The Warthin-like variant of papillary thyroid carcinomas: a clinicopathologic analysis report of two cases

Case 1

A 60-year-old man presented with a complaint of a neck tumor. The patient did not report tenderness, polyphagia, or emaciation. Physical examination revealed a painless mass measuring 1.5 × 1.5 cm on the left lobe of the thyroid gland; the mass had a smooth surface and moved up and down with swallowing. The right lobe of the thyroid gland appeared normal, and no vascular murmurs were detected. Thyroid ultrasound revealed diffuse lesions in the thyroid gland. Two solid nodules were detected on the left side of the thyroid, with Thyroid Imaging Reporting and Data System (TIRADS) classifications of 3 and 3–4. No abnormal lymph nodes were found on either side of the neck (Figure 1A). Laboratory test results showed increased thyroid hormone levels (151.92 nmol/L) and decreased thyroid stimulating hormone (TSH; 0.1621 nIU/L).

Figure 1:

Thyroid ultrasound and HE staining results of case 1. (A) Thyroid ultrasound image shows a solid nodule in the left lobe of the thyroid gland. (B) The tumor cells in the central area exhibited solid nests growth while lining the papillae and gland growth in the surrounding area. HE 100×. (C) Neoplastic cells show the cytological features of PTC. HE 400×.

The patient underwent left and isthmus thyroidectomy. The tumor was sent for frozen-section pathological examination, which confirmed the presence of PTC. As per institutional guidelines, the patient then underwent left neck lymphadenectomy. A gross examination of the tumor revealed a pale white-tan nodule measuring 1 cm, with a clear boundary and medium consistency. The specimens were fixed in buffered formalin for 24 h, embedded in paraffin, cut into 4 µm slides, and stained with hematoxylin and eosin. Microscopic examination of the tumor showed two different histological structures: tumor cells in the central area exhibiting solid nests, and the surrounding papillary processes and glands. The cores of the papillae and glands contained dense lymphoid cells with focal germinal centers. At high magnification, the tumor exhibited papillary structure surrounded by a monolayer or pseudostratified epithelium. The neoplastic cells showed eosinophilic cytoplasm with characteristic cytological features of PTC, including ground glass appearance, nuclear groove, and psammoma bodies (Figure 1B and C). Immunohistochemistry analysis revealed that the tumor cells were strongly positive for cytokeratin 19 (CK19) (Figure 2A), thyroid transcription factor 1 (TTF-1) (Figure 2B), Galectin-3 (Figure 2C), Braf-V600E mutation (Figure 2D), marker MC (Figure 2E), and marker CK (data not shown). The tumor cells showed weak focal positivity for thyroglobulin (data not shown). The Ki-67 proliferative index was approximately 5 % (Figure 2F). Gene mutations analysis detected a BRAF V600E mutation in the tumor (Figure 3).

Figure 2:

Immunohistochemistry (IHC) results of case 1 (IHC 100×). (A) The tumor cells were positive for CK19, (B) the tumor cells were positive for TTF-1. (C) The tumor cells were positive for Galectin-3. (D) The tumor cells were positive for Braf-V600E. (E) The tumor cells were positive for MC. (F) The IHC result shows a low Ki-67 proliferative index.

Figure 3:

Detection of gene mutations BRAF V600E showed that the tumor was mutant.

Based on these results, the patient was diagnosed with WLV-PTC without lymph node metastasis. The patient had a good postoperative recovery and no obvious abnormalities were found during the 15-month follow-up consultations.

Case 2

In April 2022, a 47-year-old woman presented at the Surgery Department with nodules detected in bilateral thyroid glands during a physical examination. A previous examination conducted four years ago had revealed hard and regular nodules, with a maximum diameter of 1.7 cm. The patient denied experiencing weight loss, dysphagia, or hyperhidrosis. Physical examination revealed a 1.5 × 1.0 cm nodule at the supra-thyroid gland level pole of the right lobe, with a regular shape, smooth surface, and clear boundary. Ultrasound imaging revealed bilateral thyroid enlargement, with hypoechoic nodules measuring 18.8 × 13.1 × 12.3 mm and scattered multiple strong echoes. Another hypoechoic nodule measuring 15.8 × 12.0 × 6.0 mm was detected in the inferior thyroid pole of the right side (Figure 4A). Thyroid function blood tests revealed a low level of serum thyroid hormone (6.70 pg/mL).

Figure 4:

Thyroid ultrasound results and HE staining results of case 2. (A) Thyroid ultrasound image shows a solid nodule in the right lobe of the thyroid gland. (B) The stalk of papillae showed dense lymphoplasmacytic infiltrate. HE 100×. (C) The tumor cells are arranged in pseudostratified. HE 400×.

In general, two nodules were detected on the right side and in the thyroid isthmus, measuring 1.9 × 1.4 × 1.2 × 1 cm × 1 cm, respectively. The larger nodule was tan-white in color, and the smaller one appeared yellowish. Paraffin sections revealed that the tumor exhibited a remarkable feature of papillary and glandular architectural growth pattern.

Histopathological examination revealed that the papillary stalk showed dense lymphoplasmacytic infiltration (Figure 4B). The tumor cells were arranged in a pseudostratified manner and appeared eosinophilic and large. These histological features were similar to those of Warthin tumor originating from the salivary gland origin. The majority of tumor cells showed nuclear clearing and grooves (Figure 4C). Immunohistochemical analysis showed that the tumor cells were positive for CK19 (Figure 5A), TTF-1 (Figure 5B), Galectin-3 (Figure 5C), and CK (data not shown), and showed a Ki-67 proliferative index of approximately 10 % (Figure 5D). However, the tumor cells were negative for marker MC (Figure 5E) and Braf-V600E mutation (Figure 5F). Gene mutations analysis showed that the tumor was wild-type for the BRAF V600E mutation (Figure 6). Based on these findings, the patient was diagnosed with WLV-PTC without lymph node metastasis. The patient had no recurrences or metastasis at the two-month follow-up.

Figure 5:

Immunohistochemistry (IHC) results of case 2 (IHC 100×). (A) CK19 was diffusely expressed in tumor cells. (B) TTF-1 was diffusely expressed in tumor cells. (C) The tumor cells were positive for Galectin-3. (D) The proliferation index of Ki-67 in tumor cells was low. (E) Tumor cells were negative for BRAF-V600E. (F) Tumor cells were negative for MC.

Figure 6:

Detection of gene mutation BRAF V600E showing that the tumor was wild-type for this particular mutation.

Clinical characteristics

Limited epidemiological data on WLV-PTC are available. WLV-PTC predominantly affects women and tends to occur at slightly older ages compared to conventional PTC with ages ranging from 19–85 years [6]. Table 1 shows these characteristics of WLV-PTC patients in the case report literature [6], [7], [8], [9], [10], [11], [12], [13]. The WLV-PTC mainly occurs in women and is often complicated by Hashimoto’s thyroiditis. In some individual cases, IgG4-positive plasma cells have been identified in the tumor stroma of WLV-PTC [7, 14]. The presence of IgG4-positive plasma cells in the tumor stroma suggests a potential link to Hashimoto’s thyroiditis [8, 15]. In this study, although a large number of lymphocytes were found in both patients with WLV-PTC, no eosinophilic follicular epithelial cells were found, which does not meet the diagnostic criteria for Hashimoto’s thyroiditis. Importantly, the patients’ serology showed normal thyroid function.

Pathological characteristics

There are few reports on the macroscopical characteristics of WLV-PTC. Based on the summary of 79 cases of WLV-PTC in the literature, Sahoo [11] reported that the tumor size of WLV-PTC can range from 0.3 to 6.1 cm, with a median diameter of 1.5 cm. In this study, the tumor diameters of the two patients were 1.0 and 1.9 cm. The cut surface of the tumor was grayish white and grayish yellow, making it difficult to distinguish it from classic PTC based on macroscopic examination alone. Under low-power microscopy, the histological characteristics of WLV-PTC are similar to those of Warthin tumor, which originate from salivary glands [3, 9], showing papillary growth pattern. The papillary axis is accompanied by a large number of lymphoblast cells, consistent with chronic lymphocytic thyroiditis. As an autoimmune response, Hashimoto’s thyroiditis is often involved in the pathogenesis of thyroid cancer. A recent study reported a singular case of WLV-PTC in a patient with multiple sclerosis but without Hashimoto thyroiditis and hypothesized multiple sclerosis systemic autoimmune diseases may also contribute to the determination of WLV-PTC [12]. A report of three cases provided clinical, grossing, cytological, and histological correlation, revealing the feasible diagnosis of WLV-PTC based on cytomorphological aspects [13]. The tumor cells have eosinophilic cytoplasm and can be arranged in a monolayer, multilayer, or pseudo-multilayer manner. The nuclei show the typical nuclear characteristics of PTC. In Case 1 reported in this study, a predominance of diffuse eosinophilic tumor cells was observed, whereas Warthin tumor-like papillary structures rich in lymphocytic stroma were only seen in the adjacent normal thyroid tissue surrounding the tumor. Initially, metastasis from salivary gland-derived tumors was suspected, but further investigation, including an inquiry about the history of the patient’s salivary gland tumors and immunohistochemical differentiation (CD117-, p63-, TTF-1+), ruled out metastasis and conformed the diagnosis of WLV-PTC. In Case 2, histological examination showed typical Warthin tumor-like structures and PTC-like nuclear features, enabling a clear and definitive diagnosis.

Genetic characteristics

Gene mutations, particularly in the PTC and BRAF genes, have been observed in WLV-PTC [10, 16]. A case report with two cases of WLV-PTC emphasized the role of histomorphology and assessment of BRAF mutation in the diagnosis of WLV-PTC [17]. The BRAF gene mutation is commonly detected in the majority of patients with the most frequent mutation site being BRAF V600E. In addition to BRAF-V600E, BRAF-V600K mutations have been detected in a few patients with WLV-PTC [18], which may have a role in promoting the occurrence and development of the condition. BRAF mutations are associated with aggressive clinical features of thyroid cancer, such as lymph node metastasis and extra-thyroidal spread, higher rates of tumor recurrence, and resistance to radioiodine therapy [19]. Gene mutation analysis revealed the presence of BRAF V600E mutation in the tumor, confirming the presence of this mutation in Case 1. Here, Case 1 has BRAF V600E mutation, and Case 2 has no mutation, however, both have no lymph node metastasis and with good postoperative recovery. This emphasized the need to monitor patients for lymph node metastasis and analyze histological subtypes in all PTC cases that might be considered to be aggressive classic variants might as well be WLV-PTC.

The treatment strategy and prognosis of WLV-PTC are still controversial. Lymph node metastasis has been observed in a few cases. Furthermore, the presence of sarcoma or undifferentiated components within the tumor has been associated with a poor prognosis. The short follow-up time for the two cases in this report emphasizes the need for more extensive research and longer-term data collection for a better and more comprehensive understanding of this rare histological variant.