ANATOMIC PATHOLOGY
Review Article
Papillary Neoplasms of the Thyroid
Pathologic and Prognostic Features
VIRGINIA A. LiVOLSI, M.D.
Papillary lesions of the thyroid gland include papillary
hyperplasia (diffuse or focal and sometimes associated
with hyperfunction) and papillary carcinoma and its variants.
What are papillae? Kini1 compared neoplastic papillae
in thyroid tumors to ears of corn: the neoplastic papilla
contains a central core of fibrovascular (sometimes just
fibrous) tissue (the "cob") lined by one or sometimes several layers of cells (the "kernels") with crowded oval nuclei.
On the other hand, the hyperplastic papilla arises when
hyperplasia of thyroid follicles exaggerates into papillary
change: there is infolding of the lining epithelium composed of tall columnar cells with basal round and uniform
nuclei. There is either no central core or there may be a
core of edematous or myxomatous paucicellular stroma,
often including small follicles (subfollicle formation).
PAPILLARY HYPERPLASIA
perplasia is diffuse. Although the nuclei are enlarged they
are round.
Papillary Hyperplasia in Follicular Nodule
Papillary hyperplasia is the term that is preferred to
"papillary adenoma." The basic lesion is a follicular adenoma or adenomatous nodule in which hyperplastic
changes occur. This lesion tends to occur, most often in
children and adolescents, as a solitary thyroid nodule that
develops approximately at the age of puberty. Pathologic
examination reveals that the nodule is always well circumscribed, often even encapsulated, and may show cystic
change centrally. The papillae, which are directed to the
center of the nodule, contain extremely edematous stalks
with follicles in them. The nuclei are round, not clear as
in carcinomas, and tend to be polarized at the basal or
central part of the cell (Fig. 1).
PAPILLARY CARCINOMA
Papillary hyperplasia is best described, pathologically,
as the lesion found in untreated autoimmune hyperthyroidism. The immunologic abnormality superimposed on
genetic predisposition to the disease2 leads to production
of immunoglobulins, which attach to the thyrotropin
(thyroid-stimulating hormone) receptor on the follicular
epithelial cell. This triggers the follicular cells to grow and
increase output of thyroid hormones, actions that are
similar to those of thyroid-stimulating hormone. Too
many cells that are bigger than normal no longer "fit" on
the framework of the follicle and infoldings or "papulations" form. In autoimmune hyperthyroidism, the hy-
This neoplasm is the most common malignant tumor
of the thyroid gland in countries having iodine-sufficient
or iodine-excessive diets,3 comprising about 80% of the
cases of thyroid cancer. These common tumors tend to
be biologically indolent and have an excellent prognosis
(more than 90% survival at 20 years).4"13 The tumors avidly invade lymphatics, leading to "multifocal" lesions
and to regional node metastases. Distant metastases outside the neck are unusual (only in about 5% to 7% of
cases).9-"-17
Papillary carcinoma can occur at any age, although
most tumors are diagnosed in patients in the third and
9 121418 20
" Although the incidence varies
From the Department of Pathology and Laboratory Medicine, Uni- fifth decades. '"
versity of Pennsylvania Medical Center. Philadelphia, Pennsylvania. among different series, women seem to be affected more
often than men in ratios of 2:1 to 4:1. 7 1 1 1 2 1 4 1 8 1 9
Received October 15, 1991, and accepted for publication October 30,
The gross appearance of papillary thyroid cancer in1991.
cludes small (microcarcinoma, minute carcinoma, tiny
Presented as the Arthur Purdy Stout Memorial Lecture, New Orleans,
Louisiana, September 1991.
carcinoma), intrathyroidal (encapsulated, diffuse), and
Address reprint requests to Dr. Livolsi: Department of Pathology,
extrathyroidal.710" Occult papillary cancer is a pathoHospital of the University of Pennsylvania, 3400 Spruce Street, Philalogically unacceptable term because it has no meaning as
delphia, Pennsylvania 19104.
426
LiVOLSI
427
Papillary Neoplasms of the Thyroid
FIG. 1. Papillary hyperplastic nodule. Papillary structures lined by cells
with polarized rounded nuclei (hematoxylin and eosin, X400).
a morphologic descriptor.21"23 Hawk and Hazard7 and
others10'24'25 prefer the term small papillary cancer or
papillary microcarcinoma.7,9,14,17,26-29 Most pathologists
agree that a lesion that can be classified into this category
should measure 1 cm or less.30'31 Vickery and associates10
noted that most of these tumors measure between 4 and
7 mm.
Several Japanese studies32-35 have subdivided these tumors into minute cancers (defined as smaller than 5 mm
in diameter) and tiny carcinomas (defined as 5 to 10 mm
in diameter). Such lesions found in surgical material often
were incidental lesions in glands removed for adenomatous goiter (29%), thyroiditis (21%), adenoma (8.6%), or
toxic goiter (5.3%).35 The minute carcinoma presumably
arises from a few follicles as a nonencapsulated lesion
(often completely follicular in pattern) that may or may
not be associated with sclerosis. Some progress to become
encapsulated at least partially; the latter may progress to
clinically evident lesions. Those lesions that for unknown
reasons remain sclerosing apparently remain clinically silent throughout the lifetime of the patient.35"37
How common are these lesions? The incidences reported range from about 5% to 35.6% of the population
studied.21'22,38"44 The statistics depend on the population
examined and the care with which the thyroid is sectioned
for pathologic examination. Harach and co-workers44
suggested that tumors measuring less than 5 mm should
be considered a "normal" finding and should be left untreated. However, documented instances of lymph node
metastases from lesions and even extracervical spread less
than 0.5 cm are known.30'45"47 Clinically, lesions of this
size are often the "primary" tumor in the thyroid of a
patient with nodal metastases. The gross appearance of
the small papillary carcinoma is that of a nonencapsulated
sclerotic white to tan nodule that often is located in a
subcapsular area of the gland. Histologically, the tumors
may be completely follicular or papillary and follicular.
The lesions are nonencapsulated and often infiltrate the
surrounding thyroid.
Papillary cancer may be located anywhere in the gland
including, the isthmus." 1 2 These intrathyroidal lesions,
which usually measure more than 1.5 cm, may appear
on gross examination as firm nonencapsulated or partly
encapsulated lesions. Calcification may be present. Gross
cystic changes may be present; however, in a papillary
cancer, there is always a portion of the cystic tumors that
contains solid lesional tissue. Encapsulated papillary carcinoma, which is always confined to the gland, comprises
8% to 13% of overt papillary cancers7 and resembles an
adenoma on gross examination.10'48
Some papillary carcinomas (estimates range from 2%
to 39%), usually large lesions (5 cm or larger), will extend
grossly beyond the thyroid capsule and into cervical soft
tissues.7
Microscopically, papillary carcinomas share certain
features. Many will contain predominantly or focally
papillary areas.20 Most will contain follicular areas as well.
Published series indicate that the percentage of tumors
that are predominantly papillary ranges from 20% to 40%,
the number that are predominantly follicular ranges from
15% to 35%, and the rest are about equally mixed papillary
andfollicular. 710 - 1218 - 20 ' 49 " 51
The tumor cells are usually columnar and contain considerable amounts of amphophilic cytoplasm. The nuclei
of papillary carcinomas of the thyroid are characteristic:
they have been described as pale, clear, ground glass, water
clear, empty, or Orphan-Annie eyed. These nuclei are
larger and more ovoid than normal follicular nuclei and
contain hypodense chromatin as well as a prominent nuclear membrane. 52 Rarely the nucleolus can be seen in
the center of the nucleus; more often, it is pressed against
the thickened nuclear membrane, where it may appear
as a slight bulge. In papillary cancer, these nuclei often
appear crowded and overlap one another. The papillary
carcinoma nucleus contains intranuclear cytoplasmic invaginations, as noted by electron microscopic studies, and
represent a prominent diagnostic clue in cytologic preparations.53,54 Another characteristic of the papillary carcinoma nucleus is the nuclear groove. 5556 Some authors
have identified the grooved nucleus in noncancerous lesions, but in these cases, the grooves are found in few cells
and not as prominently as in carcinoma. 5355 ' 56 The characteristic clear nuclei are found in more than 80% of papillary carcinomas, intranuclear inclusions in 80% to 85%,
and nuclear grooves in almost all cases.
Psammoma bodies are formed by focal areas of infarction of the tips of papillae; presumably the delicate vessels
within the fibrous cores undergo thrombosis or damage
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ANATOMIC PATHOLOGY
Review Article
as a result of minimal trauma. The resulting infarction
attracts calcium salts, which are deposited on the dying
cells. Progressive infarction of the papilla and ensuing calcium deposition lead to characteristic lamellation of the
psammoma body.57"59 In some examples, residual neoplastic cells will be found intimately associated with the
psammoma body. Psammoma bodies usually are found
within the cores of papillae or in the tumor stroma (possibly lymphatics).
Many papillary carcinomas (as many as 40%) contain
foci of squamous differentiation.10'1218'20,50 These areas
often are seen within neoplastic follicles or abutting papillae. Almost all usual papillary carcinomas show areas
of desmoplasia, either in the central portions of the tumor
or more commonly at the peripheral invasive zones of
the lesions.7'10"12'18'20'35-37'50'60 Scattered lymphocytes frequently are found at the invasive edges of papillary carcinomas.7,10"12,18,20,60 Rarely an intense lymphocytic infiltrate, even with the presence of germinal centers, will
be seen. This infiltrate, localized to the invasive tumor
foci, does not indicate a preexisting underlying chronic
thyroiditis. It is probably as postulated by Volpe61 that
the lymphocytes react to altered cell-surface antigens on
the tumor cells or to abnormal tumor cell products. Increased numbers of dendritic cells are found in these lesions.62 Kamma and colleagues63 noted HLA-DR expression in the tumor cells and the peritumor lymphocytes
were predominantly of the T-cell type, findings that are
similar to those of chronic lymphocytic thyroiditis.
Papillary carcinoma has a propensity to invade the
glandular lymphatics. 58,64-66 This feature leads to two
commonly noted consequences: so-called multifocality of
the tumor and a high incidence of regional node metastases. Papillary carcinoma is not a lesion in which multiple
clones of cells undergo neoplastic transformation at the
same time; that is, it is not a multicentric tumor. Studies
by Fialkow67 using isoenzyme technology and by Hicks
and associates68 and Namba and Fagin69 using restriction
fragment length polymorphism technology have shown
that of those papillary carcinomas studied, all appear to
be clonal proliferations. The multifocality must be due
to intrathyroidal lymphatic spread.
Regional lymph node metastases are very common in
papillary cancer, with 50% or more patients having nodal
metastases at initial diagnosis. Some patients have cervical
node enlargement and no obvious clinical manifestation
of a tumor in the thyroid. Not infrequently, the nodal
metastasis involve one node, which may be cystic. Both
the surgeon and the pathologist must be knowledgeable
of papillary carcinoma that occurs as a unilocular cystic
node metastasis to avoid misdiagnosising it as a branchial
cleft cyst.70
Immunostaining studies have shown that the majority
of papillary cancers (92% to 100%) contain thyroglobulin,71'72 thyroxine, and triiodothyronine. Staining to localize keratin has yielded confusing results.72"78 Low-molecular-weight keratin is found in almost all examples of
papillary carcinoma, and the staining results show diffuse
and intense positivity in these tumors. However, although
some authors found that epidermal (high-molecular
weight) keratins also are found in papillary carcinoma
(possibly related to the squamous change in some of these
lesions), others have not reproduced these findings. If the
epidermal keratins were found uniformly in papillary
carcinomas, this would be a relatively simple way to distinguish between follicular variant of papillary cancer
(positive) and true follicular carcinoma or adenoma (negative) and between papillary hyperplastic nodule (negative) and papillary carcinoma (positive).79
Flow Cytometric Analysis
Most papillary thyroid tumors are diploid. Several
studies have shown that aneuploid DNA content by flow
cytometric analysis has been associated with a more
guarded prognosis in patients with papillary thyroid
cancer.13,80"84
Prognostic factors in usual papillary carcinoma include
some factors that are clinical and some that are pathologic.13,85"93 Various mnemomics have been applied to
these factors; AGES, which stands for Age, Grade of tumor, Extent of tumor, and Size of tumor, was introduced
by the Mayo Clinic group. 13 Other catchwords have been
proposed by different groups, but all assess similar prognostic parameters.
Age. Patients who are older than 50 years at diagnosis
of papillary carcinoma tend to have a more serious prognosis than younger patients.13'51,94"101 Papillary carcinoma
in children is associated with an excellent outlook, even
in the presence of lung metastases.102,103
Sex. In some series,14 men had more aggressive lesions
than did women.
Size. Larger lesions are more biologically aggressive as
a rule. Some of these tumors also extending grossly beyond
the thyroid capsule, and it may be that these two factors
combine to produce a more guarded prognosis. Extrathyroidal extension noted on gross examination is associated
with a worse prognosis 7,104 "" 2 ; microscopic penetration
of the gland capsule, however, does not appear to be associated with an unfavorable outlook.
Differentiation. Most papillary carcinomas are well
differentiated and can contain and produce thyroglobulin." 3 Dedifferentiation is a poor prognostic indicator. 49,50,114 "" 6
A.J.C.P.- March 1992
LiVOLSI
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Papillary Neoph of the Thyroid
SUBTYPES OF PAPILLARY CARCINOMA
Although most clinical papillary cancers morphologically fit into the usual pattern of this tumor, certain less
common patterns have been recognized. These comprise
about 15% to 20% of papillary carcinomas; some have
important prognostic implications, whereas others appear
to be histologic curiosities.
Follicular Variant of Papillary Cancer
On gross and/or histologic examination, the tumor may
appear encapsulated.10'97"7"8 In the follicular variant,
despite the almost total or complete follicular pattern in
the primary site, there may be psammoma bodies (the
ghosts of dead papillae) and even papillae in nodal metastases. Features that suggest that a tumor with a follicular
pattern is a follicular variant of papillary cancer include
the clear nuclei, psammoma bodies, desmoplastic response at invasive areas, and lymphocytic infiltration (Fig.
2). In this variant, the follicles comprising the tumor often
contain colloid with peripheral scalloping, mimicking the
appearance of a hyperplastic gland. In addition, clearing
of the cytoplasm in addition to the nuclear clearing can
be seen. The prognosis of the follicular variant is apparently similar to more usual papillary carcinomas, although
some series indicate a greater propensity of this variant
to metastasize outside the neck.4950
The macrofollicular variant described by Albores-Saavedra and colleagues"9 in 17 patients resembles nodular
goiter on gross and microscopic examinations but demonstrates papillary cancer cytologic findings. Nodal metastases were documented in some of the reported cases.
A more biologically aggressive lesion related morphologically to the follicular variant of papillary cancer is the
FIG. 3. Papillary carcinoma, tall cell type. Note papillae lined by cells
with voluminous cytoplasm. These are twice as long as they are wide.
Note easily found mitoticfigures(hematoxylin and eosin, X400).
diffuse follicular variant. The series of eight patients reported by Sobrinho-Simoes and associates120 indicated
that these patients (all women) had goiters and some were
clinically hyperthyroid. The tumors resembled follicular
variant of papillary carcinoma on cytologic analysis but
show more frequent vascular invasion and distant metastases.
Rare cases of thyroid neoplasms'20 share some of the
features of papillary (nuclear, sclerosis) and follicular
(vascular invasion, encapsulation) carcinoma. I have seen
three cases that fit into this combined feature category.
No metastases have developed so far in these cases and
the tumors have been confined to the lobe of origin.
Whether this subgroup deserves segregation into a separate
category remains to be defined by future studies.
Tall Cell Variant
FIG. 2. Papillary carcinoma, follicular variant. Note elongated clear nuclei
with some showing grooves (hematoxylin and eosin, X400).
Hawk and Hazard7 described the tall cell variant of
papillary cancer and found that in their material this tumor comprised about 10% of the papillary carcinomas.
When the patient is first examined, the tumor often appears large (more than 6 cm), extends beyond the thyroid,
and shows vascular invasion, more often than usual papillary cancer. The tumor tends to occur in elderly patients.
The tumors are composed of cells that are twice as tall
as they are wide and the cytoplasm is often quite eosinophilic (Fig. 3)."' By electron microscopic examination,
the cytoplasm of the tumor cells contains increased numbers of mitochondria but do not show all the features of
true Hurthle cells.121 Mitotic figures are easily found.10
The tumors tend to be very papillary and often a heavy
lymphocytic infiltration is present in and/or around the
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ANATOMIC PATHOLOGY
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tumor. Some tall cell tumors arise in glands with extensive
histologic evidence of chronic thyroiditis.
The prognosis for this variant is worse than for usual
papillary cancer; these patients tend to suffer local recurrences in the neck, often with invasion of the trachea, and
many will succumb to this complication. It is difficult to
be sure that the histologic findings alone are responsible
for this prognosis or if the influence of older age, extrathyroidal growth, and vascular invasion contribute. No
studies using multivariate analysis have been published,
probably because the number of available cases is too
small. 7122 The possibility that aneuploidy was responsible
for the aggressive biological behavior of tall cell variant
was discounted by Flint and associates123; their study disclosed no significant differences in DNA ploidy between
tall cell and usual papillary carcinomas.
My colleagues and I recently noted a propensity for the
tall cell variant to be associated with a spindle squamous
carcinoma when anaplastic transformation occurs.124
three patients had measurable titers of anti-thyroid antibodies in the serum.
In some reported series, the lesions appear to have a
somewhat more serious prognosis than usual papillary
cancer; this is especially true in the pediatric population.
Affected patients have a greater incidence of lymph node
and lung metastases than ordinary papillary carcinoma;
follow-up shows less favorable overall outcome. 130131
However, the three patients described by Chan and
associates129 were alive and well, but the follow-up was
less than 2 years in these cases. Other series132"135 report
either a poorer or a similar prognosis for this variant when
compared to the usual type. Whether differences in population groups studied could account for these discrepant
results is not clear. Morphologic descriptions in the series
so far reported seem similar; hence it appears that the
various series were examining the same type of tumor.
Larger numbers of patients followed for long time periods
will need to be evaluated to define the biologic features
of the diffuse sclerosis variant.
Columnar Cell Variant of Papillary Carcinoma
Encapsulated
Only four published cases of this variant are available.125"127 In three, the affected patient was male and in
each of these cases the patient died of metastatic tumor,
usually within 5 years (follow-up information was not
available for the other case).127 The curious histologic features of this lesion are extreme papillarity, tall columnar
cells, and nuclear stratification. Clearing of the nucleus
usually is not seen.127 Cytoplasmic clearing is present and
the tumor cells resemble the cellular changes seen in secretory endometrium. In the cases described by Evans,125
zones of less well-differentiated tumor were recognized.
One unusual case of a thyroid tumor with mixed tall cell
and columnar cell features has been described.128
Diffuse Sclerosis Variant
Variant
This tumor, which has the gross appearance of an adenoma, comprises 8% to 13% of papillary cancers.7,45'48136
Microscopically, such lesions also can show total encapsulation; however, there are cytologic features of papillary
cancer, including nuclear changes and psammoma bodies.
Some of these lesions will show focal invasion into the
capsule.48-136
Although this subgroup of tumors is associated with an
even better prognosis than papillary cancer in general,
some lesions (25% in Bocker and co-workers'45 series) have
shown lymph node metastases and thus they are considered carcinomas. 48136 Distant spread or death due to tumor has not been documented. 45
Other Variants
10
Vickery and associates described this tumor, which
often affects children, as a more aggressive type of papillary
cancer. Such lesions often do not occur with a dominant
mass but rather with bilateral goiter. The tumor freely
permeates the gland as though outlining the course of the
lymphatic system of the thyroid. The tumor nests are
composed of papillae with associated solid areas resembling endometrial morules (these have been called as
squamous metaplasia); these solid zones may comprise
more than 50% of the lesion. Many psammoma bodies
are found. The gross impression related to this is that of
a gritty cut surface. A prominent lymphocytic infiltrate
is found around the tumor foci. Chan and associates129
noted the presence of large numbers of S-100-stained
dendritic cells in these lesions; in addition, two of their
Isolated cases or small series of cases of unusual variants
of papillary cancer have been reported: solid variant,45
clear cell type,137 oxyphil variant,138 papillary cancer with
fatty stroma, 139140 papillary carcinoma with fasciitis like
stroma,141 and cribriform papillary carcinoma.142 These
variants are too few in number to assess their prognostic
implications at the present time.
It has been my experience that papillary cancers of the
thyroid that arise in the setting of immunoderegulation,
such as after chemotherapy for leukemia, tend to appear
like ordinary papillary tumors but may behave clinically
in a more serious manner. The follow-up data on patients
developing papillary thyroid cancer after radiation to the
neck for Hodgkin's disease will provide information on
this group of tumors. 143
A.J.C.P. • \ larch 1992
LiVOLSI
Papillary Neoplasms of the Thyroid
Dedifferention in papillary carcinoma can occur and
usually consists of solid patterns of growth, often containing many mitoses and zones of necrosis. Some of these
areas recapitulate an insular pattern of growth. Such tumors, which often are large and extend grossly beyond
the thyroid, have a more guarded prognosis. The insular
carcinoma as described by Carcangiu and associates144
may have, in both primary and metastatic sites, foci of
ordinary papillary or follicular carcinoma. My colleagues
and I have noted similar cases and think that this pattern
may represent dedifferentiation of well-differentiated thyroid cancer in some patients. The prognosis in these cases
is poorer than in well-differentiated tumors. 144145 Such
cases must be separated from anaplastic carcinomas, in
which focal residual papillary zones are noted.
Papillary Variant of Medullary Carcinoma
This unusual tumor is mentioned for completeness,
but it needs to be recognized as a medullary cancer. True
papillae are formed; however, the nuclear characteristics
are absent. 146147
THE FUTURE
The developments of molecular biology in the understanding of human neoplasms have not bypassed papillary
thyroid cancer. Studies of c-myc and c-ras oncogenes also
have disclosed amplification in some papillary thyroid
tumors.85148"152 In 1987, Fusco and colleagues153 described
an oncogene called PTC, or papillary thyroid cancer oncogene, which apparently was specific for papillary cancer
and was not found in any other thyroid lesion studied.153"155 Whether the specific oncogene remains so and
whether it can become diagnostically useful, such as immunostaining for it or its product on fine-needle aspiration
samples or using polymerase chain reaction techniques
to amplify DNA from a small cellular sample to assess
the presence of the oncogene, await future studies.152 Of
great biological interest is that the PTC oncogene has been
localized to the same chromosome in which MEN 2 is
found (chromosome 10)154; this suggests that genes regulating growth and proliferation of the thyroid gland may
be localized to this part of the genome and could lead to
exciting developments in our understanding of thyroid
neoplasia.
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