randomized study that continued over the next 3 years. Sublingual or supralingual immunotherapy (SLIT) was performed in the same way, keeping the drops under or on the tongue, respectively, for 1-2 minutes before swallowing them. Data about symptoms scores and rescue medication intake during grass pollen seasons, as well as skin-prick test results, levels of specific IgG, and IgE antibodies were collected after each pollen season. It was clearly shown that both routes of administration were effective, leading to a significant decrease of clinical symptoms of grass pollen allergy after SIT lasting 3-4 years. No statistically significant difference between sublingually and supralingually treated patients was observed at the end of the study. Adverse effects were limited to a small number of generally mild local and/or systemic reactions with no significant difference between both administration ways of SIT. The significant therapeutic effect of both SLIT and supralingual immunotherapy lasting 3-4 years was clearly achieved. Despite no significant difference between efficacy of both administration ways of SIT, the onset of sublingual SIT effect seems to be slightly faster than that of supralingual SIT.

The placebo effect in allergen-specific immunotherapy trials.

Double-blind, placebo-controlled (DBPC) trials are the gold standard for demonstrating clinical efficacy and tolerability. The placebo effect, although an important feature in placebo-controlled studies, has never been systematically investigated in allergen-specific immunotherapy (SIT) studies. This study was performed to examine the placebo response in SIT trials that employed a baseline observational period and two treatment years using a symptom-medication-score (SMS) as the primary endpoint. The placebo effect was evaluated in six DBPC SIT studies (five studies using subcutaneous SIT (SCIT) and one sublingual (SLIT)), two grass, two birch and two house dust mite (HDM) SIT, including a total of 472 adult patients treated with a placebo. The results were reported as changes from baseline of the SMS area under the curve after two years of perennial placebo therapy during the respective evaluation periods. Pollen counts and IgG4 levels were additionally analysed. Subcutaneously treated placebo patients displayed a marked decrease in the SMS. The mean placebo effect in the SCIT trials with comparable allergen exposure was up to 41% in the second treatment year and, in contrast, reached only 1% in the SLIT trial. Allergen exposure had an inverse influence on the placebo effect. No changes from baseline in allergen specific IgG4 antibodies were observed in the placebo-treated patients. SIT studies display a significant placebo effect, mainly observed in subcutaneous immunotherapy, with high variability depending on the route of application and allergen exposure. Our findings indicate the differential role of the placebo effect in SIT efficacy depending on the route of administration and pollen exposure.

Efficacy and safety of birch pollen allergoid subcutaneous immunotherapy: A 2-year double-blind, placebo-controlled, randomized trial plus 1-year open-label extension.

Previous clinical trials with birch pollen subcutaneous immunotherapy have been conducted over a 1- to 2-year treatment period and involved mostly a single geographic location. This study (EudraCT-Number: 2005-000025-35) intended to evaluate the effect of subcutaneous immunotherapy with high-dose hypoallergenic birch pollen allergoid in patients with confirmed moderate to severe seasonal allergic rhinitis/rhinoconjunctivitis over a 3-year course in 19 European centres. Adults with confirmed birch pollen allergy (n = 253) were randomized to preseasonal placebo (n = 129) or active treatment (n = 124). Primary endpoint was change in Symptom Medication Score after 2 years treatment (2007). The change in Symptom Medication Score of active- vs placebo-treated patients for the Full Analysis Set (n = 227, 15.2% reduction, P = 0.0710) and Per-Protocol Set (n = 216, 16.7% reduction, P = 0.0523) showed a positive trend, although significance was not achieved. The primary endpoint, assessed in 2007, coincided with the lowest pollination during the study period. In a subgroup analysis of patients in the north-eastern region (n = 102), where birch is the major tree and consequently patients' exposure is higher, changes in Symptom Medication Score (32.7% reduction, P = 0.0034) and median number of well days (P = 0.0232) were highly significant in favour of the active group. During the open-label third year of treatment, the mean Symptom Medication Score of active-treated patients was further reduced despite an increased pollen count. Subcutaneous immunotherapy was well tolerated and consistent with the known safety profile. Although the primary endpoint was not reached for the Full Analysis Set, a significant and clinically relevant effect on Symptom Medication Score was clearly demonstrated for the subgroup of patients in the north-eastern region of Europe, where birch is the predominant tree species. Proving efficacy of birch allergen subcutaneous immunotherapy is challenging due to the numerous factors influencing birch pollen allergen exposure in field studies.

Double-blind, placebo-controlled evaluation of grass pollen specific immunotherapy with oral drops administered sublingually or supralingually.

Forty-one patients suffering from grass pollen allergy underwent specific immunotherapy with standardized allergen extract consisting of six grass pollens (H-Al per os) administered either sublingually or supralingually for one year. In order to investigate clinical and immunological changes induced by the administration of allergens via the oral mucosa, the double-blind, placebo-controlled, randomized design of the trial with 30 other patients enrolled in placebo groups was applied. Specific immunotherapy with oral drops administered sublingually or supralingually was performed in the same way, keeping the drops under or on the tongue, respectively, for 1-2 min before swallowing them; at the end of the trial the cumulative dose of the allergen was almost 20 times higher than that of the subcutaneous therapy with corresponding allergen preparation. Data about symptoms scores and drugs intake during grass pollen season, as well as skin reactivity, levels of specific IgG and IgE antibodies, before the study and after the study's completion, were obtained. It was found that both routes of administration are effective according to subjective clinical parameters and drug consumption, with a highly significant reduction of symptoms and drug intake favoring sublingual administration where a reduction of more than 60% was achieved. Only sublingual active group showed a significant increase in Dactylis glomerata-specific IgG serum levels. Adverse effects were limited to a small number of generally mild local and/or systemic reactions. The results suggest that the administration of allergens via the oral mucosa is safe and clinically effective, favoring the sublingual rather than supralingual route.

Allergic conjunctivitis

Many of the eye drops can cause burning and stinging, and have side-effects. Proper eye hygiene can improve symptoms, especially with contact lenses. Avoiding precipitants, such as pollen or mold can be preventative. Immunotherapy Allergen immunotherapy (AIT) treatment involves administering doses of allergens to accustom the body to substances that are generally harmless (pollen, house dust mites), thereby inducing specific long-term tolerance. Allergy immunotherapy can be administered orally (as sublingual tablets or sublingual drops), or by injections under the skin (subcutaneous). Discovered by Leonard Noon and John Freeman in 1911, allergy immunotherapy represents the only causative treatment for respiratory allergies.

Allergen immunotherapy

When accounting for a person’s age, type of allergen, and severity of allergy, there is a high probability that subcutaneous allergen immunotherapy may provide greater clinical and immunological responses than sublingual allergen immunotherapy. Compared to sublingual allergen immunotherapy, there are no significant differences observed in quality of life. It is possible, but rare (1/2.5 million), that people undergoing subcutaneous allergen immunotherapy may experience a fatal anaphylactic event. Subcutaneous allergen immunotherapy adverse events vary significantly depending on different allergenic extracts and the application of different allergen immunotherapy schedules.

Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis.

We wondered whether short-term coseasonal sublingual immunotherapy (SLIT) can reduce the development of asthma in children with hay fever in an open randomized study. We sought to determine whether SLIT is as effective as subcutaneous immunotherapy in reducing hay fever symptoms and the development of asthma in children with hay fever. One hundred thirteen children aged 5 to 14 years (mean age, 7.7 years) with hay fever limited to grass pollen and no other clinically important allergies were randomized in an open study involving 6 Italian pediatric allergy centers to receive specific SLIT for 3 years or standard symptomatic therapy. All of the subjects had hay fever symptoms, but at the time of study entry, none reported seasonal asthma with more than 3 episodes per season. Symptomatic treatment was limited to cetirizine, loratadine, nasal budesonide, and salbutamol on demand. The hay fever and asthma symptoms were quantified clinically. The actively treated children used less medication in the second and third years of therapy, and their symptom scores tended to be lower. From the second year of immunotherapy, subjective evaluation of overall allergy symptoms was favorable in the actively treated children. Development of asthma after 3 years was 3.8 times more frequent (95% confidence limits, 1.5-10.0) in the control subjects. Three years of coseasonal SLIT improves seasonal allergic rhinitis symptoms and reduces the development of seasonal asthma in children with hay fever.

Allergen

An example of nasal decongestants is pseudoephedrine and its side-effects include insomnia, restlessness, and difficulty urinating. Some other nasal sprays are available by prescription, including Azelastine and Ipratropium. Some of their side-effects include drowsiness. For eye symptoms, it is important to first bath the eyes with plain eyewashes to reduce the irritation. People should not wear contact lenses during episodes of conjunctivitis. Allergen immunotherapy treatment involves administering doses of allergens to accustom the body to induce specific long-term tolerance. Allergy immunotherapy can be administered orally (as sublingual tablets or sublingual drops), or by injections under the skin (subcutaneous). Immunotherapy contains a small amount of the substance that triggers the allergic reactions. See also References

Basophil sensitivity reflects long-term clinical outcome of subcutaneous immunotherapy in grass pollen-allergic patients.

Allergic rhinoconjunctivitis is a public health problem. Allergen Immunotherapy is an effective and safe treatment, that modifies the natural course of allergic disease and induces long-term tolerance. To correlate basophil and antibody biomarkers of subcutaneous immunotherapy to clinical outcomes and cellular changes in target tissue. Adults suffering from allergic rhinoconjunctivitis due to grass pollen allergy were randomized to receive subcutaneous immunotherapy (n = 18) or to an open control group (n = 6). Patients reported daily symptom and medication scores and weekly rhinitis related quality of life scores during four pollen seasons. Biomarkers were measured every 3 months for three years treatment and every 6 months in the follow-up year. Nasal and cutaneous allergen challenge tests were performed annually. Leukocyte subsets were assessed in nasal mucosa biopsies at baseline and after treatment. Subcutaneous immunotherapy led to a 447-fold decrease in basophil sensitivity during the first treatment year. This remained 100-fold lower than baseline during the 3 year-treatment period and 10-fold lower during the follow-up year (n = 18, P = .03). Decrease in basophil sensitivity after three weeks of treatment predicted long-term improvement in seasonal combined symptom and medication scores (ῥ=-0.69, P = .0027) during three years of treatment. AUC of IgE-blocking factor correlated to nasal allergen challenge (ῥ = 0.63, P = .0012) and SPT (ῥ = 0.45, P = .03). Plasma cell numbers in the nasal mucosa increased during treatment (P = .02). Decrease in basophil sensitivity after three weeks of subcutaneous allergen immunotherapy predicted the clinical outcome of this treatment.

Advances in upper airway diseases and allergen immunotherapy.

The purpose of this review is to highlight important articles on upper airway diseases and immunotherapy that appeared during 2006. Studies from Europe continue to examine the usefulness of the Allergic Rhinitis and its Impact on Asthma classification of allergic rhinitis as intermittent or persistent and its levels of severity as mild or moderate/severe. A number of physical agents were shown to effect nasal inflammation: sudden temperature changes in patients with allergic rhinitis increased eosinophilic inflammation; in children with allergic asthma, the personal exposure to particles <2.5 microm air pollution correlated with percent of nasal eosinophils and levels of markers of nasal exudation; and in patients who developed rhinorrhea on exposure to cold and windy weather, nasal challenge with cold dry air caused sloughing of nasal epithelial cells. A 3-month double-blind, placebo-controlled study of nasal washes with amphoteracin B showed no benefit in patients with chronic rhinosinusitis. Studies of immunotherapy with grass and dog dander extracts confirmed the need for doses containing 15 to 20 microg of the major allergen for optimal effectiveness. The protective effect of immunotherapy on the development of asthma in children with allergic rhinitis was shown to still be present 2 years after completion of a 3-year course of treatment. Injection immunotherapy with a moderate dose of house dust mite extract in house dust-sensitive adults with atopic dermatitis reduced symptoms and use of corticosteroids and antihistamines compared with treatment with about 1/1000 of that dose of the same extract. Pretreatment for 9 weeks with the monoclonal anti-IgE antibody omalizumab reduced systemic reactions during rush immunotherapy 5-fold and allowed further build-up at weekly intervals without systemic reactions. A review of sublingual immunotherapy confirmed both efficacy and safety, but evidence for appropriate dosing and for the effectiveness of sublingual immunotherapy employing multiple allergen mixes was still lacking. Two studies with a sublingual grass pollen extract tablet showed a clear dose response and the ability to initiate sublingual immunotherapy without an up-dosing phase. A pilot study with cytosine phosphorothionate quanosine DNA conjugated to the major allergen of ragweed reported impressive improvement in symptoms the first pollen season that persisted during the second pollen season without any further administration of the conjugate. In conclusion, studies on rhinitis and sinusitis explored the pathophysiology of the disease more than offering new therapeutic approaches. Studies on immunotherapy addressed optimal dosing, but also a variety of safer and more convenient approaches such as reduction of IgE with omalizumab, conjugating allergen to immunostimulatory DNA sequences, or administration by the sublingual route.

[Efficacy and safety of sublingual immunotherapy--a detailed analysis].

Sublingual immunotherapy (SLIT) was developed to avoid the risk of severe systemic side effects which occur in subcutaneous immunotherapy. Data from more than 20 controlled studies clearly show the efficacy and safety of this type of immunotherapy in patients with allergic rhino-conjunctivitis due to pollen and mites. The data for allergic asthma still need confirmation. Sublingual immunotherapy is no substitute for subcutaneous immunotherapy but an additional option for defined groups of patients. The application of a sufficient amount of allergen is important for the efficacy of SLIT. According to the recommendation of the ARIA working group, a 50- to 100-fold cumulative dose should be applied as compared to subcutaneous immunotherapy. SLIT can be used preseasonally, during the saison or perennially. Therapy starts with a daily increase of the dose. In some cases, e. g., in adult patients with pollen allergy, doses can be increased within hours. The well-tolerated maintenance dose should be taken three times a week or daily. The sublingual seasonal short-time immunotherapy may become an additional option for subgroups of patients, e. g., for adolescents.

Effect of 2 Years of Treatment With Sublingual Grass Pollen Immunotherapy on Nasal Response to Allergen Challenge at 3 Years Among Patients With Moderate to Severe Seasonal Allergic Rhinitis: The GRASS Randomized Clinical Trial.

Sublingual immunotherapy and subcutaneous immunotherapy are effective in seasonal allergic rhinitis. Three years of continuous treatment with subcutaneous immunotherapy and sublingual immunotherapy has been shown to improve symptoms for at least 2 years following discontinuation of treatment. To assess whether 2 years of treatment with grass pollen sublingual immunotherapy, compared with placebo, provides improved nasal response to allergen challenge at 3-year follow-up. A randomized double-blind, placebo-controlled, 3-parallel-group study performed in a single academic center, Imperial College London, of adult patients with moderate to severe seasonal allergic rhinitis (interfering with usual daily activities or sleep). First enrollment was March 2011, last follow-up was February 2015. Thirty-six participants received 2 years of sublingual immunotherapy (daily tablets containing 15 µg of major allergen Phleum p 5 and monthly placebo injections), 36 received subcutaneous immunotherapy (monthly injections containing 20 µg of Phleum p 5 and daily placebo tablets) and 34 received matched double-placebo. Nasal allergen challenge was performed before treatment, at 1 and 2 years of treatment, and at 3 years (1 year after treatment discontinuation). Total nasal symptom scores (TNSS; range; 0 [best] to 12 [worst]) were recorded between 0 and 10 hours after challenge. The minimum clinically important difference for change in TNSS within an individual is 1.08. The primary outcome was TNSS comparing sublingual immunotherapy vs placebo at year 3. Subcutaneous immunotherapy was included as a positive control. The study was not powered to compare sublingual immunotherapy with subcutaneous immunotherapy. Among 106 randomized participants (mean age, 33.5 years; 34 women [32.1%]), 92 completed the study at 3 years. In the intent-to-treat population, mean TNSS score for the sublingual immunotherapy group was 6.36 (95% CI, 5.76 to 6.96) at pretreatment and 4.73 (95% CI, 3.97 to 5.48) at 3 years, and for the placebo group, the score was 6.06 (95% CI, 5.23 to 6.88) at pretreatment and 4.81 (95% CI, 3.97 to 5.65) at 3 years. The between-group difference (adjusted for baseline) was -0.18 (95% CI, -1.25 to 0.90; [P = .75]). Among patients with moderate to severe seasonal allergic rhinitis, 2 years of sublingual grass pollen immunotherapy was not significantly different from placebo in improving the nasal response to allergen challenge at 3-year follow-up. clinicaltrials.gov Identifier: NCT01335139; EudraCT Number: 2010-023536-16.

30 years of sublingual immunotherapy.

Allergen Immunotherapy (AIT) was introduced in clinical practice on an empirical basis more than 100 years ago. Since the first attempts, AIT was administered subcutaneously. Indeed, other routes of administration were proposed and studied, in particular to improve the safety, but only the sublingual route (SLIT) achieved a credibility based on evidence and was then accepted as a viable "alternative" option to the subcutaneous route. SLIT was largely used in clinical trials and clinical practice in this last 30 years. Thus, a large amount of data is available, coming from either controlled trials and postmarketing surveillance studies. It is clear that SLIT is overall effective, but it is also clear that the efficacy is not "class-related," as derived from meta-analyses, but restricted to each specific product. The 30-year lasting use of SLIT allowed to clarify many clinical aspects, such as efficacy, safety, use in asthma, regimens of administration, and optimal doses. In parallel, the mechanisms of action of AIT were elucidated, and new indications were proposed (eg food allergy, atopic dermatitis). In addition, the introduction of molecular-based diagnosis, allowed to better refine the prescription of SLIT, based on specific sensitization profiles. The present article will describe the origin and evolution of SLIT for respiratory allergy, taking into account the clinical context that suggested this form of treatment, the recently developed aspects, the future perspectives and unmet needs, This is not, therefore, a systematic review, rather a narrative historical description of the past history, and a look forward to the future opportunities.

Allergy Immunotherapy -- Clinical Significance -- Asthma

Allergen immunotherapy can reduce short-term symptoms in allergic asthma; however, there is a moderate increase in the risk of systemic and local reactions based on a meta-analysis. [6] A 3-year course of either sublingual or subcutaneous immunotherapy prevents asthma for up to 2 years in children and adolescents with grass/birch pollen that triggers moderate to severe allergic rhinitis. However, this still requires further research. [4]


Typical medullary thyroid RET (C cells, elevated calcitonin, inherited MEN-2nd, typical MIR question).

A 32-year-old woman with multiple endocrine neoplasia syndrome type 2A (MEN-2A) and carrier of a mutation in RET. In a neck ultrasound a 6 mm hypoechogenic nodule with calcifications inside is identified. It was decided to perform a total thyroidectomy and cervical lymph node removal. In the macroscopic study a total of three nodules were identified, two in the right lobe of 5 and 6 mm, and one in the left lobe of 4 mm. In the microscopic study the three lesions are constituted by a uniform proliferation of rounded cells arranged in a solid pattern and accompanied by calcifications and amyloid deposits. The nuclei are not clear, nor do they show clefts or pseudoinclusions. Immunohistochemical staining for synaptophysin is positive. In the cervical lymph node clearance metastases are identified. What is the pathologic diagnosis of the lesions identified in the total thyroidectomy?

Histopathologic and clinical features of medullary microcarcinoma and C-cell hyperplasia in prophylactic thyroidectomies for medullary carcinoma: a study of 42 cases.

Prophylactic thyroidectomies are increasingly performed on patients at risk for developing medullary thyroid carcinoma (MTC); consequently, pathologists are more commonly encountering these specimens in routine practice. To describe the detailed clinicopathologic features of prophylactic thyroidectomies for medullary carcinoma. We present a retrospective series of 42 prophylactic thyroidectomies for MTC performed for one or more of the following: family history of multiple endocrine neoplasia (MEN) or MTC, elevated serum calcitonin level, or detection of a RET proto-oncogene mutation. Patients included 22 men and 20 women (mean age, 26.2 years). Among those with known RET proto-oncogene mutations, affected sites included exons 10, 11, 14, and 16. In 93% (n = 39) of cases, either C-cell hyperplasia (n = 36), medullary microcarcinoma (MMC; n = 29), or medullary macrocarcinoma (n = 1) was found. C-cell hyperplasia was often multifocal (n = 30) and bilateral (n = 23) and included both nonnodular and nodular patterns. A total of 94% of C-cell hyperplasia cases and all MMC cases were microscopically detectable using hematoxylin-eosin stains. The MMCs were characterized by a complex microarchitectural pattern with a desmoplastic stromal response (n = 29) and focal amyloid deposition (n = 12). Most MMCs exhibited a solid pattern (n = 24) of round, polygonal, spindled, or plasmacytoid-shaped cells. Only 1 case of MMC showed evidence of metastatic disease to a pretracheal lymph node. Based upon our clinicopathologic findings and review of the literature, we conclude that thyroidectomies in at-risk patients are very frequently associated with C-cell hyperplasia and/or MMC; however, the clinical prognosis for these patients is very good.

Ultrasonographic findings of thyroglossal duct papillary carcinoma: A case report.

Reports on thyroglossal duct cyst carcinoma (TGDCCa) are rare, occurring in approximately 1% of thyroglossal duct cyst (TGDC) cases. The origin and treatment of carcinoma arising in TGDC are controversy. A 38-year-old woman presented with a midline neck mass at the thyrohyoid level for 3 years. Ultrasound revealed a 2.4cm cystic mass with a solid mural component and microcalcification. A small right thyroid nodule was also detected. Sistrunk's operation was performed and the pathology was a primary carcinoma arising in the TGDC with a close surgical margin. Total thyroidectomy was done and revealed a 4mm papillary carcinoma with partial invasion through the thyroid capsule of the right lobe with a 1mm papillary carcinoma at the isthmus. The diagnosis was a primary TGDCCa with multifocal papillary thyroid carcinoma. Sistrunk's operation is an accepted procedure for the treatment of both TGDC and TGDCCa. Additional total thyroidectomy has been proposed but still controversial. The aims of preoperative ultrasound and ultrasound-guided fine needle aspiration biopsy (FNAB) are differential diagnosis of the possible diseases and operative planning. The results which suggest a carcinoma arising in the TGDC, synchronous thyroid malignancy and metastatic cervical lymph nodes are helpful in determining the magnitude of the operation. Ultrasound and FNAB of the TGDC, thyroid gland and cervical lymph nodes are the useful preoperative evaluations leading to the accurate diagnosis. The definitive treatment is Sistrunk's operation with the possible addition of total thyroidectomy and neck dissection when indicated.

Papillary thyroid cancer

Papillary thyroid carcinomas are also discovered when a hard nodule is found in multinodular goiter, when enlarged cervical lymph nodes are detected, or when there are unidentified metastatic lesions elsewhere in the body. Expanding lesions found in the thyroid gland, especially if they are painful, should be examined as they may indicate the presence of papillary thyroid carcinoma. Other clinical signs that could indicate papillary thyroid are fixation to the trachea, a firm neck mass, damage to recurrent laryngeal or cervical sympathetic nerves. Five percent of the population can have thyroid nodules, and the majority will be benign. Appropriate workup includes an ultrasound of the neck, followed by lab studies. Patients will usually meet with both an endocrinologist and a surgeon (head and neck surgeon or endocrine surgeon).

Fibro-hyaline involution of a papillary thyroid carcinoma metastasis in a lymph node, consecutive to radioiodine therapy, mimicking a parathyroid adenoma. A case presentation.

The aim of the study is to present the unusual changes that a lymph node metastasis of papillary thyroid carcinoma (PTC) underwent after radioiodine therapy, leading to the confusion with a parathyroid adenoma (PA). Eight years after a total thyroidectomy and radioiodine ablation with 73.35 mCurie 131I for PTC, a 67-year-old female presented with an enlarged, painless, nodular mass in the left lateral neck region. Clinical examination revealed a firm nodule located on the site of the left inferior parathyroid gland. Elevated serum parathyroid hormone level (120 pg/mL) and parathyroid scintigraphy led to a suspicion of PA. A minimally invasive surgical procedure was performed to remove the mass, which was sent to the Department of Pathology, Emergency County Hospital, Tirgu Mures, Romania, as left PA. It was fixed and processed for microscopic evaluation. On macroscopic examination, the surgical specimen was oval; it had 13 mm at the largest diameter and weighted 2 g. On microscopy, the lesion appeared as a fibro-hyaline, intensely acidophilic, acellular mass, with calcifications. It was limited by a delicate capsule in which one typical psammoma body was present. At the periphery, on one single level, a small mass of cells of indefinite origin was noticed. Immunohistochemistry (IHC) was done to ascertain the origin of these cells: they were negative for Pan-Cytokeratin AE1/AE2, Parathormone and Thyroglobulin antibodies, but positive for Leukocyte Common Antigen (LCA) antibody, proving that they were lymphocytes, most likely residual from a lymph node. These IHC data, together with the microscopic feature, the presence of the psammoma body and the patient's history, excluded a PA and led to a diagnosis of fibro-hyaline involution of a PTC metastasis in a lymph node, consecutive to radioiodine therapy. Without careful microscopic examination and accurate clinical information, this lesion could represent a real diagnostic challenge.

Pathoma_Husain

Invasion through the capsule helps distinguish follicular carcinoma from follicular adenoma. 2. Entire capsule must be examined microscopically. 3. FNA only examines cells and not the capsule; hence, a distinction between follicular adenoma and follicular carcinoma cannot be made by FNA. B. Metastasis generally occurs hematogenously. V. A. Malignant proliferation of parafollicular C cells; comprises 5% of thyroid carcinomas 1. C cells are neuroendocrine cells that secrete calcitonin. 2. Calcitonin lowers serum calcium by increasing renal calcium excretion but is inactive at normal physiologic levels. 3. High levels of calcitonin produced by tumor may lead to hypocalcemia. 4. Calcitonin often deposits within the tumor as amyloid. B. Biopsy reveals sheets of malignant cells in an amyloid stroma (Fig. 15.7). C. Familial cases are often due to multiple endocrine neoplasia (MEN) 2A and 2B, which are associated with mutations in the RET oncogene. 1.

[A Case of Carcinoma Showing Thymus-Like Differentiation (CASTLE) of the Thyroid].

The case presented herein was a 70-year-old woman who had no compliant, but had a mass in the lower part of the right lobe of the thyroid detected by ultrasound (US). The US image of the tumor, measuring 13 mm in diameter, showed a low and heterogeneous internal echo level with calcification and an irregular margin. The tumor appeared to extend to the adjacent sternothyroid muscle, and cervical lymph node swelling was detected in a computer tomography (CT) image, but no metastatic lesion was found by positron emission tomography (PET)-CT. In a fine needle aspiration cytology of the tumor, papillary thyroid carcinoma was suggested because of the atypical epithelial cells having some changes other than intranuclear inclusion bodies. A subtotal thyroidectomy and central neck lymph node dissection were performed. The excised tumor was histologically composed of irregular nests or sheets of atypical squamoid epithelial cells with some ductal structures that leached to the sternothyroid muscle and involved the right lower parathyroid gland. Carcinoma showing thymus-like differentiation (CASTLE) was diagnosed histopathologically and immunohistochemically with the following immunohistochemical results: Cluster of differentiation 5 (CD5) (+), tumor protein p63 (p63) (+), KIT proto-oncogene receptor tyrosine kinase (c-KIT(CD117)) (+), thyroglobulin (-), and thyroid transcription factor-1 (TTF-1) (-). CASTLE is a rare carcinoma of the thyroid that architecturally resembles thymic epithelial tumors. Many CASTLE patients have been misdiagnosed as other carcinomas, such as anaplastic carcinoma, poorly differentiated carcinoma or squamous cell carcinoma of the thyroid. Immunohistochemical examination, including CD5 played an important role in the final diagnosis of CASTLE, although the distinction from diagnosis as squamous cell carcinoma or mucoepidermoid carcinoma in Hematoxylin-Eosin staining was challenging in our case. Nodal metastasis and perithyroidal tumor extension of CASTLE can predict its worse prognosis. Thus, at least careful follow-up studies are mandatory in cases of CASTLE.

Computed tomography of the thyroid

Thyroid calcifications on a CT scan can be seen in both benign and malignant thyroid lesions. Sonographic examination of the thyroid can differentiate between micro-calcifications, which are highly associated with papillary thyroid carcinoma, and eggshell calcifications, which favour a benign process such as colloid cysts (Figs. 1 and and2)2). In a retrospective review of preoperative CT scan, 35 % (135 of 383) of the patients had detectable intra-thyroidal calcifications. Among them, 48 % had a histopathologically proven thyroid cancer. Calcified nodules had a significantly higher incidence of thyroid cancer and lymph node metastases. The incidence of thyroid cancer among nodules with different calcifications patterns were 79 % of nodules with multiple punctate calcifications, 58 % of nodules with a single punctate calcification, 21 % of nodules with coarse calcification, and 22 % of nodules with peripheral calcification. Most of the single calcified nodules were malignant. However,

[Surgical management of medullary thyroid carcinoma. Personal experience].

Medullary Thyroid Carcinoma (MTC) is a rare malignancy of the parafollicular C cells of the thyroid gland. Aim of our study is reporting retrospective analysis of our experience about the surgical treatment of MTC, especially pointing on lymphadenectomy. from January 2000 to March 2006, were performed 546 thyroidectomy, 6 of them for MTC (1.09%): 5 sporadic and 1 familiar. All the patients were operated with standard technique (total thyroidectomy) and submitted to endocrinologic and instrumental follow-up. in our experience, we do not registered early or late complications as bleeding, laryngeal nerves lesions and parathyroid lesions or intra-postoperative deaths. MTC occurs sporadically or as part of the multiple endocrine neoplasia type 2 (MEN 2 a/b) syndromes in patients who have inherited a mutation in the RET proto-oncogene. The diagnosis is made by fine needle aspiration biopsy (FNAB) and by measuring calcitonin levels in the blood. Primary treatment consists of surgical resection including a total thyroidectomy, central neck nodal dissection and functional lateral neck nodal dissections. Most patients with a palpable primary tumour have nodal disease at the time of operation, and nodal involvement is often bilateral. adequate resection of the primary tumour and cervical lymph nodes is important to optimize outcome and minimize the risk of recurrent disease. Following primary surgical resection, more than 50% of the patients will have recurrent disease with persistent elevation of calcitonin levels. Currently, there is no adequate systemic therapy for recurrent disease. Surgical reoperation or conservative observation are the best available options.

Papillary Thyroid Carcinoma -- Histopathology -- Gross Findings

Grossly, PTC typically presents as an invasive neoplasm with poorly defined margins, a firm consistency, and a granular white-cut surface. Calcifications may be present. The size is widely variable, with a mean diameter of 2-3 cm. Papillary thyroid carcinoma has three classification categories based on the size and extent of the primary lesion. Minimal carcinoma or occult carcinoma/micro-carcinoma tumors are 1.5 cm or smaller and show no evidence of invasiveness through the thyroid capsule or cervical lymph nodes. These lesions are typically nonpalpable, and they are usually found as incidental findings during operative or autopsy examination. Intra-thyroid tumors are greater than 1.5 cm in diameter but remain confined to the thyroid gland with no evidence of extra-thyroid invasion. Extra-thyroid tumors extend through the thyroid capsule to involve the surrounding viscera. [16]

Multiple endocrine neoplasia type 2

The common feature among the three sub-types of MEN2 is a high propensity to develop medullary thyroid carcinoma. A variant of MEAs 2A was described in 1989. This variant also has patches of cutaneous amyloidosis in the mid/upper back and is inherited in an autosomal dominant fashion. Management Management of MEN2 patients includes thyroidectomy including cervical central and bilateral lymph nodes dissection for MTC, unilateral adrenalectomy for unilateral pheochromocytoma or bilateral adrenalectomy when both glands are involved and selective resection of pathologic parathyroid glands for primary hyperparathyroidism. Familial genetic screening is recommended to identify at risk subjects who will develop the disease, permitting early management by performing prophylactic thyroidectomy, giving them the best chance of cure.

Follicular thyroid cancer

Hurthle cell variant Hurthle cell thyroid cancer is often considered a variant of follicular cell carcinoma. Hurthle cell forms are more likely than follicular carcinomas to be bilateral and multifocal and to metastasize to lymph nodes. Like follicular carcinoma, unilateral hemithyroidectomy is performed for non-invasive disease, and total thyroidectomy for invasive disease. Diagnosis It is difficult to correctly diagnose follicular neoplasms (FNs) on fine-needle aspiration cytology (FNAC) because it shares many cytological features with other mimicking lesions.

Concomitant medullary thyroid carcinoma with paraganglioma-like pattern and papillary thyroid carcinoma.

A 74-year-old man was referred to the Endocrinology Unit because of multinodular goiter. The dominant nodule (1.7 × 1.9 × 2.4 cm), at the medium-superior third of the left lobe, was inhomogeneously hypoechoic, with irregular margins, macrocalcifications and intranodular vascularization. Fine-needle aspiration biopsy (FNAB) was performed. The cytological diagnosis was TIR 2, benign, according to the 2013 Italian thyroid cytology classification system. Moderately high serum calcitonin (s-Ct) (61.5 pg/mL, n.r. 0-7.5) and normal CEA were detected. The Ct level in FNAB wash-out fluid (Ct-FNAB) was 1450 pg/mL. Based on s-Ct and Ct-FNAB levels, patient underwent total thyroidectomy. Macroscopically, a dominant circumscribed nodule of 2 ecm was described; the histological and immunohistochemical features identified medullary thyroid carcinoma (MTC) with paraganglioma (PG)-like pattern positive for Ct, CEA and chromogranin and negative for S-100 sustentacular cells (SC). Moreover, papillary carcinoma of 3 mm in the right lobe was also associated. No areas of hyperaccumulation of the tracer were documented at Ga68 PET/CT. No RET-proto-oncogene mutations were found. Post-surgery s-Ct levels were within normal range (4 pg/mL). Two years after thyroidectomy, the patient is still disease-free. We reported a case of sporadic and rare variant of MTC: this is the ninth described case of PG-like MTC. In this case, cytologically benign, the clinical suspicion arose from high Ct values at FNAB wash-out fluid. Even if clinical behavior of this variant seems indolent, additional studies are necessary to understand prognoses and predictive factors. Several unusual histological variants of medullary thyroid carcinoma (MTC) have been described such as spindle cell, giant cell, clear cell, melanotic, squamous, angiosarcoma-like variants; even rarer is the paraganglioma (PG)-like pattern. We here describe a case of medullary PG-like thyroid carcinoma in a 74-year-old man. This is a rare histological variant of MTC hardly diagnosed by cytology, since immunohistochemical investigations are necessary. Measurement of calcitonin both in serum and in wash-out fluid from fine-needle aspiration could be an additional tool for an early and non-invasive identification of these variants.

Papillary thyroid cancer

Papillary thyroid cancer gets its name from the papillae among its cells, visible on microscopy. Features include: Characteristic Orphan Annie eye nuclear inclusions (nuclei with uniform staining, which appear empty due to powdery chromatin and marginal micronucleoli) and psammoma bodies on light microscopy. The former is useful in identifying the follicular variant of papillary thyroid carcinomas. Lymphatic spread is more common than hematogenous spread Multifocality is common The so-called lateral aberrant thyroid is usually a lymph node metastasis from a papillary thyroid carcinoma.

[Multiple endocrine neoplasia 2a: late manifestation of a newly-discovered mutation].

A 55-year-old patient presented with a painless right-sided cervical swelling, which had been present for four months and seemed to get larger. The patient denied dyspnea, dysphagia, "a lump in the throat" or thyroid disease. Two of his paternal aunts had thyroid carcinoma and an adrenal tumor. Ultrasonography revealed an enlarged lymphoid nodule and a large lesion in the right thyroid lobe, the latter with deficient technetium uptake on scintigraphy. A total thyroidectomy with bilateral centrocervical and lateral neck dissection was performed. Histology revealed a bilateral medullary thyroid carcinoma [MTC: pT3, pN1b (9/34), pM0 (UICC 2002)] and the genetic screening showed a double mutation in codon 611 (TGC>TAT; p.Cys611Tyr; C611Y), and exon 10 of the RET proto-oncogene, which has not been described before. Pheochromocytoma and hyperparathyroidism were excluded. Genetic screening of all close family members was initiated and showed that four of them were gene carriers. Three of them have been operated and a MTC found. The described newly discovered mutation is associated with MTC and pheochromocytoma. This case underlines the need of genetic screening in all patients who present with a MTC only, no matter what the person's age of manifestation, even in the absence of any other MEN-related disease.

Multiple Endocrine Neoplasias Type 2 -- Pathophysiology -- Thyroid Gland

Medullar thyroid cancer (MTC) is the most common manifestation of MEN2A and MEN2B with 100% penetrance and usually the first manifestation in MEN2 patients. MTC is a neuroendocrine tumor of the thyroid gland caused by the hyperplasia of calcitonin-producing parafollicular C-cells, the only cells in the thyroid gland derived from neural crest cells. [5] Almost 100% of patients with MEN2A and MEN2B develop MTC, particularly early in life, with the highest incidence in the third decade, while 25% of MTC cases have RET proto-oncogene mutation. MTC most commonly presents with a solitary thyroid nodule and/or cervical lymphadenopathy.

Thyroid nodule

Fine needle biopsy Fine Needle Aspiration Cytology (FNAC) is a cheap, simple, and safe method in obtaining cytological specimens for diagnosis by using a needle and a syringe. The indications to do FNAC are: nodules more than 1 cm with two ultrasound criteria suggestive of malignancy, nodules of any size with extracapsular extension or lymph nodes enlargement with unknown source, any sizes of nodules with history of head and neck radiation, family history of thyroid carcinoma in two or more first degree relatives, multiple endocrine neoplasia type II, and increased calcitonin levels. However, increased calcitonin levels can also be attributable to smoking, chronic alcohol consumption, usage of proton pump inhibitors, and renal failure. The Bethesda System for Reporting Thyroid Cytopathology is the system used to report whether the thyroid cytological specimen is benign or malignant. It can be divided into six categories:

Thyroidectomy

Hemithyroidectomy — Entire isthmus is removed along with 1 lobe. Done in benign diseases of only 1 lobe. Subtotal thyroidectomy — Removal of majority of both lobes leaving behind 4-5 grams (equivalent to the size of a normal thyroid gland) of thyroid tissue on one or both sides—this used to be the most common operation for multinodular goitre. Partial thyroidectomy —Removal of gland in front of trachea after mobilization. Done in nontoxic MNG. Its role is controversial. Near total thyroidectomy — Both lobes are removed except for a small amount of thyroid tissue (on one or both sides) in the vicinity of the recurrent laryngeal nerve entry point and the superior parathyroid gland. Total thyroidectomy — Entire gland is removed. Done in cases of papillary or follicular carcinoma of thyroid, medullary carcinoma of thyroid. This is now also the most common operation for multinodular goitre.

Medullary thyroid cancer

Markers While the increased serum concentration of calcitonin is not harmful, it is useful as a marker which can be tested in blood. A second marker, carcinoembryonic antigen (CEA), also produced by medullary thyroid carcinoma, is released into the blood and it is useful as a serum or blood tumor marker. In general, measurement of serum CEA is less sensitive than serum calcitonin for detecting the presence of a tumor, but has less minute to minute variability and is therefore useful as an indicator of tumor mass. Diagnosis Diagnosis is primarily performed via fine needle aspiration of the lesion of the thyroid to distinguish it from other types of thyroid lesions. Microscopic examination will show an amyloid stroma with hyperplasia of parafollicular cells.

Paraganglioma-like medullary thyroid carcinoma: fine needle aspiration cytology features with histological correlation.

Two cases of an extremely rare paraganglioma-like variant of medullary thyroid carcinoma (MTC) are reported. The patients were a 65-year-old male (case 1) and a 14-year-old female (case 2). Unilateral thyroid nodule and homolateral cervical lymphadenopathy was present in case 1; bilateral thyroid nodules were seen in case 2. Fine needle aspiration cytology (FNAC) was performed from thyroid nodules (in both cases) and from a cervical lymph node (in case 1). The cytological smears contained predominantly ovoid to spindled epithelial cells arranged in cohesive three-dimensional clusters with sharp margins; isolated individual cells were seen only rarely. No colloid or other material was present in the background. The tumour cells showed significant nuclear atypia with occasional bizarre and/or binucleated cells. The nuclear chromatin was coarse and granular, sometimes with grooves and intranuclear inclusions. The cytoplasm was inconspicuous. Polygonal or triangular cells, amyloid and azurophillic cytoplasmic granules were absent in both cases. Calcitonin expression was demonstrated in case 2. Histological examination confirmed the paraganglioma variant of MTC in both cases. Mutation of RET proto-oncogene in exon 16 (Met918Thr) - germline in case 2 and somatic in case 1 was detected by sequencing of DNA in both cases. This is the first description of cytological findings in the paraganglioma-like variant of MTC. Despite its rarity, it can be reliably diagnosed by FNAC if material for immunocytochemistry is obtained.

Papillary thyroid cancer

Diagnosis Papillary thyroid carcinoma is usually discovered on routine examination as an asymptomatic thyroid nodule that appears as a neck mass. In some instances, the mass may have produced local symptoms. This mass is normally referred to a fine needle aspiration biopsy (FNA) for investigation. FNA accuracy is very high and it is a process widely used in these cases. Other investigation methods include ultrasound imaging and nuclear scan. The ultrasound is a useful test to distinguish solid from cystic lesions and to identify calcifications. The thyroid ultrasound is also very effective to discover microcarcinomas, which refer to very small carcinomas (<1 cm).

Computed tomography of the thyroid

On CT scans, a malignant lesion is suspected when the margins are ill-defined and there is extra-thyroid extension, lymph node involvement, or invasion of the surrounding structures. The absence of these features does not exclude malignant tumours, especially papillary, follicular, and medullary thyroid carcinomas (Fig. 3). Therefore, ultrasound is the modality of choice for thyroid lesion evaluation, due to its superior spatial resolution compared to CT examinations. Sonographic features of malignancy are micro-calcifications, acoustic shadowing, anti-parallel orientation, marked hypoechogenicity, irregular or microlobulated margins, and increased vascularity. CT scans lack the ability to detect these reliable sonographic signs of malignancy. Therefore, further management of ITNs, if required, usually begins with thyroid ultrasound and FNA should be considered according to the ultrasound findings.

Intermixed medullary and papillary thyroid cancer in a patient with renal cell carcinoma.

We report a rare case of concurrent medullary thyroid cancer (MTC) and papillary thyroid cancer (PTC) with intermixed disease in several of the lymph node (LN) metastases in a patient who was subsequently diagnosed with clear cell renal cell carcinoma (RCC). A 56 year old female presented with dysphagia and was found to have a left thyroid nodule and left superior cervical LN with suspicious sonographic features. Fine needle aspiration biopsy (FNAB) demonstrated PTC in the left thyroid nodule and MTC in the left cervical LN. Histopathology demonstrated multifocal PTC with 3/21 LNs positive for metastatic PTC. One LN in the left lateral neck dissection exhibited features of both MTC and PTC within the same node. In the right lobe, a 0.3 cm focus of MTC with extra-thyroidal extension was noted. Given persistent calcitonin elevation, a follow-up ultrasound displayed an abnormal left level 4 LN. FNAB showed features of both PTC and MTC on the cytopathology itself. The patient underwent repeat central and left radical neck dissection with 3/6 LNs positive for PTC in the central neck and 2/6 LNs positive for intermixed PTC and MTC in the left neck. There was no evidence of distant metastases on computed tomography and whole body scintigraphy, however a 1.9 x 2.5 cm enhancing mass within the right inter-polar kidney was discovered. This lesion was highly suspicious for RCC. Surgical pathology revealed a 2.5 cm clear cell RCC, Fuhrman grade 2/4, with negative surgical margins. She continues to be observed with stable imaging of her triple malignancies. Mixed medullary-papillary thyroid neoplasm is characterized by the presence of morphological and immunohistochemical features of both medullary and papillary thyroid cancers within the same lesion. Simultaneous occurrence of these carcinomas has been previously reported, but a mixed disease within the same lymph node is an infrequent phenomenon. Prognosis of mixed medullary-papillary thyroid carcinomas is determined by the medullary component. Therefore, when PTC and MTC occur concurrently, the priority should be given to the management of MTC, which involves total thyroidectomy and central lymph node dissection. Patients with thyroid cancer, predominantly PTC, have shown higher than expected rates of RCC. To our knowledge, this is the first report describing the combination of MTC, PTC, and RCC in a single patient.

High frequency ultrasound features and pathological characteristics of medullary thyroid carcinoma.

To study high-frequency ultrasound features and pathological characteristics of medullary thyroid carcinoma (medullary thyroid carcinoma, MTC) with the purpose to improve the diagnostic accuracy of this disease. The clinical data of 20 cases of patients with MTC confirmed by the clinical surgery were retrospectively analyzed. And the high-frequency ultrasound features were analyzed and compared with the pathological characteristics. There were 16 cases with tumor invasion into one side of the thyroid gland; 17 cases with tumor in the middle-upper pole of the thyroid gland. And 8 cases were detected with uneven echo of high frequency ultrasound appearance and pathological manifestations of cystic degeneration to necrosis seen under the light microscope or normal thyroid tissue within part of the lump. 16 cases were tested with even echo of high frequency ultrasound appearance, and tumor cells were formed in the solid and block-like shape under the light microscope. And 18 cases were manifested with low echo, with proliferation of fibrous tissue within the intercellular substance under the light microscope. 18 cases could be seen the calcification points and often amyloid-like content deposited in the intercellular substance seen under the light microscope. In addition, the pathological manifestations of the 8 cases combined with lymph node metastasis were the "lash tumor" of the metastatic lymph nodes and primary tumor. MTC was commonly located in the middle-upper region of the thyroid gland and in one leaf of the thyroid gland, combined with lymph node metastasis. The high frequency ultrasound appearance was the even low-echo tumor in round or quasi-circular shape, with obscure boundary and often combined with rough calcification. High frequency ultrasound could be used as the prior physical diagnostic method for medullary thyroid carcinoma.

Prophylactic thyroidectomy in ethnic Chinese patients with multiple endocrine neoplasia type 2A syndrome after the introduction of genetic testing.

To evaluate the impact of genetic testing in the management of familial multiple endocrine neoplasia 2A patients. Retrospective study. University teaching hospital, Hong Kong. Twenty-two patients from eight multiple endocrine neoplasia 2A families underwent prophylactic total thyroidectomy based on a positive RET mutation genetic testing. All mutations were located at codon 634 of exon 11. Nineteen patients had preoperative basal serum calcitonin measured, and the 12 with normal levels had pentagastrin stimulation tests. Preoperative thyroid ultrasound examination was performed for 17 patients. There were 13 females and 9 males with a median age of 25.1 (range, 6.1-71.9) years. Histopathology revealed medullary thyroid carcinoma in 17 (77%), C-cell hyperplasia in four (18%), and normal pathology in one (5%) of the patients. Five patients with either C-cell hyperplasia or normal pathology were among the youngest (age range, 6-9 years). The youngest patient with medullary thyroid carcinoma was nearly 9 years old. The median size of medullary thyroid carcinomas was 8.3 (range, 0.1-18) mm, but there were no lymph node metastases. Of 15 patients with normal basal calcitonin levels, 10 had medullary thyroid carcinoma, though two tested negative with the pentagastrin-stimulated calcitonin assay. Five of six patients with normal preoperative ultrasonographic examinations had medullary thyroid carcinoma. Three (14%) of the patients were prescribed long-term calcium and vitamin D supplementation. After a median follow-up of 49 (range, 13-128) months, no patient had recurrence of medullary thyroid carcinoma. Genetic testing has replaced conventional biochemical and radiological modalities to identifying multiple endocrine neoplasia 2A carriers, in order to offer them prophylactic thyroidectomy. Chinese multiple endocrine neoplasia 2A patients with codon 634 mutation seem to have less aggressive forms of medullary thyroid carcinoma, for whom prophylactic thyroidectomy can be considered at the age of 8 years.

Concurrent lymph node metastases of medullary and papillary thyroid carcinoma in a case with RET oncogene germline mutation.

We report the case of a 72 yr-old woman who underwent total thyroidectomy and resection of neck lymph nodes because of a firm nodule in the right lobe, which was consistent with medullary thyroid carcinoma (MTC) on cytological examination. Histology showed multifocal bilateral MTC; a 2 mm papillary thyroid carcinoma (PTC) was also detected in the right lobe, next to a focus of MTC; five cervical lymph nodes contained MTC. In one right perithyroidal lymph node, concurrent metastases of MTC and PTC were demonstrated. DNA analysis showed a point mutation in exon 14 at codon 804 of the RET proto-oncogene locus, as frequently found in cases of familial MTC (FMTC). To our knowledge, this case represents the first documented case of concurrent lymph node metastases of MTC and PTC in a patient with RET proto-oncogene germline mutation. We report this unique case, discuss related thyroid malignancies, and suggest possible underlying pathogenetic mechanisms.

Clinical and pathological analysis of 19 cases of medullary thyroid carcinoma without an increase in calcitonin.

Medullary thyroid carcinoma (MTC), defined as a malignant tumour with C-cell differentiation, is of neuroendocrine origin and is characterized by the synthesis and secretion of calcitonin (CT). MTC without CT secretion has been reported on rare occasions. The purpose of this study was to evaluate the histological, immunohistochemical, and molecular pathologic features as well as the clinical significance of non-secretory MTC (NCR-MTC). A retrospective analysis of patients with NCR-MTC was performed. The clinical features of NCR-MTC, including age, gender, tumour size and number, clinical signs of hypocalcaemia and diarrhoea, and the presence of lymph node metastasis, as well as the pathologic features of the disease, including tumour morphology, presence of neuroendocrine structures, capsular invasion, and immunohistochemical expression and presence of mutations in the RET gene, were evaluated. Nineteen patients with NCR-MTC were identified among 158 patients with MTC, resulting in a prevalence rate of 12.02%. Patients with NCR-MTC typically had masses less than 1cm in size (73.7%, 14/19). Hypocalcaemia was not present in 94.7% (18/19) of patients. While 42.1% (8/19) of patients with NCR-MTC did not have amyloid deposits, only 18% (25/139) of patients with secretory MTC did not have such deposits. While 95.7% (133/139) of the control group of patients with secretory MTC had neuroendocrine tumour structure, only 84.2% (16/19) of the patients with NCR-MTC had this type of tumour structure. Patients with NCR-MTC were also less likely to have vascular tumour thrombus, lymph node metastasis or thyroid capsular invasion. With regard to immunohistochemistry, CT expression was mostly negative, and carcinoembryonic antigen (CEA) expression was positive in 21.1% (4/19) of patients with NCR-MTC, while only 5.8% (8/139) of patients in the control group had positive CEA expression. The prevalence of NCR-MTC was low (12.02%). This type of tumour was smaller in size and more differentiated. Compared with the control group, relatively few patients had obvious symptoms, hypocalcaemia, lymph node metastasis, thyroid capsular or vascular invasion, or tumours with amyloid or neuroendocrine tumour structure.

Very early detection of RET proto-oncogene mutation is crucial for preventive thyroidectomy in multiple endocrine neoplasia type 2 children: presence of C-cell malignant disease in asymptomatic carriers.

Multiple endocrine neoplasia type 2 (MEN 2) is an inherited disease caused by germline mutations in the RET proto-oncogene, and is responsible for the development of endocrine neoplasia. Its prognosis is dependent on the appearance and spread of medullary thyroid carcinoma (MTC). Relatives at risk can be identified before clinical or biochemical signs of the disease become evident. Twenty-one families with MEN 2 (16 families with MEN 2A and 5 families with MEN 2B) were studied. Peripheral blood DNA was amplified by polymerase chain reaction. DNA sequence or restriction enzyme analysis was performed to detect mutations of RET proto-oncogene exons 10, 11, and 16. Molecular analysis was carried out in all index patients as well as in 98 relatives of MEN 2A patients (60 juveniles, ages 6 months to 21 years, and 38 adults, ages 22 to 81 years) and in 13 relatives (6 juveniles ages 10 to 21 years, and 7 adults ages 41 to 66 years) from MEN 2B families. Molecular studies showed a mutation at codon 634, exon 11 in all MEN 2A patients. All MEN 2B patients showed an ATG to ACG (Met918Thr) mutation. In MEN 2A families, 42 out of 98 relatives were affected. Total thyroidectomy was performed in 18 juvenile carriers ages 17 months to 21 years. Histopathologic studies of the glands revealed parafollicular cell (C-cell) hyperplasia in all of these carriers, medullary thyroid carcinoma in 15 carriers, and only one carrier with lymph node metastases. The consistent finding of C-cell disease in all the juvenile carriers who underwent preventive thyroidectomy emphasizes the relevance of early screening in children at risk of developing MTC. The presence of MTC in the specimen of prophylactic thyroidectomy from a 17 month old girl highlights the importance of thyroidectomy as soon as the molecular diagnosis is confirmed.

[Unusual non-neoplastic lesions in the "surgical pathology" of the thyroid].

This review aims to describe and assist in the categorization of most of the unusual non-neoplastic conditions, encountered in the surgical pathology of the thyroid. The conditions included are: normal intrathyroidal vestigial tissues/structures (i.e. rests of the ultimobranchial body and thyroglossal duct) and their relevant pathological derivatives (ultimobranchial body cyst, intrathyroidal lymphoepithelial cyst, thyroglossal duct cyst); mature intrathyroidal heterologous tissues/organs of either metaplastic or heterotopic origin (adipose tissue, striated skeletal muscle, cartilage, parathyroid glands, thymus, salivary gland tissue) and their relevant pseudotumoural lesions; varieties of metaplastic and non-metaplastic morphologic changes of the thyroid follicular epithelium (oncocytic, clear cell/signet ring cell, darkly pigmented cell, mucinous (myxoid), squamous, spindle cell); amyloid goiter; some reactive and/or degenerative cytologic and nuclear atypicalities (nuclear pseudoclearing and cell pleomorphism) as well as some hyperplastic or peculiar growth patterns (capsular pseudoinvasion; vascular invasion; papillary carcinoma-like and paraganglioma-like patterns) of benign conditions mimicking neoplasia; and finally. some pseudotumoural lesions of the stroma (pseudoangiosarcomatous vascular proliferation, and post-fine-needle aspiration spindle cell nodule). The pathogenetic mechanism, the morphologic interpretation, and the differential diagnosis of each of the above-listed conditions are discussed and pertinent illustrations for many of them are also provided. Lesions of thyroid tissue situated outside of the gland itself are not discussed.

Cervical lymph nodes

Clinical significance Infectious mononucleosis (glandular fever) affects the cervical lymph nodes which become swollen. The characterization of cancerous lymph nodes on CT scan, MRI or ultrasound is difficult, and usually requires confirmation by other nuclear imaging techniques such as PET scans. Tissue diagnosis by fine needle aspiration (which has a high rate of accuracy), may also be required. Involvement of the cervical lymph nodes with metastatic cancer is the single most important prognostic factor in head and neck squamous cell carcinoma and may be associated with a halving of survival. Where the cancer has penetrated the capsule of the lymph gland (extracapsular extension) survival may be decreased by a further 50%. Other important factors are the level, the number of nodes and their size, which are also correlated with the risk of distant metastases. Cervical lymph node metastasis is also a common feature of papillary thyroid carcinoma. Additional images References

Medullary and papillary carcinoma of the thyroid gland occurring as a collision tumor with lymph node metastasis: A case report.

Papillary thyroid carcinoma and medullary thyroid carcinoma are two different thyroid neoplasia. The simultaneous occurrence of medullary thyroid carcinoma and papillary thyroid carcinoma as a collison tumor with metastases from both lesions in the regional lymph nodes is a rare phenomenon. A 32-year-old Iranian man presented with a fixed anterior neck mass. Ultrasonography revealed two separate thyroid nodules as well as a suspicious neck mass that appeared to be a metastatic lesion. The results of thyroid function tests were normal, but the preoperative calcitonin serum value was elevated. Our patient underwent a total thyroidectomy with neck exploration. Two separate and ill-defined solid lesions grossly in the right lobe were noticed. Histological and immunohistochemical studies of these lesions suggested the presence of medullary thyroid carcinoma and papillary thyroid carcinoma. The lymph nodes isolated from a neck dissection specimen showed metastases from both lesions. The concomitant occurrence of papillary thyroid carcinoma and medullary thyroid carcinoma and the exact diagnosis of this uncommon event are important. The treatment strategy should be reconsidered in such cases, and genetic screening to exclude multiple endocrine neoplasia 2 syndromes should be performed. For papillary thyroid carcinoma, radioiodine therapy and thyroid-stimulating hormone suppressive therapy are performed. However, the treatment of medullary thyroid carcinoma is mostly radical surgery with no effective adjuvant therapy.

Marginal vacuoles in thyroid aspirates.

To report on two cases of metastatic follicular carcinoma with marginal vacuoles (MVs) and review smear results in 441 solitary nodular goiters (SNGs) for this cytologic feature. The first case was a 55-year-old male who presented with a huge mass in the left hip region; the second case was a 50-year-old male with a thyroid nodule and a large mass on the scalp. The age of the 441 ultrasonographically diagnosed SNG cases ranged from 11 to 75 years. The May-Grünwald-Giemsa-stained fine needle aspiration (FNA) smears of these cases were reviewed by one of the authors (D.K.D.) for various cytomorphologic features, including MVs. FNA smears from the mass in the hip in the first case showed follicular cells with acinar formation and MVs, indicating metastatic follicular thyroid carcinoma (FTC). These features were of help in detecting the thyroid primary, which had previously gone undetected. Aspiration smears from the thyroid nodule and the mass on the scalp in the second case showed tumor cells of FTC with MVs and microfilariae. Review of 441 SNG cases revealed MVs in 42.6% of hyperplastic nodules; that rate was significantly higher (P < .001) than that of colloid goiter (5.2%) and neoplastic goiter (13.3%) but lower (P < .05) than that of thyrotoxic goiter (100%). MVs were limited to neoplasms with a follicular component; that included 15% of follicular neoplasms and 50% of follicular variant of papillary carcinoma (FVPC). The difference between FVPC and the rest of the neoplastic goiters (6%) was statistically significant (P = .002).

A nonfunctioning parathyroid carcinoma misdiagnosed as a follicular thyroid nodule.

Parathyroid carcinoma (PC) is a rare endocrine malignancy. The tumor is mostly functioning, causing severe primary hyperparathyroidism, with high serum calcium and parathyroid hormone (PTH) levels. Nonfunctioning PC is extremely rare. We report a 50-year-old male patient who was referred to our Department for a right thyroid nodule, incidentally detected on carotid Doppler ultrasound scan, with a fine-needle aspiration cytology showing a follicular lesion. At the time of our evaluation, neck ultrasound showed a 1.3 cm right hypoechoic thyroid nodule with irregular margins and the absence of enlarged bilateral cervical lymph nodes. Thyroid function tests were normal. Serum calcium was normal and plasma PTH slightly above the upper limit of the normal range. The patients underwent right lobectomy. The intraoperative frozen-section pathological examination raised the suspicion of a PC. Definitive histology showed a markedly irregular infiltrative growth of the tumor with invasion of the thyroid tissue and cervical soft tissues. Immunostaining for thyroglobulin was negative, whereas staining for chromogranin A and PTH showed a strong reactivity. Based on the microscopic findings and the immunohistochemical profile, the tumor was diagnosed as a PC. Postoperative serum calcium and phosphate levels were in the normal range. One month after surgery, serum calcium and PTH were normal. Neck ultrasound and total body computed tomography scan were negative for local and metastatic disease. Eight months later, serum calcium was normal and plasma PTH level remained around the upper limit of normal range. Neck ultrasound did not show any pathological lesions. This is the first case of a nonfunctioning sporadic PC misdiagnosed prior of surgery as a follicular thyroid nodule. The parathyroid nature of the neck lesion could not be suspected before surgery. Fine-needle aspiration cytology (FNAC) may fail to distinguish a parathyroid tumor from a benign thyroid nodule because at FNAC, parathyroid and thyroid lesions have some morphological similarities. Histological criteria are not always sufficient for the differential diagnosis, which can definitely be established using immunohistochemistry.