James P Dworkin-Valenti*, Esmael H Amjad, Noah Stern and Samba SR Bathula
Department of Otolaryngology, Head & Neck Surgery, Detroit Medical Center, Detroit, Michigan, USA
Received: 04 December, 2017; Accepted: 28 December, 2017; Published: 29 December, 2017
Dworkin-Valenti JP, Ph.D., Department of Otolaryngology, Head & Neck Surgery, Detroit Medical Center, Detroit, Michigan, USA, 5807 Cedar Ridge Dr. Ann Arbor, MIM, USA, 48103, E-Mail:
Dworkin-Valenti JP, Amjad EH, Stern N, Samba SR Bathula (2017) Aggressive Thyroid Gland Carcinoma: A Case Series. Arch Otolaryngol Rhinol 3(4): 129-137. DOI: 10.17352/2455-1759.000064
© 2017 Dworkin-Valenti JP, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
In 2017 there were approximately 62000 new cases of thyroid cancer (TC) in the United States, with a death toll of less than 5%. This relatively low mortality rate is based on a grouping of all TC subtypes, which masks the small minority of patients with biologically aggressive tumors who have dismal prognoses for survival. The paper begins with a brief overview of TC variants relative to their alternative differential diagnostic characteristics, risk factors, and treatment options. We then proceed with presentations of 5 patients with different forms of aggressive TC, two of whom suffered from very rare collision tumor subtypes. Four of these individuals died of persistent disease, notwithstanding complex treatments with curative intent; the fifth patient suffers from metastatic disease and numerous postoperative morbidities. This case series highlights the significant shortcomings of current diagnostic and treatment methodologies for aggressive thyroid gland tumors. We discuss our clinical experiences with these patients, and we offer suggestions regarding methods that might facilitate early identification of aggressive TC and rational treatment decisions.
The lifetime relative risk of developing thyroid cancer (TC) is 1.2%. According to the American Cancer Society there were 62000 new cases of TC in the United States over the past year, which accounted for 3% of all new cancer diagnoses. There is a 4:1 female to male incidence ratio. Virtually all thyroid gland tumors present as palpable neck masses that can be evaluated via fine needle aspiration procedures followed by cytological appraisal (FNAC). The vast majority of these masses are benign lesions that may or may not require intervention. When FNAC or open biopsy of a suspicious growth reveals underlying malignancy, there is a 90% chance that the diagnosis of a well-differentiated TC will be rendered [1-3]. In each case, after appropriate treatments, the long-term prognosis for disease free survival is usually very good [4,5]. Whereas the exact mechanism for malignant tissue transformation and growth remains unclear, a causal association has been shown in many individuals whose histories include X-ray treatments for tonsillitis, thymus gland edema, acne, and cancers such as Hodgkin’s disease . Interestingly, numerous cases of TC were reported by health authorities following the Chernobyl nuclear plant melt-down [7,8].
Papillary TC is the most common type, accounting for approximately 80% of all patients with thyroid malignancies. This tumor variant is usually slowly growing or indolent, and often only involves one lobe of the gland. Diagnosis is normally achieved via FNAC. Treatment modalities usually include total thyroidectomy (+/- central neck dissection, +/- radioactive iodine treatment [RAI]) . The histological features of the tumor and clinical presentation of the patient are important predictors, relative to treatment choice, local-regional control, and disease free survival. Tall cell, columnar cell, solid, diffuse sclerosing, and some follicular variants are considered aggressive subtypes of papillary TC. In general, patients with extra-thyroidal extension, nodal disease, and/or distant metastasis are considered to have poorer prognoses from the outset .
Follicular TC is the second most common (~10%) malignancy of the thyroid gland, and it usually presents as a solitary tumor. Classically, it is defined as a carcinoma with follicular cell differentiation that lacks papillary nuclear features . These papillary nuclear features, when identified during pathological analysis, constitute a diagnosis of a follicular variant of papillary TC .
There are three subtypes of follicular TC: 1) minimally invasive without angioinvasion, 2) minimally invasive with angioinvasion, and 3) widely invasive. High risk patients are those who present with any one or more of the following conditions: over 45 years of age, tumors greater than 4 cm, extra-capsular invasion, extra-thyroidal disease, widely invasive tumor, angioinvasion, and Hurthle cell features . Total thyroidectomy is usually the treatment of choice for all high risk patients; level VI neck dissection is often recommended for those with nodal disease . Because tumor invasion is only detectable at the level of the gland capsule, FNAC has a limited role in patients with follicular TC; excision biopsy is most often required for the differential diagnosis .
Medullary TC arises from parafollicular C-cells of the thyroid gland. This tumor type accounts for about 4% of all thyroid gland malignancies . Diagnosis often is achieved via FNAC . Total thyroidectomy with prophylactic or therapeutic central neck dissection (level VI) is considered the standard of care. Because this tumor subtype doesn’t concentrate iodine, RAI treatment is not effective . External beam radiation may be considered for those patients with postoperative residual disease and for those with distant metastasis. However, overall survival following such adjuvant therapy may not be significantly improved [18,19]. Chemotherapy is considered when surgery and/or radiation therapy are not options [20-23]. Overall, 10-year survival rate is 90% when the disease is confined to the thyroid gland; involvement of cervical lymph nodes and/or distant sites reduces this rate to 70% and 20%, respectively [24-29].
Mucoepidermoid carcinomas, sclerosing mucoepidermoid carcinomas with eosinophilia, squamous cell carcinomas, and mucinous carcinomas are considered thyroid gland epithelial tumors of uncertain cell origin [30-34]. For mucoepidermoid TC, total thyroidectomy often yields a good prognosis; the remaining epithelial subtypes often act rather aggressively with poor prognoses, irrespective of treatments rendered [35-37].
Insular thyroid gland carcinoma is a very rare entity, with recurrence/metastasis rates ranging from 20% to 60%; the 10-year mortality rate ranges from 13% to 41% [38-42]. For this subtype, total thyroidectomy plus central lymphadenectomy are often the treatments of choice; followed by prophylactic RAI, which may improve survival . Anaplastic TC is another very rare disease. It is observed most often in older females and in those with preexisting goiter or follicular or papillary TC. Even with aggressive palliative treatment, this disease is almost always fatal within the first year. Surgical resection, with adjuvant chemoradiation therapy, may improve survival and quality of life [44,45].
Mixed medullary and follicular carcinomas [46,47], mixed medullary and papillary carcinomas , papillary and squamous cell carcinomas [49,53], and follicular and squamous cell carcinomas of the thyroid gland represent collision tumor variants . These are also very rare conditions with dismal prognoses in most cases, irrespective of the traditional surgical or adjuvant treatment alternatives that may be employed for control.
When grouped together, the five year survival for all patients with TC is greater than 95%. However, when segregated, there are tumor subgroups that act very aggressively. These variants of thyroid gland malignancies are often fatal. For patients with these cancers, comprehensive diagnostic testing is of paramount importance to the formation of prompt, appropriate, and rational treatment recommendations. Currently, most standard surgical and non-surgical approaches to management are less than effective for these unfortunate individuals.
The primary objective of this paper is to present a series of patients who were referred to our department for differential diagnoses and treatments of thyroid gland masses that were later delineated as aggressive cancers with very poor prognoses. The full work-up, treatment paradigm, clinical course, and final outcome in each case are described in detail along with a comprehensive discussion about the important pathological distinctions and similarities between commonly occurring non-aggressive thyroid carcinomas and their rare aggressive counterparts.
This investigation is based on retrospective chart reviews of 5 patients with unusually aggressive thyroid cancer variants. Specific focus during analysis of each patient’s chart was placed on: 1) clinical presenting symptoms, 2) results of the physical examination, 3) thyroid ultrasound and CT and MRI scan findings, 4) preliminary cytopathology results obtained via FNAC or excisional biopsy, 5) thyroid specimen pathology post-operatively, 6) all treatments rendered, and 7) final outcomes relative to local control and disease free survival. All 5 patients were treated by board certified otolaryngologists at the Detroit Medical Center. All chart data and pathology specimens were independently analyzed by at least 2 pathologists or otolaryngologists to ensure inter-rater reliability of all results reported. When rater differences were noted, discrepant chart extractions were reviewed carefully with the outcome objective of achieving 100% inter-rater agreement for each of the pertinent study variables listed above. To be included in this case series each patient had to present initially with an abnormal thyroid mass that proved to be an unusually aggressive form of cancer; the poor clinical course and treatment outcome in each case could not have been attributable to significant co-morbid medical conditions.
Charts of 5 female patients who met the previously defined inclusion criteria were comprehensively analyzed by the team of judges to assemble the data described below for each case. Inter-rater agreement achieved the benchmark of 100% for the specific focus points of this investigation, as listed earlier. Summarily, two patients were middle aged and three were elderly. Their diagnoses varied as follows: 1) well-differentiated follicular variant of papillary thyroid carcinoma with lympho-vascular and capsular invasion, 2) well-differentiated mixed papillary and follicular variant of papillary thyroid carcinoma with lympho-vascular and capsular invasion, 3) poorly differentiated insular thyroid carcinoma, 4) poorly differentiated follicular thyroid carcinoma with widely invasive malignant high grade neuroendocrine carcinoma (collision tumor), and 5) moderately well-differentiated papillary thyroid carcinoma with poorly differentiated squamous cell carcinoma (collision tumor).
This is a 68 year old African American female who presented with a 3 month history of a left sided painful neck mass. Past medical history was negative for radiation exposure. She had breast cancer for which she had undergone a right modified radical mastectomy and adjuvant chemotherapy 12 years earlier. Social history was positive for cigarette smoking. There was no history of thyroid cancer among her family members. Clinical examination revealed a 2X2 cm lymph node in the left supraclavicular region. Due to excessive adipose neck tissue, the thyroid was not able to be appreciated. Laryngoscopic findings were normal. A neck MRI with contrast was obtained because the patient refused CT imaging. The MRI revealed a large left thyroid mass with extensive involvement of neck structures, including a tumor thrombus in the left internal jugular vein and a subcarinal lymph node. Thyroid gland core biopsy results demonstrated papillary thyroid carcinoma. A PET CT scan showed FDG avidity in the left thyroid lobe, left side of the neck, and left sacral ala. The patient refused a recommended sacral biopsy. The cancer was staged as T4bN1bMx. The Tumor Board recommendation was for adjuvant RAI after surgical management. The patient underwent a total thyroidectomy, left radical neck dissection, mediastinoscopy with mediastinal lymphadenectomy. Intra-operatively, the tumor encircled the vagus & recurrent laryngeal nerves on the left, and was tightly adhered to the left carotid artery with a concurrently thrombosed left internal jugular vein. The right thyroid gland was grossly uninvolved.
The final pathology result was consistent with a well-differentiated follicular variant of papillary thyroid carcinoma. The tumor size, localized to the left, was 5 cm in its greatest dimension with significant capsular invasion and extra-thyroidal extension, lympho-vascular invasion, and involvement of two level 2 nodes with extra-nodal extension. There was also transmural invasion of the left internal jugular vein. The right thyroid lobe was free of disease. Figure 1 illustrates the pathological features of this patient’s thyroid carcinoma as described.