Nongynecologic Cytopathology Acta Cytologica 2014;58:262–268 DOI: 10.1159/000360805
Received: September 10, 2013 Accepted after revision: February 23, 2014 Published online: June 4, 2014
Secondary or Second Primary Malignancy in the Thyroid? Metastatic Tumors Suggested Clinically: A Differential Diagnostic Task Jaroslava Dušková a, b Pavel Rosa c Pavel Přeučil c Eva Svobodová c Jindřich Lukáš d a
Cytopathology Laboratory, Institute of Pathology, 1st Medical Faculty, Charles University and Medical College, Centre of Gynaecology and Oncology Prevention, Ltd., c Private Practice in Endocrinology, and d Department of ENT, Head and Neck Surgery, Na Homolce Hospital, Prague, Czech Republic b
Abstract Objective: To describe the algorithms employed to explore the suggestion or consideration of metastatic malignancy in the thyroid. Study Design: Thirty-seven cases with a history of malignancy (n = 21) and/or uncommon fine-needle aspiration biopsy (FNAB) findings (n = 37) were reviewed and reclassified according to The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). Results: The group was heterogeneous in terms of the final histopathology results: the suggested metastasis was confirmed in only half of the cases (11/21; 52.4%). Primary thyroid malignancies were mostly nondifferentiated, medullary, or rare. However, 3 papillary carcinomas (the less common variants) were also found. Finally, 5 out of 37 cases were surprisingly benign upon histopathological investigation (uncommon repair and fibrotizing Hashimoto thyroiditis). Conclusions: The metastatic nature of thyroid gland nodule(s) must be considered in cases of generalization of malignancy and/or uncom-
© 2014 S. Karger AG, Basel 0001–5547/14/0583–0262$39.50/0 E-Mail [email protected] www.karger.com/acy
mon FNAB findings. We must be as open-minded as possible from the outset. Additional techniques are helpful if available – cytoblock and immunocytochemistry can contribute substantially. Morphological comparisons with the previous malignancy are recommended whenever possible. To avoid overtreatment, cases without precise typing should not be classified as TBSRTC diagnostic category VI – malignant, but should remain in TBSRTC diagnostic category V – suspicious for malignancy. Repeated FNAB to enable additional techniques may be suggested. © 2014 S. Karger AG, Basel
Introduction
After the launch of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) [1], information for both Czech pathologists [2] and clinical specialists [3] was published in the local journals and the system was adopted into our daily routine diagnostics.
Presented as poster No. 338 at the 18th International Congress of Cytology in Paris, France, in 2013.
Correspondence to: Prof. Jaroslava Dušková Institute of Pathology, 1st Medical Faculty, Charles University Studničkova 2 CZ–12000 Prague 2 (Czech Republic) E-Mail jaroslava.duskova @ lf1.cuni.cz
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Key Words Thyroid · Fine-needle aspiration biopsy · Metastases · Second malignancy · The Bethesda System for Reporting Thyroid Cytopathology · Repair
Results
By the year 2012, four hundred thirty-three cases from the 36,552 thyroid FNAB diagnoses made over a 25-year period (1987–2012) were included in the continually growing teaching collection of cases. Furthermore, a part of the teaching collection created prior to the introduction of TBSRTC has been reclassified, and newer cases are being added using this classification as it represents a consistent part of the report. Thirty-seven cases (0.1% of the total of number FNABs performed in the center) with a history of malignancy (n = 21) and/or cytopathology featuring the designation TBSRTC diagnostic category V – suspicious for malignancy, or TBSRTC diagnostic category VI – malignant (n = 37), from the collection were reviewed. In this selection, no cases classified as TBSRTC diagnostic category III – atypia of undetermined significance/follicular lesion of undetermined significance were involved. Thirty other cases had to be excluded from the study for not (yet) having histopathology correlates at the time of the analysis.
The set of selected cases considered to have metastatic involvement was heterogeneous in terms of the final histopathological results: the suggested metastases were confirmed in only half of the cases (11/21; 52.4%) with a known history of malignancy. The 3 groups with confirmed metastases, primary malignancies, and surprisingly benign histopathological results of suspicious cytopathology findings did not differ substantially in terms of the prevalence of female patients, the mean age, or a wide age interval. Not surprisingly, patients with confirmed metastases (group 1) had the highest percentage of positive history of malignancy (92%). Also, the diagnostic certainty for TBSRTC diagnostic category VI – malignancy was the highest in this group (75%) (table 1). Clear cell kidney carcinoma followed by squamous cell carcinoma of the larynx and right tonsil and breast carcinoma were the most frequent primary malignancies (table 2). The last case in this group (case 12; table 2) was not excluded, although the metastatic nature of the generalized solid carcinoma could not be proven with absolute certainty. Both thyroidal markers (thyroglobulin and calcitonin) and the pulmonary marker (thyroid transcription factor 1) proved negative. Thyroid primary malignancies (n = 20; table 3) were mostly non-differentiated, medullary, or rare. However, 3 differentiated (papillary) carcinomas were also found, although 2 were poorly differentiated solid papillary carcinomas (one of these had minor follicular parts seen histopathologically) and the third was a tall cell papillary carcinoma in a patient with a known submandibular gland adenocarcinoma. The proportion of patients with a positive history of malignancy (40%) was substantially lower than in the group with confirmed metastatic involvement, although the diagnostic certainty for TBSRTC diagnostic category VI – malignancy remained high in this group (65%). Finally, 5 out of 37 (13.5%) cases with metastatic involvement considered in the differential diagnosis were surprisingly benign upon detailed histopathological examination, represented namely by an uncommon repair and fibrotizing Hashimoto thyroiditis (table 4). Although the percentage of patients with a positive history of malignancy in this group was identical (40%) to that of the previous group with a second primary malignancy in the thyroid gland, the diagnostic certainty of TBSRTC diagnostic category VI decreased substantially and 1 out of 5 cases in this group was thus discharged. In
Secondary or Second Primary Malignancy in the Thyroid?
Acta Cytologica 2014;58:262–268 DOI: 10.1159/000360805
Materials and Methods
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Metastatic involvement of the thyroid gland was initially described more than a century ago [4], and during the first decades of the 20th century these surprising findings were reported mostly in surgery journals [5, 6]. Clinically, they were described in surgeries with the expectation of finding a thyroid primary malignancy [7] and the surprising postoperative diagnosis was, already back then, indicative of the need to change the treatment plans. With the introduction of fine-needle aspiration biopsy (FNAB) for the investigation of thyroid nodules, the chance to diagnose thyroid metastases and to tailor the therapy emerged, but this remains difficult. Metastasis is a rare diagnostic finding in thyroid FNABs. Nevertheless, the clinical suggestion of a metastatic involvement of the thyroid gland has become more frequent because of the improved treatment and survival rate of patients with different malignancies and the high frequency of thyropathies (5–7%) in the Czech population [8]. In the majority of these cases, a metastatic lesion of the thyroid gland can be excluded in favor of just the concomitant nonneoplastic thyroid nodule. If the FNAB exhibits an uncommon cytological pattern (starting with TBSRTC diagnostic category III – atypia of undetermined significance, but especially in the case of TBSRTC diagnostic category V – suspicious for malignancy), a decision regarding a possible relationship has to be made. A similar differential diagnostic consideration of the metastasis must be made in cases of uncommon findings without a history of malignancy. The objective of this study was to illustrate the algorithms employed to explore the suggestion or consideration of a metastatic malignancy in the thyroid.
Table 1. Cases with clinically suggested metastatic involvement of the thyroid gland and/or uncommon FNAB findings grouped according to the results of the histopathology investigation
Female/male ratio Mean age (range), years Patients with a positive history of malignancy, n (%) TBSRTC diagnostic category V, n (%) TBSRTC diagnostic category VI, n (%)
Group I (n = 12)
Group II (n = 20)
Group III (n = 5)
8/4 65 (31 – 80) 11 (92) 4 (33) 8 (67)
12/8 69 (37 – 92) 8 (40) 7 (35) 13 (65)
4/1 57 (27 – 82) 2 (40) 4 (80) 1 (20)
Group I: Metastases or secondary malignancies in the thyroid gland confirmed or found; group II: primary malignancies confirmed in the thyroid gland; group III: malignancy in the thyroid gland not confirmed.
Table 2. Group I – metastases or secondary malignancies in the thyroid gland confirmed or found
Case Sex Age, History of malignancy No. years
TBSRTC FNAB differential diagnosis diagnostic category
Histopathological diagnosis
1
F
76
squamous cell ca. of the right tonsil
V
susp. metastasis of squamous cell ca. metastasis of squamous ca. of the tonsil
2
F
70
B CLL
V
susp. infiltration with B CLL
B CLL infiltration
3
M
55
squamous cell ca. of the larynx
VI
squamous cell carcinoma
metastasis of squamous cell ca. of the larynx
4
F
72
B CLL
V
susp. infiltration with nH ML
B CLL infiltration
5
F
62
clear cell kidney ca.
VI
metastasis of clear cell ca.
metastasis of clear cell kidney ca.
6
M
69
lung adenocarcinoma
V
adenocarcinoma, lung origin highly probable
metastasis of lung adenocarcinoma
7
M
31
clear cell kidney ca.
VI
clear cell ca., kidney origin highly probable
metastasis of clear cell kidney ca.
8
F
78
clear cell kidney ca.
VI
clear cell kidney ca.
metastasis of clear cell kidney ca.
9
F
80
invasive ductal cell breast ca.
VI
breast ca. metastasis, ER positive
metastasis of breast ca.
10
M
69
melanoma
VI
melanoma metastasis
metastasis of melanoma
11
F
70
undifferentiated breast ca.
VI
breast ca. metastasis highly probable
metastasis of breast ca.
12
F
67
none
VI
adenocarcinoma, metastatic origin highly probable
generalized adenocarcinoma – autopsy uncertain origin
264
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F = Female; M = male; ca. = carcinoma; V = suspicious for malignancy; VI = malignant; susp. = suspicious; B CLL = B-cell chronic lymphatic leukemia; nH ML = non Hodgkin malignant lymphoma.
Table 3. Group II – primary malignancies confirmed in the thyroid gland
Case Sex No.
Age, History of malignancy years
TBSRTC FNAB differential diagnosis diagnostic category
Histopathological diagnosis
1
F
79
none
VI
nH ML? undiff. ca., metastasis?
DLBCL
2
F
77
none
VI
undiff. ca., medullary ca., metastasis?
undiff. ca.
3
F
58
none
VI
oat cell ca., medullary ca.?
medullary ca.
4
M
67
none
V
susp. nH ML
DLBCL
5
F
72
none
V
susp. poorly diff. follicular ca., metastasis?
poorly diff. papillary ca. with follicular parts
6
M
75
none
V
susp. medullary ca., oncocytic ca., metastasis
oncofollicular ca.
7
M
92
none
V
susp. undiff. ca., metastasis?
undiff. sarcoma
8
M
63
none
V
susp. nH ML
nH ML
9
F
68
clear cell kidney ca.
V
susp. metastasis of clear cell ca.
angiosarcoma
10
M
50
seminoma
VI
medullary ca., oncocytic ca., metastasis highly improbable
medullary ca.
11
F
37
breast ca.
VI
medullary ca. calcitonin +
medullary ca.
12
F
72
multinodular goitre and VI cervical lymphadenopathy
undiff. ca., metastasis?
undiff. ca.
13
F
50
breast ca. – DCIS
VI
undiff. ca.
undiff. ca.
14
F
76
none
VI
undiff. ca., metastasis, medullary ca., oncocytic ca.?
follicular ca., Hürthle cell variant
15
M
78
none
VI
medullary ca., metastasis, poorly diff. follicular ca.?
mixed medullary and follicular ca.
16
M
85
metastasis in the lung
VI
poorly diff. ca TGB+
poorly diff. ca.
17
M
74
follicular ca. irradiated
VI
undiff. ca., metastasis, poorly diff. follicular ca.?
poorly diff. follicular ca.
18
F
66
breast ca.
V
susp. breast ca. metastasis
papillary ca., partly poorly differentiated
19
F
68
submandibular gland ca.
VI
metastasis of submandibullar gland ca.
tall cell papillary ca.
20
F
73
none
VI
undiff. ca., medullary ca., metastasis?
papillary microcarcinoma with lipomatous stroma
F = Female; M = male; ca. = carcinoma; V = suspicious for malignancy; VI = malignant; susp. = suspicious; nH ML = non Hodgkin malignant lymphoma; diff. = differentiated; undiff. = undifferentiated; DCIS = ductal carcinoma in situ.
Secondary or Second Primary Malignancy in the Thyroid?
Discussion
The common denominator of the cases in our study was the consideration of a metastatic tumor on FNAB with either a positive or a negative history of a previous malignancy. Acta Cytologica 2014;58:262–268 DOI: 10.1159/000360805
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this case, the biopsy diagnosis after an immunohistochemical investigation was multinodular goitre with an uncommon highly cellular repair in one nodule mimicking malignancy on FNAB.
Table 4. Group III – malignancy in the thyroid gland not confirmed
Case Sex Age, History of No. years malignancy
TBSRTC FNAB differential diagnosis diagnostic category
Histopathological diagnosis
1
F
62
breast ca.
V
metastasis of breast ca.? thyroid primary?
Hashimoto thyroiditis and oncocytic adenoma
2
F
82
ca. of thyroid V unknown type
papillary ca.? oncocytic ca.? metastasis?
suture granulomas following repeated surgeries
3
F
46
none
V
oncocytic ca.? medullary ca.? metastasis?
hyperplastic goitre with oncocytes
4
F
68
none
VI
medullary ca.? undiff. ca.? metastasis.?
highly cellular repair in a hyperplastic nodule
5
M
27
none
V
susp. medullary ca.
fibrotizing Hashimoto thyroiditis
The thyroid gland is richly vascularized and therefore susceptible to the hematogenous spread of malignancy [9]. FNAB is generally accepted as the first step in thyroid nodule microscopic evaluation. The difficulty in achieving a correct diagnosis of metastatic involvement can be explained by the variety of extrathyroidal malignancies. The available meta-analyses share sites of the most common primary malignancies, with these clearly being cell kidney carcinoma, breast carcinoma, and lung carcinoma [10]. The history of previous neoplastic disease treatments may be missing and the disease-free interval is long [7, 11]. The wide spectrum of thyroid primary malignancies and their histo-/cyto-/pathological variants can interfere with the diagnosis [12]. Some primary thyroid malignancies (without referring to the persistent FNAB limits for evaluating the nature and biological behavior of the follicular lesions) are especially difficult to diagnose, though they do possess defined cytomorphological features, especially the follicular variant of papillary carcinoma [13–16]. The correct interpretation of thyroid FNABs depends on the nodule(s), the macromorphology (ultrasound), and the clinical information. Recently, many thyroidal and extrathyroidal malignancies have been treated successfully. Longer survival times and migration, combined with the fact that the nationwide cancer registry does not allow tracing of an individual patient’s cancer history, contribute to the diagnostic challenge found in FNAB cases exhibiting an uncommon cytomorphology combined with an incomplete patient history. 266
Acta Cytologica 2014;58:262–268 DOI: 10.1159/000360805
In the scientific literature, many cases of metastatic tumors in the thyroid have been published as case reports describing the pitfalls of individual case diagnosis supported by a literature overview, stressing the specific context of the more frequent primary malignancies or the reporting a rare malignancy metastasizing to the thyroid [11, 17–31]. Meta-analyses are available for the most frequent primary malignancies [32, 33]. Our study does not differ from the known statistics in terms of the most frequent primary malignancies involved. The knowledge of preceding extrathyroidal or intrathyroidal malignancies contributed diagnostically, (table 2) but was also misleading, contributing to the overdiagnosis (table 4). Additional techniques were, in some cases, limited due to the quantity and type of FNA material supplied. Combined diagnoses are common in the thyroid and are frequently represented by the mixture of cell populations aspirated. The hyperplastic, inflammatory, or even neoplastic background makes the identification of metastasis more difficult [30, 31, 34]. The pseudotumorous nature of a repair nodule can be difficult to ascertain without additional techniques, even histopathologically [33–38]. In thyroid FNA diagnoses, false negatives are mentioned more frequently than false positives. Thyrotoxic changes and inflammatory atypia are known to increase the risk of overdiagnosis [39–41]. Nevertheless, strictly following the criteria defined by TBSRTC, even highly cellular and atypical findings should remain designated as suspicious for malignancy unless they cannot be otherwise specified using additionDušková /Rosa /Přeučil /Svobodová /Lukáš
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F = Female; M = male; ca. = carcinoma; V = suspicious for malignancy; VI = malignant; susp. = suspicious.
al methods such as immunocytochemistry. This was a mistake made in 1 of our 5 benign cases which was incorrectly classified as TBSRTC diagnostic category VI – malignant. Correct diagnosis of the metastatic involvement of the thyroid gland requires strict adherence to the known algorithms: (1) Complete history of the disease. (2) Material for the cytoblock providing the possibility of additional methods – especially immunocytochemistry. (3) Broad differential diagnostic thinking – the diagnostic tetrad of nonneoplastic versus neoplastic and, if neoplastic, primary versus secondary is to be considered, but also the frequent presence of combined diagnoses within the thyroid should be taken into account. (4) Combined stainings, immunocytochemistry, and comparison with the previous primary malignancy (including the immunophenotype if available). (5) Unless the diagnosis of a metastatic tumor can be fully evidence based, the Bethesda classification should remain TBSRTC diagnostic category V – SFN NOS (suspicious for neoplasia not otherwise specified), not TBSRTC diagnostic category VI – malignant, to avoid possible overtreatment. A new perspective on tumor diagnostics is opening up with the achievements in molecular pathology of neoplasms. FNAB of the thyroid gland has been proven to provide sufficient material for the testing of recently available molecular markers [42]. Studies performed in sets of cases classified as suspicious have reported an increase in diagnostic accuracy [43], thereby influencing
the indication for and extent of surgical treatment [44, 45]. The tested BRAF (B-type rapidly accelerating fibrosarcoma kinase) mutation is known to predict tumor progression as well as the recurrence of papillary carcinoma [46]. In medullary carcinoma diagnostics, the RET (rearranged during transfection) proto-oncogene germline mutation can be diagnosed via molecular methods much earlier than in the past. Prophylactic thyroidectomy can be offered to carriers of the MEN 2B (multiple endocrine neoplasia type 2B) syndrome gene as early as by the age of 1 year [47]. These recent studies have focused mainly on increases in the certainty of the diagnosis of thyroid primary malignancies and their prognostication. For the rare cases with a more complex differential diagnosis, including the possibility of a metastatic tumor, the recent spectrum of available molecular markers does not solve the problem of a shared presence in both thyroid primary malignancies and some frequent metastatic processes (e.g. BRAF in papillary carcinoma of the thyroid, malignant melanoma, and colon carcinoma). However, this quickly developing field holds promise for an increase in the certainty of FNAB thyroid diagnoses once more molecular markers specific to individual cancer types have been found and tested.
Conclusion
Diagnosis of the metastatic involvement of the thyroid gland is a challenge that requires strict adherence to all of the known algorithms of cytopathology diagnostics.
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Received: September 10, 2013 Accepted after revision: February 23, 2014 Published online: June 4, 2014
Secondary or Second Primary Malignancy in the Thyroid? Metastatic Tumors Suggested Clinically: A Differential Diagnostic Task Jaroslava Dušková a, b Pavel Rosa c Pavel Přeučil c Eva Svobodová c Jindřich Lukáš d a
Cytopathology Laboratory, Institute of Pathology, 1st Medical Faculty, Charles University and Medical College, Centre of Gynaecology and Oncology Prevention, Ltd., c Private Practice in Endocrinology, and d Department of ENT, Head and Neck Surgery, Na Homolce Hospital, Prague, Czech Republic b
Abstract Objective: To describe the algorithms employed to explore the suggestion or consideration of metastatic malignancy in the thyroid. Study Design: Thirty-seven cases with a history of malignancy (n = 21) and/or uncommon fine-needle aspiration biopsy (FNAB) findings (n = 37) were reviewed and reclassified according to The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). Results: The group was heterogeneous in terms of the final histopathology results: the suggested metastasis was confirmed in only half of the cases (11/21; 52.4%). Primary thyroid malignancies were mostly nondifferentiated, medullary, or rare. However, 3 papillary carcinomas (the less common variants) were also found. Finally, 5 out of 37 cases were surprisingly benign upon histopathological investigation (uncommon repair and fibrotizing Hashimoto thyroiditis). Conclusions: The metastatic nature of thyroid gland nodule(s) must be considered in cases of generalization of malignancy and/or uncom-
© 2014 S. Karger AG, Basel 0001–5547/14/0583–0262$39.50/0 E-Mail [email protected] www.karger.com/acy
mon FNAB findings. We must be as open-minded as possible from the outset. Additional techniques are helpful if available – cytoblock and immunocytochemistry can contribute substantially. Morphological comparisons with the previous malignancy are recommended whenever possible. To avoid overtreatment, cases without precise typing should not be classified as TBSRTC diagnostic category VI – malignant, but should remain in TBSRTC diagnostic category V – suspicious for malignancy. Repeated FNAB to enable additional techniques may be suggested. © 2014 S. Karger AG, Basel
Introduction
After the launch of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) [1], information for both Czech pathologists [2] and clinical specialists [3] was published in the local journals and the system was adopted into our daily routine diagnostics.
Presented as poster No. 338 at the 18th International Congress of Cytology in Paris, France, in 2013.
Correspondence to: Prof. Jaroslava Dušková Institute of Pathology, 1st Medical Faculty, Charles University Studničkova 2 CZ–12000 Prague 2 (Czech Republic) E-Mail jaroslava.duskova @ lf1.cuni.cz
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Key Words Thyroid · Fine-needle aspiration biopsy · Metastases · Second malignancy · The Bethesda System for Reporting Thyroid Cytopathology · Repair
Results
By the year 2012, four hundred thirty-three cases from the 36,552 thyroid FNAB diagnoses made over a 25-year period (1987–2012) were included in the continually growing teaching collection of cases. Furthermore, a part of the teaching collection created prior to the introduction of TBSRTC has been reclassified, and newer cases are being added using this classification as it represents a consistent part of the report. Thirty-seven cases (0.1% of the total of number FNABs performed in the center) with a history of malignancy (n = 21) and/or cytopathology featuring the designation TBSRTC diagnostic category V – suspicious for malignancy, or TBSRTC diagnostic category VI – malignant (n = 37), from the collection were reviewed. In this selection, no cases classified as TBSRTC diagnostic category III – atypia of undetermined significance/follicular lesion of undetermined significance were involved. Thirty other cases had to be excluded from the study for not (yet) having histopathology correlates at the time of the analysis.
The set of selected cases considered to have metastatic involvement was heterogeneous in terms of the final histopathological results: the suggested metastases were confirmed in only half of the cases (11/21; 52.4%) with a known history of malignancy. The 3 groups with confirmed metastases, primary malignancies, and surprisingly benign histopathological results of suspicious cytopathology findings did not differ substantially in terms of the prevalence of female patients, the mean age, or a wide age interval. Not surprisingly, patients with confirmed metastases (group 1) had the highest percentage of positive history of malignancy (92%). Also, the diagnostic certainty for TBSRTC diagnostic category VI – malignancy was the highest in this group (75%) (table 1). Clear cell kidney carcinoma followed by squamous cell carcinoma of the larynx and right tonsil and breast carcinoma were the most frequent primary malignancies (table 2). The last case in this group (case 12; table 2) was not excluded, although the metastatic nature of the generalized solid carcinoma could not be proven with absolute certainty. Both thyroidal markers (thyroglobulin and calcitonin) and the pulmonary marker (thyroid transcription factor 1) proved negative. Thyroid primary malignancies (n = 20; table 3) were mostly non-differentiated, medullary, or rare. However, 3 differentiated (papillary) carcinomas were also found, although 2 were poorly differentiated solid papillary carcinomas (one of these had minor follicular parts seen histopathologically) and the third was a tall cell papillary carcinoma in a patient with a known submandibular gland adenocarcinoma. The proportion of patients with a positive history of malignancy (40%) was substantially lower than in the group with confirmed metastatic involvement, although the diagnostic certainty for TBSRTC diagnostic category VI – malignancy remained high in this group (65%). Finally, 5 out of 37 (13.5%) cases with metastatic involvement considered in the differential diagnosis were surprisingly benign upon detailed histopathological examination, represented namely by an uncommon repair and fibrotizing Hashimoto thyroiditis (table 4). Although the percentage of patients with a positive history of malignancy in this group was identical (40%) to that of the previous group with a second primary malignancy in the thyroid gland, the diagnostic certainty of TBSRTC diagnostic category VI decreased substantially and 1 out of 5 cases in this group was thus discharged. In
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Materials and Methods
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Metastatic involvement of the thyroid gland was initially described more than a century ago [4], and during the first decades of the 20th century these surprising findings were reported mostly in surgery journals [5, 6]. Clinically, they were described in surgeries with the expectation of finding a thyroid primary malignancy [7] and the surprising postoperative diagnosis was, already back then, indicative of the need to change the treatment plans. With the introduction of fine-needle aspiration biopsy (FNAB) for the investigation of thyroid nodules, the chance to diagnose thyroid metastases and to tailor the therapy emerged, but this remains difficult. Metastasis is a rare diagnostic finding in thyroid FNABs. Nevertheless, the clinical suggestion of a metastatic involvement of the thyroid gland has become more frequent because of the improved treatment and survival rate of patients with different malignancies and the high frequency of thyropathies (5–7%) in the Czech population [8]. In the majority of these cases, a metastatic lesion of the thyroid gland can be excluded in favor of just the concomitant nonneoplastic thyroid nodule. If the FNAB exhibits an uncommon cytological pattern (starting with TBSRTC diagnostic category III – atypia of undetermined significance, but especially in the case of TBSRTC diagnostic category V – suspicious for malignancy), a decision regarding a possible relationship has to be made. A similar differential diagnostic consideration of the metastasis must be made in cases of uncommon findings without a history of malignancy. The objective of this study was to illustrate the algorithms employed to explore the suggestion or consideration of a metastatic malignancy in the thyroid.
Table 1. Cases with clinically suggested metastatic involvement of the thyroid gland and/or uncommon FNAB findings grouped according to the results of the histopathology investigation
Female/male ratio Mean age (range), years Patients with a positive history of malignancy, n (%) TBSRTC diagnostic category V, n (%) TBSRTC diagnostic category VI, n (%)
Group I (n = 12)
Group II (n = 20)
Group III (n = 5)
8/4 65 (31 – 80) 11 (92) 4 (33) 8 (67)
12/8 69 (37 – 92) 8 (40) 7 (35) 13 (65)
4/1 57 (27 – 82) 2 (40) 4 (80) 1 (20)
Group I: Metastases or secondary malignancies in the thyroid gland confirmed or found; group II: primary malignancies confirmed in the thyroid gland; group III: malignancy in the thyroid gland not confirmed.
Table 2. Group I – metastases or secondary malignancies in the thyroid gland confirmed or found
Case Sex Age, History of malignancy No. years
TBSRTC FNAB differential diagnosis diagnostic category
Histopathological diagnosis
1
F
76
squamous cell ca. of the right tonsil
V
susp. metastasis of squamous cell ca. metastasis of squamous ca. of the tonsil
2
F
70
B CLL
V
susp. infiltration with B CLL
B CLL infiltration
3
M
55
squamous cell ca. of the larynx
VI
squamous cell carcinoma
metastasis of squamous cell ca. of the larynx
4
F
72
B CLL
V
susp. infiltration with nH ML
B CLL infiltration
5
F
62
clear cell kidney ca.
VI
metastasis of clear cell ca.
metastasis of clear cell kidney ca.
6
M
69
lung adenocarcinoma
V
adenocarcinoma, lung origin highly probable
metastasis of lung adenocarcinoma
7
M
31
clear cell kidney ca.
VI
clear cell ca., kidney origin highly probable
metastasis of clear cell kidney ca.
8
F
78
clear cell kidney ca.
VI
clear cell kidney ca.
metastasis of clear cell kidney ca.
9
F
80
invasive ductal cell breast ca.
VI
breast ca. metastasis, ER positive
metastasis of breast ca.
10
M
69
melanoma
VI
melanoma metastasis
metastasis of melanoma
11
F
70
undifferentiated breast ca.
VI
breast ca. metastasis highly probable
metastasis of breast ca.
12
F
67
none
VI
adenocarcinoma, metastatic origin highly probable
generalized adenocarcinoma – autopsy uncertain origin
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F = Female; M = male; ca. = carcinoma; V = suspicious for malignancy; VI = malignant; susp. = suspicious; B CLL = B-cell chronic lymphatic leukemia; nH ML = non Hodgkin malignant lymphoma.
Table 3. Group II – primary malignancies confirmed in the thyroid gland
Case Sex No.
Age, History of malignancy years
TBSRTC FNAB differential diagnosis diagnostic category
Histopathological diagnosis
1
F
79
none
VI
nH ML? undiff. ca., metastasis?
DLBCL
2
F
77
none
VI
undiff. ca., medullary ca., metastasis?
undiff. ca.
3
F
58
none
VI
oat cell ca., medullary ca.?
medullary ca.
4
M
67
none
V
susp. nH ML
DLBCL
5
F
72
none
V
susp. poorly diff. follicular ca., metastasis?
poorly diff. papillary ca. with follicular parts
6
M
75
none
V
susp. medullary ca., oncocytic ca., metastasis
oncofollicular ca.
7
M
92
none
V
susp. undiff. ca., metastasis?
undiff. sarcoma
8
M
63
none
V
susp. nH ML
nH ML
9
F
68
clear cell kidney ca.
V
susp. metastasis of clear cell ca.
angiosarcoma
10
M
50
seminoma
VI
medullary ca., oncocytic ca., metastasis highly improbable
medullary ca.
11
F
37
breast ca.
VI
medullary ca. calcitonin +
medullary ca.
12
F
72
multinodular goitre and VI cervical lymphadenopathy
undiff. ca., metastasis?
undiff. ca.
13
F
50
breast ca. – DCIS
VI
undiff. ca.
undiff. ca.
14
F
76
none
VI
undiff. ca., metastasis, medullary ca., oncocytic ca.?
follicular ca., Hürthle cell variant
15
M
78
none
VI
medullary ca., metastasis, poorly diff. follicular ca.?
mixed medullary and follicular ca.
16
M
85
metastasis in the lung
VI
poorly diff. ca TGB+
poorly diff. ca.
17
M
74
follicular ca. irradiated
VI
undiff. ca., metastasis, poorly diff. follicular ca.?
poorly diff. follicular ca.
18
F
66
breast ca.
V
susp. breast ca. metastasis
papillary ca., partly poorly differentiated
19
F
68
submandibular gland ca.
VI
metastasis of submandibullar gland ca.
tall cell papillary ca.
20
F
73
none
VI
undiff. ca., medullary ca., metastasis?
papillary microcarcinoma with lipomatous stroma
F = Female; M = male; ca. = carcinoma; V = suspicious for malignancy; VI = malignant; susp. = suspicious; nH ML = non Hodgkin malignant lymphoma; diff. = differentiated; undiff. = undifferentiated; DCIS = ductal carcinoma in situ.
Secondary or Second Primary Malignancy in the Thyroid?
Discussion
The common denominator of the cases in our study was the consideration of a metastatic tumor on FNAB with either a positive or a negative history of a previous malignancy. Acta Cytologica 2014;58:262–268 DOI: 10.1159/000360805
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this case, the biopsy diagnosis after an immunohistochemical investigation was multinodular goitre with an uncommon highly cellular repair in one nodule mimicking malignancy on FNAB.
Table 4. Group III – malignancy in the thyroid gland not confirmed
Case Sex Age, History of No. years malignancy
TBSRTC FNAB differential diagnosis diagnostic category
Histopathological diagnosis
1
F
62
breast ca.
V
metastasis of breast ca.? thyroid primary?
Hashimoto thyroiditis and oncocytic adenoma
2
F
82
ca. of thyroid V unknown type
papillary ca.? oncocytic ca.? metastasis?
suture granulomas following repeated surgeries
3
F
46
none
V
oncocytic ca.? medullary ca.? metastasis?
hyperplastic goitre with oncocytes
4
F
68
none
VI
medullary ca.? undiff. ca.? metastasis.?
highly cellular repair in a hyperplastic nodule
5
M
27
none
V
susp. medullary ca.
fibrotizing Hashimoto thyroiditis
The thyroid gland is richly vascularized and therefore susceptible to the hematogenous spread of malignancy [9]. FNAB is generally accepted as the first step in thyroid nodule microscopic evaluation. The difficulty in achieving a correct diagnosis of metastatic involvement can be explained by the variety of extrathyroidal malignancies. The available meta-analyses share sites of the most common primary malignancies, with these clearly being cell kidney carcinoma, breast carcinoma, and lung carcinoma [10]. The history of previous neoplastic disease treatments may be missing and the disease-free interval is long [7, 11]. The wide spectrum of thyroid primary malignancies and their histo-/cyto-/pathological variants can interfere with the diagnosis [12]. Some primary thyroid malignancies (without referring to the persistent FNAB limits for evaluating the nature and biological behavior of the follicular lesions) are especially difficult to diagnose, though they do possess defined cytomorphological features, especially the follicular variant of papillary carcinoma [13–16]. The correct interpretation of thyroid FNABs depends on the nodule(s), the macromorphology (ultrasound), and the clinical information. Recently, many thyroidal and extrathyroidal malignancies have been treated successfully. Longer survival times and migration, combined with the fact that the nationwide cancer registry does not allow tracing of an individual patient’s cancer history, contribute to the diagnostic challenge found in FNAB cases exhibiting an uncommon cytomorphology combined with an incomplete patient history. 266
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In the scientific literature, many cases of metastatic tumors in the thyroid have been published as case reports describing the pitfalls of individual case diagnosis supported by a literature overview, stressing the specific context of the more frequent primary malignancies or the reporting a rare malignancy metastasizing to the thyroid [11, 17–31]. Meta-analyses are available for the most frequent primary malignancies [32, 33]. Our study does not differ from the known statistics in terms of the most frequent primary malignancies involved. The knowledge of preceding extrathyroidal or intrathyroidal malignancies contributed diagnostically, (table 2) but was also misleading, contributing to the overdiagnosis (table 4). Additional techniques were, in some cases, limited due to the quantity and type of FNA material supplied. Combined diagnoses are common in the thyroid and are frequently represented by the mixture of cell populations aspirated. The hyperplastic, inflammatory, or even neoplastic background makes the identification of metastasis more difficult [30, 31, 34]. The pseudotumorous nature of a repair nodule can be difficult to ascertain without additional techniques, even histopathologically [33–38]. In thyroid FNA diagnoses, false negatives are mentioned more frequently than false positives. Thyrotoxic changes and inflammatory atypia are known to increase the risk of overdiagnosis [39–41]. Nevertheless, strictly following the criteria defined by TBSRTC, even highly cellular and atypical findings should remain designated as suspicious for malignancy unless they cannot be otherwise specified using additionDušková /Rosa /Přeučil /Svobodová /Lukáš
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F = Female; M = male; ca. = carcinoma; V = suspicious for malignancy; VI = malignant; susp. = suspicious.
al methods such as immunocytochemistry. This was a mistake made in 1 of our 5 benign cases which was incorrectly classified as TBSRTC diagnostic category VI – malignant. Correct diagnosis of the metastatic involvement of the thyroid gland requires strict adherence to the known algorithms: (1) Complete history of the disease. (2) Material for the cytoblock providing the possibility of additional methods – especially immunocytochemistry. (3) Broad differential diagnostic thinking – the diagnostic tetrad of nonneoplastic versus neoplastic and, if neoplastic, primary versus secondary is to be considered, but also the frequent presence of combined diagnoses within the thyroid should be taken into account. (4) Combined stainings, immunocytochemistry, and comparison with the previous primary malignancy (including the immunophenotype if available). (5) Unless the diagnosis of a metastatic tumor can be fully evidence based, the Bethesda classification should remain TBSRTC diagnostic category V – SFN NOS (suspicious for neoplasia not otherwise specified), not TBSRTC diagnostic category VI – malignant, to avoid possible overtreatment. A new perspective on tumor diagnostics is opening up with the achievements in molecular pathology of neoplasms. FNAB of the thyroid gland has been proven to provide sufficient material for the testing of recently available molecular markers [42]. Studies performed in sets of cases classified as suspicious have reported an increase in diagnostic accuracy [43], thereby influencing
the indication for and extent of surgical treatment [44, 45]. The tested BRAF (B-type rapidly accelerating fibrosarcoma kinase) mutation is known to predict tumor progression as well as the recurrence of papillary carcinoma [46]. In medullary carcinoma diagnostics, the RET (rearranged during transfection) proto-oncogene germline mutation can be diagnosed via molecular methods much earlier than in the past. Prophylactic thyroidectomy can be offered to carriers of the MEN 2B (multiple endocrine neoplasia type 2B) syndrome gene as early as by the age of 1 year [47]. These recent studies have focused mainly on increases in the certainty of the diagnosis of thyroid primary malignancies and their prognostication. For the rare cases with a more complex differential diagnosis, including the possibility of a metastatic tumor, the recent spectrum of available molecular markers does not solve the problem of a shared presence in both thyroid primary malignancies and some frequent metastatic processes (e.g. BRAF in papillary carcinoma of the thyroid, malignant melanoma, and colon carcinoma). However, this quickly developing field holds promise for an increase in the certainty of FNAB thyroid diagnoses once more molecular markers specific to individual cancer types have been found and tested.
Conclusion
Diagnosis of the metastatic involvement of the thyroid gland is a challenge that requires strict adherence to all of the known algorithms of cytopathology diagnostics.
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