- Email: [email protected]
Anaplastic thyroid cancer in young patients: A contemporary review
AM ER IC AN JOUR NA L OF OTOLARY NG OLOG Y –H EA D A N D N E CK ME D I CI NE AN D SUR G E RY XX ( 2 0 13 ) XXX –XXX
Available online at www.sciencedirect.com
ScienceDirect www.elsevier.com/locate/amjoto
Anaplastic thyroid cancer in young patients: A contemporary review☆,☆☆ Mingsi Li, MD a , Mira Milas, MD b , Christian Nasr, MD c , Jennifer A. Brainard, MD d , Mumtaz J. Khan, MD a , Brian B. Burkey, MD a , Joseph Scharpf, MD a,⁎ a
Head and Neck Institute, Cleveland Clinic Foundation, Cleveland, OH Department of Endocrine Surgery, Cleveland Clinic Foundation c Department of Endocrinology, Cleveland Clinic Foundation d Department of Anatomical Pathology, Cleveland Clinic Foundation b
ARTI CLE I NFO
A BS TRACT
Article history:
Purpose: Little is known about prognostic factors and treatment outcomes in young patients
Received 17 June 2013
with anaplastic thyroid cancer (ATC). The goal of this study is to define the clinical features of this subgroup. Material and methods: Patients age 55 or younger with either ATC or well-differentiated thyroid cancer (WDTC) with anaplastic changes were identified using electronic medical record at the Cleveland Clinic. The same number of patients older than 55 was randomly selected to serve as control. Progression-free survival (PFS), overall survival time (OST) and cause-specific mortality (CSM) were measured against age, tumor histology, extent of disease, and treatment modalities. Results: Twelve patients age 55 or younger were identified. The median age was 51 years. Four patients had WDTC with anaplastic components — mixed tumor group (MTG). Their median PFS, OST, and CSM at 24 months were 21.5 months, 51 months, and 25%, respectively. For the other 8 patients who had pure ATC, their median PFS, OST, and CSM were 3.5 months, 6 months, and 100%, respectively. Patients in the MTG had better survival compared to the pure ATC and control group in terms of PFS (p = 0.0047 and p = 0.0053), OST (p = 0.0028 and p = 0.0029) and the CSM at 24 months (p = 0.0339 and p = 0.0096). In the pure ATC group, patients with positive cervical lymph node and distant metastases had similar overall survival outcomes (6 vs. 8 months, p = 0.4995). Conclusion: Prognostic factors favoring survival in young patients with ATC include ATC arising within WDTC. Once full anaplastic transformation occurs, age was not a significant factor in survival. © 2013 Elsevier Inc. All rights reserved.
1.
Introduction
Malignant thyroid cancers account for approximately 1% of all new cancers [1]. Of these, more than 95% of the cancers are
derived from the follicular epithelial cells of the thyroid gland and are further divided into subgroups depending on the degree of differentiation. These groups range from WDTC which comprises of > 90% of all thyroid cancer, including
☆
This protocol was approved by the Cleveland Clinic Institutional Review Board (IRB #11-733). Presentation: a poster of this manuscript was presented at the 8th International Conference on Head and Neck Cancer in Toronto, ON, Canada on July 21–25th, 2012. ⁎ Corresponding author. Head and Neck Institute, Cleveland Clinic Foundation, Cleveland, OH 44195. Tel: + 1 216 445 8252. E-mail address: [email protected] (J. Scharpf). ☆☆
0196-0709/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjoto.2013.07.008
Please cite this article as: Li M, et al, Anaplastic thyroid cancer in young patients: a contemporary review, Am J Otolaryngol– Head and Neck Med and Surg (2013), http://dx.doi.org/10.1016/j.amjoto.2013.07.008
2
AM ER IC AN JOURNAL OF OTOLARYNGO LOGY –H EAD AN D N E CK ME D I CI NE AN D SUR GE RY XX ( 2 0 13 ) XXX–X XX
papillary and follicular carcinoma, to the rare undifferentiated or ATC which encompasses less than 2%–5% of all thyroid malignancies [2–4]. Even though ATC accounts for only a small percentage of all thyroid malignancy, it is highly aggressive and is accountable for more than 50% of all thyroid cancerrelated deaths in the United States in 2006 [5]. ATC commonly arises in patient population older than age 60 with a peak incidence in the 6th to 7th decade of life [6]. Despite improved understanding of this disease in recent years, treatment options remain limited and largely ineffective due to the aggressive nature of the cancer. Most patients present with nodal involvement or distant metastasis at the time of diagnosis. Majority of patients with ATC eventually die within two years of diagnosis, and long-term survival is exceedingly rare. Furthermore, there are very few reports of ATC in the younger patient population. The literature mainly consists of case reports, and therefore very little is known about prognostic factors and treatment outcomes in this subgroup of patients. The goal of this study is to define the clinical features of this younger ATC subgroup and to identify factors that might influence the long-term survival.
2.
Methods
Patient data were retrospectively collected from a computer database at the Head and Neck Institute and the Department of Pathology at the Cleveland Clinic from the period of 1997– 2011. The inclusion criteria for subgroup analysis were age 55 years or younger at time of diagnosis showing either ATC or WDTC with anaplastic changes on pathology. Patients with only WDTC or poorly differentiated thyroid cancer without signs of anaplastic change were excluded. The diagnosis was confirmed by dedicated, subspecialty head and neck pathologists through histological analysis of surgical specimens or through cytology in cases where surgery could not be performed. For survival comparison, an equal number of patients older than age of 55 with ATC were randomly selected from the same computer database using the same criteria to serve as the control group. Standard descriptive statistics were used to analyze patient demographic information, surgical, pathological, and nonsurgical treatment and follow-up data. Presenting signs and symptoms were evaluated and included those reported by patients prior to diagnosis (Table 1). Patients in the younger age group were further divided into two separate groups depending on the tumor histology at the time of diagnosis — MTG and pure ATC group. The MTG consists of WDTC with early anaplastic transformation where the anaplastic component was less than 40% of the specimen. On the other hand, the purely ATC group consists of ATC without (or with minor foci of) well differentiated components. The extent of tumor involvement at the time of diagnosis was also evaluated and was divided into 4 groups — focal (intrathyroidal), local (extrathyroidal invasion of the surrounding soft tissue without regional lymph node metastasis), regional nodal involvement, and distant metastasis. The size of tumor was determined from imaging studies including ultrasound, computed tomography, magnetic resonance imaging or positron emission tomography. PFS was
Table 1 – Overall patient demographics.
N Median age (range) Gender Male Female Median tumor size (cm) Extend of disease at diagnosis Intrathyroidal Local Nodal Metastasis Clinical presentation Enlarging neck mass Hoarseness Dysphagia Dyspnea Respiratory distress
Younger age group (age < 55)
Control group (age > 55)
12 51 (38–55)
12 75.5 (66–83)
8 4 5.9 ± 2.53
3 9 5.6 ± 2.6
0 2 5 5
0 3 2 7
11 7 4 4 0
5 5 3 0 3
determined from the date of diagnosis to the date of documented progression. OST was determined from the date of diagnosis to the date of death or date of last follow-up. The overall CSM rates at 6, 12 and 24 months were also evaluated. PFS, OST, and CSM rates were measured against age, tumor histology, extent of disease at the time of diagnosis, and treatment modality. PFS and OST were analyzed using the Kaplan Meier analysis and survival comparisons were made using the log-rank test. All patients were followed until death, hospice, or up to December of 2011. This protocol was approved by the Cleveland Clinic Institutional Review Board.
3.
Results
A total of 12 patients, with age 55 or younger, were identified from the computer database. Demographic data are shown in Table 1. In this younger age group, the MTG consisted of 4 patients who were identified as having mixed histology with early anaplastic changes or anaplastic transformations arising in the background of existing well-differentiated thyroid malignancy (Table 2). The anaplastic component consisted of < 5% in 3 patients, and 30%–40% in one patient. The welldifferentiated components comprised some variants of papillary carcinoma with no features of follicular carcinoma. The patient in this group with the largest anaplastic component (30%–40% of the tumor) had the worst PFS of only 7 months compared to 20–30 months in the other patients of this group, and was also the only patient in the group who after the initial treatment developed metastatic disease to lungs, mediastinum and bone. In this group, two patients had local invasion and two patients had nodal disease at the time of diagnosis. All 4 patients underwent total thyroidectomy and radioactive iodine (RAI) ablation. Additionally, among patients with local disease, one patient received a central neck node dissection without chemotherapy or radiation and is alive at 30 months
Please cite this article as: Li M, et al, Anaplastic thyroid cancer in young patients: a contemporary review, Am J Otolaryngol– Head and Neck Med and Surg (2013), http://dx.doi.org/10.1016/j.amjoto.2013.07.008
AM ER IC AN JOUR NA L OF OTOLARY NG OLOG Y –H EA D A N D N E CK ME D I CI NE AN D SUR G E RY XX ( 2 0 13 ) XXX –XXX
Table 2 – Younger age group (age < 55). MTG N Extent of disease at diagnosis Intrathyroidal Local Nodal Metastasis Survival Progression-free survival (months) Overall survival time (months) Cause-specific mortality at 6 months at 12 months at 24 months
Pure ATC group
4
8
0 2 2 0
0 0 3 5
21.5 (range 7–30) 3.5 (range 2–7) 51 (range 23–51) 6 (range 3–14)
0% 0% 25%
57% 57% 100%
Abbreviations: MTG: Mixed Tumor Group; ATC: Anaplastic Thyroid Cancer.
of follow-up. The other patient, who died of disease at 23month time, received concurrent external beam radiation (EBR) of 60 Gray (Gy) with Adriamycin, Cisplatin and Paclitaxel. For the two patients with regional nodal disease, both received neck dissections with additional EBR of 60 Gy in one patient and an unknown dose in the other. The former also received chemotherapy with Paclitaxel and died at 51 months; the latter is alive at 26-month follow-up. It should be noted that, regardless of treatment modalities, all of these patients eventually succumbed to recurrent anaplastic disease within 2 years of diagnosis. In aggregate, the median PFS in this MTG was 21.5 months (range 7–30 months), the OST was 51 months (range 23–51 months), and the overall CSM rate at 6, 12 and 24 months was 0%, 0%, and 25%, respectively. The other 8 patients had pure ATC on histology and only two of these patients had additional small foci of papillary cancer (Table 2). In this pure ATC group, 3 patients had regional nodal diseases, 4 patients had pulmonary metastases and one patient had mediastinal and skeletal metastases. Among the 3 patients with only regional nodal disease, two patients received total thyroidectomy with concurrent EBR and chemotherapy. Additionally, one patient received bilateral neck dissection and the other one received pretracheal nodal dissection (death at 22 and 6 months respectively). The third patient received incisional biopsy without neck dissection followed by EBR and chemotherapy (death at 5 months). The dose of radiotherapy is 60 Gy, and the chemotherapy regimens consisted of Paclitaxel, Cisplatin, Etoposide or a combination of the three. Among the 5 patients with metastatic disease, two received surgical intervention; one underwent a total thyroidectomy and the other had a partial thyroidectomy; both patients also received additional definitive EBR and chemotherapy consisting of Paclitaxel or Adriamycin/Cisplatin (death at 13 and 14 months, respectively). Two other patients received only radiotherapy without surgical intervention; one with definitive radiotherapy of 60 Gy and the other with palliative EBR (death at 3 months for both). The last patient received incisional biopsy with planned palliative radiotherapy without chemotherapy (alive at 1 month follow-up). Neck dissection was not performed in
3
any of the patients with metastatic disease. Regardless of treatment, 7 out of 8 patients in pure ATC group eventually developed other distant metastasis including lungs, anterior mediastinum, orbit, pleura, pericardium, brain, liver, vertebra, pelvis or subcutaneous metastasis. As a whole, the median PFS of this pure ATC group was 3.5 months (range: 2– 7 months), the median OST was 6 months (range: 3– 14 months), and CSM rates at 6, 12, and 24 months were 57%, 57% and 100%. The OST in patients with nodal disease was 6 months compared to 8 months in patients with metastatic disease (p = 0.4995). Four patients in this subgroup were considered to have unresectable disease at the time of diagnosis and their median OST was 3 months following biopsy or palliative radiotherapy. Four patients with resectable disease who underwent total or partial surgical resection with additional definitive chemotherapy and radiotherapy had a median OST of 14 months (range 6–22 months, p = 0.0046). A total of 12 patients older than age of 55 were also randomly selected from the database to serve as control group for survival analysis. The detailed demographic data of these patients were shown in Table 1. In this control group, two patients were described as having ATC arising from the background of papillary cancer. However, the exact percentage of the anaplastic component was unclear, and therefore separation of the group based on histology was not made. The median PFS in this group was 2.5 months (range 1–15 months), median OST was 3.5 months (range 2–24 months), and CSM rate at 6, 12 and 24 months was 66%, 83%, 100%, respectively. Comparison of survival was made against the younger age group (Fig. 1). Compared to the MTG, the control group had significantly shorter PFS (2.5 vs. 23 months, p = 0.0053), OST (4.5 vs. 51 months, p = 0.0029) and CSM at 24 months (100% vs. 25%, p = 0.0096). However, when compared to the pure ATC group, the PFS (2.5 vs. 4 months, p = 0.8009), OST (4.5 vs. 6 months, p = 0.6631) and CSM rate at 24 months (100% vs. 100%, p = 0.5023), were not statistically significant.
Fig. 1 – Kaplan–Meier survival curve of ATC in control group, mixed tumor group and pure ATC group.
Please cite this article as: Li M, et al, Anaplastic thyroid cancer in young patients: a contemporary review, Am J Otolaryngol– Head and Neck Med and Surg (2013), http://dx.doi.org/10.1016/j.amjoto.2013.07.008
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AM ER IC AN JOURNAL OF OTOLARYNGO LOGY –H EAD AN D N E CK ME D I CI NE AN D SUR GE RY XX ( 2 0 13 ) XXX–X XX
4.
Discussion
ATC is a rare malignancy that occurs in elderly patients with a mean age at diagnosis of 71.3 years [7]. Younger patients have rarely been described in the literature, and mostly in case reports [8–12]. Demographically, previously reported female predominance was not observed in our series [7,13]. While the pathogenesis of ATC is currently unknown, it has been postulated that ATC can develop de novo or from existing WDTC that undergoes de-differentiation [14,15]. Histological evidence seemed to support the latter, as a large portion of patients with ATC tend to have mixed histology consisting of a combination of anaplastic and WDTC. A previous study has reported upward of 47% of ATC to be associated with WDTC [16]. Similar patterns were found in 33% of our patients, all of whom had papillary cancer as their well-differentiated component, suggesting that papillary thyroid carcinoma could be the most common type of WDTC associated with ATC. While there are previous reports of ATC arising from follicular origin, this was not observed in our series [17]. ATC is difficult to manage due to its propensity to grow rapidly, often within weeks to months from the initial onset of symptoms. Tumors limited within the thyroid gland are uncommon, and patients often present with advanced disease invading the surrounding soft tissues as well as the presence of nodal and distant metastasis at the time of diagnosis. Large retrospective studies found extrathyroidal extension or lymph node involvement in 38%–57% of patients; 25%–38% of patients had distant metastasis and only 8%–9% of patients had purely intrathyroidal disease [7,13]. Comparable results were found in our younger patient series where approximately 59% of patients had local or nodal invasion and 41% had metastatic disease at the time of diagnosis. However, patients with solely intrathyroidal disease were not identified. Interestingly, in patients whose ATC was only a small component of the overall tumor, distant metastases were much less prevalent suggesting that their cancer at least in the early period behaved more like WDTC than ATC. Our results also seem to support that as the percentage of the anaplastic component increases, the aggressiveness of the tumor increases as well and that approximately 75% of patients will eventually develop distant metastasis with the lung being the most common site followed by mediastinum, skeleton and brain, similar to the distribution described in previous studies [17]. However, due to rarity of ATC within this age group and the limited sample size, further studies are needed to determine if there is indeed a linear relationship between the anaplastic tumor burden and the rate of distant metastasis or recurrence of disease. Although it is likely that once the percentage of anaplastic component reaches a certain threshold in patients with mixed histology, the disease will progress at a rate similar to that of pure ATC regardless of the presence of concomitant WDTC. Traditionally, the diagnosis of ATC is almost uniformly fatal. A study by Kebebew et al. examining 516 ATC patients in all age groups using the National Cancer Institute’s Surveillance, Epidemiology, and End Results Data base (SEER) found an overall CSM rate of 68.4% at 6 months and
80.7% at 12 months [7]. Chang et al. report a mean survival time of 4.3 months in their study of 47 patients with ATC [17]. Despite our smaller sample size of 12 patients, we found that those patients with pure ATC on histology carried a significantly worse survival outcome compared to patients with mixed WDTC/ATC in terms of PFS (3.5 vs. 21.5 months, p = 0.0047), OST (6 vs. 51 months, p = 0.0028) and CSM rate at 24 months (100% vs. 25%, p = 0.0339). This was independent of age since similar results were found when compared to the control group. It is unclear from our small series whether this represents an earlier and more treatable stage of disease evolution or in fact an actual increase in survival. Since all the patients in the MTG eventually developed full anaplastic disease, it would be interesting to know if their disease progression would be similar to the pure ATC group after the transformation. Unfortunately, such data were not available and longer follow-up was needed. In the pure ATC group, no significant differences in OST were noted between patients with nodal disease and those with distant metastasis (6 vs. 8 months, p = 0.4995), suggesting that similar to WDTC, the presence of nodal metastasis had little bearing on long-term survival in ATC [4]. Finally, the treatment of ATC remained controversial as there are no established protocols shown to be largely effective in treating ATC, and that the management of ATC often consisted of a combination of surgery, radiotherapy and chemotherapy. Surgical treatment can be separated into palliative and oncological procedures. Palliative surgeries include tracheostomy and tumor debulking, whereas oncological procedures consist of thyroidectomy, neck dissection, partial laryngectomy and tracheal resection [18]. However, since advanced disease is commonly found at the time of presentation, oncological procedures were often unfeasible. It was established that surgery alone rarely offer an increase in survival except in the rare instances where the disease is confined to the thyroid gland. Once the tumor spreads outside of the thyroid, the effectiveness of surgery is uncertain. McIver et al. [19] found that despite complete tumor resection, survival was not affected, and given the aggressive nature of ATC, both radiotherapy and chemotherapy were often used in addition to surgery. Despite this common practice, the effectiveness of radiation and chemotherapy remained uncertain. Some studies reported that radiotherapy and chemotherapy in addition to surgery showed an improvement in survival [7,20–22], whereas others did not [17,19]. These issues will likely remain unresolved until further trials are established. Nevertheless, in our series, those patients with mixed histology all received total thyroidectomy with RAI therapy, and most patients also received additional neck dissection, radiation and chemotherapy. Their survival was fairly good, ranging from 23 to 51 months. In the pure ATC group, patients with resectable disease who received complete or partial resection of the tumor with EBR and chemotherapy had a significantly longer survival time compared to those with unresectable disease who received only biopsy or palliative radiotherapy (14 vs. 3 months, p = 0.0046). Based on these observations, we feel that a combination of surgery, RAI, neck dissection, EBR and chemotherapy can offer the best possibility for prolonged survival in patients with
Please cite this article as: Li M, et al, Anaplastic thyroid cancer in young patients: a contemporary review, Am J Otolaryngol– Head and Neck Med and Surg (2013), http://dx.doi.org/10.1016/j.amjoto.2013.07.008
AM ER IC AN JOUR NA L OF OTOLARY NG OLOG Y –H EA D A N D N E CK ME D I CI NE AN D SUR G E RY XX ( 2 0 13 ) XXX –XXX
ATC under the age of 55 and should be considered especially in patients with ATC as a minor component of their WDTC.
REFERENCES
[1] Sherman SI. Thyroid carcinoma. Lancet 2003;361:501–11. [2] Hundahl SA, Fleming ID, Fremgen AM, et al. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the US, 1985–1995. Cancer 1998;83: 2638–48. [3] Gilliland FD, Hunt WC, Morris DM, et al. Prognostic factors for thyroid carcinoma. A population-based study of 15,698 cases from the Surveillance, Epidemiology and End Results (SEER) program 1973–1991. Cancer 1997;79:564–673. [4] Sahaha AR. Management of the neck in thyroid cancer. Otolaryngol Clin North Am 1998;31:823–31. [5] Are C, Shaha AR. Anaplastic thyroid carcinoma: biology, pathogenesis, prognostic factors and treatment approaches. Ann Surg Oncol 2006;13:453–64. [6] Aschebrook-Kilfoy B, Ward MH, Sabra MM, et al. Thyroid cancer incidence patterns in the United States by histological type, 1992–2006. Thyroid 2011;21:125–34. [7] Kebebew E, Greenspan FS, Clark OH, et al. Anaplastic thyroid carcinoma treatment outcome and prognostic factors. Cancer 2005;103:1330–5. [8] Bezos Capelastegui J, Morales Angulo C, Garcia Mantilla J, et al. Anaplastic carcinoma of thyroid in a young man. A report of a case. An Otorrinolaryngol Ibero AM 1999;26: 413–9. [9] Vescini F, Di Gaetano P, Vigna E, et al. Anaplastic thyroid carcinoma in a 49 year-old woman with a long-standing goiter. A case report. Minerva Endocrinol 2000;25:81–3. [10] Pichardo-Lowden A, Durvesh S, Douglas S, et al. Anaplastic thyroid carcinoma in a young woman: a rare case of survival. Thyroid 2009;19:775–9.
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[11] Koussis H, Maruzzo M, Scola A, et al. A case of anaplastic thyroid cancer with long-term survival. Anticancer Res 2010;30:1273–8. [12] Alagöl F, Tanakol R, Boztepe H, et al. Anaplastic thyroid cancer with transient thyrotoxicosis: case report and literature review. Thyroid 1999;9:1029–32. [13] Kim TY, Kim KW, Jung TS, et al. Prognostic factors for Korean patients with anaplastic thyroid carcinoma. Head Neck 2007;29:765–72. [14] Wiseman SM, Loree TR, Rigual NR, et al. Anaplastic transformation of thyroid cancer: review of clinical, pathologic, and molecular evidence provides new insights into disease biology and future therapy. Head Neck 2003;25: 662–70. [15] Patel KN, Shaha AR. Poorly differentiated and anaplastic thyroid cancer. Cancer Control 2006;13:119–28. [16] Demeter JG, De Jong SA, Lawrence AM, et al. Anaplastic thyroid carcinoma: risk factors and outcome. Surgery 1991;110:956–63. [17] Chang HA, Nam KH, Chung WY, et al. Anaplastic thyroid carcinoma: a therapeutic dilemma. Yonsei Med J 2005;46: 759–64. [18] Cornett WR, Sharma AK, Day TA, et al. Anaplastic thyroid carcinoma: an overview. Curr Oncol Rep 2007;9:152–8. [19] McIver B, Hay ID, Giuffrida DF, et al. Anaplastic thyroid carcinoma: a 50-year experience at a single institution. Surgery 2001;130:1028–34. [20] Haigh PI, Ituarte P, Wu HS, et al. Completely resected anaplastic thyroid carcinoma combined with adjuvant chemotherapy and irradiation is associated with prolonged survival. Cancer 2001;91:2235–42. [21] Foote RL, Molina JR, Kasperbauer JL, et al. Enhanced survival in locoregionally confined anaplastic thyroid carcinoma: a single-institution experience using aggressive multimodal therapy. Thyroid 2011;21:25–30. [22] Brignardello E, Gallo M, Baldi I, et al. Anaplastic thyroid carcinoma: clinical outcome of 30 consecutive patients referred to a single institution in the past 5 years. Eur J Endocrinol 2007;156:425–30.
Please cite this article as: Li M, et al, Anaplastic thyroid cancer in young patients: a contemporary review, Am J Otolaryngol– Head and Neck Med and Surg (2013), http://dx.doi.org/10.1016/j.amjoto.2013.07.008
Available online at www.sciencedirect.com
ScienceDirect www.elsevier.com/locate/amjoto
Anaplastic thyroid cancer in young patients: A contemporary review☆,☆☆ Mingsi Li, MD a , Mira Milas, MD b , Christian Nasr, MD c , Jennifer A. Brainard, MD d , Mumtaz J. Khan, MD a , Brian B. Burkey, MD a , Joseph Scharpf, MD a,⁎ a
Head and Neck Institute, Cleveland Clinic Foundation, Cleveland, OH Department of Endocrine Surgery, Cleveland Clinic Foundation c Department of Endocrinology, Cleveland Clinic Foundation d Department of Anatomical Pathology, Cleveland Clinic Foundation b
ARTI CLE I NFO
A BS TRACT
Article history:
Purpose: Little is known about prognostic factors and treatment outcomes in young patients
Received 17 June 2013
with anaplastic thyroid cancer (ATC). The goal of this study is to define the clinical features of this subgroup. Material and methods: Patients age 55 or younger with either ATC or well-differentiated thyroid cancer (WDTC) with anaplastic changes were identified using electronic medical record at the Cleveland Clinic. The same number of patients older than 55 was randomly selected to serve as control. Progression-free survival (PFS), overall survival time (OST) and cause-specific mortality (CSM) were measured against age, tumor histology, extent of disease, and treatment modalities. Results: Twelve patients age 55 or younger were identified. The median age was 51 years. Four patients had WDTC with anaplastic components — mixed tumor group (MTG). Their median PFS, OST, and CSM at 24 months were 21.5 months, 51 months, and 25%, respectively. For the other 8 patients who had pure ATC, their median PFS, OST, and CSM were 3.5 months, 6 months, and 100%, respectively. Patients in the MTG had better survival compared to the pure ATC and control group in terms of PFS (p = 0.0047 and p = 0.0053), OST (p = 0.0028 and p = 0.0029) and the CSM at 24 months (p = 0.0339 and p = 0.0096). In the pure ATC group, patients with positive cervical lymph node and distant metastases had similar overall survival outcomes (6 vs. 8 months, p = 0.4995). Conclusion: Prognostic factors favoring survival in young patients with ATC include ATC arising within WDTC. Once full anaplastic transformation occurs, age was not a significant factor in survival. © 2013 Elsevier Inc. All rights reserved.
1.
Introduction
Malignant thyroid cancers account for approximately 1% of all new cancers [1]. Of these, more than 95% of the cancers are
derived from the follicular epithelial cells of the thyroid gland and are further divided into subgroups depending on the degree of differentiation. These groups range from WDTC which comprises of > 90% of all thyroid cancer, including
☆
This protocol was approved by the Cleveland Clinic Institutional Review Board (IRB #11-733). Presentation: a poster of this manuscript was presented at the 8th International Conference on Head and Neck Cancer in Toronto, ON, Canada on July 21–25th, 2012. ⁎ Corresponding author. Head and Neck Institute, Cleveland Clinic Foundation, Cleveland, OH 44195. Tel: + 1 216 445 8252. E-mail address: [email protected] (J. Scharpf). ☆☆
0196-0709/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjoto.2013.07.008
Please cite this article as: Li M, et al, Anaplastic thyroid cancer in young patients: a contemporary review, Am J Otolaryngol– Head and Neck Med and Surg (2013), http://dx.doi.org/10.1016/j.amjoto.2013.07.008
2
AM ER IC AN JOURNAL OF OTOLARYNGO LOGY –H EAD AN D N E CK ME D I CI NE AN D SUR GE RY XX ( 2 0 13 ) XXX–X XX
papillary and follicular carcinoma, to the rare undifferentiated or ATC which encompasses less than 2%–5% of all thyroid malignancies [2–4]. Even though ATC accounts for only a small percentage of all thyroid malignancy, it is highly aggressive and is accountable for more than 50% of all thyroid cancerrelated deaths in the United States in 2006 [5]. ATC commonly arises in patient population older than age 60 with a peak incidence in the 6th to 7th decade of life [6]. Despite improved understanding of this disease in recent years, treatment options remain limited and largely ineffective due to the aggressive nature of the cancer. Most patients present with nodal involvement or distant metastasis at the time of diagnosis. Majority of patients with ATC eventually die within two years of diagnosis, and long-term survival is exceedingly rare. Furthermore, there are very few reports of ATC in the younger patient population. The literature mainly consists of case reports, and therefore very little is known about prognostic factors and treatment outcomes in this subgroup of patients. The goal of this study is to define the clinical features of this younger ATC subgroup and to identify factors that might influence the long-term survival.
2.
Methods
Patient data were retrospectively collected from a computer database at the Head and Neck Institute and the Department of Pathology at the Cleveland Clinic from the period of 1997– 2011. The inclusion criteria for subgroup analysis were age 55 years or younger at time of diagnosis showing either ATC or WDTC with anaplastic changes on pathology. Patients with only WDTC or poorly differentiated thyroid cancer without signs of anaplastic change were excluded. The diagnosis was confirmed by dedicated, subspecialty head and neck pathologists through histological analysis of surgical specimens or through cytology in cases where surgery could not be performed. For survival comparison, an equal number of patients older than age of 55 with ATC were randomly selected from the same computer database using the same criteria to serve as the control group. Standard descriptive statistics were used to analyze patient demographic information, surgical, pathological, and nonsurgical treatment and follow-up data. Presenting signs and symptoms were evaluated and included those reported by patients prior to diagnosis (Table 1). Patients in the younger age group were further divided into two separate groups depending on the tumor histology at the time of diagnosis — MTG and pure ATC group. The MTG consists of WDTC with early anaplastic transformation where the anaplastic component was less than 40% of the specimen. On the other hand, the purely ATC group consists of ATC without (or with minor foci of) well differentiated components. The extent of tumor involvement at the time of diagnosis was also evaluated and was divided into 4 groups — focal (intrathyroidal), local (extrathyroidal invasion of the surrounding soft tissue without regional lymph node metastasis), regional nodal involvement, and distant metastasis. The size of tumor was determined from imaging studies including ultrasound, computed tomography, magnetic resonance imaging or positron emission tomography. PFS was
Table 1 – Overall patient demographics.
N Median age (range) Gender Male Female Median tumor size (cm) Extend of disease at diagnosis Intrathyroidal Local Nodal Metastasis Clinical presentation Enlarging neck mass Hoarseness Dysphagia Dyspnea Respiratory distress
Younger age group (age < 55)
Control group (age > 55)
12 51 (38–55)
12 75.5 (66–83)
8 4 5.9 ± 2.53
3 9 5.6 ± 2.6
0 2 5 5
0 3 2 7
11 7 4 4 0
5 5 3 0 3
determined from the date of diagnosis to the date of documented progression. OST was determined from the date of diagnosis to the date of death or date of last follow-up. The overall CSM rates at 6, 12 and 24 months were also evaluated. PFS, OST, and CSM rates were measured against age, tumor histology, extent of disease at the time of diagnosis, and treatment modality. PFS and OST were analyzed using the Kaplan Meier analysis and survival comparisons were made using the log-rank test. All patients were followed until death, hospice, or up to December of 2011. This protocol was approved by the Cleveland Clinic Institutional Review Board.
3.
Results
A total of 12 patients, with age 55 or younger, were identified from the computer database. Demographic data are shown in Table 1. In this younger age group, the MTG consisted of 4 patients who were identified as having mixed histology with early anaplastic changes or anaplastic transformations arising in the background of existing well-differentiated thyroid malignancy (Table 2). The anaplastic component consisted of < 5% in 3 patients, and 30%–40% in one patient. The welldifferentiated components comprised some variants of papillary carcinoma with no features of follicular carcinoma. The patient in this group with the largest anaplastic component (30%–40% of the tumor) had the worst PFS of only 7 months compared to 20–30 months in the other patients of this group, and was also the only patient in the group who after the initial treatment developed metastatic disease to lungs, mediastinum and bone. In this group, two patients had local invasion and two patients had nodal disease at the time of diagnosis. All 4 patients underwent total thyroidectomy and radioactive iodine (RAI) ablation. Additionally, among patients with local disease, one patient received a central neck node dissection without chemotherapy or radiation and is alive at 30 months
Please cite this article as: Li M, et al, Anaplastic thyroid cancer in young patients: a contemporary review, Am J Otolaryngol– Head and Neck Med and Surg (2013), http://dx.doi.org/10.1016/j.amjoto.2013.07.008
AM ER IC AN JOUR NA L OF OTOLARY NG OLOG Y –H EA D A N D N E CK ME D I CI NE AN D SUR G E RY XX ( 2 0 13 ) XXX –XXX
Table 2 – Younger age group (age < 55). MTG N Extent of disease at diagnosis Intrathyroidal Local Nodal Metastasis Survival Progression-free survival (months) Overall survival time (months) Cause-specific mortality at 6 months at 12 months at 24 months
Pure ATC group
4
8
0 2 2 0
0 0 3 5
21.5 (range 7–30) 3.5 (range 2–7) 51 (range 23–51) 6 (range 3–14)
0% 0% 25%
57% 57% 100%
Abbreviations: MTG: Mixed Tumor Group; ATC: Anaplastic Thyroid Cancer.
of follow-up. The other patient, who died of disease at 23month time, received concurrent external beam radiation (EBR) of 60 Gray (Gy) with Adriamycin, Cisplatin and Paclitaxel. For the two patients with regional nodal disease, both received neck dissections with additional EBR of 60 Gy in one patient and an unknown dose in the other. The former also received chemotherapy with Paclitaxel and died at 51 months; the latter is alive at 26-month follow-up. It should be noted that, regardless of treatment modalities, all of these patients eventually succumbed to recurrent anaplastic disease within 2 years of diagnosis. In aggregate, the median PFS in this MTG was 21.5 months (range 7–30 months), the OST was 51 months (range 23–51 months), and the overall CSM rate at 6, 12 and 24 months was 0%, 0%, and 25%, respectively. The other 8 patients had pure ATC on histology and only two of these patients had additional small foci of papillary cancer (Table 2). In this pure ATC group, 3 patients had regional nodal diseases, 4 patients had pulmonary metastases and one patient had mediastinal and skeletal metastases. Among the 3 patients with only regional nodal disease, two patients received total thyroidectomy with concurrent EBR and chemotherapy. Additionally, one patient received bilateral neck dissection and the other one received pretracheal nodal dissection (death at 22 and 6 months respectively). The third patient received incisional biopsy without neck dissection followed by EBR and chemotherapy (death at 5 months). The dose of radiotherapy is 60 Gy, and the chemotherapy regimens consisted of Paclitaxel, Cisplatin, Etoposide or a combination of the three. Among the 5 patients with metastatic disease, two received surgical intervention; one underwent a total thyroidectomy and the other had a partial thyroidectomy; both patients also received additional definitive EBR and chemotherapy consisting of Paclitaxel or Adriamycin/Cisplatin (death at 13 and 14 months, respectively). Two other patients received only radiotherapy without surgical intervention; one with definitive radiotherapy of 60 Gy and the other with palliative EBR (death at 3 months for both). The last patient received incisional biopsy with planned palliative radiotherapy without chemotherapy (alive at 1 month follow-up). Neck dissection was not performed in
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any of the patients with metastatic disease. Regardless of treatment, 7 out of 8 patients in pure ATC group eventually developed other distant metastasis including lungs, anterior mediastinum, orbit, pleura, pericardium, brain, liver, vertebra, pelvis or subcutaneous metastasis. As a whole, the median PFS of this pure ATC group was 3.5 months (range: 2– 7 months), the median OST was 6 months (range: 3– 14 months), and CSM rates at 6, 12, and 24 months were 57%, 57% and 100%. The OST in patients with nodal disease was 6 months compared to 8 months in patients with metastatic disease (p = 0.4995). Four patients in this subgroup were considered to have unresectable disease at the time of diagnosis and their median OST was 3 months following biopsy or palliative radiotherapy. Four patients with resectable disease who underwent total or partial surgical resection with additional definitive chemotherapy and radiotherapy had a median OST of 14 months (range 6–22 months, p = 0.0046). A total of 12 patients older than age of 55 were also randomly selected from the database to serve as control group for survival analysis. The detailed demographic data of these patients were shown in Table 1. In this control group, two patients were described as having ATC arising from the background of papillary cancer. However, the exact percentage of the anaplastic component was unclear, and therefore separation of the group based on histology was not made. The median PFS in this group was 2.5 months (range 1–15 months), median OST was 3.5 months (range 2–24 months), and CSM rate at 6, 12 and 24 months was 66%, 83%, 100%, respectively. Comparison of survival was made against the younger age group (Fig. 1). Compared to the MTG, the control group had significantly shorter PFS (2.5 vs. 23 months, p = 0.0053), OST (4.5 vs. 51 months, p = 0.0029) and CSM at 24 months (100% vs. 25%, p = 0.0096). However, when compared to the pure ATC group, the PFS (2.5 vs. 4 months, p = 0.8009), OST (4.5 vs. 6 months, p = 0.6631) and CSM rate at 24 months (100% vs. 100%, p = 0.5023), were not statistically significant.
Fig. 1 – Kaplan–Meier survival curve of ATC in control group, mixed tumor group and pure ATC group.
Please cite this article as: Li M, et al, Anaplastic thyroid cancer in young patients: a contemporary review, Am J Otolaryngol– Head and Neck Med and Surg (2013), http://dx.doi.org/10.1016/j.amjoto.2013.07.008
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AM ER IC AN JOURNAL OF OTOLARYNGO LOGY –H EAD AN D N E CK ME D I CI NE AN D SUR GE RY XX ( 2 0 13 ) XXX–X XX
4.
Discussion
ATC is a rare malignancy that occurs in elderly patients with a mean age at diagnosis of 71.3 years [7]. Younger patients have rarely been described in the literature, and mostly in case reports [8–12]. Demographically, previously reported female predominance was not observed in our series [7,13]. While the pathogenesis of ATC is currently unknown, it has been postulated that ATC can develop de novo or from existing WDTC that undergoes de-differentiation [14,15]. Histological evidence seemed to support the latter, as a large portion of patients with ATC tend to have mixed histology consisting of a combination of anaplastic and WDTC. A previous study has reported upward of 47% of ATC to be associated with WDTC [16]. Similar patterns were found in 33% of our patients, all of whom had papillary cancer as their well-differentiated component, suggesting that papillary thyroid carcinoma could be the most common type of WDTC associated with ATC. While there are previous reports of ATC arising from follicular origin, this was not observed in our series [17]. ATC is difficult to manage due to its propensity to grow rapidly, often within weeks to months from the initial onset of symptoms. Tumors limited within the thyroid gland are uncommon, and patients often present with advanced disease invading the surrounding soft tissues as well as the presence of nodal and distant metastasis at the time of diagnosis. Large retrospective studies found extrathyroidal extension or lymph node involvement in 38%–57% of patients; 25%–38% of patients had distant metastasis and only 8%–9% of patients had purely intrathyroidal disease [7,13]. Comparable results were found in our younger patient series where approximately 59% of patients had local or nodal invasion and 41% had metastatic disease at the time of diagnosis. However, patients with solely intrathyroidal disease were not identified. Interestingly, in patients whose ATC was only a small component of the overall tumor, distant metastases were much less prevalent suggesting that their cancer at least in the early period behaved more like WDTC than ATC. Our results also seem to support that as the percentage of the anaplastic component increases, the aggressiveness of the tumor increases as well and that approximately 75% of patients will eventually develop distant metastasis with the lung being the most common site followed by mediastinum, skeleton and brain, similar to the distribution described in previous studies [17]. However, due to rarity of ATC within this age group and the limited sample size, further studies are needed to determine if there is indeed a linear relationship between the anaplastic tumor burden and the rate of distant metastasis or recurrence of disease. Although it is likely that once the percentage of anaplastic component reaches a certain threshold in patients with mixed histology, the disease will progress at a rate similar to that of pure ATC regardless of the presence of concomitant WDTC. Traditionally, the diagnosis of ATC is almost uniformly fatal. A study by Kebebew et al. examining 516 ATC patients in all age groups using the National Cancer Institute’s Surveillance, Epidemiology, and End Results Data base (SEER) found an overall CSM rate of 68.4% at 6 months and
80.7% at 12 months [7]. Chang et al. report a mean survival time of 4.3 months in their study of 47 patients with ATC [17]. Despite our smaller sample size of 12 patients, we found that those patients with pure ATC on histology carried a significantly worse survival outcome compared to patients with mixed WDTC/ATC in terms of PFS (3.5 vs. 21.5 months, p = 0.0047), OST (6 vs. 51 months, p = 0.0028) and CSM rate at 24 months (100% vs. 25%, p = 0.0339). This was independent of age since similar results were found when compared to the control group. It is unclear from our small series whether this represents an earlier and more treatable stage of disease evolution or in fact an actual increase in survival. Since all the patients in the MTG eventually developed full anaplastic disease, it would be interesting to know if their disease progression would be similar to the pure ATC group after the transformation. Unfortunately, such data were not available and longer follow-up was needed. In the pure ATC group, no significant differences in OST were noted between patients with nodal disease and those with distant metastasis (6 vs. 8 months, p = 0.4995), suggesting that similar to WDTC, the presence of nodal metastasis had little bearing on long-term survival in ATC [4]. Finally, the treatment of ATC remained controversial as there are no established protocols shown to be largely effective in treating ATC, and that the management of ATC often consisted of a combination of surgery, radiotherapy and chemotherapy. Surgical treatment can be separated into palliative and oncological procedures. Palliative surgeries include tracheostomy and tumor debulking, whereas oncological procedures consist of thyroidectomy, neck dissection, partial laryngectomy and tracheal resection [18]. However, since advanced disease is commonly found at the time of presentation, oncological procedures were often unfeasible. It was established that surgery alone rarely offer an increase in survival except in the rare instances where the disease is confined to the thyroid gland. Once the tumor spreads outside of the thyroid, the effectiveness of surgery is uncertain. McIver et al. [19] found that despite complete tumor resection, survival was not affected, and given the aggressive nature of ATC, both radiotherapy and chemotherapy were often used in addition to surgery. Despite this common practice, the effectiveness of radiation and chemotherapy remained uncertain. Some studies reported that radiotherapy and chemotherapy in addition to surgery showed an improvement in survival [7,20–22], whereas others did not [17,19]. These issues will likely remain unresolved until further trials are established. Nevertheless, in our series, those patients with mixed histology all received total thyroidectomy with RAI therapy, and most patients also received additional neck dissection, radiation and chemotherapy. Their survival was fairly good, ranging from 23 to 51 months. In the pure ATC group, patients with resectable disease who received complete or partial resection of the tumor with EBR and chemotherapy had a significantly longer survival time compared to those with unresectable disease who received only biopsy or palliative radiotherapy (14 vs. 3 months, p = 0.0046). Based on these observations, we feel that a combination of surgery, RAI, neck dissection, EBR and chemotherapy can offer the best possibility for prolonged survival in patients with
Please cite this article as: Li M, et al, Anaplastic thyroid cancer in young patients: a contemporary review, Am J Otolaryngol– Head and Neck Med and Surg (2013), http://dx.doi.org/10.1016/j.amjoto.2013.07.008
AM ER IC AN JOUR NA L OF OTOLARY NG OLOG Y –H EA D A N D N E CK ME D I CI NE AN D SUR G E RY XX ( 2 0 13 ) XXX –XXX
ATC under the age of 55 and should be considered especially in patients with ATC as a minor component of their WDTC.
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Please cite this article as: Li M, et al, Anaplastic thyroid cancer in young patients: a contemporary review, Am J Otolaryngol– Head and Neck Med and Surg (2013), http://dx.doi.org/10.1016/j.amjoto.2013.07.008