Distinctive Hobnail Variant of Papillary Thyroid Carcinoma: A Case Series From a Tertiary Referral Center

doi:10.21203/rs.3.rs-5284983/v1

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Distinctive Hobnail Variant of Papillary Thyroid Carcinoma: A Case Series From a Tertiary Referral Center

https://doi.org/10.21203/rs.3.rs-5284983/v1

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Introduction: The hobnail variant of papillary thyroid carcinoma (HVPTC) is a rare and aggressive subtype, comprising 1-2% of all PTC cases. It is characterized by poor prognosis, frequent BRAF and p53 mutations, and a high recurrence rate. Given the limited data on HVPTC, especially in the Indian population, this case series aims to provide valuable insights into its clinical behavior, mutational profile, and treatment outcomes.

Materials and Methods: A retrospective analysis was conducted from January 2021 to December 2023. Histological reports were reviewed for cases with ≥5% hobnail features, and molecular testing was performed for BRAF and p53 mutations. Patient demographics, tumor characteristics, and follow-up data were collected. Follow-up included clinical exams, thyroid function tests, thyroglobulin, anti-thyroglobulin antibody levels, and imaging when necessary.

Results: Among 600 PTC cases, 4 were identified as HVPTC (0.67% incidence). The median follow-up was 40 months. Mean tumor size of 3.3 cm. BRAF and p53 positivity were found in 75%. Lymphovascular invasion (LVI) was present in 50% of patients. Recurrence occurred in two patients, both with LVI, despite receiving radioactive iodine and radiotherapy. The largest tumor (6 cm) did not show lymph node metastasis, while smaller tumors (2.2 cm, 2.3 cm) were metastatic. Neither BRAF nor p53 positivity correlated with thyroglobulin levels.

Conclusion: HVPTC exhibits aggressive behavior, particularly in cases with LVI. While BRAF and p53 mutations are common and cause aggressiveness. Risk stratification, early, aggressive management and molecular characterization are essential to improve treatment and outcomes.

Hobnail variant papillary thyroid carcinoma

BRAF

p53

Lymphovascular invasion

Thyroid cancer recurrence

Aggressive thyroid carcinoma

Thyroid cancer is the most prevalent endocrine malignancy, with the latest incidence of thyroid cancer in India based on data from 2006 to 2014. During this period, the age-standardized incidence rates (ASRs) for thyroid cancer in India increased from 2.5 to 3.5 per 100,000 women (+ 37%) and from 1.0 to 1.3 per 100,000 men (+ 27%) between 2006–2008 and 2012–2014 (1). Among the various types of thyroid cancer, the most common is papillary thyroid carcinoma (PTC), constituting approximately 80% of all cases (2, 3). Generally, well-differentiated PTC is considered an indolent tumor, with long-term survival rates more than 95% (4). However, certain variants of PTC exhibit more aggressive behavior and are associated with less favorable disease-free and overall survival rates. These variants exhibit differences in histology, cytology, molecular markers, treatment strategies, and clinical outcomes. (5) .

The hobnail variant of papillary thyroid carcinoma (HVPTC) has gained recognition as a more aggressive subtype of PTC. Although specific prevalence rates can vary, estimates suggest that HVPTC accounts for approximately 1–2% of all papillary thyroid carcinoma diagnosis. (6)

Published literature on HVPTC is limited, with only a handful of case reports and small case series available. Notably, studies such as those by Kakudo et al. (2004) and Motosugi et al. (2009) have provided foundational insights (7, 8), but comprehensive reviews and larger cohort analyses remain scarce. As a result, the understanding of HVPTC's clinical characteristics, prognosis, and treatment responses is still evolving.

Our case series, the first from a single institute in India, aims to contribute valuable insights to the limited global literature. We also propose a risk stratification system to better treat and follow up patients suffering from this rare disease.

A retrospective review was performed using the institutional database to identify histological reports of HVPTC from January 2021 to December 2023. Expert pathologists examined hematoxylin and eosin-stained slides to quantify the percentage of hobnail features. Tumors with at least 5% hobnail characteristics were included. All cases were staged according to the 8th AJCC/TNM classification.

Patient data collected included age and sex. Pathologic data encompassed stage and TNM classification, tumor size, the presence of lymphovascular invasion (LVI), extrathyroidal extension (ETE), the percentage of hobnail features within the tumor, distant or lymph node metastasis and molecular markers. Patients were followed up one month post-surgery with a radioiodine scan. In the absence of functioning residual thyroid tissue, follow-up occurred every three months for the first two years, followed by six-month intervals for the subsequent three years. For patients with residual thyroid tissue detected on the initial scan, radioactive iodine therapy was administered, after which follow-up proceeded according to the same schedule. Follow-up assessments included monitoring disease status, locoregional recurrence (LRR), and mortality. At each visit, clinical examination, thyroid-stimulating hormone (TSH), thyroglobulin, and anti-thyroglobulin levels were measured. Additionally, contrast-enhanced CT scans of the chest were performed when clinically indicated to assess for any recurrence or metastasis. Repeat surgery and adjuvant radiation were advised after discussion in the multidisciplinary tumor board.

Nucleic Acid Extraction:

For nucleic acid extraction, one paraffin block was selected for each case. Four 10-µm-thick tissue sections were obtained and subjected to standard deparaffinization. Areas containing tumor cells were manually dissected. DNA and RNA were extracted using the QIAamp DNA FFPE Tissue Kit and RNeasy FFPE Kit (Qiagen, Hilden, Germany), respectively.

Molecular Analysis:

Mutational analysis of BRAF exon 15 was performed using PCR. RET/PTC fusions and TP53 were analyzed using NGS.

From 2021 to 2024, our institute recorded 600 cases of papillary thyroid carcinoma, of which 4 were identified as hobnail variants. This results in an incidence rate of 0.67%. The median follow-up is 40 months (Range − 9–48). The mean tumor size was 3.3 cm (SD − 1.57). The clinical and pathological characteristics and treatment is outlined in Table 1. The architectural growth pattern was predominantly micropapillary, characterized by small papillae. Additional common histological features included the loss or inversion of cellular polarity, increased eosinophilic cytoplasm, elevated nuclear-to-cytoplasmic ratios, and pleomorphic nuclei predominantly situated at the apical portion of the cytoplasm.(Fig. 1–5)

Table 1

Table showing patient characteristics
	Patient 1	Patient 2	Patient 3	Patient 4
Age(Years)	24	71	57	62
Sex	M	M	F	M
Stage	I	II	II	I
pT	T3a	T3a	T2	T2
pN	N1a	N1a	N1a	N0
Tumor Size	2.7 cm	6 cm	2.2 cm	2.3 cm
Tumor Focality	Unifocal	Unifocal	Unifocal	Unifocal
LVI	Present	Absent	Present	Absent
PNI	Present	Absent	Absent	Absent
ETE	Absent	Absent	Absent	Absent
Hobnail %	15	> 30	> 30	> 30
Lymph node Metastasis	50/118	0/8	4/8	0/5
Largest Node	2.3 cm	NA	1.5 cm	NA
Largest Deposit	2	NA	1.5 cm	NA
ENE	Present	NA	Absent	NA
Molecular Markers	BRAF +, p53 -	BRAF+, P53 +	BRAF -, P53 +, RET -	BRAF +, p53 +
Adj RT	Yes	No	Yes	No
RAI	Yes	Yes	Yes	Yes
Recurrence	Yes	No	Yes	No
Last Thyroglobulin (ng/ml)	0.1	1.9	< 0.20	6.96
Last Anti-Thyroglobulin (IU/ml)	43.9	< 15	< 15	72.2
Survival	42 months	38 months	48 months	9 months
Mortality	Alive	Alive	Alive	Alive

(LVI - Lymphovascular invasion, PNI - Perineural invasion, ETE - Extrathyroidal extension, RT - Radiotherapy, ENE - Extranodal extension, RAI - Radioactive iodine therapy)

Clinical course of each patient -

Patient 1 is a 25-year-old normotensive, non-diabetic male, presented with a non tender firm left neck swelling for 4 months. Preoperative USG showed an approx 3 X 3 cm echogenic mass in the left lobe of the thyroid, along with > 1 cm nodes in bilateral cervical regions. USG guided FNAC was reported as PTC. Surgical intervention, including total thyroidectomy with central compartment neck dissection, bilateral selective neck dissection (levels II-V), retroclavicular and suprasternal nodal dissection was performed in March 2021. This was followed by RAI in April 2021. Post ablation scan showed no evidence of recurrence. A follow up USG of the neck identified a recurrence in the thyroid bed in December 2021, necessitating further surgical clearance of the right thyroid bed and bilateral cervical nodal clearance.

Diagnostic imaging via PET CT in January 2022 revealed a metabolically active discrete lymph node in level II, juxtaposed to surgical sutures. A subsequent ultrasound of the neck identified a rounded lymph node measuring 0.5cm in level III. FNAC guided by ultrasound confirmed the presence of malignant cells, indicative of metastatic carcinoma in the context of a known history of HVPTC.

The patient underwent modified radical neck dissection in February 2022, with histopathological examination revealing metastatic involvement in a single lymph node. In view of multiple recurrences, the case was discussed in multidisciplinary tumor board and adjuvant radiotherapy measuring 60 Gy in 30# was administered until April 15, 2022, alongside a regimen of Thyronorm at a dosage of 125 mcg/day. The patient was kept on follow up. Subsequent USG of the neck in April 2023 detected right level 1b lymph node alterations characterized by the loss of fatty hilum, alongside other lymph nodes in the neck. USG guided FNAC was done, however, it was unable to gather representative material. The patient was kept under close follow up.

In the last followup in April 2024, the patient remained on Thyronorm 125 mcg/day, with TSH levels measuring 0.039 uIU/ml. Thyroglobulin panel results indicated thyroglobulin at 0.1 ng/ml with elevated anti-thyroglobulin antibodies at 43.9 IU/ml. USG examination of the neck revealed no abnormal findings. The patient is currently alive with no recurrence.

Patient 2, a normotensive, non-diabetic 71-year-old male, presented with a history of voice changes persisting for 7 months and swelling on the left side of the neck for 1 month. Clinical examination revealed a soft, cystic swelling measuring 8 x 8 cm involving the left thyroid lobe and isthmus, without retrosternal extension or significant lymphadenopathy. USG neck revealed enlargement of the left thyroid lobe measuring 76 x 53 x 41 mm with multiple cystic nodular areas. FNAC demonstrated findings suspicious for malignancy categorized as Bethesda V. Preoperative endoscopy revealed normal mobile bilateral vocal cords. Consequently, the patient underwent a left hemithyroidectomy followed by frozen section assessment which revealed malignancy and subsequent total thyroidectomy in July 2021. Histopathological examination confirmed HVPTC.

After 1 month an I-131 whole-body scan revealed evidence of residual functioning thyroid tissue in the neck. The patient was optimized prior to radioiodine treatment. A dosage of 116mCi of I-131 was administered for radioiodine ablation therapy. Post-ablation imaging revealed no residual functioning thyroid tissue. The patient is currently under regular follow-up and last imaging done in March 2024 showed no evidence of disease recurrence.

Patient 3, a normotensive and non diabetic lady, initially presented with a one-month history of lower neck swelling, prompting evaluation that revealed a thyroid lesion suspicious of malignancy on USG Neck. FNAC confirmed the malignant nature of the lesion. Subsequently, the patient underwent Total Thyroidectomy with Central Neck Dissection (CND) in September 2020, followed by RAIA involving the administration of 201 mCi of I131 in October 2020. A PET CT scan performed in October 2020, identified an enlarged lymph node in the right paratracheal region with increased uptake, further confirmed by FNAC demonstrating malignant involvement.

The patient subsequently underwent Cervical Mediastinoscopy with Mediastinal Lymph Node Clearance in October 2020. Histopathological examination revealed metastatic involvement in two lymph nodes (involving the highest 2R and Level VI). Following this, External Beam Radiation Therapy (EBRT) was administered measuring 60 Gy in 30#. The patient had been maintained on Thyronorm at a dosage of 125 mcg/day.

A subsequent ultrasound of the neck conducted on July 8, 2021, detected sub-centimeter to centimeter-sized lymph nodes in both right and left level II regions with loss of fatty hilum. TSH levels measured 0.13 uIU/ml at this time. FNAC confirmed the presence of malignant cells consistent with metastatic carcinoma in the context of thyroid cancer.

In September 2021, the patient underwent bilateral neck dissection, revealing metastatic involvement in 5 out of 10 nodes examined. Following a disease-free period of six months, the patient experienced a recurrence of bilateral neck disease and was subsequently referred to medical oncology. Treatment was initiated in March 2022 with Lenvatinib 24 mg once daily, currently resulting in stable disease status with thyroglobulin < 0.2 ng/ml. Presently, the patient remains alive with ongoing management.

Patient 4, a normotensive and nondiabetic 62-year-old male, presented with a one-month history of right neck swelling. Clinical examination revealed a mobile, non-tender right thyroid nodule measuring 3 x 2cm, with no significant lymphadenopathy noted.

USG neck conducted in Nov 2023 identified a well-defined, solid, isoechoic lesion, measuring approximately 17 x 15 x 17mm, which was observed in the superior aspect of the right lobe. Additionally, a few subcentimeter-sized lymph nodes in the right level II and III regions, with preserved fatty hilum, were detected, measuring up to 5mm. FNAC indicated a Bethesda VI classification.

The patient underwent Total Thyroidectomy with Bilateral Central Compartment Lymph Node Dissection in December 2023. Subsequent to surgery, the patient received RAI therapy. Post ablation scan did not show any residual functioning thyroid tissue. In the last followup in July 2024, the patient is alive and exhibiting satisfactory clinical progress.

The hobnail variant of papillary thyroid carcinoma is a rare and aggressive subtype characterized by distinct morphological features and a more aggressive clinical course compared to classical papillary thyroid carcinoma. First described in 2010 (9), HPTC has garnered increasing attention due to its association with poor prognosis and increased risk of recurrence.

Histologically, Kakudo et al.(7) first observed an elevated nuclear position resembling a hobnail appearance, suggesting that this loss of cellular polarity could be a marker of poor cellular differentiation. Asioli et al. (9) established three criteria for diagnosing HVPTC: (1) a nonsolid PTC type, (2) ≤ 10% of the tumor showing tall/columnar or diffuse sclerosing features, and (3) hobnail features in ≥ 30% of cells with loss of polarity and cohesiveness. They also investigated the correlation between clinicopathologic variables and the presence of a hobnail pattern in at least 30% of the tumor (10). Their analysis concluded that even a minimal proportion of hobnail features is indicative of aggressive tumor behavior. Consequently, we included a patient with 15% hobnail features in our case series to enhance our understanding of the association between the percentage of hobnail features and clinical outcomes. The patient is alive without disease till date.

HVPTC retains the characteristic nuclear features of PTC along with well-formed fibrovascular cores. Micropapillary architecture, observed in a subset of adenocarcinomas, is frequently associated with poor prognosis, as seen in malignancies of the breast, ovary, lung, and urinary bladder (11–14).

Our institute recorded an incidence of 0.67%, with 4 cases representing HVPTC out of 600 PTC from 2021 to 2023, which is consistent with other studies reporting an incidence rate of approximately 1.08% (6).This signifies the extreme rarity of the disease.

The clinical and pathological characteristics of HVPTC cases at our institution exhibited both similarities and differences compared to those reported in the largest published case series (10). The mean tumor size in our cohort was equivalent to that in the larger series (3.3 cm vs. 3.3 cm). However, our cases exhibited less lymphovascular invasion (50% vs. 71%), similar rates of lymph node metastasis (50% vs. 60%), similar local recurrence rates ( 50% vs 36%) and no incidence of distant metastasis (0% vs. 43.3%). Moreover, disease-specific survival was higher in our cohort (100% vs. 61.3%), although it is important to note that the median follow-up period was shorter in our study (slightly over 3 years vs. over 6 years). Our study suggests that although the disease might be predisposed to early and multiple recurrences, early intervention in the disease's natural course and aggressive management leads to favorable outcomes.

Recurrence occurred in two patients, both of whom had LVI and lymph node metastasis, indicating a potential link between LVI and recurrence risk. Additionally, extranodal extension (ENE) was associated with a higher number of involved lymph nodes. This has been seen in the systematic review and meta-analysis by Donaldson LB et al (6), who saw a higher incidence of lymph nodal metastasis, LVI and ENE in HVPTC patients. Additionally, both these patients were p53 negative, suggesting a possible association, but larger studies are required to substantiate this. Both of these patients had received adjuvant radiation and RAI, but developed recurrence nonetheless.

Additionally, despite all tumors in this series being unifocal, all showed varied aggressive behaviors, such as LVI and lymph node metastasis,

Tumor size did not show a clear relationship with lymph node metastasis or recurrence, although it has been postulated that HVPTC have a larger tumor size (6). The largest tumor (6 cm) occurred in the oldest patient (71 years) but did not exhibit lymph node involvement, while smaller tumors (2.2 cm and 2.3 cm) were associated with lymph node metastasis. Interestingly, the youngest patient (24 years) had the most extensive lymph node involvement (50/118 nodes) and also presented with both LVI and PNI. This suggests a possible association between these invasive features and more aggressive lymph node spread, as stated earlier.

In terms of molecular markers, all patients with > 30% hobnail features were p53-positive, while the one patient with 15% hobnail features was p53 negative. 2 patients out of 3 with more than 30% hobnail features were BRAF positive. This suggests that a high percentage of hobnail features is associated with BRAF and p53 positivity. This has been noted in multiple case series and reports (6). This has clinical implications, as these mutations are targettable and can be used to improve outcomes. In our series, older patients tended to have both BRAF and p53 positivity. However, BRAF status did not appear to influence thyroglobulin levels, treatment response or recurrence in our cohort. This may be attributed to the small sample size, as previous investigations have consistently linked BRAF and p53 positive mutations with aggressive clinical characteristics and heightened recurrence rates (15, 16).

Considering the data from our case series and the previously mentioned literature, we therefore propose a risk stratification system (Table 2).

Table 2

Risk stratification system
Low Risk	High Risk
Hobnail features < 30%	Hobnail features >/= 30%
Tumor size < 3.3 cm	Tumor size >/= 3.3 cm
Absence of LVI and PNI	Presence of LVI and/or PNI
No lymph node metastasis	Presence of lymph node metastasis
BRAF and p53 negative	BRAF and/or p53 positive
Age </= 55 years	Age > 55 years

FOOTNOTE - This stratification is based on a small case series (n = 4) and should be interpreted with caution. The 30% cut-off for hobnail features is based on previous literature (Asioli et al., 2013) and observations in this series. Due to the small sample size, precise cut-off for tumor size should be viewed as preliminary. Individual patient factors and multidisciplinary team decisions should guide final management.This stratification requires validation in larger cohorts before clinical application.

Based on this system, one can consider standard PTC management protocols with close follow-up for the low risk category, while opting for a more aggressive treatment plan and surveillance strategy for the high risk category, particularly in the first 2 years following surgery.

Our series has a small sample size of 4, is retrospective, with a relatively short follow-up period (median of 40 months) due to the novelty of the described entity. Nevertheless, it constitutes the first case series published to date from a single institution in India, significantly extending our understanding of this rare variant of PTC, particularly regarding the mutational profile of these tumors.

In conclusion, the hobnail variant of papillary thyroid carcinoma (HVPTC) demonstrates aggressive behavior, frequently associated with BRAF and p53 mutations and high nodal recurrence. Early intervention and aggressive management by a multidisciplinary team are crucial, especially for patients with limited access to multiple surgeries or targeted therapies. Recognizing hobnail patterns, even in smaller proportions, is important for prognosis, and BRAF and p53 mutations offer potential therapeutic targets. Our risk stratification system supports a personalized treatment approach. Given its rarity, multicenter studies and further molecular characterization are needed.

SOURCES OF FUNDING - The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

CONFLICTS OF INTEREST -

The authors have no relevant financial or non-financial interests to disclose

ETHICAL COMMITTEE APPROVAL -

This is an observational study. The Institutional Research Ethics Committee has confirmed that no ethical approval is required.

Author Contribution

All authors contributed to the study conception and design. Material preparation and analysis were performed by A.L and V.Y. Data collection was done by S.P The first draft of the manuscript was written by A.L. Dr A.K.D commented, edited all previous versions of the manuscript and finalized the manuscript. All authors read and approved the final manuscript

ACKNOWLEDGMENTS -

None

CONSENT - Informed consent was obtained from all individual participants included in the study.

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No competing interests reported.

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Distinctive Hobnail Variant of Papillary Thyroid Carcinoma: A Case Series From a Tertiary Referral Center

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Abstract

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MATERIALS AND METHODS

Nucleic Acid Extraction:

Molecular Analysis:

RESULTS

Clinical course of each patient -

DISCUSSION

Declarations

CONFLICTS OF INTEREST -

ETHICAL COMMITTEE APPROVAL -

Author Contribution

ACKNOWLEDGMENTS -

References

Additional Declarations

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