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11 Tumors ofthePharynx
277
Most cases are, however, are advanced at the time
of presentation, and the overall survival rate
rarely exceeds 25% in any series. General local
control rates have been reported to be around
80% [48]. Distant metastatses occur in approximately 25% of patients. The lungs, liver, and
bones are the main organs affected. The principle
cause of death is local tumor recurrence. Distant
metastases, second primary cancers, and comorbid diseases are secondary causes.
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t.me/Dr_Mouayyad_AlbtousH
Benign Thyroid Disease
MahmoudSakr
12
12.1 Introduction
12.1.1 Surgical Anatomy
The thyroid gland is a brownish-red and highly
vascular endocrine gland located anteriorly in
the lower neck, extending from the level of the
fth cervical vertebra (C5) down to the rst thoracic (T1). The normal gland weighs between 20
and 35g in adults and consists of two elongated
lateral lobes with superior and inferior poles
connected by a median isthmus overlying the
second to fourth tracheal rings. The superior
poles extend toward the oblique line of the thyroid cartilage, lying deep to the sternothyroid
muscle, and supercial to the cricothyroid muscle [1]. A conical pyramidal lobe often ascends
from the isthmus or the adjacent part of either
lobe (more often the left) toward the thyroid cartilage to which it may be attached by a brous or
bromuscular band, the levator of the thyroid
gland. Remnants of the thyroglossal duct may
persist as accessory nodules or cysts of thyroid
tissue between the isthmus and the foramen
cecum of the tongue base. Usually, two pairs of
parathyroid glands (PTGs) lie in proximity to the
thyroid gland.
12.1.1.1 Fascia andLigaments
The thyroid gland is enveloped by a brous capsule condensed from the pretracheal fascia. The
anterior suspensory ligament extends from the
superior-medial aspect of each thyroid lobe to the
cricoid and thyroid cartilages. The postero- medial
aspect of the gland is attached to the side of the
cricoid cartilage, rst and second tracheal rings,
by the posterior suspensory ligament (Berry’s
ligament), which is responsible for the movement
of the thyroid gland and related structures during
swallowing. On its way to the larynx, the recurrent laryngeal nerve (RLN) usually passes deep to
Berry’s ligament or between the main ligament
and its lateral leaf [2]. Modern surgical resection
of the thyroid gland involves a “capsular dissection.” The maintenance of the capsule helps
reduce damage to the plexus of veins that lie on its
surface and its highly vascular parenchyma.
Additionally, it reduces the chance of injury to the
adjacent neurovascular structures.
12.1.1.2 Arterial Supply
The arterial supply to the thyroid gland comes
from the superior and inferior thyroid arteries
and, occasionally, the thyroidea ima. These arteries have abundant collateral anastomoses with
each other, both ipsilaterally and contralaterally.
M. Sakr (*)
Department of Surgery, Faculty of Medicine,
Alexandria University, Alexandria, Egypt
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
M. Sakr (ed.), Head and Neck and Endocrine Surgery,
https://doi.org/10.1007/978-3-031-64102-2_12
t.me/Dr_Mouayyad_AlbtousH
Superior Thyroid Artery (STA)
The superior thyroid artery (STA) arises as the
rst branch of the external carotid artery (ECA)
279
280
M. Sakr
and passes in a caudal direction to join the superior pole of the thyroid. It has close relations to
the external branch of the superior laryngeal
nerve (SLN), which lies deep into the artery
before turning medially to supply the cricothyroid muscle. High ligation of the STA during thyroidectomy places this nerve at risk of inadvertent
injury that alters pitch regulation. The STA
divides into anterior and posterior branches.
From the posterior branch, a small parathyroid
artery passes to the superior PTG [3].
Inferior Thyroid Artery (ITA)
The inferior thyroid artery (ITA) arises from
thyrocervical trunk, a branch of the subclavian
artery, and passes in the tracheaesophageal
groove into the postero-lateral aspect of the
each lobe. It has a variable branching pattern
and a variable relationship with the RLN, most
commonly passing in front of the nerve. The
RLN can be found after it emerges from the
superior thoracic outlet, in a triangle bounded
laterally by the common carotid artery (CCA),
medially by the trachea, and superiorly by the
thyroid gland [4]. Another hint to the location of
the RLN is the “Zuckerkandl tubercle,” an
extension of the thyroid, close to Berry’s ligament. On rare occasions, the nerve may pass
directly from the vagus to the larynx, close to
the superior thyroid vessels [5].
Thyroidea Ima Artery
The “thyroidea ima” is a single artery that arises
from the brachiocephalic artery or the arch of the
aorta. It enters the thyroid gland at the inferior
border of the isthmus and is present in <10% of
patients.
12.1.1.3 Venous Drainage
Veins of the thyroid gland form a plexus of vessels lying in the substance and on the surface of
the gland. This plexus is drained by three pairs of
veins. The superior and middle thyroid veins
drain into the internal jugular vein (IJV), while
the inferior thyroid veins follow different paths
on each side. The right passes anterior to the
innominate artery to the right brachiocephalic
vein or anterior to trachea to the left brachioce-
phalic vein. On the left side, drainage is to the left
brachiocephalic vein. Occasionally, both inferior
veins form a common trunk called the “thyroid
ima vein,” which empties into the left brachiocephalic vein.
12.1.1.4 Lymphatics
Lymphatic drainage of the thyroid gland is extensive with intra-glandular and sub-capsular lymphatic drainage into the IJV.Immediate lymphatic
drainage ows to the peri-glandular lymph nodes
(LNs), to the pre-laryngeal (Delphian), pretracheal, and para-tracheal nodes along the RLN
and then to mediastinal LNs. Regional metastases of thyroid carcinoma can also be found laterally, higher in the neck along the IJV.This can be
explained by tumor invasion of the pretracheal
and para-tracheal nodes causing an obstruction of
normal lymph ow.
12.1.1.5 Innervation andRelated
Nerves
Principal innervation of the thyroid gland derives
from the autonomic nervous system.
Parasympathetic bers come from the vagus
nerves, and sympathetic bers are distributed
from the superior, middle, and inferior ganglia of
the sympathetic trunk [6]. The relationship of the
thyroid gland to the RLN and the external branch
of the SLN is of major surgical signicance
because damage to these nerves leads to disability in phonation or difculty in breathing. Both
nerves are branches of the vagus nerve.
Recurrent Laryngeal Nerve (RLN)
The right RLN arises from the vagus nerve, loops
posteriorly around the subclavian artery, and
ascends behind the right lobe of the thyroid. It
enters the larynx behind the cricothyroid muscle
and the inferior cornu of the thyroid cartilage and
innervates all the intrinsic laryngeal muscles
except the cricothyroid. The left RLN comes
from the left vagus, loops posteriorly around the
arch of the aorta, and ascends in the tracheaesophageal groove (TEG) posterior to the left lobe
of the thyroid, where it enters the larynx and
innervates the musculature in a similar fashion as
the right nerve. The RLN may not lie in the TEG
t.me/Dr_Mouayyad_AlbtousH
12 Benign Thyroid Disease
281
and thus it is vulnerable to injury if not visualized
and traced up to the larynx during thyroidectomy.
In addition, it has a variable relationship to the
ITA as it often passes anterior, posterior, or
through the branches of the ITA.Ligation of this
artery may be dangerous if the nerve is not identied rst. Moreover, in the presence of large nodules, the RLNs may not be in their “regular”
anatomical location but may be found even anterior to the thyroid gland. Finally, there may be a
“non-RLN,” which occurs more on the right side
(0.6%) than on the left side (0.04%) and is associated with vascular anomalies.
External Branch oftheSuperior Laryngeal
Nerve (SLN)
The external branch of SLN innervates the cricothyroid muscle. It is important to the pitch of
voice as the cricothyroid muscle is the tensor of
the vocal cords. In most cases, this nerve lies
close to the vascular pedicle of the superior pole
of the thyroid lobes descending on the fascia of
the inferior pharyngeal constrictor. In some
patients, it lies on the anterior surface of the thyroid lobe, making the possibility of damage during thyroidectomy even greater [7].
12.1.1.6 Parathyroid Glands (PTGs)
The PTGs are small glands that secrete parathyroid hormone (PTH) that controls serum calcium
(Ca) homeostasis. In about 80% of cases, four
glands are present; two on each side, but three to
six glands have been reported. Because of their
small size, their delicate blood supply, and their
usual anatomical position adjacent to the thyroid
gland, these glands are at risk of being accidently
removed, traumatized, or devascularized during
thyroidectomy.
The superior PTGs arise embryologically
from the fourth pharyngeal pouch. They descend
only slightly during embryologic development,
and their position remains quite constant, being
adjacent to the posterior surface of the middle
part of the thyroid lobe, often just anterior to the
RLN as it enters the larynx. The inferior PTGs
arise from the third pouch, along with the thymus; hence, they often descend with the thymus
and have a wide range of distribution in adults,
from just beneath the mandible to the anterior
mediastinum [8]. With experience, one becomes
much more capable of recognizing the PTGs by
their tan appearance and small vascular pedicle
and of differentiating them from either LNs or
adipose tissue [9].
12.1.1.7 Micro-anatomy (Histology)
The thyroid gland is formed of connective tissue
stroma and parenchyma of endocrine cells. The
connective tissue (true) capsule of the thyroid
gives off multiple brous septa (trabeculae)
passing into the gland, carrying blood vessels,
nerves, and lymphatics to form lobules. The
gland is further divided into 20–40 much smaller
functional subunits called follicles that store a
colloid substance that functions as a hormone
store. The colloid is maintained by a single layer
of follicular epithelial cells sitting on a basal lamina. These follicles are surrounded by fenestrated
capillaries, lymphatics, and so-called parafollicular or C-cells.
Microscopically, each lobe or lobule is made
of two types of secretory cells; follicular cells
that secrete thyroxin (T4) and tri-iodothyronine
(T3), and in smaller number, the para-follicular
or clear cell (C-cells), which secrete thyrocalcitonin. The follicles are separated from each other
by a highly vascular connective tissue, and each
follicle is lined with a single layer of attened to
low columnar epithelium depending on their
degree of activity.
Oncocytes (Hürthle cells, oxyphilic cells, and
Ashkenazy cells) are large follicular cells with
abundant deeply eosinophilic granular cytoplasm
and numerous mitochondria. They are commonly
seen in long-standing Graves’ disease, autoimmune thyroiditis, radiation-induced thyroiditis,
follicular-derived neoplasms, and some adenomatoid goiters [10–12].
12.1.2 Physiology
The function of the thyroid gland is to synthesize,
store, and secrete T4 and T3. Mono-iodotyrosin
(MIT) and di-iodotyrosine (DIT) are also found
in thyroid venous blood.
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M. Sakr
Inorganic iodide (I−) is absorbed from gastrointestinal tract and actively trapped by the acinar
cells of the thyroid gland via a transport mechanism that is frequently called the “I-trapping
mechanism” or “I-pump.” A transporter named
“pendrin” is located on the luminal surface of the
follicular cell and is responsible for allowing passage of I− into the follicle. In the acinar cells, I− is
oxidized to iodine (I2) and bound to the third posi-
tion of tyrosin molecules with the aid of the
enzyme thyroid peroxidase (TPO) to form MIT,
and then to the fth position to form DIT.Two
DIT molecules then undergo an oxidative con-
densation with the release of an alanine residue
and the formation of T4. Condensation of MIT
with DIT results in T3 formation. These reactions
occur while the tyrosin molecules are attached to
thyroglobulin (Tg). The peptide bonds between
the iodinated residues and Tg are broken by proteases in lysosomes, and so T4, T3, DIT, and MIT
are liberated into the cytoplasm. The iodinated
tyrosins are de-iodinated by a microsomal iodotyrosin dehalogenase. Then, T3 and T4 are
released into the circulation [13].
Most circulating T3 derives from peripheral
conversion of T4, which is really a pro-hormone
and is signicantly less potent than the more metabolically active hormone T3. In the blood, the
majority of circulating T3 and T4 is bound to the
plasma proteins, mainly thyroxin-binding globulin (TBG) and pre-albumin. It is only the ‘free’
unbound forms of hormones that are metabolically active, and T3 is quick acting within few
hours while T4 acts more slowly from 4 to
14days.
Production of T3 and T4 is regulated by the
hypothalamic-pituitary-thyroid axis, which is a
multi-loop feedback circuit. The production of
T3 and T4 from the thyroid is stimulated directly
by the thyroid-stimulating hormone (TSH), produced by the anterior pituitary. Levels of T3 and
T4 are also increased indirectly by thyrotrophinreleasing hormone (TRH), which is produced by
the hypothalamus in response to low levels of T3/
T4 and acts on the pituitary to increase TSH production. Conversely, TRH and TSH production
are suppressed by high levels of T3 and T4.
Additionally, TRH production is also suppressed
by high levels of TSH.Thus, the circulating levels of active thyroid hormones are normally selfregulating [14].
The thyroid also contains “para-follicular
C-cells,” which produce “calcitonin” that reduces
serum Ca levels, counteracting the actions of
PTH, by inhibiting osteoclast activity in bone,
renal resorption of Ca, and absorption of Ca in
the intestines. Blood levels of PTH are far more
clinically relevant to Ca homeostasis than calcitonin, and no exogenous replacement for calcitonin is required following thyroidectomy.
12.1.3 Investigating theThyroid
Gland
12.1.3.1 Serological Investigations/
Thyroid Function Tests
The serum level of TSH should be routinely measured, while T3 and T4 levels are required if TSH
level is abnormal (Table 12.1). When hypothyroidism is conrmed, thyroid peroxidase (TPO)
antibodies should be requested to check for autoimmune thyroid disease such as Hashimoto’s
thyroiditis. Serum Thyroglobulin (Tg) level does
not help in the initial management of thyroid
nodule and is not recommended. Serum Tg levels
may be elevated in patients with cancer, but are
not diagnostic, since similar increases are seen in
benign thyroid disorders. However, serum Tg is
Table 12.1 Serological tests in thyroid disease
TSH
Normal Not needed Euthyroid
Decreased
Increased
Additional
testing Diagnosis
– Free T4 ↑
– Free T4
normal
– Free T4 ↓
– Free T4 ↑
– Free T4
normal
– Free T4 ↓
– Hyperthyroid
– T3 thyrotoxicosis
– Non-thyroid disease
or drugs
– Thyroid resistance or
pituitary tumor
– Subclinical
hypothyroid
– Hypothyroid
t.me/Dr_Mouayyad_AlbtousH
12 Benign Thyroid Disease
useful in the follow-up of patients after total thyroidectomy (TT) for well-differentiated thyroid
cancer (WDTC). A level >10ng/mL is a reliable
indicator of locally recurrent or metastatic disease and predicts the need for ablative dose of
131
[15, 16].
Basal plasma calcitonin levels may be useful
if medullary thyroid carcinoma (MTC) is suspected. In addition, pheochromocytoma is associated with MTC in multiple endocrine neoplasia
(MEN) Type II, presenting with sympathetic nervous system hyperactivity [17].
12.1.3.2 Imaging Studies
283
I
Ultrasonography (US)
Ultrasonography (US) is the imaging study of
choice for thyroid nodules. It can identify nodules too small to be palpated, the presence of
multiple nodules, central or lateral neck lymphadenopathy, and provide accurate measurements
of nodule diameter, allowing serial scans and better assessment of growth. Additionally, it allows
the characterization of nodules by sonographic
features that suggest malignancy. Comet tail sign
and coarse calcication suggest very low risk of
malignancy. Hypo-echoicity and absent halo with
indistinct margin are associated with moderate
risk of malignancy. The presence of microcalcication is highly suggestive of malignancy,
especially papillary thyroid carcinoma (PTC)
(Fig.12.1) [18].
Color ow patterns are categorized as (a) Type
1: no blood ow, (b) Type 2: peri-nodular ow,
and (c) Type 3: intra-nodular blood ow (perinodular vessels may or may not be present).
Although nonspecic, thyroid cancers may have
internal hypervascularity, whereas benign nodules may have peripheral vascularization.
However, type 3 vascularization can be found in
both benign and malignant nodules [19].
Completel avascular nodules are more likely to
be benign.
There is certainly some subjectivity to sonographic features, which cannot, alone, reliably
distinguish malignant from benign lesions but are
very useful in selecting the site within a nodule
for ne needle aspirate biopsy (FNAB) in order
Fig. 12.1 Ultrasonography showing hypoechoic, illdened margin, and micro-calcications. Biopsy proved
to be a papillary thyroid carcinoma (PTC)
to improve diagnostic yield or select appropriate
nodules to aspirate within a multinodular goiter
(MNG) [20, 21].
Magnetic Resonance Imaging (MRI)
andComputed Tomography (CT)
Magnetic resonance imaging (MRI) is superior to
scintigraphy in evaluating retrosternal goiters
(RSGs). It is noninvasive, easily tolerated, and
unlike contrast media used with CT; contrast
media used in MRI does not inuence thyroid
function. CT scan gives structural information
about the gland and its relationship to adjacent
structures. Both CT and MRI are relatively
expensive and have a limited ability in distinguishing between benign and malignant lesions.
However, they are necessary in some cases for
staging and planning surgery. Indications of CT
and/or MRI include the presence of a xed thyroid mass, hemoptysis indicating pulmonary
metastasis, cervical LNs, and RSGs. They can
also show involvement of the larynx, pharynx,
trachea, esophagus, or major blood vessels [22].
Thyroid Scintigraphy
The use of radionuclide agents is helpful in delineating the presence, size, and function of thyroid
nodules. Scanning with
123
I has the advantages of
low-dose radiation (30 mrad) and a short half-life
t.me/Dr_Mouayyad_AlbtousH
284
M. Sakr
(12–14h). This compares favorably with the use
131
of
I with a higher dose (500 mrad) and a longer
half-life (8–10days).
123
I scanning is usually used
for patients with a suspected lingual thyroid or
RSG, whereas
131
I is used in patients with WDTC
to screen for distant metastasis. Malignancy
occurs in 15–20% of “cold” nodules and, additionally, in 5–9% of nodules with uptake that is
“warm” or “hot,” mandating continued aggressive approach to clinically suspicious nodules
even if they are not “cold” [23].
Technetium-pertechnetate-99m (
99m
Tc) is also
used for evaluation of thyroid nodules. It is
trapped by the thyroid, but not organied, and has
a short half-life and a low radiation dose.
Screening with
99m
Tc also shows uptake in salivary glands and major vascular structures, and
therefore, requires a higher sophistication of
interpretation [16].
12.1.3.3 Biopsy
Fine Needle Aspiration Cytology (FNAC):
Free-Hand or US-Guided
The most important step (cornerstone) in the
management of thyroid nodules is FNAC. Freehand or palpation-guided FNAC has a sensitivity
of 65–98% and a specicity of 72–100% [24].
The US-guided FNAC improves the accuracy of
FNAC. The acellular or nondiagnostic (Thy 1)
aspirate is reduced from 14% to 8% with
US-guidance [25], sensitivity increases from 92
to 98%, and specicity from 69 to 71% [26]. It
can also be used to help localize impalpable nodules, lesions <1cm, or when initial FNAC was
nondiagnostic.
The indications for FNA are all thyroid nodules with a maximal diameter >1cm and smaller
nodules with suspicious features on US.A lower
limit for the maximal diameter does not exist;
however, there are technical difculties in the
sampling procedure in tiny lesions (<0.5 cm),
even under US-guidance [27]. The aims of the
FNAB include the following [27]:
– To conrm the benign diagnosis of a nodule
justifying the clinicians for a conservative
approach avoiding an unnecessary surgery.
– To conrm the clinical diagnosis of a diffuse
goiter like Hashimoto’s thyroiditis or subacute
de Quervain thyroiditis.
– To recognize an aggressive thyroid tumor and
to recognize or at least to suspect a clinically
relevant low-grade tumor among all nodular
enlargements of thyroid.
– To classify or to suspect some tumor types
demanding a special therapeutic approach
such as MTC, lymphoma, anaplastic carcinoma, or metastatic carcinoma.
– To clarify eventual postoperative enlarge-
ments in the thyroid region, differentiating
mainly between residual or recurrent disease
versus granulomas or LN enlargements.
– To explore various neck enlargements outside
the thyroid gland, mainly cystic lesions of the
neck, and differentiating between ectopic thyroid cysts, thyroglossal cysts, branchial cysts,
and cystic degenerated LN metastases of PTC.
– To conrm the presence of LN metastases.
Fine-needle aspiration cytology is not successful in (1) detection of a microscopic focus of
PTC, (2) differentiation of follicular adenoma
from follicular carcinoma, (3) determination of
the extent of a thyroid tumor, (4) exclusion of LN
metastases, and (5) the safe recognition of a parathyroidal lesion [28].
Cytology results can be placed in ve diagnostic categories (Thy 1–Thy 5) as indicated by
the British Thyroid Association (BTA) Guidelines
[24] (Table 12.2). The probability of a benign
thyroid nodule being accurately diagnosed as
benign from a single FNAC is 90%. However, the
accuracy of diagnosis increases signicantly to
98% if two separate aspirates were performed on
separate occasions [29].
The recently issued Bethesda System for
Reporting Thyroid Cytopathology (BSRTC) [22],
based on an NCI-sponsored conference (2007), is
currently considered to be the most suitable for
communicating ndings from thyroid smears
(Table12.3).
A positive nding of a metastasis is principally a safe diagnosis, whereas a negative smear
does not exclude the presence of a metastasis
since it might be missed by sampling. Cervical
t.me/Dr_Mouayyad_AlbtousH
12 Benign Thyroid Disease
285
Table 12.2 Diagnostic FNA categories and recommended actions (BTA guidelines) [24]
Category Description
Thy 1
Thy 2
Thy 3 Follicular or Hurthle
Thy 4 Suspicious of
Thy 5 Diagnostic of
MDT multidisciplinary team
– Nondiagnostic,
insufcient sample
– Cyst containing
colloid or
histiocytes only, in
the absence of
epithelial cells
– Benign,
nonneoplastic.
– Cyst containing
benign epithelial
cells
cell lesion/suspected
folic, or Hurthle tumor
malignancy
malignancy
Recommended
action
– To repeat
FNAC (US
guidance may
help)
– If the cyst is
aspirated to
dryness with
no residual
swelling,
clinical/US
follow-up
alone may be
sufcient
Repeat FNAC in
3–6months. Two
nonneoplastic
results
3–6months apart
should exclude
neoplasia
MDT
discussion—
diagnostic
lobectomy
MDT
discussion—Total
thyroidectomy
MDT
discussion—Total
thyroidectomy
LN metastases frequently undergo extensive cystic degeneration, resulting in “acellular smears.”
Cystic foci in LNs remain highly suspicious,
even by negative FNA results. The measurement
of thyroglobulin (Tg) in the cystic uid would be
helpful option to conrm a suspicion if the
amount of cancer cells is not sufcient for the
diagnosis [27].
Core Biopsy (with or Without
US-Guidance)
A core biopsy, preferably under US guidance,
should be considered after two aspiration procedures showing nondiagnostic specimen (Thy 1)
or when a thyroid lymphoma is suspected, typically in an elderly woman or on a background of
autoimmune thyroiditis.
12.1.3.4 Flexible Laryngoscopy
Indirect laryngoscopy is important to assess
vocal cord movements. Patients with difculty
breathing (increased respiratory rate or diminished oxygen saturation) or stridor should be
referred as an “emergency.”
12.2 Multinodular Goiter (MNG)
12.2.1 Introduction
Table 12.3
pathology recommended diagnostic categories [22]
Category Description
I Nondiagnostic or unsatisfactory: Cyst uid
II Benign: Consistent with a benign follicular
III Atypia of undetermined signicance or
IV Follicular neoplasm or suspicious for a
V Suspicious for malignancy
VI Malignant
Bethesda system for reporting thyroid cyto-
only—virtually acellular specimen, other
(obscuring blood, clotting artifact, etc.)
nodule (adenomatoid nodule, colloid nodule,
etc.), consistent with Hashimoto’s
thyroiditis, consistent with granulomatous
(subacute) thyroiditis
follicular lesion of undetermined
signicance
follicular neoplasm
t.me/Dr_Mouayyad_AlbtousH
Goiter is derived from the Latin word ‘tumidum
gutter,’ which means “swollen throat.” Thyroid
Enlargement may be diffuse or nodular (multinodular or a solitary nodule), hormonal status
may be euthyroid, hypothyroid, or hyperthyroid,
and histologically, the enlarged thyroid may be
benign or malignant.
Multinodular goiter (MNG), dened as an
“enlarged thyroid gland with multiple nodules,” is
a common condition with a marked female preponderance. It affects about 13% of the world’s population, ranging from 5% in the Americas to 32% in
the Eastern Mediterranean area [30]. Iodine (I
2
deciency, naturally occurring goitrogens, thyroid
growth factors (GFs), and heredity have been postulated as possible causes of goiter [31]. Thyroid
nodules may lead to a variety of clinical sequelae
)
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