The Work-up of a Thyroid Nodule: A Case Presentation and

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The Work-up of a Thyroid Nodule A Case
Presentation and DiscussionJunko
OzaoPGY-3Mount Sinai General Surgery
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• CC thyroid nodule on PET scan
• HPI A.P. is a 52 y.o. F s/p sigmoid resection
  for a 4.9 cm mod-differentiated adenoca c 2/14
  lymph nodes positive on 5/6/2005 (T3bN1Mx). In
  preparation for surgery, the pt underwent a PET
  scan, where an increased uptake in her thyroid
  was noted. Pt denies pain, trouble breathing,
  hoarseness or dysphagia. No hx of radiation
  exposure.
• Med and Surg Hx hysterectomy 2000 for fibroids.
  
• Meds none All none
• Fam Hx mother with hypothyroidism

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• P.E.- 2cm firm nodule in right mid-pole of
  thyroid, no LAD
• Labs TSH 2.24 (0.35-5.5) PTH 42(10-65)
• Ultrasound2.4x1.6x1.3cm nodule on R lobe with
  calcifications seen, smaller 0.5x0.3x0.5cm nodule
  in R superior pole left lobe unremarkable
• Thyroid scan non-diagnostic
• FNA papillary thyroid cancer

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• Uncomplicated total thyroidectomy was performed
  on 6/5/2005
• Pathology-1.7cm papillary thyroid carcinoma,
  uninvolved tissue Hashimotos thyroiditis, 2
  lymph nodes negative for tumor
• Currently undergoing chemo for sigmoid ca
• Possibility and timing of iodine ablation being
  discussed with oncology

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Work-up of a Thyroid Nodule

• Prevalence and risk factors
• HP
• Labs
• Imaging Modalities
• Biopsy
• Management
• Controversial topics

6
Prevalence

• Large population studies-Framingham study showed
  clinically significant nodules in 6.4 women and
  1.5 men¹ ages 30-59 (total 4.2) but thought to
  be significantly understated
• Ultrasounds- 20 to 76 of females had at least
  one thyroid nodule on ultrasound²
• Autopsy surveys show 37 to 57 of patients with
  thyroid nodules³
• ¹ Vander JB, et al. The significance of
  nontoxic thyroid nodules. Final report of a 15
  year study of the incidence of thyroid
  malignancy. Ann Intern Med 196869537.
• ²Belfiore et al. High frequency of cancer in
  cold thyroid nodules occuring at a young age.
  Acta Endocrinol 1989121197
• ³ Rice CO et al. Incidence of nodules in the
  thyroid. Arch Surg 193224505. Mortensen JD,
  Woolner LB, Bennett, WA. Gross and microscopic
  findings in clinically normal thyroid glands. J
  Clin Endocrinol Metab 1955 151220

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Risk Factors of nodules and of carcinoma

• Increased risk of nodules with age
• Increased risk of carcinoma in adults over 60 and
  under 30
• Solitary palpable nodules are about 4x more
  prevalent in women than in men
• However, among pts with nodules- rate of
  carcinoma 2x as high in men as in women (8 vs.
  4)
• Wong CKM, et al. Thyroid nodules Rational
  management. World J Surg 200024934-941
• Mazzaferri EL. Management of a solitary thyroid
  nodule. NEJM 1993328553-559

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• Nodules are very common estimates of 9 million
  adults in the US have a thyroid nodule
• New nodules appear at a rate of 0.8/yr
• Thyroid cancer is rare 4/100,000 per year-12,000
  new cases/yr in US
• 1 of all malignancies
• 0.5 of all cancer deaths-1,000/yr
• Up to 35 of thyroids at autopsy contain
  clinically silent carcinoma
• Wong CKM, et al. Thyroid nodules Rational
  management. World J Surg 200024934-941
• Mazzaferri EL. Management of a solitary thyroid
  nodule. NEJM 1993328553-559

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• Exposure to radiation, especially in childhood is
  associated with increased prevalence of thyroid
  nodules and malignancy¹-2/yr increased risk with
  peak incidence 15-20 years
• Presence of a nodule in a child is 2x as likely
  to be carcinoma
• Two large series 20-27 of patients with prior
  radiation exposure had thyroid nodularity and 30
  to 33 of the nodules were carcinomas²
• Prior family history of thyroid cancer
• ¹Schneider AB et al. Radiation-induced tumors of
  the head and neck following childhood
  irradiation.J Clin Endocrinol Metab.
  198561(3)547-50. ²Favus MJ et al. Thyroid
  cancer occurring as a late consequence of head
  and neck irradiation. Evaluation of 1056
  patients. N Engl J of Med 19762941019 Cerletty
  JM et al. Radiation-related thyroid carcinoma.
  Arch Surg 19781131072.

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Rate of Carcinoma in Thyroid Nodules

• Significant selection bias in surgical series
• North Carolina study in a community hospital pts
  with nodules were referred to surgery without
  biopsy and 6.5 of excised nodules were
  carcinomas¹
• Catania, Italy 2327 pts with nodules were evaled
  by FNA and of those 391 were selected for
  surgery. Carcinomas were found in 28 which was
  5 of total²
• ¹Werk EE, Vernon BM, Gonzalez, JJ. Cancer in
  thyroid nodules. A community hospital survey.
  Arch Intern Med 1984 144474.
• ²Belfiore et al. High frequency of cancer in
  cold thyroid nodules occuring at a young age.
  Acta Endocrinol 1989121197

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Causes of Thyroid Nodules

• Benign- gt90
• Multinodular goiter (colloid adenoma)
• Hashimotos (chronic lymphocytic) thyroiditis
• Cysts colloid, simple, or hemorrhagic-7-14 can
  be malignant- most commonly papillary ca with a
  cystic component with most increased size 2-4cm
• Follicular Adenoma
• Macrofollicular adenoma
• Microfollicular or cellular
• Hurthle-cell (oxyphil cell) adenomas- macro or
  microfollicular

• Malignant -about 6
• Papillary
• Follicular
• Minimally or widely invasive
• Oxyphilic type
• Medullary
• Anaplastic
• Primary thyroid lymphoma
• Metastatic carcinoma

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Toxic Multinodular Goiter
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Papillary Carcinoma
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Work-up of a Thyroid Nodule

• Prevalence and risk factors
• HP
• Labs
• Imaging Modalities
• Biopsy
• Management
• Controversial topics

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HP

• Age and gender
• Recent history of hoarseness, dysphagia or
  dyspnea
• Sxs of hypothyroidism or hyperthyroidism
• Family h/o thyroid or endocrine disease
• h/o prior radiation exposure, especially early in
  life

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• Thorough history of other endocrine disorders-MEN
  type II and other malignant syndromes
  ---familial adenomatous polyposis, Gardners
  syndrome
• Palpate thyroid determine size and consistency
  of thyroid nodule(s), shape, location and
  mobility
• Examine for cervical LAD
• Hard, fixed, irregular-shaped nodules and LAD are
  suggestive of malignancy

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Work-up of a Thyroid Nodule

• Prevalence and risk factors
• HP
• Labs
• Imaging Modalities
• Biopsy
• Management
• Controversial topics

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Laboratory

• Thyroid function tests- should be assessed
• Calcitonin if suspect medullary thyroid disease
• Most thyroid nodules are euthyroid
• However, if TSH is low, the possibility of a hot
  nodule is increased- may want to consider thyroid
  scintigraphy
• TSH is high suggestive of Hashimotos
  thyroiditis- may want to ultrasound to see if
  nodularity is lymphocytic infiltrate vs. TSH
  induced hyperplasia vs. thyroid tumor
• Still should fully evaluate a nodule- may have
  co-existence of malignancy and thyroiditis

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Work-up of a Thyroid Nodule

• Prevalence and risk factors
• HP
• Labs
• Imaging Modalities
• Biopsy
• Management
• Controversial topics

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Imaging- Thyroid Scintigraphy

• Utilizes iodine or technetium-99m pertechnate-
  more is taken up and organified by functional
  tissue
• Non-functioning thyroid nodule is cold and
  mandates further work-up by FNA
• The scan is often used in working up nodules in
  patients with high TSH levels but has many
  problems
• Nelson et al. showed that only slightly more than
  one-half of their excised malignant thyroid
  nodules appeared cold¹ because the scan is 2-D
  there is apposition of normal thyroid tissue next
  to abnormal tissue
• ¹Nelson RL et al. Rectilinear thyroid scanning
  as a predictor of malignancy. Ann of Intern Med
  19788841.

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• Also although 80 of nodules greater than 2cm
  appear cold- smaller nodules can be
  indeterminate¹
• Malignancy has been shown to occur 15-20 of
  cold nodules and, additionally, in 5-9 of
  nodules with uptake that is warm or hot²
• This is not very sensitive or specific for
  malignancy thus, warm or hot nodules still
  mandate a continued aggressive approach to
  work-up- may not really change management
• Traditionally hot nodules rxed in past with
  radioactive iodine or taken to surgery
• Thyroid scintigraphy has fallen out of favor-
  definitely questions about how cost-effective it
  is for routine evaluation for patients with
  nodules
• ¹Nelson RL et al. Rectilinear thyroid scanning as
  a predictor of malignancy. Ann of Intern Med
  19788841.
• ²Price DC et al. Radioisotopic evaluation of the
  thyroid and the parathyroid. Radiol Clin North Am
  31967-989. 1993.

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Ultrasound

• Provides considerable anatomic information but no
  functional information
• Determine the volume of a nodule, multicentricity
  and whether it is cystic or solid- often
  performed before FNA
• Extremely useful in also following patients being
  managed conservatively for possible increasing
  size of lesion
• Unable, however, to accurately predict the
  diagnosis of solid nodules

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• Cystic lesion are reassuring but only 1-5 of
  total thyroid nodules
• In addition, as many as 25 of well-differentiated
  thyroid cancers had cystic components¹ and up to
  60-70 of all nodules²
• Physician can correlate the nuclear medicine and
  u/s finding and determine the function of the
  particular nodule
• Additional nodules can be found 20-48 of
  patients²
• Many times the u/s findings differ from the
  physical exam, in one retrospective series up to
  63 of the time³
• ¹Burch HB et al. Evaluation and management of the
  solid thyroid nodule. Endocrinol Metab Clin
  North Am 24663-710
• ²Tan GH et al. Thyroid incidentalomas
  management approaches to non-palpable nodules
  discovered incidentally on thryoid imaging. Ann
  Intern Med 1997126226.
• ³Marqusee E et al. Usefulness of ultrasonography
  in the management of nodular disease. Ann Intern
  Med 1997126226.

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Work-up of a Thyroid Nodule

• Prevalence and risk factors
• HP
• Labs
• Imaging Modalities
• Biopsy
• Management
• Controversial topics

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FNA

• Simple, safe office procedure
• Tissue sample obtained by 25 gauge needle
• With experience adequate sample may be obtained
  in 90 -97 of aspirates of solid nodules¹,²
• False negative rate (FNA benign but nodule turn
  out malignant) is 0-5 usually due to sampling
  error
• False positive rates (malignant but turns out
  benign) lt5 due to focal hyperplasia in a
  macrofollicular adenoma or cellular atypia in a
  degenerating adenoma
• ¹Gershengorn et al. FNA cytology in the
  preoperative diagnosis of thyroid nodules. Ann
  Intern Medicine 197787265.
• ²Hall TL et al. Sources of diagnostic error in
  error in FNA of the thyroid. Cancer 198963718.

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• La Rosa et al. series of 5605 FNA procedures
  false negatives in 2.3 and false positives in
  1.1. Overall accuracy exceeds 95.¹
• Euthyroid patients should be evaluated with FNA
  as first step per endocrine often surgeons will
  send for u/s first to find out if cystic or solid
• Results- benign (70), malignant (5),
  indeterminate (10), nondiagnostic (15)
• ¹La Rosa GL et al. Evaluation of the fine needle
  aspiration biopsy in the preoperative selection
  of cold nodules. Cancer 199190967.

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Work-up of a Thyroid Nodule

• Prevalence and risk factors
• HP
• Labs
• Imaging Modalities
• Biopsy
• Management
• Controversial topics

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FNA results

• Malignant- pt needs to have surgical management
• Benign- observation with interval ultrasounds and
  clinical examinations
• Inderminate- radioisotope scan- perform
  suppression scan and if cold proceed to surgical
  management- if hot nodule consider observation
• Non diagnostic- repeat FNA or U/S guided FNA

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Wong CKM, et al. Thyroid nodules Rational
management. World J Surg 24(2000)934-941.
31
Work-up of a Thyroid Nodule

• Prevalence and risk factors
• HP
• Labs
• Imaging Modalities
• Biopsy
• Management
• Controversial topics

32
U/S-guided FNA
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• Often used after FNA comes back non-diagnostic
  rather than repeating another FNA
• Inadequate sampling cited as most common reason
  for false negative rates
• Repeat FNA with u/s can decrease nondiagnostic
  smears from 15 to 3¹,²
• May be particularly valuable for smaller nodules
  lt1.5cm
• Also very useful in complex cysts-can see the
  needle sample the solid component of the cyst
• Probably will have a more prominent role
• ¹Carmeci C et al. Ultrasound-guided fine-needle
  aspiration biopsy of thyroid masses. Thyroid.
  19988284-239.
• ²Danese D et al. Diagnostic accuracy of
  conventional versus sonography-guided fine-needle
  aspiration biopsy of thyroid nodules. Thyroid.
  1998815-21.

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Routine Calcitonin Screening

• Calcitonin screening is advocated in several
  reports to identify those with medullary cancer
• Italian report- 10,864 patients screened after
  1991, 44 (0.4) had an elevated calcitonin and
  ALL had medullary cancer¹
• 59 of these patients maintained a full remission
  of cancer as compared to 2.7 of patients who
  were not screened²
• French study only 41 of their patients with
  elevated calcitonin had MTC
• Some false positives as high as 59 -so routine
  screening remains controversial
• ¹Elisei et al. Impact of routine measurement of
  serum calcitonin on the diagnosis and outcome of
  medullary and thyroid cancer experience in
  10,864 patients with nodular thyroid disorders. J
  of Endocrinol Metab 200489163.
• ²Niccoli P et al. Interest of routine measurement
  of serum calcitonin study in a large series of
  thyroidectomized patients. J Clin Endocrinol
  MEtab 199782338.

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PET Scans and the Thyroid Nodule
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• History 56 year old female with a history of
  papillary thyroid carcinoma, status post
  thyroidectomy with rising thyroglobulin level and
  negative I-131 scan.
• Nuclear Medicine
• In this particular case, a small normal
  appearing jugulodigastric lymph node was found to
  have FDG uptake and was subsequently resected and
  found to be positive for recurrent papillary
  carcinoma.
• Courtesy of Todd Blodgett, MD, University of
  Pittsburgh Medical Center

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• PET scan-reflects glucose metabolism of tissues
  in vivo
• Consensus considers faint homogenous uptake of
  FDG by thyroid tissue to be physiologic¹
• Cohen et al. found 102/4250 (2.3) thyroid
  incidentalomas²
• Cytology only available in 15 pts but 47 were
  carcinoma 40 nodular hyperplasia and 1
  thyroiditis/1 atypical cells
• ¹McDougall IR et al. Positron emission tomography
  of the thyroid, with an emphasis on thyroid
  cancer. Nucl Med Commun 22485-492.
• ²Cohen MS et al. Risk of malignancy in thyroid
  incidentalomas identified by fluorodeoxyglucose-
  positron emission tomogrpahy.
  Surgery 130941-946.

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• Adler et al. showed by pooling data that if a
  peak standard uptake value (SUV)gt8 used that
  successfully able to indentify 7/7 thyroid
  cancers and 31/33 of benign lesions¹
• Others studies show that papillary and follicular
  carcinoma have significantly different SUV values
  compared to benign nodules²
• Other studies show that regardless of SUV-
  malignancy rates are high in positive PET scans³
• However, still not known if PET scans can
  reliably distinguish between benign and malignant
  disease
• ¹Adler LP et al. Positron emission tomography of
  thyroid masses. Thyroid 3957-963.
• ²Sasaki M et al. An evaluation of FDG-PET in the
  detection and differentiation of thyroid tumors.
  Nucl Commun 18957-963.
• ³Kim TY. 18F-fluorodeoxyglucose uptake in thyroid
  from positron emission tomogram (PET) for
  evaluation in cancer patients high prevalence of
  malignancy in thyroid PET incidentaloma.
  Laryngoscope. 2005115(6)1074-8.

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• Never advance anything that cannot be proved in
  a simple and decisive fashion. Worship the
  spirit of criticism. If reduced to itself, it is
  not an awakener of ideas or a stimulant to great
  things, but, without it, everything is fallible
  it always has the last word.
• -Louis Pasteur 1888 on the opening of the
• Pasteur Institute (Paris, France)