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Hürthle Cell Tumors
Using Molecular Techniques to Define a Novel Classification System
Greg Belchetz, MD;
Carol C. Cheung, MD;
Jeremy Freeman, MD;
Irving B. Rosen, MD;
Ian J. Witterick, MD;
Sylvia L. Asa, MD
Arch Otolaryngol Head Neck Surg. 2002;128:237-240.
ABSTRACT
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Background Since ret/PTC gene rearrangements are specific
to papillary thyroid carcinoma (PTC), the diagnosis of Hürthle cell PTC
(HCPTC) has recently been expanded to include a subset of Hürthle cell
tumors (HCTs) that may lack both papillary architecture and/or classic nuclear
features but that harbor a ret/PTC gene rearrangement.
We hypothesize that such HCPTCs behave in a fashion analogous to other papillary
carcinomas, while Hürthle cell carcinomas (HCCs) behave similarly to
follicular carcinomas.
Educational Objectives At the conclusion of this article, participants should be able to discuss
HCTs and to identify HCPTCS using molecular techniques.
Methods A retrospective chart review was carried out on 56 patients with HCTs.
All pathological specimens were analyzed for ret/PTC
gene rearrangements. Hürthle cell adenoma (HCA) was defined as an HCT
that did not exhibit capsular and/or vascular invasion and that lacked a ret/PTC gene rearrangement when evaluated by immunohistochemical
and reverse transcription polymerase chain reaction analysis. An HCC was defined
as an HCT with capsular and/or vascular invasion that lacked a ret/PTC gene rearrangement, and an HCPTC was defined as any HCT that
harbored a ret/PTC gene rearrangement.
Results The subclassification of the 56 HCTs was as follows: 21 HCAs, 15 HCCs,
and 20 HCPTCs. No patients with HCA or HCC were ret/PTC positive. Five of the 6 patients with definite lymph node metastasis
were in the HCPTC group, demonstrating that molecular analysis helps to explain
biological behavior.
Conclusions Hürthle cell neoplasms can now be classified using histopathological
as well as molecular criteria. It appears that the new subclassification of
malignant HCTs into follicular (HCC) and papillary (HCPTC) variants identifies
2 distinct biological groups.
INTRODUCTION
Hürthle cells (Askanazy cells, oxyphilic cells) are thyroglobulin-producing,
mitochondria-rich, thyroid epithelial cells.1
They are found in a variety of thyroid conditions, including Hashimoto thyroiditis,
Graves disease, nodular goiters, and thyroid neoplasms.2-3
Oxyphilic change has also been described in parathyroid, pancreatic, hepatic,
renal, pituitary, and salivary gland tissue.3
Hürthle cell tumors (HCTs) are defined as being composed of at
least 75% Hürthle cells.4 They have been
traditionally classified as benign (Hürthle cell adenoma [HCA]) and malignant
(Hürthle cell carcinoma [HCC]). It is generally believed that HCC is
a variant of follicular carcinoma; the World Health Organization classification
of 1987 describes HCC as follicular carcinoma, oxyphilic variant.5 Papillary thyroid carcinomas (PTCs) composed of Hürthle
cells have been described.6-10
Until recently, this diagnosis was based on the presence of papillary architecture
and not on the characteristic nuclear features of this entity. The recognition
of the diagnostic nuclear features of papillary carcinoma is confounded by
the fact that they are often obscured by the nuclear hyperchromasia that accompanies
Hürthle cell metaplasia.6-10
Because ret/PTC gene rearrangements are specific
to PTCs,11-12 the diagnosis of
Hürthle cell PTC (HCPTC) has recently been expanded to include those
tumors that lack papillary architecture but harbor a ret/PTC gene rearrangement.13
Predicting the clinical behavior of HCCs and therefore selecting appropriate
treatment is controversial. Reports in the literature vary with regard to
the clinical behavior of HCCs. Some authors believe that HCCs behave in a
clinically indolent fashion, similar to other well-differentiated thyroid
cancers,14-16
while others believe them to be very aggressive.17-18
The behavior of apparently benign HCTs is equally confusing.18 Several authors have reported tumors initially diagnosed
as HCAs that later recurred or metastasized.17-18
Unfortunately, the inability to accurately predict the clinical behavior of
HCTs has led some authors to advocate aggressive surgical treatment for all
HCTs.17, 19-22
Until the identification of the HCPTC, there was no adequate explanation as
to why some HCTs developed lymph node metastasis, particularly in tumors that
were morphologically classified as HCAs.
We hypothesize that HCCs behave in keeping with other follicular carcinomas
with hematogenous spread and a more aggressive clinical course and that HCPTCs
behave in a fashion analogous to other PTCs, with lymphatic spread and a more
indolent clinical course.
PATIENTS AND METHODS
A retrospective chart review was carried out on 56 patients who had
been diagnosed as having HCT between January 1993 and April 1999. The patients
were referred by 4 surgeons at Mount Sinai Hospital, Toronto, Ontario. One
surgical pathologist (S.L.A.) analyzed all pathology reports. The HCTs were
classified as HCA, HCC, or HCPTC according to Cheung et al.13
An HCA was defined as an HCT that did not exhibit capsular and/or vascular
invasion and that lacked a ret/PTC gene rearrangement
when evaluated by immunohistochemical and reverse transcription polymerase
chain reaction analysis. An HCC was defined as an HCT with capsular and/or
vascular invasion that lacked a ret/PTC gene rearrangement
when evaluated by immunohistochemical and reverse transcription polymerase
chain reaction analysis. An HCPTC was defined as any tumor that harbored a ret/PTC gene rearrangement when evaluated by immunohistochemical
and reverse transcription polymerase chain reaction analysis.
Data were collected for each patient with respect to age, sex, clinical
presentation, result of fine-needle aspiration, extent of surgery, size of
primary lesion, presence of extracapsular extension, presence of lymph node
metastasis, and presence of distant metastasis. Data on whether the patients
received radioactive iodine treatment and/or external beam radiation therapy,
whether the tumor recurred after treatment, and whether the patients died
of their disease were also recorded. Follow-up care ranged from 1 month to
106 months or death, with a mean follow-up duration of 30 months.
RESULTS
The features of 56 HCTs are summarized in Table 1. Of the 56 tumors, 15 (27%) were diagnosed as HCC, 20 (36%)
were diagnosed as HCPTC, and 21 (38%) were diagnosed as HCA. There was a female
predominance both overall (43 of the 56 tumors) and in each subgroup. The
age of patients ranged from 26 to 89 years. The average age of the patients
was higher in the HCC group (mean age, 63.4 years) than in the HCPTC group
(mean age, 49.4 years) and the HCA group (mean age, 48.0 years). None of the
patients had a history of exposure to radiation. The majority of patients
presented with an asymptomatic nodule of the thyroid. Other presentations
included multinodular goiters, symptomatic goiters (choking, dysphagia), thyroid
mass on chest x-ray film, hypothyroidism, and a thyroglossal duct cyst.
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Clinical and Pathological Features in 56 Patients With Hürthle
Cell Tumors*
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Only 3 of the patients in the series did not undergo fine-needle aspiration
biopsy as part of their workup. The most common result of cytological examination
was "Hürthle cell lesion" (24/56), with "follicular neoplasm" (8/56)
being the second most common reported finding. Only 1 patient had a cytology
report of "carcinoma" that went on to a final diagnosis of HCC, whereas 7
patients had a cytology report of "papillary carcinoma" and went on to a final
diagnosis of HCPTC. One HCA was mistakenly called carcinoma on cytological examination.
Of the 15 patients with the final diagnosis of HCC, 9 underwent total
thyroidectomy and 7 underwent hemithyroidectomy, with the completion thyroidectomy
at a later date. One patient underwent a comprehensive neck dissection for
grossly positive neck disease. Of the 20 patients with the final diagnosis
of HCPTC, 17 underwent total thyroidectomy and 3 underwent hemithyroidectomy,
with the completion thyroidectomy at a later date. Three patients underwent
neck dissection for grossly positive neck disease. Of the 21 patients with
HCA, 19 underwent hemithyroidectomies as their only treatment. Two patients
with HCA underwent total thyroidectomy because intraoperative frozen sections
were reported as carcinoma.
The size of the primary lesion ranged from 1.0 to 10.6 cm in maximum
diameter. This size was comparable across all 3 groups. The mean maximal diameters
for the follicular, papillary, and adenoma groups were 4.0, 3.4, and 3.1 cm,
respectively.
Three patients with a final diagnosis of HCC had extrathyroidal extension
noted on their final pathology report. Seven patients with a final diagnosis
of HCPTC had extrathyroidal extension noted on their final pathology report.
No patients with a final diagnosis of HCA had extrathyroidal extension.
Only 1 patient with a final diagnosis of HCC was histologically positive
for lymph node metastasis. Five patients with a final diagnosis of HCPTC were
positive for lymph node metastasis histologically or on radioactive iodine
body scan. No patients with a final diagnosis of HCA had lymph node metastasis.
No patients in any group had distant metastasis during the follow-up period.
Radioactive iodine treatment was given to 14 of 15 patients with HCC
patients and to 18 of 20 patients with HCPTC. No patients with HCA received
radioactive iodine treatment. External beam radiation therapy was administered
to 3 of 20 patients with HCPTC and gross local residual disease. No patients
with HCC or HCA received external beam radiation therapy.
After surgical treatment, 2 patients with HCPTC had a recurrence of
their disease. Both of these recurrences were in the form of lymph node metastases
and were treated with subsequent doses of radioactive iodine. There was only
1 death in the series. The patient, who had HCC in a thyroglossal duct cyst,
died of carotid artery erosion.
COMMENT
The Hürthle cell variant of papillary carcinoma has been described
in the literature. It was diagnosed on the basis of papillary architecture.
Recently, Cheung et al13 established the molecular
basis of HCPTC with the identification of ret/PTC
gene rearrangements in a subset of HCTs. In the absence of papillary architecture,
the diagnosis of a "follicular variant papillary carcinoma" with a Hürthle
cell morphological appearance cannot rely on nuclear features, as the nuclear
hyperchromasia that often accompanies Hürthle cell metaplasia may obscure
the diagnostic nuclear features.
Being able to accurately divide malignant HCTs into follicular and papillary
variants may account for the heterogeneity in clinical behavior that has caused
major controversy in the past.14-15
One would expect HCPTCs to behave in keeping with other PTCs, with a tendency
for lymph node metastasis and a more indolent clinical course4;
HCCs might account for the reports of more aggressive HCTs.
All the HCTs in our large series were analyzed for the presence of ret/PTC gene rearrangements. There was a definite predominance
of lymph node metastasis in the group that was ret/PTC
positive, with only 1 ret/PTC-negative tumor displaying
lymph node metastasis. Since ret/PTC gene rearrangements
are identified in only a percentage of papillary carcinomas, it may be that
other markers of papillary carcinoma will identify this lesion as a PTC as
well.
Recurrence of disease after treatment was uncommon in all groups. Recurrence
occurred twice in the HCPTC group, and in both cases it was in the form of
lymph node metastasis. The overall low recurrence and mortality rates in all
groups may be a true reflection of the biological behavior of Hürthle
cell cancers, but the duration of follow-up was too short in many cases to
confirm this theory. The only death in the series happened in a patient with
HCC arising in a thyroglossal duct cyst, an extremely rare occurrence.
Previous reports of aggressive behavior suggested that the diagnosis
of HCA could not be trusted.17-18
The recognition of HCPTC identified a group of lesions that demonstrated no
invasive behavior at the time of diagnosis but that harbored a ret/PTC gene rearrangement. These tumors have the potential to metastasize,
explaining the occurrence of malignancy in patients with a histopathological
diagnosis of adenoma. These data indicate the need for application of analysis
for ret rearrangements as a diagnostic tool.
This series of HCTs suggests that being able to divide malignant HCTs
into follicular and papillary groups does identify 2 biologically different
groups, which may enable the clinician to predict which HCT will behave in
a more aggressive fashion (as traditionally has been believed) and which will
behave in a more indolent fashion, as many authors have more recently noted.
AUTHOR INFORMATION
Accepted for publication October 26, 2001.
We wish to acknowledge the generosity of Temmy Latner/Dynacare in funding
this study.
This study was presented at the annual meeting of the American Head
and Neck Society, Palm Desert, Calif, May 16, 2001.
Corresponding author: Jeremy Freeman, MD, Department of Otolaryngology,
Mount Sinai Hospital, 600 University Ave, Suite 401, Toronto, Ontario, Canada
M5G 1X5.
From the Departments of Otolaryngology (Drs Belchetz, Freeman, and
Witterick), Pathology (Drs Cheung and Asa), and Surgery (Dr Rosen) and the
Freeman Centre in Endocrine Oncology (Drs Freeman and Asa), Mount Sinai Hospital,
Toronto, Ontario.
REFERENCES
| |
1. Saul SC, Kimmelman CP. Hürthle cell tumors of the thyroid gland. Otolaryngol Head Neck Surg. 1985;93:58-62.
PUBMED
2. McLeod MK, Thompson NW. Hürthle cell neoplasms of the thyroid. Otolaryngol Clin North Am. 1990;23:441-452.
PUBMED
3. Azadian A, Rosen IB, Walfish PG, Asa SL. Management considerations in Hürthle cell carcinoma. Surgery. 1995;118:711-715.
PUBMED
4. LiVolsi VA. Surgical Pathology of the Thyroid. Philadelphia, Pa: WB Saunders Co; 1990.
5. Hedinger C. Histological Typing of Thyroid Tumours. Vol 7. New York, NY: Springer-Verlag NY Inc; 1987.
6. Dickersin GR, Vickery AL, Smith SB. Papillary carcinoma of the thyroid, oxyphil cell type, "clear cell"
variant: a light and electron microscopic study. Am J Surg Pathol. 1980;4:501-509.
PUBMED
7. Goyal A, Jain S, Kakar AK, Chauhan S. Papillary Hürthle cell tumours of thyroid: diagnositc features
in eight cases with review of literature. Indian J Cancer. 1996;33:130-135.
PUBMED
8. Hill JH, Werkhaven JA, Demay RM. Hürthle cell variant of papillary carcinoma of the thyroid gland. Otolaryngol Head Neck Surg. 1988;98:338-341.
PUBMED
9. Apel RL, Asa SL, LiVolsi VA. Papillary Hürthle cell carcinoma with lymphatic stroma: "Warthin-like
tumor" of the thyroid. Am J Surg Pathol. 1995;19:810-814.
ISI
| PUBMED
10. Becker ME, Heffess CS, Oertel JE. Oxyphilic papillary thyroid carcinoma. Am J Clin Pathol. 1995;103:280-287.
PUBMED
11. Sugg SL, Zheng L, Rosen IB, Freeman JL, Ezzat S, Asa SL. ret/PTC-1, -2 and -3 oncogene rearrangements in human thyroid carcinomas:
implication for metastatic potential? J Clin Endocrinol Metab. 1996;81:3360-3365.
ABSTRACT
12. Sugg SL, Zheng L, Rosen IB, Freeman JL, Ezzat S, Asa SL. Distinct multiple ret/PTC gene rearrangements in mutifocal papillary
thyroid neoplasia. J Clin Endocrinol Metab. 1998;83:4116-4122.
FREE FULL TEXT
13. Cheung CC, Ezzat S, Ramyar L, Freeman JL, Asa SL. Molecular basis of Hürthle cell papillary thyroid carcinoma. J Clin Endocrinol Metab. 2000;85:878-882.
FREE FULL TEXT
14. Khafif A, Khafif RA, Attie JN. Hürthle cell carcinoma: a malignancy of low-grade potential. Head Neck. 1999;21:506-511.
PUBMED
15. Rosen IB, Luk S, Katz I. Hürthle cell tumor behavior: dilemma and resolution. Surgery. 1985;98:777-783.
PUBMED
16. Heppe H, Armin A, Calandra DB, Lawrence AM, Paloyan E. Hürthle cell tumors of the thyroid gland. Surgery. 1985;98:1162-1165.
PUBMED
17. Thompson WW, Dunn EL, Butsakis JG, et al. Hürthle cell lesions of the thyroid gland. Surg Gynecol Obstet. 1974;139:555-560.
PUBMED
18. Grant CS, Barr D, Goellner JR, Hay ID. Benign Hürthle cell tumours of the thyroid: a diagnosis to be
trusted? World J Surg. 1988;12:488-495.
PUBMED
19. McDonald AP, Sanders LE, Silverman ML, Chan HS, Buyske J. Hürthle cell carcinoma of the thyroid gland: prognostic factors
and results of surgical treatment. Surgery. 1996;120:1000-1005.
FULL TEXT
| PUBMED
20. Shaha AR, Shah JP, Loree TR. Patterns of nodal and distant metastasis based on histological varieties
in differentiated carcinoma of the thyroid. Am J Surg. 1996;172:692-694.
FULL TEXT
|
ISI
| PUBMED
21. Tollefsen HR, Shah JP, Huvos AG. Hürthle cell carcinoma of the thyroid. Am J Surg. 1975;130:390-394.
PUBMED
22. Samaan NA, Maheshwari YK, Nader S, et al. Impact of therapy for differentiated carcinoma of the thyroid: an analysis
of 706 cases. J Clin Endocrinol Metab. 1983;56:1131-1138.
ABSTRACT
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