Messages from Kennichi Kakudo, MD, PhD to a person to be an expert of the cytopathology

Dr Kitayama and I wrote an essay for patients to understand thyroid cancer.

I hope it helps patients to understand it before surgery.

Available at a link: http://www.med.osaka-u.ac.jp/pub/labo/JCJTC/EE1.html

Naomi Kitayama Graduate Student, Department of Dermatology, Kyoto University Graduate School of Medicine Kennichi Kakudo Izumi City General Hospital, Department of Pathology and Thyroid Disease Center

Dermatologist Kitayama herself noticed a lump in her thyroid gland, underwent a medical examination, and was diagnosed with thyroid cancer. She was notified of cancer by an endocrinologist and referred to a hospital for a surgical treatment. She asked a surgeon for a second opinion in order to examine and decide the treatment modality and surgery. In the process, a doctor who was not an expert in thyroid cancer worked hard to understand thyroid cancer and select better treatments. This process is described here and we hope it will be useful for those receiving treatment as a patient. The peculiarities of thyroid cancer, such as its differences and characteristics from other cancers, are also discussed. For the sake of brevity/clarity, the author focused on Stage I papillary thyroid cancer found in a 32-year-old Japanese woman. See Table 1 for cancer types in the human thyroid gland (References 1 and 2). Papillary thyroid cancer is the most common thyroid cancer, accounting for 80-90% of all thyroid malignancies and has the best prognosis of all human cancers. For cancer staging, refer to References 3 and 4. In brief, if the patient is 55 years of age or younger, all cases with no distant metastases are classified as Stage I regardless of lymph node metastases or extrathyroid extensions. As a result, over 85% of papillary cancers are Stage I cancers; therefore, the topics discussed apply to most thyroid cancer patients.

Diagnosis of thyroid cancer

One day in 2019 >> Kitayama I consulted about my illness. Yesterday, I noticed a lump in my thyroid and visited the clinic of a thyroid specialist. Ultrasonography revealed two large nodules with microcalcification in the left and right thyroid lobes, and swollen lymph nodes in the neck. Fine-needle aspiration (FNA) cytology was performed on the two suspicious nodules. Although I have yet to receive the results, the probability of thyroid cancer is high. (Note 1) My endocrinologist advised me that the larger nodule on the left lobe was approximately 3 cm and total thyroidectomy may be necessary. (Note 2) [See Table 2 for the flow of thyroid cancer diagnosis and treatment.] >> Kakudo That is a little worrisome. The increased incidence of thyroid cancer is a hot topic worldwide. (References 5 and 6) At present, over-diagnosis/over-treatment of low-risk thyroid cancer has become a hot topic, and non-surgical follow-up of papillary cancers of 1 cm or less was added to global guidelines (References 7-10). It was also recommended to stop the screening of asymptomatic adults for thyroid cancer (Reference 11). That means “Many thyroid cancers do not need require surgery.” As it is such a low-grade cancer, do not be afraid. On average, over 70% of patients with small papillary cancers (papillary cancers smaller than 1 cm are called papillary microcarcinomas) do not need surgical treatment. According to a national survey by Sugitani et al., less than half of patients with low-risk papillary microcancer chose surgery immediately. More than 50% of patients chose follow-up in Japan (Reference 12). To date, non-surgical follow-up has been selected by more than 2000 patients with microcarcinomas, and no patients died due to thyroid cancer even after treatment by conversion surgery. There are many cases in which the size increases at a young age, as in your case, and immediate surgery is an option even if it is less than 1 cm (Reference 9). In cases with lymph node metastasis/extrathyroid invasion, surgical treatment is recommended. If there is invasion into the muscle or other surrounding tissues by the tumor, removal of these involved organs is recommended for curative intent. If the 3-cm left lobe tumor is papillary cancer and lymph node metastasis is confirmed, surgical treatment will be unavoidable, but the extent of surgery is controversial. Please consult with your surgeon about the best and standard procedure. Clinical guidelines, including the selection of surgical procedures, are published by the American Thyroid Association, the Japanese Thyroid Association, and the Japanese Society of Thyroid Surgery (References 10, 13, and 14). (Note 3) >> Kitayama Contrast-enhanced CT examination revealed a nodule with a rich blood flow of 25 mm on the left and 12 mm on the right. There was a 1-cm lymph node suspected of metastasis near the right common carotid bifurcation. No distant metastases were found. When I contacted the XX hospital, the schedule was full. They said that the operation would be three to four months later. What would happen while waiting for surgery for three months? I was worried about significant cancer progression during the waiting time because my endocrinologist recommended undergoing surgical removal as soon as possible. >> Kakudo Thyroid cancer is a malignant tumor, but treatments should not be rushed until you have sufficient knowledge of the best treatments. Doing things quickly leads to poor results. Please understand how harmless papillary thyroid cancer in patients younger than 55 years is. Cancer is Stage I until distant metastasis appears and Stage II even if there is distant metastasis (Reference 3). As we have not confirmed cancer yet, it will be checked (Table 2) by imaging diagnosis and FNA cytology. If necessary, both the large nodule in the left lobe and the smaller nodule and swollen lymph nodes on the right side will be evaluated. From CT, there is a slight chance they are benign adenomatous nodules with calcification. The left and right nodules are encapsulated or well-demarcated. Even if they are papillary cancer by FNA cytology, they are of low-grade cancer and cannot be high-risk. >> Kitayama It seems rare having two types of tumors in the thyroid, one papillary cancer and another benign or borderline malignant. Is this a common observation? I am concerned about primary cancer in one lobe and metastatic lesion in the other lobe. >> Kakudo According to Shimura, thyroid echo analysis for cancer screening revealed that 20-30% of the general adult population has thyroid nodules, but only 0.79% were thyroid cancer (Reference 15). As there are 30-times as many benign nodules, I think it is a relatively common finding. There are many benign nodules coexisting in patients with thyroid cancer (being in 20-30%).

Surgery and postoperative pathological diagnosis

FNA cytology revealed that both nodules were papillary cancer. Following the second opinion consultation, both thyroid surgeons recommended total thyroidectomy and right cervical lymph node dissection as standard procedures. Total thyroidectomy and right side cervical lymph node dissection were performed by an experienced thyroid surgeon at XX hospital, a high-volume thyroid hospital. The histopathological diagnosis of the surgical specimen was multiple papillary carcinomas, common (classic) type, with lymph node metastases and Stage I (pT2(m), ex0, pN1b[9/15], M0). The risk classification by the Japanese Society of Thyroid Surgery was an intermediate risk (Reference 16). The Ki-67 labeling index (growth fraction) was less than 2% and prognostic classification by Kakudo (Table 4) (Reference 17) was low-risk.

Is it fatal cancer?

Thyroid cancer is abnormal in that has a low growth rate different from other cancers. It grows slowly like a uterine fibroid. However, benign uterine fibroids differ from thyroid cancer in that they do not metastasize. If you look at the definition of cancer in a textbook, it is defined as a lesion that meets the following two requirements. 1) Invasion and metastatic potential to nearby tissues. 2) Abnormal cell proliferation without control. Thyroid cancers that meet these two requirements are high-grade cancers, such as anaplastic cancers and poorly differentiated cancers, C-cell (medullary) cancers, and a small portion of papillary cancers (aggressive variants) and follicular cancers (angio-invasive and widely invasive) (Table 1). Many thyroid cancers lack the second requirement (abnormal cell proliferation without control), being common (classic) types of papillary cancer and capsular invasion-only follicular cancers. Cancers can be classified into two groups based on the growth speed according to Welch, one in which the patient dies of thyroid cancer if left untreated (red and green arrows) and the other in which the patient does not die of cancer even if left untreated (blue arrow) (Fig.1) (Reference 5). Among the papillary cancers, most of the classic type is slow-growing tumors (Welch named it very slow growing cancer), indicated by the blue arrow (Fig.1). It grows slowly and remains small and not large enough to kill the patient. Welch included a fourth type of cancer that disappears spontaneously (spontaneous regression) in his original illustration, which was excluded from Fig.1 to make it an original illustration. In this fourth group, patients die of other diseases (death from other illnesses) without symptoms of thyroid tumors. Thyroid cancer that is incidentally found by pathological examination at autopsy (latent cancer) belongs to this group. Many symptomatic cancers and cancers with lymph node metastases have a Ki-67 labeling index of less than 5%. They can be of this type (very slow growing shown by the blue arrow in Fig.1). Thyroid cancer is not always the cause of death of the patient in such cases. Du et al. analyzed the Surveillance, Epidemiology and End Results (SEER) thyroid cancer database, and reported that if a patient with papillary cancer survives for more than 10 years (cases confirmed to be slow growing cancer), 90% of all deaths are not due to thyroid cancer such as second cancer in other organs and cardiovascular disease (Reference 18). Please refer to the prognostic data from Kuma Hospital by Ito et al. (Reference 4). The disease-specific survival rate of patients with Stage I papillary cancer at 20 years after surgery was 99.3%. The 0.7% risk of death from thyroid cancer is significantly lower than the 2-3% total risk of death in people in their 30s by the time they are in their 50s after 20 years. Thyroid cancer is a mysterious cancer in which patients with thyroid cancer live longer (there is no significant difference, but the relative survival rate exceeds 100%) than the general population without thyroid cancer. Patients are long-lived and live for more than 20 years as thyroid cancer survivors, and for more than 40 years if treated at young age. How to avoid treatment-related complications is one of the important issues. Severe treatment-related complications shown in Table 3 (Reference 19). Treatments with the least to most related complications are as follows: 1) no surgery (follow-up), 2) unilateral surgery (lobectomy), 3) total thyroidectomy, and 4) total thyroidectomy + lymph node dissection. Therefore, we should not select total thyroidectomy with lymph node dissection due to concerns of recurrence or just in case. We should consider how to reduced treatment-related complications and select more conservative surgery as much as possible. >> Kitayama Is my thyroid cancer a slow growing cancer (abbreviated as a rabbit) or a very slow-growing type (abbreviated as a turtle) in Fig.1? How do you judge? >> Kakudo Very slow growth cancer by Welch (Reference 5) and IDLE by Essermann (Reference 6) are not disease names that correspond to histopathological criteria. These are concepts of cancers that do not progress and do not kill the patient, and do not require treatment. Finding and treating these by cancer screening harms society as a whole (psychologically intimidating the patient, harming the patient in the name of treatment, profits to doctors and hospitals, and negative economic impacts on the health care system and society). Epidemiologists are ringing a warning bell to the stop over-diagnosis and over-treatment of these tumors (5, 6, 11, 20-22). On the other hand, the histopathological risk classification using the Ki-67 proliferation index (Table 4) is carried out by immunohistochemical examination of surgical specimens. Thus, it is possible only for patients who underwent surgery. Thyroid borderline tumors with a Ki-67 labeling index less than 3% demonstrated almost no recurrence or metastasis. Low-risk cancer with a Ki-67 labeling index less than 5% can be cured if removed, moderate-risk cancer defined as a Ki-67 labeling index between 5 and 10% relapses in approximately 20% after surgery, and high-risk cancer with a Ki-67 labeling index between 10 and 30% has a high rate of recurrence and metastasis. High-risk thyroid cancer has a 5-year cause-specific survival rate of approximately 50%. I proposed this prognostic classification of thyroid tumors for designing post-surgical follow-up and further treatment. Many parts of borderline tumors and low-risk carcinoma in this classification overlap with Esserman’s IDLE and Welch’s very slow growing cancer, who advocated not to operate. The Ki-67 labeling index is evaluable only after surgery. Therefore, the borderline tumors and low-risk carcinoma in my classification are not exactly the same as IDLE and very slow growing cancer. Several methods assess tumor growth potential, which is useful in determining the surgical indication for thyroid cancer, determining the completeness of surgery, and predicting recurrent cases at different time points, 1) before surgery, 2) immediately after surgery, and 3) after relapse/metastasis (References 17, 23). How to measure/evaluate proliferative ability and how to predict/determine prognosis based on proliferative ability is shown in Table 5.

What can be elucidated from the pathology report?

>> Kakudo Let me explain the clinical flow of Kitayama’s case using Table 2 and Table 5. In the initial step of Kitayama’s case, there was a maximum probability of high-grade thyroid cancer of 3% (malignant lymphoma, C cell cancer, etc. in Table 1). FNA cytology confirmed that her thyroid nodules were papillary carcinomas and excluded high-grade cancers. There is a maximum risk of 5% of aggressive variants of papillary cancer, shown in Table 1, and moderate risk cancer, shown in Table 4. By histopathological examination of surgical specimens, these aggressive variants and moderate risk cancers were excluded, and it was confirmed it to be low-risk common (classic) papillary cancer. Therapeutic removal of the thyroid tumor and lymph nodes to confirm that the tumor is a low-risk tumor is also beneficial for the patient’s psychological state. Completeness of surgery can be examined using the surgical specimen (cut margins were negative for tumor, and no invasion over the thyroid capsule and lymph node capsule), and serum thyroglobulin (TG) measurements (TG value is low after total thyroidectomy) (Note 5). These results confirmed that this thyroid tumor was highly unlikely to recur and cause cancer death. I believe these observations created a great deal of leeway in the patient’s future life planning. For confirmation, I recommended that Dr. Kitayama undergo surgery instead of further follow-up. >> Kitayama Well, I remembered what I felt before surgery. It would be much better to be able to judge whether my thyroid tumor is a rabbit in need of treatment or a very slowly growing turtle by ultrasound or cytology. It would be great if the tumor is a turtle and surgery is not necessary. It was unfortunate that I was unable to confirm this without surgery because a postoperative specimen is necessary for definitive pathology diagnosis. At the moment, it is impossible. My thyroid cancer is probably a turtle, but I cannot eliminate the small possibility of moderate-risk cancer rabbits without surgery. I would choose surgery for a definitive diagnosis, whether it is a turtle or rabbit, using postoperative specimens. I agree with you that this step is useful, as removing the tumor is therapeutic and a low-risk tumor can be confirmed. It is essential to tell the patient that the prognosis is excellent after a definitive postoperative diagnosis. This information is a great help for the patient to have peace of mind for the rest of their life. Even after surgery, I would be delighted to know it was a turtle. I did not know much about what can be elucidated from the pathology report. After knowing the meanings, I am completely relieved. >> Kakudo I am pleased to hear that you understood my theory that the Ki-67 labeling index can predict the patients’ future. As Dr. Kitayama will have a healthy life expectancy, please think about your future life planning seriously. Of course, you can attend your children’s ceremonies and the faces of your grandchildren.

Peace of mind for the patient

>> Kitayama Come to think of it, dermatologists have a similar disease. Basal cell carcinoma is a tumor that does not metastasize/relapse and is cured after removal. However, even if the clinical diagnosis is basal cell carcinoma, it is necessary to confirm the excised specimen for definitive diagnosis. In the dermatology clinic, complete excision is performed for the time being. The diagnosis of basal cell carcinoma is confirmed by looking at the pathology specimen. After that, the dermatologist usually says, “It was okay; I was able to confirm that it was basal cell carcinoma. I removed all of it, so it has been cured.” This explanation is prepared in order for the patient to feel secure. The tumor names for skin cancer clearly distinguishes cancer with a risk of recurrence and metastasis from that cured by removal. If thyroid cancer made this distinction clear, patients may feel more peace of mind. >> Kakudo I think it is “problematic” to name both tumors as papillary cancers without distinguishing between cases with possible recurrence/cancer death and those with no recurrence/cancer death. More than 80% of papillary cancers do not recur and more than 99% of Stage I papillary cancer do not kill the patient. By naming them as cancer, many patients develop a “fear of recurrence/cancer death,” as Dr. Kitayama experienced. These patients often accept unnecessary over-surgery and radioiodine treatments because of the terminology. These overtreatments increase the rate of significant treatment-related complications and life-long thyroid hormone replacement therapy. In 2015, the NIFTP international conference was held in Boston, USA, and Ms. Kathryn B Wall (Thyroid Cancer Survivor Association Inc.) participated as a representative of the patient association and expressed her opinion. “If the non-invasive encapsulated papillary thyroid cancer follicular variant is a tumor that does not recur and the patient does not die, I strongly hope that the word cancer should not be included in the diagnosis.” The diagnostic name NIFTP was born. I thought we needed to hear more from the patient. I am working on renaming this low-risk tumor from cancer to borderline tumor (Reference 24-27). However, from surgeons and pathologists, there is strong opposition such as “Strangely, the patient does not have cancer and does not die,” “It is cancer because many have metastases,” “It is dangerous if the patient understands it is not cancer and does not come to the hospital,” “Patients are in trouble if they cannot use cancer insurance,” “It is also safer for the patient and doctor. Who should take responsibility if there is recurrence and the patient complains,” or “Shouldn’t it be cancer because cancer is better for hospital profit?” I downgraded very low-risk thyroid cancers (papillary microcarcinoma, encapsulated papillary carcinoma, and capsular invasion only follicular carcinoma) to a borderline tumor category independent of papillary thyroid cancer. However, there was resistance among clinicians/pathologists about referring to non-cancer/no operation as benign. Then, I proposed the risk stratification of thyroid carcinomas into low-risk, moderate-risk, and high-risk cancers using the Ki-67 labeling index. However, it did not distinguish between cancers causing death and those that did not recur or cause death. The distinction by name in dermatology between basal cell carcinoma with no recurrence and squamous cell carcinoma with possible recurrence is a good solution. It may be more comfortable for patients to use a completely different name, as in the dermatology field.

Notes

Note 1: The ultrasonographic diagnosis was papillary thyroid cancer. Irregular shapes, unclear boundaries, coarseness, heterogeneity, microcalcifications, etc., are suspected to be malignant on ultrasonography. Note 2: Operating on lesions less than 1 cm is optional, but if they are greater than 1 cm, surgical treatment is indicated, and if there is lymph node metastasis/extrathyroid extension, surgery is usually recommended. Note 3: If possible lobectomy is desired, there is a large difference in the patient burden (Table 3) between total thyroidectomy and lobectomy on one side (surgery to leave the other side). Most papillary cancer patients in Japan are treated by lobectomy. As this patient had lesions on both sides, it was decided that both should be excised. Note 4: Thyroid cancer has a favorable prognosis. According to a report by Ito et al. (Reference 4), the tumor-specific 10-year survival rate of Stage I papillary cancer was 99.8% and the 20-year survival rate was 99.3%. The prognosis of control subjects without thyroid cancer was similar. Although papillary thyroid cancer is called cancer, it has a different prognosis from other gastric cancers, colon cancer, lung cancer, etc. For example, Stage I lung cancer has a 5-year survival rate of 80% or less and 20% or more of patients die of lung cancer within 5 years, whereas thyroid cancer causes 0.7% of patients to die within 20 years. There is a greater than 2% chance of dying in 20 years at any age, and with Stage I thyroid cancer, most patients die of diseases other than thyroid cancer. Note 5: Normal thyroid follicular epithelium and well-differentiated cancers (papillary cancer and follicular cancer) produce thyroglobulin and secrete it into the blood. Thus, serum thyroglobulin is used as a tumor marker for thyroid cancer recurrence after total thyroidectomy. Thyroglobulin is usually low (< 2 ng/ml) in patients who underwent complete total thyroidectomy because they do not have thyroid tissue. However, it increases when there is metastasis/recurrence or thyroid tissue remains. The change in this value is considered to correlate with the amount of tumor tissue and tumor growth rate, and the doubling time of thyroglobulin is used to measure the tumor growth rate and determine the prognosis (Reference 23).

References

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