Endocr Pathol https://doi.org/10.1007/s12022-017-9502-7
Hobnail Variant of Papillary Thyroid Carcinoma: a Literature Review Francesca Ambrosi 1 & Alberto Righi 2 & Costantino Ricci 1 & Lori A. Erickson 3 & Ricardo V. Lloyd 4 & Sofia Asioli 1
# Springer Science+Business Media, LLC 2017
Abstract Papillary thyroid carcinoma is the most common thyroid malignancy and it is usually associated with a good prognosis. However, recurrence, metastases, and cancer death may occur in 10 to 15% of patients with more aggressive types of papillary thyroid carcinoma, such as tall cell, columnar cell, solid variant, or the more recently described hobnail variant of papillary thyroid carcinoma. Papillary thyroid carcinoma with a prominent hobnail pattern is a moderately differentiated papillary thyroid carcinoma variant with aggressive clinical behavior and significant mortality. The hobnail variant of papillary thyroid carcinoma shows prominent hobnail features, which have also been referred to as micropapillary. The typical hobnail/micropapillary morphological features show loss of cellular polarity/cohesiveness and support an epithelial-mesenchymal transition as a possible mechanism of metastasis. BRAF p.V600E is the most common mutation in papillary thyroid carcinoma, including the hobnail variant; recent and continuing studies are focused on defining other molecular anomalies that may be useful for prognostic stratification and may provide therapeutic targets.
* Sofia Asioli [email protected] 1
Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology BM. Malpighi^ at Bellaria Hospital, University of Bologna, Via Altura No. 3, 40126 Bologna, Italy
2
Department of Pathology, Rizzoli Institute, Bologna, Italy
3
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
4
University of Wisconsin School of Medicine and Public Health Madison, Madison, WI, USA
Keywords Hobnail . Papillary thyroid carcinoma . Aggressive variant . BRAF mutation . Epithelial-mesenchymal transition
Introduction Hobnail variant of papillary thyroid carcinoma (HPTC) is an aggressive variant of papillary thyroid carcinoma (PTC), described in a series of eight cases from the Mayo Clinic in 2010 [1]. PTC is the most common thyroid malignancy, constituting more than 70% of thyroid carcinomas [2, 3]. Patients are often young when they are diagnosed with PTC, and there is usually a very good long-term and disease-specific survival [4]. However, there are numerous histological variants of PTC, which show unique constellations of growth patterns, cell types, stromal changes, and molecular mutations. Recurrence, metastases, and cancer death may occur in 10 to 15% of patients with more aggressive variants, such as tall cell, columnar cell, solid, or hobnail variants of PTC [5]. HPTC is strongly associated with aggressive clinicopathologic features, radioactive iodine refractoriness, disease progression, and a higher mortality rate compared to classic PTC [6]. The surgical pathologist plays a key role in identifying these aggressive subtypes and in the multidisciplinary management of these patients [7]. In 2004, Kakudo et al. [8] suggested that the loss of cellular polarity Bmay be a phenotypic expression and histological characteristic of poor cellular differentiation^. They indicated that three fundamental parameters define aggressive behavior: growth pattern, encapsulation, and loss of polarity (in at least 20% of tumor cells). They noticed recurrences in tumors with loss of polarity, and those without loss of polarity but with invasive growth and no capsule. In 2009, Motosugi et al. [9]
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reported a case of aggressive PTC with an invasive growth pattern, prominent micropapillary structures, and hobnail cytological features. One year later, a series of eight cases from the Mayo Clinic was described as PTC with prominent hobnail features, a new aggressive variant of moderately differentiated PTC [1]. Today, HPTC is a new and recognized variant of PTC [10–12].
Clinicopathological Characteristics To date, 94 cases of HPTC (Table 1) have been described in literature [1, 5, 6, 13–19]. There is a female predominance (F/M = 2:1), with an average age at diagnosis of 53 years old. Often, patients present with a thyroid or cervical palpable mass, some associated with dyspnea due to compression of trachea, cervical lymphadenopathy, a history of multinodular goiter, and in one case, with hemoptysis [20]. Ultrasound (US) examination may show a hypoechoic and highly vascularized thyroid nodule. Thyroid nodules which undergo fine needle aspiration (FNA) under US guidance are diagnosed as positive for PTC and total thyroidectomy may be indicated as primary treatment [21]. The mean size of primary tumor is 24 mm (range, 5–90 mm), and in 60.9% of cases, a presence of linfovascular invasion is evident on histology with an extrathyroidal invasion observed in 43% of cases reported in literature. At the time of presentation, metastasis to regional lymph nodes occurs in 57% of patients [1, 5, 6, 13–19]. Frequently, HPTC shows little response to iodine treatment [22], and may be a candidate for target therapies. Morandi et al. [18] analyzed 18 HPTC, and only six cases were responsive to radioactive iodine therapy (for an average of 50 months) [18]. During follow-up (mean of 62 months of cases reported in literature), 25.4% of cases (15 out of 59 cases) showed a local/regional recurrence and 36% of cases (27 out of 75 cases) developed distant metastases, mainly in the lung and in the bone and rarely in the brain. At the last follow-up available, 21.2% of patients died of disease and 22.1% of patients were alive with disease.
Cytological Features The cytological diagnosis on a pre-operative FNA is usually formulated according to the diagnostic categories (British Thyroid Association, Royal College of Physician, London, UK and the Bethesda system [23, 24]). Frequently, hobnail features are found in papillary, micropapillary, or discohesive cell clusters in HPTC. Cytological smears are highly cellular, with a bloody background, and scant colloid. Cells are arranged in papillary-
like clusters and/or in micropapillary groups [6, 16], and a few cases show a predominant follicular pattern. The cells vary in size from small to medium with tear-drop cytoplasm, so called comet-like cells [25]. Nuclei are apically placed, occasionally grooved, and produce a surface bulge leading to a hobnail appearance with high nuclear/ cytoplasm (N/C) ratio. High magnification shows nuclear pleomorphism, occasionally pseudo-inclusions with multiple soap bubble-like inclusions, and possibly mitotic figures. The presence on FNA of Bcomet-like^ cells may lead to pre-operative suspicion of HPTC (Fig. 1). The cytological characteristics, in particular nuclear features, of usual (classic) PTC are occasionally evident on smear in cases of HPTC [6, 16]. The differential diagnosis of HPTC in FNA includes usual (classic) PTC and tall-cell variant of PTC characterized by eccentric nuclei, columnar cells, abundant cytoplasm, and distinct cell borders [26]. Both these two tumors are characterized by the absence of cytological hobnail appearance and comet-like cells. Table 2 summarizes possible differential diagnosis on cytological smears.
Histological Features HPTC was originally described using the following criteria for the histological diagnosis: (i) non-solid type of PTC, (ii) ≤ 10% of the tumor showed tall/columnar or diffuse sclerosing features, and (iii) loss of polarity/cohesiveness with hobnail features in ≥ 30% of tumor cells [1, 5, 6]. It is identified by hobnail and micropapillary patterns, a high nuclearcytoplasmatic N/C ratio, and hobnail cells (Figs. 2, 3, and 4a). Hobnail cells vary in size and shape from small lymphocytoid cells to larger cuboidal cells, rarely tall/ columnar cells may also be present [13, 14, 16]. The cytoplasm is usually abundant, eosinophilic, and sometimes finely granular [11]. Tumors with eosinophilic cytoplasm are included in the differential diagnoses for tumors with oncocytic features [27]. In HPTC, the nuclei are apically placed, moderately to highly pleomorphic, occasionally grooved, or located in the middle of the cytoplasm. The bulging nuclei form characteristic hobnail cells that can be present in varying amounts in a tumor. Vascular invasion and foci of necrosis may be seen as well as mitotic figures. The mean mitotic rate is 2–3/10 high-powered fields (400× magnification), with atypical mitoses in a minority of cases [5–14, 16]. The main differential diagnoses of HPTC include usual (classic) PTC, tall-cell PTC, columnar cell PTC, oncocytic PTC, and other oncocytic/Hurthle cell tumors. Table 3 describes the main histologic features among these various subtypes. Hobnail architecture may be observed in some Hurthle cell adenomas and carcinomas and in rare follicular adenomas. However, the distinctive cytological features of HPTCs are absent.
3:1
1.5:1
1:2
Lubitz et al. 2014 USA
Asioli et. Al. 2014 Italy
Amacher et Al. 2015 USA
45 (23–67)
65 (27–86)
54.1 (21–80)
16.3 (6–40)
2.71 (6.5–0.9)
42 (20–90)
37 (5–65)
10–30
27 (10/50)
61.5 (40–100)
(10–100)
43.5 (39.5–50.5) 12.1 (5–20)
57.3 (28–78) 22.95 (10–70)
45 (27–68)
1.5:1 50.4 (32–68)
3:1
Asioli et. Al. 2013 Italy/USA
Lino-Silva et al. 1:1.3 2012 Mexico
67.5 (30–100)
57.6 (28–78)
3:1
Asioli et. Al. 2010 Italy/USA
25 (10–40)
Mean age, Mean tumor size, Mean of hobnail years (range) mm (range) features (range)
F:M ratio
Clinical and pathological features of major studies of HPTC cases
Cases
Table 1
(8/10) 80%
(4/5) 80%
(5/12) 42%
(17/24) 70.8%
(5/7) 71.5%
(7/8) 87.5%
I (4/10) 40%
(1/10) 10%
(5/6) 83.3%
(1/5) 20%
(6/6) 100%
(2/6) 33.3%
(3/5) 60%
12 (9–28)
39 (7–104)
8 (2–24)
26.5 (14–35.5)
106 (4–274)
(8/24) 33.3%
(8/10) 80%
103 (40–158)
(3/7) 42.8%
77.2 (4–236)
DOD (1/11) 9.2% AND (7/11) 63.6% AWD (3/11) 27.2% AND (4/5) 80% AWD (1/5) 20% DOD (2/6) 33.3% AND (3/6) 50% AWD (1/6) 16.6%
DOD (4/7) 57.2% AWD (3/7) 42.8% DOD (8/24) 33.3% AND (9/24) 25% AWD (6/24) 4.2% DND (1/24) 9.2%
DOD (4/8) 50% AND (2/8) 25% AWD (2/8) 25%
(4/8) 50%
(3/8) 37.5%
(5/8) 62.5%
Outcome
Recurrence Metastasis BRAF Mean follow-up, mutation months (range)
I (5/12) 42% II (0/12) (4/12) 33% (3/12) 25% III (3/12) 25% IV (4712) 33%
I–II 9/24 (37.5%) III–IV 15/24 (62.5%)
I–II 3/7 (42.8%) III–IV 4/7 (57.2%)
(6/8) 75% IV (6/6) 100%
(3/5) 60%
(10/12) 83.3%
(7/24) 29.1%
(5/7) 71.5%
(6/8) 75% I (0/8) II (1/8)12.5% III (2/8) 25% IV (5/8) 62.5%
Linfovascula Nodal AJCC 2010 (7th ed) invasion metastasis stage
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41.8 (23–78)
253 (100–500)
62.2 (40–100)
(2/18) 11.1% (10/18) 58.8%
I (2/18) 11.1 II (2/18) 11.1 III (4/18) 22.2 IV (10/18) 55.5
F female, M male, AND alive with no disease, DOD died of disease, AWD alive with disease, DND died not of disease
Teng et al. 2017 13:5 China
(15/18) 83.3%
3.5:1
(4/8) 50%
Morandi et al. 2017 USA
41.87 (30–70)
(2/8) 25% I (4/8) 50% II (2/8) 25% III (2/8) 25% IV 0
55 (46–69) 17.75 (10–32)
3:1
II (0/10) III (4/10) 40% IV (2/10) 20%
Linfovascula Nodal AJCC 2010 (7th ed) invasion metastasis stage
Ieni A. et al. 2016 Italy
Mean age, Mean tumor size, Mean of hobnail years (range) mm (range) features (range) (8/10) 80%
F:M ratio
Lee et al. 2015 South Korea
Cases
Table 1 (continued)
(1/18) 5.5%
(2/18) 11.1%
(16/17) 94%
(15/18) 83.3%
(4/8) 50%
(8/10) 80%
71.88 (12–101)
40 (6–12)
47.75 (39–60)
Recurrence Metastasis BRAF Mean follow-up, mutation months (range)
DOD (4/18) 22.2% AND (7/18) 38.8% AWD (7/18) 38.8% AND (13/16) 81.2% AWD (1/16) 6.2% DND (1/16) 6.2% DOD (1/16) 6.2%
DOD (0/10) AND (9/10) 90% AWD (1/10) 10% AND (8/8) 100%
Outcome
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Occasional chromatin clearing Uniform, finely granular Chromatin clearing Chromatin clearing Chromatin clearing
Chromatin clearing, micronucleoli
Yes No Yes Yes Rare
Yes Rare Yes Rare
Yes
Elongated and overlapped, pleomorphic Yes Oval and elongated, pseudostratified No Enlarged Enlarged
Microfollicular, flat syncitial Papillary fragments Round or oval, scant Oxyphilic cytoplasm, indistinct borders, enlarged oval Enlarged, oval Enlarged
Cluster Papillary, monolayer architecture sheets Cells Round or oval, scant cytoplasm, indistinct borders Nuclei Elongated and overlapping Nuclear Yes inclusions Nuclear Yes grooves Chromatin Chromatin clearing
Syncitial fragments or sheets Pleomorphic
Occasional squamous metaplasia
Papillary, follicular, acinar, Occasional micropapillary solid monostratified Columnar, supra, or subnuclear Tear-drop, hobnail, vacuoles Bcomet-like^
Bloody Clean, no colloid
No stringly colloid, many psammoma bodies, lymphocites Micropapillary, solid Lymphocytes Clean with little thick colloid Thick and thin colloid
High Moderate Variable High Cellularity
Follicular PTC
Cytological aspects and differential diagnoses on cytological smears
The most common genetic abnormalities in PTC include RET/PTC rearrangements and BRAF p.V600E mutations
Usual PTC
Mutational Analysis
Table 2
All cases described in the literature [1, 5, 6, 13–19] showed positive staining for thyroglobulin, thyroid transcription factor-1 (TTF-1), keratin 7, keratin 19, epithelial membrane antigen, and HBME1. Thyroglobulin may show variable intensity and focal distribution of the staining [1]. All but one case did not highlight an expression for the anti-mitochondria [1, 5, 14, 16, 18]. P53 protein was expressed in more than 25% of the neoplastic cell nuclei in 77% of cases reported in literature [1, 5, 6, 14, 16, 18] (Fig. 4b). MUC1 showed the characteristic Binside-out^ staining pattern in all cases reported, highlighted by hobnail features of the tumor cells [1, 5, 13]. Beta-catenin and E-cadherin were observed in the basolateral or lateral site of neoplastic cells in all cases reported, and in three cases a nuclear co-expression in few cells of beta-catenin was present [1, 5, 6, 14, 16, 18]. In a study by Lee et al. [16], diffusely staining for cyclin-D1 and HBME1, and focally staining for CD56 were observed in all 10 cases analyzed. The proliferative index evaluated by Ki-67 ranged from 2 to 20% [5, 14, 18].
Warthin-like Solid PTC PTC High High
Immunoistochemical Profile
Background Thick and thin colloid
Fig. 1 On cytological smears, tear-drop cells (so called comet-like cells) with high nuclear/cytoplasmic ratio are typical of HPTC (a, b Giemsa stain, 400× of magnification)
Low
Diffuse sclerosing PTC
Columnar cell PTC
Hobnail PTC
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Fig. 2 Hobnail papillary thyroid carcinoma (HPTC). It shows prominent papillary pattern of growth and follicular architecture (a H&E 20× of magnification). Usually, papillary pattern included variably sized complex papillary structures with prominent vascular cores, and focal micropapillary areas. Also, the follicular pattern is characterized by variably sized follicles lined by thick neoplastic epithelium. (b H&E 50× of magnification)
[28–30]. Rarely, gene amplifications and copy number gains are noted involving genes encoding tyrosine kinase receptors (TKRs) [31–33]. Epigenetic pathways, such as aberrant methylation of thyroid-specific genes involved in iodine
Fig. 3 Cuboidal or oval epithelium covered both papillary and follicular structures. Cells showed high nuclear/cytoplasmatic ratio and apically placed, occasionally grooved with nuclei that produce a surface bulge leading to a hobnail appearance. Thin arborizing papillae are lined by hobnail cells (H&E 200× magnification)
Fig. 4 a Occasional pink intranuclear holes are observed (black arrows, 200× magnification). b An example of strong nuclear staining of p53 protein in a case of HPTC (400× magnification)
metabolism or tumor suppression, may lead to loss of radioiodine avidity and increased tumor growth, invasion, and metastases [34]. Recent studies identified BRAF p.V600E mutation as the most common alteration in HPTC cases, in particular BRAF p.V600E mutation was found in 60 out of 82 analyzed (73.2%), and only 2 HPTC out of 30 (6.7%) tested tumor had RET/PTC1 rearrangements [1, 5, 6, 14, 16, 18]. Morandi et al. [18] confirmed BRAF p.V600E as the most common mutation, and identified a rare mutation; p.A598V. BRAF is a proto-oncogene located at 7q24 that encodes a serine/threonine kinase from the family of RAFkinase, which plays a central role in the transduction of signals along the RAS/RAF/MEK/ERK pathway regulating cell growth, differentiation, and apoptosis [35]. A recent multicenter study concluded BRAF p.V600E mutation was associated with increased cancer-related mortality in patients with PTC, even if when the aggressive tumor features of lymph nodal and distant metastases and extrathyroidal invasion, were also included in the model, the association of BRAF V600E with mortality was no longer statistically significant [36]. Other reported mutations included TP53, PIK3A, hTERT, CTNNb1, EGFR, AKT1, and NOTCH 1 in 18 cases tested, without mutations of CKDN2A, PTEN, and ALK [16, 18]. The high prevalence of BRAF mutation and the association with other genes (TP53, PIK3CA, CTNNB1, and hTERT) reflect a complex pathogenetic mechanism for this aggressive
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Histological characteristics and differential diagnoses on histological sections
Hobnail
Tall cell
Columnar cell
Cuboidal or oval epithelium, with areas of discohesiveness Increased nucleo/cytoplasmatic ratio, dense eosinophilic cytoplasm with well-defined borders Enlarged overlapped, nuclear grooves, and pseudo-inclusions
Height, twice their width Eosinophilic cytoplasm
Pseudostratified columnar cells Supra and sub Squamous metaplasia and numerous psammoma bodies cytoplasmatic vacuoles Hyperchromatic and large clear nuclei, centrally located
High mitotic rate Metastasis, lympho-vascular invasion
Grooves and pseudo-inclusions Mitotic figures and necrosis Extrathyroid extension
Extrathyroidal extension
variant of PTC. Morandi et al. [18] identified BRAF as an initial driver, with second hits (TP53, TERT, PIK3CA); this mutational pattern in HPTC could be useful to better identify HPTC signaling and differentiation properties, and they recognized that BRAF p.V600E, EGFR p.A859T, NOTCH p.D1681 were present in the bulk of primary tumors, considering these mutations as early events in HPTC evolution. Other detected mutations in TP53, CTNNB1, AKT, and PIK3CA showed lower variant allele frequency, indicating later events; likely involving a limited number of cells. Furthermore, these mutations, in particular BRAF and PIK3CA in cooperation, are shared with anaplastic carcinoma, also hTERT with poorly differentiated and anaplastic carcinoma, and are significantly associated with specific disease mortality [37]. In spite of the series described by Morandi et al. [18] is limited, it reveals that a single clone gave rise to lymph node metastasis maintaining driver mutation in BRAF, TP53, or PIKC3CA, and mutations in these genes are related to a more aggressive behavior. These new perspectives may lead to treatment with selective or multi-tyrosine inhibitor to improve the patients’ outcome. The combined mutations in BRAF, TP53, and/or PIK3CA genes by molecular profiling seem to be relevant in order to use target therapies. These complex molecular studies and different pattern of mutations, in proximal future, could lead treatment of advanced thyroid cancer targeting different molecular pathways.
Metastasis Mechanisms HPTC is an extreme example of loss of cellular polarity/ cohesiveness; the literature suggests the possibility that PXRγ up-regulation may be a potential candidate for ligand therapy of PTC, especially for aggressive types of PTC with loss of cellular polarity [36]. The loss of cellular polarity is the phenotypic expression of epithelial to mesenchymal transition (EMT) in thyroid tumors. The decrease expression of thyroid
Sclerosing variant
Diffuse involvement of both lobes, multiple foci, dense lymphocytic infiltration, stromal fibrosis, and lymphatic metastasis
transcription factor-1 and E-cadherin, aberrant ß-catenin polarity, and increased vimentin expression are reliable markers to identify loss of cellular polarity/cohesiveness. The latter may be one of the morphological indicators of the role of EMT in PTC [38]. Hardin et al. [39] found that EMT is induced by transforming growth factor-ß1; PTC cells acquired increased cancer stem cell-like features and the transcription factor paired-related homebox protein (PPRX1), a newly identified inducer is markedly up-regulated. High-grade thyroid carcinomas expressed the highest level of this EMT marker. Usual PTCs on tissue micro arrays were negative for PPRX1, while two cases of HPTC were positive for PPRX1. The results of this study suggest positivity for PPRX1 is associated with metastatic disease and high rate of mortality.
New Prospective The prevalence of HPTC is only 0.6% (22/3551 cases) of a large, institutional series of primary PTC [5]; thus, there remains much to be learned about this new entity. A recent study [15] analyzed Bpure^ HPTC and other cases in association with poorly differentiated and anaplastic thyroid carcinoma. This group hypothesized hobnail features may be a sign of higher-grade transformation, because hobnail features are more common in poorly differentiated thyroid carcinomas. They showed that hobnail features are most commonly associated with poorly differentiated thyroid carcinoma (4/18 cases), compared with papillary thyroid carcinoma patients (6/478); only one of 26 anaplastic carcinoma studied had hobnail features. The more common association of hobnail pattern with poorly differentiated thyroid carcinoma was also observed by Amacher et al. [15]. However, in accordance with Turin criteria [40], the diagnosis of poorly differentiated carcinoma is primarily made on by morphology and includes solid/trabecular/insular tumors with absence of conventional nuclear features of papillary carcinoma, and presence of at
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least one of the following: convoluted nuclei, mitotic activity (≥ 3/10 HPF), or tumor necrosis HPTC does not fit the previous criteria and cannot be considered as poorly differentiated; thus, the designation as a moderately differentiated thyroid carcinoma. In summary, we need more studies to understand the molecular mechanism of tumorigenesis, tumor progression, and to establish new target therapies that are personalized for this aggressive variant of PTC. Compliance with Ethical Standards Conflict of Interest The authors declare that they have no conflict of interest.
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Hobnail Variant of Papillary Thyroid Carcinoma: a Literature Review Francesca Ambrosi 1 & Alberto Righi 2 & Costantino Ricci 1 & Lori A. Erickson 3 & Ricardo V. Lloyd 4 & Sofia Asioli 1
# Springer Science+Business Media, LLC 2017
Abstract Papillary thyroid carcinoma is the most common thyroid malignancy and it is usually associated with a good prognosis. However, recurrence, metastases, and cancer death may occur in 10 to 15% of patients with more aggressive types of papillary thyroid carcinoma, such as tall cell, columnar cell, solid variant, or the more recently described hobnail variant of papillary thyroid carcinoma. Papillary thyroid carcinoma with a prominent hobnail pattern is a moderately differentiated papillary thyroid carcinoma variant with aggressive clinical behavior and significant mortality. The hobnail variant of papillary thyroid carcinoma shows prominent hobnail features, which have also been referred to as micropapillary. The typical hobnail/micropapillary morphological features show loss of cellular polarity/cohesiveness and support an epithelial-mesenchymal transition as a possible mechanism of metastasis. BRAF p.V600E is the most common mutation in papillary thyroid carcinoma, including the hobnail variant; recent and continuing studies are focused on defining other molecular anomalies that may be useful for prognostic stratification and may provide therapeutic targets.
* Sofia Asioli [email protected] 1
Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology BM. Malpighi^ at Bellaria Hospital, University of Bologna, Via Altura No. 3, 40126 Bologna, Italy
2
Department of Pathology, Rizzoli Institute, Bologna, Italy
3
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
4
University of Wisconsin School of Medicine and Public Health Madison, Madison, WI, USA
Keywords Hobnail . Papillary thyroid carcinoma . Aggressive variant . BRAF mutation . Epithelial-mesenchymal transition
Introduction Hobnail variant of papillary thyroid carcinoma (HPTC) is an aggressive variant of papillary thyroid carcinoma (PTC), described in a series of eight cases from the Mayo Clinic in 2010 [1]. PTC is the most common thyroid malignancy, constituting more than 70% of thyroid carcinomas [2, 3]. Patients are often young when they are diagnosed with PTC, and there is usually a very good long-term and disease-specific survival [4]. However, there are numerous histological variants of PTC, which show unique constellations of growth patterns, cell types, stromal changes, and molecular mutations. Recurrence, metastases, and cancer death may occur in 10 to 15% of patients with more aggressive variants, such as tall cell, columnar cell, solid, or hobnail variants of PTC [5]. HPTC is strongly associated with aggressive clinicopathologic features, radioactive iodine refractoriness, disease progression, and a higher mortality rate compared to classic PTC [6]. The surgical pathologist plays a key role in identifying these aggressive subtypes and in the multidisciplinary management of these patients [7]. In 2004, Kakudo et al. [8] suggested that the loss of cellular polarity Bmay be a phenotypic expression and histological characteristic of poor cellular differentiation^. They indicated that three fundamental parameters define aggressive behavior: growth pattern, encapsulation, and loss of polarity (in at least 20% of tumor cells). They noticed recurrences in tumors with loss of polarity, and those without loss of polarity but with invasive growth and no capsule. In 2009, Motosugi et al. [9]
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reported a case of aggressive PTC with an invasive growth pattern, prominent micropapillary structures, and hobnail cytological features. One year later, a series of eight cases from the Mayo Clinic was described as PTC with prominent hobnail features, a new aggressive variant of moderately differentiated PTC [1]. Today, HPTC is a new and recognized variant of PTC [10–12].
Clinicopathological Characteristics To date, 94 cases of HPTC (Table 1) have been described in literature [1, 5, 6, 13–19]. There is a female predominance (F/M = 2:1), with an average age at diagnosis of 53 years old. Often, patients present with a thyroid or cervical palpable mass, some associated with dyspnea due to compression of trachea, cervical lymphadenopathy, a history of multinodular goiter, and in one case, with hemoptysis [20]. Ultrasound (US) examination may show a hypoechoic and highly vascularized thyroid nodule. Thyroid nodules which undergo fine needle aspiration (FNA) under US guidance are diagnosed as positive for PTC and total thyroidectomy may be indicated as primary treatment [21]. The mean size of primary tumor is 24 mm (range, 5–90 mm), and in 60.9% of cases, a presence of linfovascular invasion is evident on histology with an extrathyroidal invasion observed in 43% of cases reported in literature. At the time of presentation, metastasis to regional lymph nodes occurs in 57% of patients [1, 5, 6, 13–19]. Frequently, HPTC shows little response to iodine treatment [22], and may be a candidate for target therapies. Morandi et al. [18] analyzed 18 HPTC, and only six cases were responsive to radioactive iodine therapy (for an average of 50 months) [18]. During follow-up (mean of 62 months of cases reported in literature), 25.4% of cases (15 out of 59 cases) showed a local/regional recurrence and 36% of cases (27 out of 75 cases) developed distant metastases, mainly in the lung and in the bone and rarely in the brain. At the last follow-up available, 21.2% of patients died of disease and 22.1% of patients were alive with disease.
Cytological Features The cytological diagnosis on a pre-operative FNA is usually formulated according to the diagnostic categories (British Thyroid Association, Royal College of Physician, London, UK and the Bethesda system [23, 24]). Frequently, hobnail features are found in papillary, micropapillary, or discohesive cell clusters in HPTC. Cytological smears are highly cellular, with a bloody background, and scant colloid. Cells are arranged in papillary-
like clusters and/or in micropapillary groups [6, 16], and a few cases show a predominant follicular pattern. The cells vary in size from small to medium with tear-drop cytoplasm, so called comet-like cells [25]. Nuclei are apically placed, occasionally grooved, and produce a surface bulge leading to a hobnail appearance with high nuclear/ cytoplasm (N/C) ratio. High magnification shows nuclear pleomorphism, occasionally pseudo-inclusions with multiple soap bubble-like inclusions, and possibly mitotic figures. The presence on FNA of Bcomet-like^ cells may lead to pre-operative suspicion of HPTC (Fig. 1). The cytological characteristics, in particular nuclear features, of usual (classic) PTC are occasionally evident on smear in cases of HPTC [6, 16]. The differential diagnosis of HPTC in FNA includes usual (classic) PTC and tall-cell variant of PTC characterized by eccentric nuclei, columnar cells, abundant cytoplasm, and distinct cell borders [26]. Both these two tumors are characterized by the absence of cytological hobnail appearance and comet-like cells. Table 2 summarizes possible differential diagnosis on cytological smears.
Histological Features HPTC was originally described using the following criteria for the histological diagnosis: (i) non-solid type of PTC, (ii) ≤ 10% of the tumor showed tall/columnar or diffuse sclerosing features, and (iii) loss of polarity/cohesiveness with hobnail features in ≥ 30% of tumor cells [1, 5, 6]. It is identified by hobnail and micropapillary patterns, a high nuclearcytoplasmatic N/C ratio, and hobnail cells (Figs. 2, 3, and 4a). Hobnail cells vary in size and shape from small lymphocytoid cells to larger cuboidal cells, rarely tall/ columnar cells may also be present [13, 14, 16]. The cytoplasm is usually abundant, eosinophilic, and sometimes finely granular [11]. Tumors with eosinophilic cytoplasm are included in the differential diagnoses for tumors with oncocytic features [27]. In HPTC, the nuclei are apically placed, moderately to highly pleomorphic, occasionally grooved, or located in the middle of the cytoplasm. The bulging nuclei form characteristic hobnail cells that can be present in varying amounts in a tumor. Vascular invasion and foci of necrosis may be seen as well as mitotic figures. The mean mitotic rate is 2–3/10 high-powered fields (400× magnification), with atypical mitoses in a minority of cases [5–14, 16]. The main differential diagnoses of HPTC include usual (classic) PTC, tall-cell PTC, columnar cell PTC, oncocytic PTC, and other oncocytic/Hurthle cell tumors. Table 3 describes the main histologic features among these various subtypes. Hobnail architecture may be observed in some Hurthle cell adenomas and carcinomas and in rare follicular adenomas. However, the distinctive cytological features of HPTCs are absent.
3:1
1.5:1
1:2
Lubitz et al. 2014 USA
Asioli et. Al. 2014 Italy
Amacher et Al. 2015 USA
45 (23–67)
65 (27–86)
54.1 (21–80)
16.3 (6–40)
2.71 (6.5–0.9)
42 (20–90)
37 (5–65)
10–30
27 (10/50)
61.5 (40–100)
(10–100)
43.5 (39.5–50.5) 12.1 (5–20)
57.3 (28–78) 22.95 (10–70)
45 (27–68)
1.5:1 50.4 (32–68)
3:1
Asioli et. Al. 2013 Italy/USA
Lino-Silva et al. 1:1.3 2012 Mexico
67.5 (30–100)
57.6 (28–78)
3:1
Asioli et. Al. 2010 Italy/USA
25 (10–40)
Mean age, Mean tumor size, Mean of hobnail years (range) mm (range) features (range)
F:M ratio
Clinical and pathological features of major studies of HPTC cases
Cases
Table 1
(8/10) 80%
(4/5) 80%
(5/12) 42%
(17/24) 70.8%
(5/7) 71.5%
(7/8) 87.5%
I (4/10) 40%
(1/10) 10%
(5/6) 83.3%
(1/5) 20%
(6/6) 100%
(2/6) 33.3%
(3/5) 60%
12 (9–28)
39 (7–104)
8 (2–24)
26.5 (14–35.5)
106 (4–274)
(8/24) 33.3%
(8/10) 80%
103 (40–158)
(3/7) 42.8%
77.2 (4–236)
DOD (1/11) 9.2% AND (7/11) 63.6% AWD (3/11) 27.2% AND (4/5) 80% AWD (1/5) 20% DOD (2/6) 33.3% AND (3/6) 50% AWD (1/6) 16.6%
DOD (4/7) 57.2% AWD (3/7) 42.8% DOD (8/24) 33.3% AND (9/24) 25% AWD (6/24) 4.2% DND (1/24) 9.2%
DOD (4/8) 50% AND (2/8) 25% AWD (2/8) 25%
(4/8) 50%
(3/8) 37.5%
(5/8) 62.5%
Outcome
Recurrence Metastasis BRAF Mean follow-up, mutation months (range)
I (5/12) 42% II (0/12) (4/12) 33% (3/12) 25% III (3/12) 25% IV (4712) 33%
I–II 9/24 (37.5%) III–IV 15/24 (62.5%)
I–II 3/7 (42.8%) III–IV 4/7 (57.2%)
(6/8) 75% IV (6/6) 100%
(3/5) 60%
(10/12) 83.3%
(7/24) 29.1%
(5/7) 71.5%
(6/8) 75% I (0/8) II (1/8)12.5% III (2/8) 25% IV (5/8) 62.5%
Linfovascula Nodal AJCC 2010 (7th ed) invasion metastasis stage
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41.8 (23–78)
253 (100–500)
62.2 (40–100)
(2/18) 11.1% (10/18) 58.8%
I (2/18) 11.1 II (2/18) 11.1 III (4/18) 22.2 IV (10/18) 55.5
F female, M male, AND alive with no disease, DOD died of disease, AWD alive with disease, DND died not of disease
Teng et al. 2017 13:5 China
(15/18) 83.3%
3.5:1
(4/8) 50%
Morandi et al. 2017 USA
41.87 (30–70)
(2/8) 25% I (4/8) 50% II (2/8) 25% III (2/8) 25% IV 0
55 (46–69) 17.75 (10–32)
3:1
II (0/10) III (4/10) 40% IV (2/10) 20%
Linfovascula Nodal AJCC 2010 (7th ed) invasion metastasis stage
Ieni A. et al. 2016 Italy
Mean age, Mean tumor size, Mean of hobnail years (range) mm (range) features (range) (8/10) 80%
F:M ratio
Lee et al. 2015 South Korea
Cases
Table 1 (continued)
(1/18) 5.5%
(2/18) 11.1%
(16/17) 94%
(15/18) 83.3%
(4/8) 50%
(8/10) 80%
71.88 (12–101)
40 (6–12)
47.75 (39–60)
Recurrence Metastasis BRAF Mean follow-up, mutation months (range)
DOD (4/18) 22.2% AND (7/18) 38.8% AWD (7/18) 38.8% AND (13/16) 81.2% AWD (1/16) 6.2% DND (1/16) 6.2% DOD (1/16) 6.2%
DOD (0/10) AND (9/10) 90% AWD (1/10) 10% AND (8/8) 100%
Outcome
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Occasional chromatin clearing Uniform, finely granular Chromatin clearing Chromatin clearing Chromatin clearing
Chromatin clearing, micronucleoli
Yes No Yes Yes Rare
Yes Rare Yes Rare
Yes
Elongated and overlapped, pleomorphic Yes Oval and elongated, pseudostratified No Enlarged Enlarged
Microfollicular, flat syncitial Papillary fragments Round or oval, scant Oxyphilic cytoplasm, indistinct borders, enlarged oval Enlarged, oval Enlarged
Cluster Papillary, monolayer architecture sheets Cells Round or oval, scant cytoplasm, indistinct borders Nuclei Elongated and overlapping Nuclear Yes inclusions Nuclear Yes grooves Chromatin Chromatin clearing
Syncitial fragments or sheets Pleomorphic
Occasional squamous metaplasia
Papillary, follicular, acinar, Occasional micropapillary solid monostratified Columnar, supra, or subnuclear Tear-drop, hobnail, vacuoles Bcomet-like^
Bloody Clean, no colloid
No stringly colloid, many psammoma bodies, lymphocites Micropapillary, solid Lymphocytes Clean with little thick colloid Thick and thin colloid
High Moderate Variable High Cellularity
Follicular PTC
Cytological aspects and differential diagnoses on cytological smears
The most common genetic abnormalities in PTC include RET/PTC rearrangements and BRAF p.V600E mutations
Usual PTC
Mutational Analysis
Table 2
All cases described in the literature [1, 5, 6, 13–19] showed positive staining for thyroglobulin, thyroid transcription factor-1 (TTF-1), keratin 7, keratin 19, epithelial membrane antigen, and HBME1. Thyroglobulin may show variable intensity and focal distribution of the staining [1]. All but one case did not highlight an expression for the anti-mitochondria [1, 5, 14, 16, 18]. P53 protein was expressed in more than 25% of the neoplastic cell nuclei in 77% of cases reported in literature [1, 5, 6, 14, 16, 18] (Fig. 4b). MUC1 showed the characteristic Binside-out^ staining pattern in all cases reported, highlighted by hobnail features of the tumor cells [1, 5, 13]. Beta-catenin and E-cadherin were observed in the basolateral or lateral site of neoplastic cells in all cases reported, and in three cases a nuclear co-expression in few cells of beta-catenin was present [1, 5, 6, 14, 16, 18]. In a study by Lee et al. [16], diffusely staining for cyclin-D1 and HBME1, and focally staining for CD56 were observed in all 10 cases analyzed. The proliferative index evaluated by Ki-67 ranged from 2 to 20% [5, 14, 18].
Warthin-like Solid PTC PTC High High
Immunoistochemical Profile
Background Thick and thin colloid
Fig. 1 On cytological smears, tear-drop cells (so called comet-like cells) with high nuclear/cytoplasmic ratio are typical of HPTC (a, b Giemsa stain, 400× of magnification)
Low
Diffuse sclerosing PTC
Columnar cell PTC
Hobnail PTC
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Fig. 2 Hobnail papillary thyroid carcinoma (HPTC). It shows prominent papillary pattern of growth and follicular architecture (a H&E 20× of magnification). Usually, papillary pattern included variably sized complex papillary structures with prominent vascular cores, and focal micropapillary areas. Also, the follicular pattern is characterized by variably sized follicles lined by thick neoplastic epithelium. (b H&E 50× of magnification)
[28–30]. Rarely, gene amplifications and copy number gains are noted involving genes encoding tyrosine kinase receptors (TKRs) [31–33]. Epigenetic pathways, such as aberrant methylation of thyroid-specific genes involved in iodine
Fig. 3 Cuboidal or oval epithelium covered both papillary and follicular structures. Cells showed high nuclear/cytoplasmatic ratio and apically placed, occasionally grooved with nuclei that produce a surface bulge leading to a hobnail appearance. Thin arborizing papillae are lined by hobnail cells (H&E 200× magnification)
Fig. 4 a Occasional pink intranuclear holes are observed (black arrows, 200× magnification). b An example of strong nuclear staining of p53 protein in a case of HPTC (400× magnification)
metabolism or tumor suppression, may lead to loss of radioiodine avidity and increased tumor growth, invasion, and metastases [34]. Recent studies identified BRAF p.V600E mutation as the most common alteration in HPTC cases, in particular BRAF p.V600E mutation was found in 60 out of 82 analyzed (73.2%), and only 2 HPTC out of 30 (6.7%) tested tumor had RET/PTC1 rearrangements [1, 5, 6, 14, 16, 18]. Morandi et al. [18] confirmed BRAF p.V600E as the most common mutation, and identified a rare mutation; p.A598V. BRAF is a proto-oncogene located at 7q24 that encodes a serine/threonine kinase from the family of RAFkinase, which plays a central role in the transduction of signals along the RAS/RAF/MEK/ERK pathway regulating cell growth, differentiation, and apoptosis [35]. A recent multicenter study concluded BRAF p.V600E mutation was associated with increased cancer-related mortality in patients with PTC, even if when the aggressive tumor features of lymph nodal and distant metastases and extrathyroidal invasion, were also included in the model, the association of BRAF V600E with mortality was no longer statistically significant [36]. Other reported mutations included TP53, PIK3A, hTERT, CTNNb1, EGFR, AKT1, and NOTCH 1 in 18 cases tested, without mutations of CKDN2A, PTEN, and ALK [16, 18]. The high prevalence of BRAF mutation and the association with other genes (TP53, PIK3CA, CTNNB1, and hTERT) reflect a complex pathogenetic mechanism for this aggressive
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Histological characteristics and differential diagnoses on histological sections
Hobnail
Tall cell
Columnar cell
Cuboidal or oval epithelium, with areas of discohesiveness Increased nucleo/cytoplasmatic ratio, dense eosinophilic cytoplasm with well-defined borders Enlarged overlapped, nuclear grooves, and pseudo-inclusions
Height, twice their width Eosinophilic cytoplasm
Pseudostratified columnar cells Supra and sub Squamous metaplasia and numerous psammoma bodies cytoplasmatic vacuoles Hyperchromatic and large clear nuclei, centrally located
High mitotic rate Metastasis, lympho-vascular invasion
Grooves and pseudo-inclusions Mitotic figures and necrosis Extrathyroid extension
Extrathyroidal extension
variant of PTC. Morandi et al. [18] identified BRAF as an initial driver, with second hits (TP53, TERT, PIK3CA); this mutational pattern in HPTC could be useful to better identify HPTC signaling and differentiation properties, and they recognized that BRAF p.V600E, EGFR p.A859T, NOTCH p.D1681 were present in the bulk of primary tumors, considering these mutations as early events in HPTC evolution. Other detected mutations in TP53, CTNNB1, AKT, and PIK3CA showed lower variant allele frequency, indicating later events; likely involving a limited number of cells. Furthermore, these mutations, in particular BRAF and PIK3CA in cooperation, are shared with anaplastic carcinoma, also hTERT with poorly differentiated and anaplastic carcinoma, and are significantly associated with specific disease mortality [37]. In spite of the series described by Morandi et al. [18] is limited, it reveals that a single clone gave rise to lymph node metastasis maintaining driver mutation in BRAF, TP53, or PIKC3CA, and mutations in these genes are related to a more aggressive behavior. These new perspectives may lead to treatment with selective or multi-tyrosine inhibitor to improve the patients’ outcome. The combined mutations in BRAF, TP53, and/or PIK3CA genes by molecular profiling seem to be relevant in order to use target therapies. These complex molecular studies and different pattern of mutations, in proximal future, could lead treatment of advanced thyroid cancer targeting different molecular pathways.
Metastasis Mechanisms HPTC is an extreme example of loss of cellular polarity/ cohesiveness; the literature suggests the possibility that PXRγ up-regulation may be a potential candidate for ligand therapy of PTC, especially for aggressive types of PTC with loss of cellular polarity [36]. The loss of cellular polarity is the phenotypic expression of epithelial to mesenchymal transition (EMT) in thyroid tumors. The decrease expression of thyroid
Sclerosing variant
Diffuse involvement of both lobes, multiple foci, dense lymphocytic infiltration, stromal fibrosis, and lymphatic metastasis
transcription factor-1 and E-cadherin, aberrant ß-catenin polarity, and increased vimentin expression are reliable markers to identify loss of cellular polarity/cohesiveness. The latter may be one of the morphological indicators of the role of EMT in PTC [38]. Hardin et al. [39] found that EMT is induced by transforming growth factor-ß1; PTC cells acquired increased cancer stem cell-like features and the transcription factor paired-related homebox protein (PPRX1), a newly identified inducer is markedly up-regulated. High-grade thyroid carcinomas expressed the highest level of this EMT marker. Usual PTCs on tissue micro arrays were negative for PPRX1, while two cases of HPTC were positive for PPRX1. The results of this study suggest positivity for PPRX1 is associated with metastatic disease and high rate of mortality.
New Prospective The prevalence of HPTC is only 0.6% (22/3551 cases) of a large, institutional series of primary PTC [5]; thus, there remains much to be learned about this new entity. A recent study [15] analyzed Bpure^ HPTC and other cases in association with poorly differentiated and anaplastic thyroid carcinoma. This group hypothesized hobnail features may be a sign of higher-grade transformation, because hobnail features are more common in poorly differentiated thyroid carcinomas. They showed that hobnail features are most commonly associated with poorly differentiated thyroid carcinoma (4/18 cases), compared with papillary thyroid carcinoma patients (6/478); only one of 26 anaplastic carcinoma studied had hobnail features. The more common association of hobnail pattern with poorly differentiated thyroid carcinoma was also observed by Amacher et al. [15]. However, in accordance with Turin criteria [40], the diagnosis of poorly differentiated carcinoma is primarily made on by morphology and includes solid/trabecular/insular tumors with absence of conventional nuclear features of papillary carcinoma, and presence of at
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least one of the following: convoluted nuclei, mitotic activity (≥ 3/10 HPF), or tumor necrosis HPTC does not fit the previous criteria and cannot be considered as poorly differentiated; thus, the designation as a moderately differentiated thyroid carcinoma. In summary, we need more studies to understand the molecular mechanism of tumorigenesis, tumor progression, and to establish new target therapies that are personalized for this aggressive variant of PTC. Compliance with Ethical Standards Conflict of Interest The authors declare that they have no conflict of interest.
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