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Abdul Razik T
50TH Batch MBBS, Calicut medical college


Papillary carcinoma is the most common malignancy of the thyroid gland.

This tumor characterized histologically by the typical nuclear features, is a fairly
indolent lesion. Though the common presentation is in the form of neck swellings;
either thyroid or lymph nodes or both, symptoms due to invasion to adjacent
structures or rarely due to blood borne metastases are also possible. However, this
tumour has a good prognosis. A large number of variants with histological, genetic,
molecular & clinical differences demand precise diagnosis & really pose a big
challenge before the pathologist & surgeon. Here is the report of a patient who
presented with multiple lymph node swellings alone

Keywords: Thyroid, Papillary, Orphan Annie, RET, BRAF


Papillary carcinoma is the most common thyroid malignancy (75-80 % of

cases) 1 . Females are usually more affected. It can present at any age , but mostly in
the 3rd & 4th decade. 90% of thyroid malignancies in children are papillary
carcinomas. In 5-10 % of cases, there is history of radiation exposure to neck (82%
of all thyroid malignancies & 34% of all benign thyroid lesions post exposure) 2 . A
thrice high incidence is noted with hashimoto’s thyroiditis3.

Almost all patients have clinically evident disease in the neck when first seen.
The disease is localized to the thyroid in 67 %, to both thyroid & lymph nodes in 13
% & lymph nodes alone in 20 %. The common sites for metastases are bone, brain,
lungs & soft tissue. Though local invasion to larynx, trachea, pharynx & oesophagus
are common, metastases to these sites are extremely rare4.
Case report

A 38 year old male patient, smoker & alcoholic with no significant past or
family history, presented with history of severe loss of weigh, anorexia &
hoarseness of voice & progressively enlarging neck swellings for 6 months. There
was no history of dyspnoea, dysphagia or syncopial attacks. The patient had no
complaints of cold, facial edema, changing skin colour, chest pain, constipation.
Neither war there any complaints of heat intolerance, diarrhea, tremors, excessive
sweating, palpitations, anxiety or increased appetite.

On examination, multiple firm, spherical to oval masses of varying sizes were

present bilaterally, the largest being 4 by 3 centimeters in size, mobile & non tender.
No clubbing, pedal edema or pallor was noted.

Laboratory investigations revealed Hb 17.4 g/dl, total WBC count

17400/mm3, severe neutrophilia (96%), random blood sugar 106 mg/dl, ESR 35,
blood urea 39 mg/dl, s. creatinine 1.1 mg/dl, blood Na + 125.6 meqt/l, K+ 4.68
meqt/l. X ray revealed hyperdense masses on either sides of trachea.

Two days later the patient had sudden onset of dyspnoea with low B.P and
tracheostomy had to be performed.

FNAC revealed moderately differentiated papillary carcinoma metastases. A

CT scan was advised, which revealed multiple lymph nodes bilaterally, that
compressed the trachea. Bronchoscopy revealed narrowed glottic space due to
compression by the tumour. The subglottic space & trachea were spared.

The patient underwent total thyroidectomy with lymph node dissection 2

weeks after the episode.

Case Discussion

Grossly papillary carcinoma of thyroid can be microscopic to huge, solid,

white & firm. A few are encapsulated. Some show papillary formations, while some
show cystic changes.

Microscopically, numerous true but complex branching papillae are seen.

These contain a central fibro vascular core lined by a single or stratified cuboid cell
layer. The stroma is edematous or hyaline & contains scant lymphocytes, foamy
macrophages, hemosiderin, & adipose tissue. Follicular structures may also be
present, but even then they behave as papillary carcinoma.

But the characteristic pathognomic features of papillary carcinoma, even

when the papillae are absent are the nuclear features.

1. Ground glass (optically clear) or orphan Annie nucleus, which is large & of
overlapping quality. The nucleolus is inconspicuous & pushed against the
nuclear membrane, which appears thickened.
2. Nuclear pseudo inclusions, appearing as sharply outlined acidophilic
formations that represent invaginations of cytoplasm.
3. Nuclear grooves- they also are cytoplasmic infoldings and are arranged
along the longest axis of the oval/spindle nuclei.
4. Nuclear microfilaments.

Mitotic figures are very scant or absent. About half of cases show extensive
fibrosis ranging from sclerohyaline to highly cellular.

Another characteristic feature is psammoma body, seen in half of cases. They

may be located in the papillary stalk, in fibrous stroma or between tumor cells in
solid foci. They represent a very important clue to the diagnosis so much that, if they
are present in what is otherwise normal thyroid or lymph nodes in neck, a high
suspicion of papillary carcinoma must be kept. Psammoma bodies are concentric,
laminated basophilic structures that stain for calcium, mucin & iron. They arise from
necrosis of tumour cells. Osteopontin, produced by macrophages is responsible for
their development. When numerous, they can be detected even in X rays. They must
be differentiated from other calcification forms and from the inspissated secretions
in hurthle cell tumour.

Other expected changes include solid/ trabecular pattern of growth (20%),
squamous metaplasia (20%), spindle cell component (metaplastic change), and
lymphocytic infiltration (25%).

Molecular genetic features involve molecular rearrangements of the tyrosine

kinase receptors RET or NTRK1 (neurotropic tyrosine kinase receptor) that are
normally not expressed in thyroid follicular cells. Para centric inversion or t(10; 17)
for RET (located on chromosome 10 q.11) and NTKRI (located on ch. 1q.21) ,
produce fusion products ret/PTC (ret/ papillary thyroid carcinoma)that result in
constitutive activation of tyrosine kinase of RET/NTRK1.The rare coincidence of
PTC with medullary carcinoma suggests that point mutations of RET could also
evoke PTC.5 About half of PTC harbors activated BRAF oncogene.

Several morphologic variants of PTC have been reported:

1. Papillary microcarcinoma – It includes all PTCs less than 1cm in diameter. This
variant, usually presenting with a stellate configuration, is a common incidental
finding in FNACs or thyroids removed for other studies especially in males.
Though cervical metastases do occur, distant mets are extremely rare & the
prognosis is generally excellent.
2. Encapsulated variant – This variant constituting 10% of PTCs is totally
surrounded by a capsule. It ha excellent prognosis. It should be diffentiated from
an adenoma or a hyperplastic nodule. In contrast to PTC, these are hot on thyroid
scan, microscopically contain pale, vacuolated colloid & papillary areas are
limited to the area facing the cystic cavity.
3. Follicular variant – It is composed of follicles that show nuclear features of PTC. It
has 2 further variants:
a. Solid variant - Proliferation predominates over secretion producing solid
b. Macrofollicular variant - Here secretion predominates resulting in large
dilated follicles. It should be differentiated from follicular carcinoma &
hyperplastic nodule.

Follicular variants behave biologically like PTCs & have a better prognosis.

4. Oncocytic (oxyphilic) variant – It has abundant cytoplasm of granular oxyphilic

quality, but nuclear features of PTC. It shows papillary/ follicular pattern & can

be encapsulated/ invasive. It often has a large lymphocytic infiltrate & could be
confused for warthins tumour of salivary glands. The latter, which has an
excellent prognosis, differs in expression of Rb protein & E2F-1.
5. Diffuse sclerosing variant – It is characterized by diffuse involvement of one or
both lobes, dense sclerosis, abundant psammoma bodies, squamous metaplasia,
heavy lymphocytic infiltration & extensive lymph vessel permeation. It may be
misdiagnosed as hashimoto’s thyroiditis, but shows a higher incidence of distant
6. Tall cell & columnar cell variant – The former shows papillae lined by a single
layer of tall cells (height twice width) having abundant acidophilic cytoplasm, in
atleast half of the tumor. It lacks the nuclear features of PTC & is more
aggressive. The latter shows prominent stratification & clear cytoplasm with sub
nuclear vacuolization. Both usually occur in the elderly.
7. Cribriform – morular variant
8. PTC with extensive nodular fasciitis like stroma – Here the extensive stromal
reaction obscures the neoplastic epithelial component. It can be misinterpreted
as nodular fasciitis, fibromatosis or fibradenoma.
9. Hyalinising trabecular tumors – It shows organoid growth pattern, with nests &
trabeculae of elongated tumor cells within a fibro vascular stroma 6. Both intra &
extra cellular hyalinization are prominent & confer a pink hue to the tumor. The
nuclear features, psammoma bodies & RET/PTC translocation classifies it as a
variant of PTC. It shouldn’t be confused with an extradural paraganglioma.


Most PTCs present as asymptomatic thyroid nodules, but the first

manifestations may be an enlarged cervical lymph node. But in many cases, they
could persist for long without producing any swelling. The importance is so much
that, by simple screening the risk groups a 37% rise 7 in detection could be made.
The lesion moves freely during swallowing & is indistinguishable from a benign
nodule. Hoarseness, dysphasia, cough or dyspnoea suggest local invasion. Though
blood born mets are extremely uncommon, a few can be present at diagnosis,
most commonly in the lung.

A variety of diagnostic tests differentiate PTC from benign nodules, including
radionuclide scanning & FNA. Most lesions are cold masses on scintiscans.
The mainstay of treatment is surgery. Lobectomy along with isthmectomy is
done in usual cases8. Total thyroidectomy is reserved for the high risk cases. If
nodal involvement is found, modified lymph node dissection is performed by
extension of the incision. Radical neck dissections have been considered
unnecessary. Suppression of thyroid function by exogenous administration of
thyroid hormone & post operative radioactive iodine are also sometimes used 9.
External radiation is of limited use & limited for incompletely excised tumors.


PTCs have excellent prognosis, with 10 year survival rates exceeding 95%. 5-
20% have local recurrences & 10-15% have distant metastases. The prognosis
depends on several factors including age (with excellent prognosis below 40
years), sex (females with better prognosis), extra thyroidal extension,
microscopic variants, tumor size, presence of capsule, multicentricity, distant
metastases, poorly differentiated squamous or anasplastic foci, BRAF mutation10,
EMA & Leu-M1 positivity, DNA ploidy (aneuploidy correlating with
aggressiveness), RB protein expression level & presence of circulating tumor


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3. Shoichi Kikuchi, Nancy D. Perrier, Philip Ituarte, Allan E. Siperstein, Quan-Yang Duh, and
Orlo H. Clark : Latency Period of Thyroid Neoplasia After Radiation Exposure; Ann Surg.
2004 April; 239(4): 536–543. 2004 Lippincott Williams & Wilkins, Inc.

4. Bipin T Varghese, Anitha Mathews, Manoj Pandey and VM Pradeep : Unusual
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World J Surgical Oncology. 2003; 1: 7.

5. Rosa Marina Melillo, Anna Maria Cirafici, Valentina De Falco, Marie Bellantoni, Gennaro
Chiappetta, Alfredo Fusco, Francesca Carlomagno, Antonella Picascia, Donatella
Tramontano, Giovanni Tallini, and Massimo Santoro: The Oncogenic Activity of RET
Point Mutants for Follicular Thyroid Cells May Account for the Occurrence of Papillary
Thyroid Carcinoma in Patients Affected by Familial Medullary Thyroid Carcinoma;
American J Pathology. 2004 August; 165(2): 511–521

6. Cotran RD, Kumar V, AK Abbas: Robbins Pathological Basis of Disease 7th edition ; WB
Saunders Company, Philadelphia. 2005 .page 1180

7. Yoon Jung Choi, Yong Lai Park, and Jang Hyun Koh : Prevalence of Thyroid Cancer at a
Medical Screening Center: Pathological Features of Screen-detected Thyroid
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8. Williams, Bulstrode, Connell: Bailey & Love Short practice of surgery 25th edition 2008
page 783

9. Harrisons text book of internal medicine ; 6th edition page 1876

10. Electron Kebebew, MD, Julie Weng, Juergen Bauer, Gustavo Ranvier, Orlo H. Clark,
Quan-Yang Duh, Daniel Shibru, Boris Bastian and Ann Griffin : The Prevalence and
Prognostic Value of BRAF Mutation in Thyroid Cancer; Ann Surg. 2007 September;
246(3): 466–471