Liver Mass as First-Time Diagnosis of Sarcomatoid Anaplastic Thyroid Carcinoma: A Rare Malignancy Presenting at an Unexpected Body Site

Background

Anaplastic thyroid carcinoma (ATC) is an aggressive and usually fatal malignancy, classically presenting as a rapidly enlarging lower anterior neck mass in an elderly patient. It comprises 1.3–9.8% of all thyroid carcinomas [1]. While some patients with ATC have metastatic disease at the time of their original presentations, diagnoses of ATC are often based upon clinical, radiologic, and pathologic correlations centered on the workup of the primary disease in the neck. Metastases from primary ATC at the time of initial evaluation have been reported at various body sites, including but not limited to regional lymph nodes, lungs, liver, bone, GI tract, and brain [2]. We report an unusual case of a patient with ATC whose chief concern and clinical history were listed by the clinical team as “jaundice and liver mass” without mention of disease in the neck. Cytology slides were initially reviewed with only that information.

Case Report

Two days later, after core biopsy and the first round of IHC studies had been received, the pathology team discovered evidence of disease in the neck by performing review of the electronic medical record. A 66-year-old woman presented to the ED with concerns regarding jaundice. Her “yellow-green skin discoloration” had been worsening for a few weeks. She also reported worsening dyspnea and recent dysphagia with solid foods, in addition to fatigue, abdominal pain, and recent hemoptysis. Physical examination revealed conjunctival icterus, jaundice, a tender neck mass, right upper chest wall tenderness, and palpable lymphadenopathy in the lower neck. Assessment notes indicated inability to carry out self-care and being bedridden, even though she reported having been active, swimming and cycling, up to 1 month before her presentation. Imaging studies and clinical laboratory tests were performed.

CT scans confirmed findings compatible with widespread malignancy with mass lesions in her liver (Figure 1), lungs, adrenals, kidneys, neck (Figure 2), pancreas, gallbladder, and brain. Mild anemia, hemoglobin 10.5 g/dL, mild leukocytosis, and leukocytes 17 000/mm3 were confirmed. Bilirubin was 15 µmol/L and hepatic enzymes were elevated. An ultrasound-guided liver biopsy was performed and was evaluated for cytologic features (Figure 3), histologic features (Figure 4), and pattern of immunoreactivity (Figure 5). The combined cytomorphologic and histologic features were those of a pleomorphic sarcomatoid high-grade malignancy with variably spindled-to-epithelioid morphology and associated necrosis. Immunohistochemical studies performed on sections from the accompanying core biopsy confirmed the malignant cells to be positive with CK-AE1/AE3, CK 7, TTF-1, GATA3, PAX8, SATB2, and BRAF V600E. The malignant cells were nonreactive with CK 20, thyroglobulin, calcitonin, napsin, CDX2, PCEA, and ER.

The combined clinical setting, imaging findings, cytomorphology, histomorphology, and ancillary testing results together allowed for a specific diagnosis of metastatic anaplastic thyroid carcinoma. The patient was referred for palliative care services and died within a few days after diagnosis.

Discussion

ATC is the most undifferentiated form of high-grade follicular cell-derived thyroid neoplasm [3]. The classic presentation of ATC is that of a rapidly enlarging anterior lower neck mass in a person in the sixth or latter decades of life. This malignancy often invades adjacent structures, causing hoarseness, dysphagia, and dyspnea. These carcinomas are amongst the most aggressive primary thyroid malignancies and sometimes present with metastatic disease at the time of diagnosis, with involvement of regional lymph nodes and the lungs seen with greatest frequency at the time of presentation [3,4]. The median survival of patients with ATC is 4 months, and the disease is associated with a low (10–20%) median 1-year survival rate. Some genetic alterations found in ATCs are mutations in P53, BRAF V600E, RAS family, and TERT [5]. ATCs may develop in patients with goiter in regions of the world in which endemic goiter is more prevalent [3]. ATCs arise in backgrounds of pre-existing differentiated thyroid carcinomas. Current evidence does not support the theory that ATCs arise de novo [6].

The microscopic appearance of ATCs is highly variable in growth pattern and cytologic appearance. ATCs may show sarcomatoid, giant cell, and epithelioid morphologies. These morphologic appearances may occur singly or in admixed combinations. The sarcomatoid pattern is most common and is composed of malignant spindle cells, which resemble those in high-grade pleomorphic sarcomas. The giant cell pattern consists of highly pleomorphic large cells, some of which are multinucleated. Epithelial pattern ATCs show cohesive cell nests with moderately abundant cytoplasm that is often eosinophilic and may impart a squamoid appearance. True squamous differentiation with keratinization may be observed. Rare morphologies of ATC have also been described, including a paucicellular variant (which can mimic fibrosing Hashimoto’s), a rhabdoid variant, and a small cell carcinoma variant [3,7]. The diversity of histomorphologic appearances should be kept in mind when interpreting cytologic specimens, as mirroring features can be seen in cytologic preparations of the various major patterns and variant types.

PAX8 and TTF-1 are transcription factors that play a role in thyroid organogenesis. PAX8 IHC is variably positive in up to 79% of cases of ATC, but its sensitivity differs among histological subtypes. Thus, ruling out other primary malignancies and correlating PAX8 positivity with clinical, radiological, and morphological pictures is necessary for optimizing the use of this IHC marker in confirming diagnoses of metastatic ATC [1]. TTF-1 and thyroglobulin are often negative in IHC testing of ATCs. TTF-1 is retained in only 18% of ATC cases, a significantly lower percentage than for PAX8 [8]. TTF-1-positivity is expected in some metastatic lung carcinomas, an important differential to consider in the work up of ATC. BRAF V600E is frequently positive in anaplastic and differentiated thyroid carcinomas. When positive in conjunction with TTF-1 and PAX8, as in our case, it supports a diagnosis of ATC that likely arose from a differentiated cancer [9]. While positive GATA3 testing results may be of value in supporting a diagnosis of metastatic ATC from an un-confirmed primary, other diseases such as breast carcinomas, urothelial carcinomas, and mesotheliomas are also commonly GATA3-positive. It is prudent to include pankeratin IHC and calcitonin IHC in the workup of potential ATCs. It has been reported that 80% of ATCs are positive for keratins. A negative calcitonin is also useful in terms of ruling out medullary carcinoma of the thyroid, especially in conjunction with a negative result with CEA [1,10].

Histologically, ATCs often show necrosis, increased mitotic activity, and infiltrative patterns of growth. Vascular invasion is commonly present. In a recent study comparing cytomorphological features of ATC with differentiated thyroid carcinoma, the following features were statistically significant in confirming diagnoses of ATC: nuclear pleomorphism, coarse/ clumped chromatin, macronucleoli, apoptosis, and necrosis [4]. Considering morphologic features in concert is important, as some less poorly-differentiated thyroid carcinomas and even some benign lesions of the thyroid can show moderate to even marked areas of “endocrine atypia” [4].

Because our patient died shortly after diagnosis, she did not undergo thyroidectomy. Sadly, this is not an uncommon clinical course for ATC, and the disease is almost always fatal, with short survival periods. It is interesting that our patient did not present for medical care until she became jaundiced from metastatic disease, and the clinical care group chose to biopsy a large liver mass, providing the cytopathology team evaluating the case with a history of “jaundice and liver mass”. A drawback in this report is that an autopsy was not performed.

Conclusions

Metastatic disease from a sarcomatoid ATC, as diagnosed in this case, is an important differential diagnosis to keep in mind when an elderly patient presents with multisite metastases from an undefined primary source. Clinical, radiological, and laboratory correlations are of paramount importance in correlating with cytomorphology/histomorphology and in helping to determine the best panel of IHC studies to consider.