甲状腺の乳頭がん：小児における特殊な点： Part 1 診断 (作業中)

Papillary Cancer: Special Aspects in Children
Andrew J. Bauer and Merrily Poth

in Thyroid Cancer: A Comprehensive Guide to Clinical Management Second Edition
Edited by Leonard Wartofsky and Douglas Van Nostrand

INTRODUCTION
Similarly to adults, the most common form of thyroid malignancy in children is papillary thyroid cancer (PTC), accounting for approx 70–80% of newly diagnosed pediatric thyroid cancers (1–3).
(成人と同様に、小児の甲状腺悪性腫瘍の最も一般的な組織像は乳頭がん(PTC)であり、新しく診断された甲状腺がんの約70-80%を占める)

In contrast to adults, however, pediatric patients with PTC have more locally invasive disease and more pulmonary metastases at presentation, as well as a higher incidence of recurrent or persistent disease after initial treatment.
(成人と違い、乳頭がんの小児患者では、診断時に局所浸潤が起きていることが多く、肺転移を起こしていることが多い。また、初回治療後に再発・残存している頻度も高い)

Despite these apparently ominous features, 5- and 10-yr survival rates and disease-specific mortality for children with PTC remains (1–9c).
(このような不穏 ominous な臨床像にも関わらず、乳頭がんの小児での5年および10年生存率と疾患による死亡率は、良好である)

Our current approach to evaluation and treatment of PTC in children and adolescents has been extrapolated from the old treatment of PTC in adults.
(小児の乳頭がんについて、我々が現在行っている評価と治療は、成人で行われている昔からの治療の、外挿である)

Although the cancer’s histology is the same, its clinical behavior in children is much different, with pediatric PTC showing even much faster growth, often presenting with extensive regional disease and pulmonary metastases.
(がんの組織像は同様であるが、小児では臨床像が全く異っていて、小児の乳頭がんは、非常に発育が早く、しばしば局所浸潤や肺転移で発症する)

Even after treatment, 15–35% of cases recur or persist and need to be retreated.
(治療の後でさえ、15-35%に患者は再発や残存しており、再治療を必要とする)

As the medical community continues to search for the safest, most effective treatment options for children, the fact remains that much of our knowledge is based on retrospective chart reviews.
(小児に対して、最も安全で、最も効果的な、治療の選択肢を探し続けているのため、我々の知識の多くは、後方視的な調査に基づいているという事実は残る)

These reviews often cover decades of time, with great variations in length of time to diagnosis, patient age, degree of iodine sufficiency, and details of surgical and medical management.
(これらの調査は、しばしば数十年に及んでいる。このため、診断時の時間経過、年齢、ヨウ素摂取の程度、外科的内科的治療の詳細については、大きな変移がある)

The last decade has witnessed a marked increase in the number of reports on pediatric thyroid cancer, but information on 30–40-yr post-treatment follow-up remains quite limited.
(過去10年間に小児甲状腺がんについての報告数の著しく増加が見られた。しかし、治療後30〜40年の経過観察についての情報は限られている)

Because of this lack of controlled and definitive data, the ability to individualize treatment plans to ensure optimum outcome with the least risk of therapy remains limited (1–3,5,10).
(コントロールされ、明確化されたデータがないため、危険性を最も小さくし最適な結果を保証するための治療を個々に計画するのに十分でない)

The low incidence of PTC mitigates against any single center or physician group accumulating enough patients to conduct a long-term study with treatment and survival data.
(罹患率の低さのために、単一のセンターやグループが、十分な患者数を蓄積し、治療と生存率についての長期研究を行うことが困難である)

Thus, disparities and unknowns continue to create controversy in treatment as we strive to balance the use of intense treatment for cancer that, on presentation, appears aggressive with regional and pulmonary metastases but contrary to adults, seems to have a more indolent, long-term natural history.
(つまり、整合性のない事や不明な事が、治療についての論争を作り続けている)

PRESENTATION AND EVALUATION

As stated in the overview on thyroid cancer in children (Chapter 10), the most typical presentation for thyroid cancer in children and adolescents is an asymptomatic, solitary thyroid nodule, either noted in a patient followed for autoimmune thyroid disease or during routine physical exam (11–16).
(小児甲状腺がんの概説で述べたように、小児の甲状腺がんの最も典型的な発症時の症状は、無徴候性の孤発性の甲状腺腫瘤であり、自己免疫性の甲状腺疾患で経過観察中の患者か、定期的な検診で見つかる）

Thyroid nodules are thought to be relatively uncommon in children, historically reported at a prevalence of less than 2% (17); the true incidence may be higher because not all children have careful routine thyroid exams.
(甲状腺結節は小児期には少ないと考えられており、組織学的には2%以下の有病率とされている。すべての小児が注意深い甲状腺の診察を受けているとは限らないため、実際の罹患率はもっと高いかもしれない)

Unlike nodular thyroid disease in adults, up to 50% of pediatric thyroid nodules may be malignant (18,19).
(成人の結節性甲状腺疾患と異なり、小児の甲状腺結節の50％は悪性かもしれない)

Importantly, as many as 50% of children with thyroid cancer present with persistent cervical adenopathy as their initial symptom (13,15,16).
(重要な事であるが、甲状腺がんのもつ小児患者の50%は、初発症状として持続する頚部リンパ節腫大を呈している)

Because palpable cervical lymphadenopathy from benign causes is common in children, deciphering which lymph nodes are potentially malignant may present a significant challenge for clinicians (12–16).
(良性疾患のために頚部リンパ節腫大が触知されることは、小児では一般的であるため、リンパ節が悪性であると判断することは臨床医にとって難問となるかもしれない)

In our experience, several of the worst cases relating to the extent of disease at diagnosis and treatment difficulty were referred only after relatively extended evaluations for what was believed to be cervical adenitis.
(我々の経験の中で、診断時に進展していて治療に難渋する経過の悪い患者が紹介されてくるのは、頚部リンパ節炎と考えられ、かなり長く評価をされた後だ)

In each case, this evaluation included several courses of antibiotic therapy and repeated examinations. It was only when eventual biopsy of the lymph node revealed thyroid cancer that the thyroid was carefully examined and the primary lesion identified.
(それぞれが、数クールの抗生物質による治療と検査の繰り返しを受けていた)

Thus, education must be provided and emphasized to primary care providers and surgeons regarding the need for thorough examination of the thyroid gland as part of the evaluation of persistent cervical adenopathy.
(つまり、プライマリーケアを行う臨床医に対して、教育を提供し、強調する必要がある。持続する頚部リンパ節腫大を評価の一部として、甲状腺を十分な診察の必要性があることについて)

PTC in children has a high rate of metastasis, often show ing regional and distant metastasis at the time of diagnosis.
(小児の乳頭がんは高率に転移している。しばしば、診断辞意局所あるいは遠隔転移をしている)

At the time of diagnosis, 30–70% of these patients have palpable lymph nodes, and up to 90% of PTC lesions are already locally invasive at initial surgery, most commonly metastasizing to regional lymph nodes (1–5,7,8,12–16, 20–22).
(診断時に30-70%の患者で触知できるリンパ節を認める。そして、初回手術時に、90%の患者は既に局所浸潤しており、局在リンパ節に転移していることが一般的である)

Lung metastases are reported in 6–20% of children (2–4,7,9,23,24), depending on the technique used to determine their presence.
(肺転移は6-20%の患者に見られるが、その頻度の多寡は診断方法によっている)

Chest radiographs and chest computed tomography (CT) scans are relatively insensitive in detecting lung metastases, with normal chest X-rays quite common in the presence of diffuse pulmonary disease (13,21,23).
(びまん性の肺病変が存在するのに正常胸部レントゲン像を呈するのが一般であるが、胸部レントゲン撮影と胸部CTは肺転移を見つけるのに有効である)

Whole-body scanning (WBS), whether postsurgical, post- ablation, or posttherapy, is more sensitive, but this is positively correlated to the amount of 131I administered and negatively correlated with the amount of thyroid tissue present in the thyroid bed or cervical region.
(シンチは最も感度が高いが、131Iの投与量に正の相関を示し、甲状腺や頚部にある甲状腺組織の量に負の相関を示す)

In a study of 122 patients under 20 yr of age, of which 28 had pulmonary metastasis, only 7 had metastatic disease seen on chest X-ray (23).
(20歳以下の122人についての報告 ー このうち28人が肺転移をしていた ー では、胸部レントゲン写真では7人した肺転移を見つけられなかった)

Pulmonary disease was diagnosed in eight patients on first postsurgery WBS (2–3 mCi of 131I), seven patients on first postablation scan, and six on later post-therapy scans (23).
(肺転移が見つかったのは、初回手術後のシンチで8人、初回放射線ヨウ素治療後のシンチで7人、治療後しばらく経過してからのシンチで6人 だった)

Of these patients, 85% had near-total thyroidectomies as their initial treatment (23).
(この患者たちは、85%が初回治療として亜全摘を受けていた)

Therefore, in patients found to have regional lymph node metastases at diagnosis, underlying lung metastases may be present but only detected on scan after complete surgical resection of cervical disease.
(結局、局在リンパ節転移が診断時に見つかった患者では、肺転移が存在する可能性があるが、頚部病巣を完全に外科的に切除した後のシンチでしか見つけることができない)

In some cases, it may be first noted on later WBS performed during long-term follow-up, reflecting progression of disease (13–16,20–22).
(いくつかのケースでは、長期観察中に行われた後期のシンチではじめて指摘される事もあり、この事は病気の進行を示している)

One argument supporting aggressive initial surgery is based on improved sensitivity for early detection of pulmonary disease, which may stimulate the clinician to employ a higher initial 131I ablative dose to be used.
(積極的な初回手術を支持する論拠の一つは、肺転移の早期の検出の感度を高めることに基づいている。肺転移を検出することが、使用される放射線ヨウ素をより高い線量にする動機付けになるかもしれない)

The use of large quantities of 131I must be balanced with the realization that less than 10% of children and adolescents with thyroid cancer die of their disease, even with extensive, locally invasive, or recurrent disease (12–16,20–22).
(高線量の放射性ヨウ素を使うことは、局所浸潤があったり、再発したりした場合でも、小児の甲状腺がんの死亡率は10%以下であるという事実とのバランスでなければならない)

Although local invasion of tumor and metastases to the lungs are common (and long-term prognosis remains good even with this extensive disease), bone metastases are rare in children, occurring in less than 1% in all reported series.
(局所浸潤や肺転移は一般的であるが、骨転移は稀で、全報告例の1%以下である)

When bone metastases do occur in children, they carry a poor prognosis.
(小児で骨転移が起きた場合、予後は不良である)

The recommended process to evaluate a child or adolescent with a thyroid nodule has changed with the use of fine-needle aspiration (FNA) and the availability of this technique for children.

Proven to be effective in selecting patients for surgery in adult populations, FNA has now been instituted as a primary tool for younger patients (25–27).

In a recent report of 42 pediatric patients with thyroid nodules that ultimately had surgical resection, the sensitivity, specificity, and accuracy of FNA was reported to be 95%, 86.3%, and 90.4%, respectively (27).

There are well-developed guide-lines for this procedure, the most stringent and perhaps appropriate were those detailed by Hamburger (28).

He clearly articulated the need to acquire sufficient material and recommended the use of six separate aspirates in a given biopsy procedure as a technique for ensuring sufficient clinical material.

The use of local anesthesia before aspiration, and even the use of sedation in younger or more anxious patients, enable this process.

He and others have emphasized the critical need for experienced and competent cytopathologists to ensure that the pathological interpretation of material is accurate (see Chapters 18, 25).

With the use of FNA, the finding of clearly malignant cells allows the opportunity for appropriate pre-operative planning of a “cancer” operation and thoughtful counseling between parents and child before the operation (29).

Presence of the molecular marker, galectin-3, has been assessed in cells obtained by FNA in adults as an indicator of malignancy (see Chapter 19) but studies in children have not found this marker to be useful (29a).

Notably, in adults with a lower incidence of malignant thyroid nodules, it may be easier to follow a nodule after a negative or even an equivocal FNA cytology result.

In younger children and adolescents, the much higher incidence of malignancy (up to 50% vs 10–14% reported in adults) means that only the most benign and definitive FNA results will allow the endocrinologist to follow the patient expectantly (27).

Diagnostic data from preoperative FNA in a child with a thyroid nodule may obviate the need for frozen-section tissue examination during the surgical removal of the mass (lobectomy).

Many surgeons feel that frozen-section examination adds little to the data obtained with a preoperative FNA (30).

If the FNA yields cells consistent with “follicular neoplasm,” the frozen-section evaluation will rarely give more definitive results.

Most pediatric surgeons would rather remove the affected lobe and possibly the isthmus, then await the final pathology report before deciding whether to proceed with a completion subtotal thyroidectomy. However, this issue remains under debate (31).

In contrast to the increasing use of FNA in the evaluation of childhood thyroid nodules, the routine use of scintigraphic procedures to characterize a nodule as “hot,” “warm,” or “cold” is decreasing.

Numerous reports describe malignant lesions in warm or hot nodules; thus, these distinctions do not clearly define the ultimate risk of malignancy (27, 32–34).

The thyroid scan was once a standard part of the initial evaluation of a thyroid nodule, now most practitioners no longer use thyroid scans as a routine examination of thyroid lesions (27).

However, thyroid scans may be useful to rule out the entity of hemiagenesis of the thyroid in which the apparent mass is an enlarged single lobe of the thyroid gland, although this can be determined by ultrasound as well.

In our view, a reasonable plan for evaluation of thyroid nodules or persistent cervical adenopathy in children would include thyroid ultrasound to assess the size, number, centricity (bilateral, multicentric, or focal), and characteristics (cystic, solid, mixed) of the nodule, followed by FNA (35a).

Although the ultrasound findings do not predict whether a lesion is benign or malignant, the information is useful to decide where to attempt FNA (especially in the case of more than one nodule) and whether drainage of the nodule would be effective with cystic lesions.

The ultrasound results may also be helpful in planning surgical intervention.

Routine use of cervical CT scans or magnetic resonance imaging (MRI) to assess local or regional disease has not been formally assessed but may be considered on an individual basis.

If CT is used for this evaluation, it is extremely important to avoid the use of iodine-rich contrast in the study.

A subgroup of children with thyroid nodules are those with a history of exposure to radiation, whether from environmental accidents (Chernobyl) or as survivors of childhood nonthyroid cancer who received external-beam irradiation during treatment (36–42).

In these children, there are often multiple thyroid lesions that may be benign adenomas, multicentric cancers, or a mixture of these (43–45).

The overall risk of thyroid nodules has been reported to be as high as 27 times above sibling controls (37), and the increased risk of malignancy, most often PTC, is 18–53-fold higher (37,38).

Based on these data, it may be argued that the appearance of a thyroid nodule in a child with a history of significant radiation exposure is sufficient to indicate the need for surgery without any additional preoperative evaluation.

In addition to annual physical examinations in following children with previous radiation exposure, the issue of if and when to perform regular thyroid ultrasound is debated.

It is our belief that an ultrasound should be performed at least once within 5 yr of radiation treatment. Scheduled repeat exams are then individualized according to the results, physical exam, radiation dose, and age at time of radiation therapy.

Patients younger than 10 yr old at the time of initial radiation therapy, as well as patients with Hodgkin’s disease, are more closely followed.