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\begin{document}

\title{Characteristics of Patients with Head and Neck Cancer Diagnosed at
Autopsy}



\author[1]{Tam Ramsey}%
\author[2]{Tyler Ostrowski}%
\author[1]{Neil Gildener-Leapman}%
\author[1]{Lisa Galati}%
\affil[1]{Albany Medical Center}%
\affil[2]{Albany Medical College}%


\vspace{-1em}



  
  \date{May 29, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Objectives: Thyroid cancers with low T-stage and nodal burden are common
incidental findings at autopsy; however, less is known about the
frequency of non-thyroid head and neck cancers diagnosed at autopsy. It
is important to identify the prevalence of various head and neck cancers
found at autopsy and their association with morality as cancers differ
in risk factors and severity. Design: Head and neck cancers excluding
cutaneous malignancy were identified in the Surveillance, Epidemiology,
and End Results database. Case-related data was reviewed to characterize
the demographic factors associated with the head and neck cancers found
at autopsy. Fisher's Exact Test was used to identify correlations
between cancer-related mortality and cancer type. Results: We reviewed
678 cases of head and neck cancers diagnosed at autopsy from 2000 to
2017. The most common causes of death found at autopsy in non-thyroid
carcinoma were cancer-related mortality (51.40\%), heart disease
(14.95\%), and accidents (5.61\%). Thyroid carcinoma was the cause of
death in 17 (3.01\%) patients. The top three causes of death in this
group were heart disease (26.19\%), accident (9.20\%), and infection
(6.19\%). Patients with non-thyroid cancer were 17.1 (95\% CI: 9.55 -
30.6, p \textless{} 0.001) times more likely to have cancer-related
death than those with thyroid carcinoma. Conclusion: The high rate of
cancer-related deaths in postmortem diagnosis of non-thyroid head and
neck cancers reveals the need for physicians to increase detection
vigilance and emphasizes the need to improve screening in those who may
be high risk for disease development or progression.%
\end{abstract}%



\sloppy


\textbf{ABSTRACT}

\textbf{Objectives:} Thyroid cancers with low T-stage and nodal burden
are common incidental findings at autopsy; however, less is known about
the frequency of non-thyroid head and neck cancers diagnosed at autopsy.
It is important to identify the prevalence of various head and neck
cancers found at autopsy and their association with morality as cancers
differ in risk factors and severity.

\textbf{Design} : Head and neck cancers excluding cutaneous malignancy
were identified in the Surveillance, Epidemiology, and End Results
database. Case-related data was reviewed to characterize the demographic
factors associated with the head and neck cancers found at autopsy.
Fisher's Exact Test was used to identify correlations between
cancer-related mortality and cancer type.

\textbf{Results:} We reviewed 678 cases of head and neck cancers
diagnosed at autopsy from 2000 to 2017. The most common causes of death
found at autopsy in non-thyroid carcinoma were cancer-related mortality
(51.40\%), heart disease (14.95\%), and accidents (5.61\%). Thyroid
carcinoma was the cause of death in 17 (3.01\%) patients. The top three
causes of death in this group were heart disease (26.19\%), accident
(9.20\%), and infection (6.19\%). Patients with non-thyroid cancer were
17.1 (95\% CI: 9.55 - 30.6, p \textless{} 0.001) times more likely to
have cancer-related death than those with thyroid carcinoma.

\textbf{Conclusion} : The high rate of cancer-related deaths in
postmortem diagnosis of non-thyroid head and neck cancers reveals the
need for physicians to increase detection vigilance and emphasizes the
need to improve screening in those who may be high risk for disease
development or progression.

\textbf{Key Words} : head and neck neoplasm, autopsy, laryngeal
neoplasm, thyroid neoplasm, early detection of cancer

\textbf{Key Points:}

\begin{itemize}
\tightlist
\item
  Patients with non-thyroid HNC were 17.1 (95\%CI: 9.55-30.6,
  p\textless{}0.001) times more likely to have cancer-related death
  found at autopsy than patients with thyroid carcinoma.
\item
  50\% of patients with laryngeal carcinomas diagnosed at autopsy had
  their primary cause of death listed as laryngeal cancer.
\item
  Biological and psychosocial factors may contribute to the delayed
  diagnosis of head and neck cancers.
\item
  The high rate of cancer-related deaths in postmortem diagnosis of
  non-thyroid head and neck cancers reveals the need for health care
  professionals to increase vigilance in detecting these cancers in
  order to prevent misdiagnoses.
\item
  It is imperative the otolaryngology community improves awareness of
  asymptomatic head and neck cancer patients and emphasizes the need to
  improve screening in those who may be high risk for disease
  development.\emph{} \textbf{OBJECTIVES}
\end{itemize}

Head and neck cancers (HNC) accounted for 3\% of all cancer diagnoses in
the United States (51,540 cases) and 1.5\% of cancer-related deaths
(10,030 cases) in 2018.\textsuperscript{1,2} Autopsy of patients with
underlying HNC is germane to understanding the complex causes of death
associated with these cancers and is important for quality improvement
across medicine.

This study reviewed patients with HNCs diagnosed for the first time at
autopsy. We theorized both thyroid and non-thyroid HNCs diagnosed at
autopsy would be incidental findings characterized by low T stage and
nodal burden. Previous studies have extensively characterized the
prevalence of thyroid cancer upon autopsy.\textsuperscript{3-5} Our
study emphasizes the prevalence of non-thyroid HNCs first diagnosed upon
autopsy utilizing thyroid cancer as a comparative measure. It is
important to distinguish between the two disease processes as even at
lower stages, non-thyroid cancers, because their malignant nature, may
have greater influence on patient mortality than thyroidal cancer.
Neither cancer diagnosed at autopsy has been studied using a national
cancer database. This study will inform clinicians and public health
officials about the frequency and characteristics of undiagnosed HNCs
and subsequent missed treatment opportunities. Because of the malignancy
of non-thyroid cancers, the medical community must be aware of their
prevalence, particularly in cases where patients may be asymptomatic.
This understanding is imperative to improve screening and early care
measures for patients at risk for disease development or progression
based on demographic characteristics and modifiable risk factors.

\textbf{DESIGN}

The National Cancer Institute's Surveillance, Epidemiology, and End
Results (SEER) database (SEER-18 registry, November 2019) was used to
identify HNCs reported first at autopsy from 2000 to
2017.\textsuperscript{6} Patients with HNC were identified using primary
site-labeled variables in the SEER*stat program. Skin cancers were
excluded. Thyroid carcinoma was analyzed separately from non-thyroid
carcinoma. The following data were collected: age group, gender, race,
tumor site, histological type, tumor staging, tumor size, median
household income, and cause of death. Tumor histological behaviors were
classified based on \emph{International Classification of Diseases for
Oncology} ,~\emph{Third Edition} ~(\emph{ICD-O-3}
).\textsuperscript{7}Tumor staging data was derived from the American
Joint Committee on Cancer (AJCC), 6\textsuperscript{th}
edition.\textsuperscript{8} Median household income was adjusted to
2018. Fisher's Exact Test identified correlation data for cancer-related
cause of death for in laryngeal, non-thyroid head and neck, and thyroid
carcinoma and age, stage, median household income, site, race, sex, and
tumor size. Patient age was categorized as follows: under 30, 30-50,
50-70, and above 70 years old. Cancer stage was dichotomized into early
stage (1 and 2) and late stage (3 and 4). Patients were also categorized
into groups based on household income: under \$35,000;
\$35,000-\$50,000; \$50,000-\$75,000; and above \$75,000. Tumor size was
evaluated in groups of smaller and larger than 4cm. IBM SPSS Build
1.0.0.1327 statistics was used to perform all the analysis. The study
was designated exempt by the Institutional Review Board at our center.

\textbf{MAIN OUTCOME MEASURES}

There were 678 patients with HNCs diagnosed at autopsy from 2000 to 2017
(111 non-thyroid cancers and 567 thyroid cancers).

\emph{Head and neck cancers excluding thyroid carcinoma}

Of 111 non-thyroid HNCs analyzed, 4 patients (3.60\%) were pediatric;
the remainder were 30 years or older. All four pediatric patients were
under one year old at autopsy (three malignant teratomas and one
infantile fibrosarcoma). Most deaths at autopsy in this group occurred
in patients between 50 and 70 years old (57.94\%) \textbf{Figure 1} .
More specifically, 21.21\% of these deaths occurs between 55 and 59
years of age. A comparison of yearly incidence rates revealed no
statistically significant temporal trends in the diagnoses of
non-thyroid HNCs from 2000 to 2017 (p=0.993). A summary of patients'
characteristics and tumor sites is shown in \textbf{Table 1} . The most
common causes of death found at autopsy in this group was HNC-related
malignancy (51.40\%), heart disease (14.95\%), and accidents
(5.61\%)\textbf{Figure 2} . Laryngeal cancer was the most common
malignancy with cancer-related death (27 cases) followed by oral cancers
(10). In 17 patients with stage 1 and 2 non-thyroid HNC found at
autopsy, 8 (47.06\%) had HNC-related deaths; in 35 patients with stage 3
and 4 cancer, 21 (60.00\%) had HNC-related deaths. Most patients
(51.40\%) had a median income between \$50,000 and \$75,000. Fisher's
Exact Test did not yield predictive risk factors for cancer-related
death at autopsy: site (larynx, nasopharynx, oral, hypopharynx)
(p=0.733), age (p=0.757), AJCC stage (p=0.552), median household income
(p=0.235), tumor size (p=0.059), and gender (p=0.617).

Overall, 54 (50.47\%) patients had laryngeal cancers (10 supraglottic,
13 glottic, and 31 unspecified subsite). Of these, 37 (62.58\%) were
squamous cell carcinoma, 1 (1.85\%) was adeno-squamous carcinoma, and 16
(29.63\%) were unspecified. Staging of laryngeal cancers was as follows:
12 stage 1, 4 stage 2, 5 stage 3, and 11 stage 4. The median tumor size
was 40mm. The TMN staging and their frequencies were as follows: T1/T2
(61.29\%), T3/T4 (38.79\%); nodal positivity (18.18\%); M1 (3.13\%). In
addition, 50\% of these laryngeal carcinomas were listed as their
primary cause of death. Laryngeal carcinoma-related deaths were most
common between 50-70 years old (59.26\%; 27.77\% of the patients were
older than 70). Only tumors greater than 4cm in size were a
statistically significant risk factors for deaths related to laryngeal
cancer (p=0.039). Fisher's Exact Test showed none of the following were
predictive risk factors associated with laryngeal cancer death: site
(glottic and supraglottic) (p=0.990), age (p=0.861), AJCC stage
(p=0.289), and median house income (p=0.931). Race and gender were not
included in the analysis; an overwhelming number of patients in the
dataset were white and male.

\emph{Thyroid carcinoma}

Of 567 patients diagnosed with thyroid carcinoma, two patients were
children. Separately, 45.31\% of thyroid carcinomas diagnosed at autopsy
were found in patients between 50-and 70-years old \textbf{Figure 1} .
Most patients in this group died between the age of 60 and 64 (15.34\%).
There was a decrease in the incidence of thyroid cancer diagnosed at
autopsy between the years 2000 and 2017 (\selectlanguage{greek}β \selectlanguage{english}= - 1.402, p=0.001). A
summary of thyroid cancer characteristics examined is shown
in\textbf{Table 1} . Of the cases reviewed, 87.79\% of the cancers were
papillary carcinomas. Of the 277 thyroid carcinomas with documented
staging, 231 patients had stage 1, 13 patients had stage 2, 10 patients
had stage 3, and 25 patients had stage 4. The median tumor size was 7mm.
Of 271 patients with documented AJCC stages, the TMN staging, and their
frequencies were as follows: T1/T2 (91.14\%), T3/T4 (8.86\%); nodal
positivity (5.66\%), and M1 (4.95\%). Most patients (59.82\%) had a
median household income between \$50,000 and \$75,000.

Thyroid carcinoma was the cause of death in 17 (3.01\%) patients in this
group (8 papillary thyroid cancer, 3 follicular thyroid carcinoma, 1
anaplastic thyroid cancer, 1 medullary thyroid cancer, 1Hurthle cell
carcinoma, and 3 unspecified). Of the 17 patients with thyroid cancer
related deaths, 10 patients had specific AJCC staging: 3 (30.00\%) had
stage 1 disease and 7 (70.00\%) had stage 4 disease. The three most
common causes of deaths this cohort were heart disease (26.19\%),
accident (9.20\%), and infection (6.19\%). There was no significant
difference between black and white patients (RR=2.60, 95\%CI:
0.891-7.57, p=0.080). Patients over 70 years old were at lower risk of
thyroid-related deaths than those under 50 (RR=0.125, 95\%CI:
0.016-1.001, p=0.025). There was no significant difference in
thyroid-related deaths in patients 50-70 years old and patients over 70
years old (RR=0.723, 95\% CI: 0.275, 1.901, p=0.256). Thyroid
cancer-related deaths were more prevalent in females (RR=3.37, 95\% CI:
1.095-9.59, p=0.033), in tumors larger than 4cm (RR=14.47, 95\% CI:
3.155-66.36, p\textless{}0.001), and in stage 3 or 4 disease (RR=24.91,
95\%CI: 5.39-115.0, p\textless{}0.0001) compared to males, tumors less
than 4cm, and stage 1 or 2 disease, respectively.

Patients with non-thyroid HNC were 17.1 (95\%CI: 9.55-30.6,
p\textless{}0.001) times more likely to have cancer-related death found
at autopsy than thyroid carcinoma.

\textbf{RESULTS}

Autopsy reports classically document a ``Final Diagnosis'' that
describes cancer primary site, histologic findings, and tumor expansion
and metastases based upon an examination of all major
organs.\textsuperscript{9} If an autopsy report first documents the
presence of cancer post-mortem, documentation is reviewed to ensure that
no clinical cancer diagnosis was made prior. If no diagnosis is listed,
the case is identified ``diagnosed at
autopsy.''\textsuperscript{9}Autopsy reports outline a succession of
events that convey essential information in order to provide the useful
information regarding the patient's condition including but not limited
to chain of events, injuries, or complications. \textsuperscript{10} In
cases where cause of death is not apparent despite a thorough autopsy, a
judgment may be made by the coroner.\textsuperscript{10} The functional
definition of ``cause of death'' is important to understand in the
context of autopsy reporting because cancer can be an incidental finding
that could lead to misreporting of cancer-related deaths.

Sesterhenn et al. reviewed the cases of 91 HNC-related deaths from 1968
to 2007 and showed distant metastases in 46.2\% and second primary
tumors in 17.6\% of the cases reviewed.\textsuperscript{11} Multiple
studies have revealed substantial rates of discrepancy between pre- and
post-mortem diagnoses often varying from 10\% up to
40\%.\textsuperscript{12} Another case report discusses two patients who
presented clinically with no evidence of disease and were considered
`cured,' but had significant distant spread of disease upon
autopsy.\textsuperscript{13} Misdiagnoses that may have altered patient
treatment course have been quoted to range anywhere from 2.4\% to
10.7\%.\textsuperscript{12}

Of non-thyroid HNCs, laryngeal cancer is an uncommon subtype, and its
prevalence is decreasing over time.\textsuperscript{14} Despite this, it
was the most common non-thyroid HNC diagnosed upon autopsy in our study
and was the primary cause of death in half of these patients. It is
unlikely these patients were asymptomatic as 50\% of tumors were stage 3
and 4; thus, some combination of hoarseness, odynophagia, otalgia, neck
lumps, or mechanical disruptions in swallowing or breathing would likely
be present. It is unclear why the prevalence of undiagnosed laryngeal
cancer was high in our study compared to other HNCs. It is unlikely
socioeconomic status is a major contributing factor as most of the
patients examined fell into the same middle-class stratum of annual
income. Rather than misdiagnosis or socioeconomic factors, it is
possible patients who participate in heavy tobacco and alcohol use,
well-known risk factors for laryngeal cancer, are less likely to seek
medical care for any number of biopsychosocial reasons. Smoking is
associated with reduced social support, decreased intrinsic view of
self-efficacy, low health-related motivation, and a decreased likelihood
to complete pharmacologic or psychological treatment
regimens.\textsuperscript{15} Considering 27.77\% of the patients in our
study were over 70 years old, it is also plausible that primary care
physicians could interpret symptoms of non-thyroid HNC as part of the
natural aging process due to an unfamiliarity of these pathologies and
their clinical presentations.

In sum, 47.06\% of patients with non-thyroid HNC-related deaths were
found in patients with stage 1 or 2 cancers, which raises concerns
regarding documentation. Currently, otolaryngologists do not consider
stage 1 and 2 HNCs to be highly lethal. These results appear to
contradict that sentiment. Although autopsy is a powerful tool in cancer
biology, delays in autopsy and refrigeration of body tissue can decrease
the integrity of the tumor due to tissue decomposition. In addition to
macroscopic changes to tumors, delays in autopsy allow for molecular
alteration which may change the morphology of cancer
cells.\textsuperscript{16} Though small, these changes could affect
tumor grading and lead to underreporting of disease severity.
Additionally, because of the underuse of post-mortem imaging techniques
if a full-body autopsy is not completed, it is conceivable that not all
metastatic sites of disease will be discovered and reported; as of 2008,
an autopsy was performed in under 10\% of all deaths in the United
States.\textsuperscript{17}

Scarce autopsies could further the possibility of underreporting
undiagnosed HNC. It is possible that stage 1 and 2 cancers have a
higher-than-expected death rate because autopsies are usually conducted
in instances of unknown causes of death and pathologists may assume
incidental findings as causes of deaths if no other obvious pathologies
are found. All these factors can contribute to underdiagnosis or
misdiagnosis of cancer severity, which could cause lower stages of
non-thyroid HNCs to appear more malignant.

Non-thyroid HNC is over 17 times more likely to be designated as the
primary cause of death compared to thyroid cancer in patients with
undiagnosed HNCs at autopsy. One plausible explanation for this finding
is that 50.00\% of laryngeal cancers found at autopsy were stage 3 or 4
while only 11.81\% thyroid carcinoma were stage 3 or 4. Patients with
thyroid cancer had relatively similar death rates in primary cause of
death categories as the general public.\textsuperscript{18} This data
suggests thyroid cancer did not contribute to the mortality of these
patients and was an incidental finding that may or may not had
associated symptoms. It should be noted that not all thyroid cancers are
latent. Medullary, anaplastic, and Hurthle cell thyroid cancers are
often more aggressive in nature; however, these cancers only contributed
to 3.18\% of the cancers analyzed. We also found that patients over 70
years old were at lower risk of thyroid related deaths than those under
50, likely because other health issues such as cardiovascular disease
are more common causes of deaths in elderly populations. Conversely,
non-thyroid cancer is often more aggressive with poorer
prognoses.\textsuperscript{19}Consequentially, non-thyroid cancers are
more likely to be the cause of death than thyroid cancer.

Fewer patients with non-thyroid HNC were found at autopsy compared to
thyroid cancer, likely due to the higher prevalence of thyroid cancer
and decreasing incidence of HNC overall.\textsuperscript{20,21}Our study
found no identifiable temporal trends in detection of non-thyroid
cancers upon autopsy; however, there was a discernible decrease in
thyroid cancers diagnosed at autopsy over time. This is likely due to
increased screening and biopsy of thyroid cancer in recent
decades.\textsuperscript{10} This study demonstrates the malignancy of
non-thyroid cancers and their prevalence as the primary cause of death
upon autopsy in patients previously undiagnosed. These findings
demonstrate the need for the medical community's awareness of their
prevalence in asymptomatic patients and the need for screening in those
high risk for disease development or progression.

There are inherent limitations within the dataset obtained from SEER
that includes miscoding and omitting data especially in variables such
as TMN staging and tumor size. This dataset has a limited number of
reviewable patients and autopsy reports that may or may not be
representative of the total population of the United States. Because the
SEER database only covers about 28\% of the U.S. population, the results
may not be completely generalizable.\textsuperscript{22} In addition,
many of the variables within SEER have a significant number of data
points missing; therefore, non-statistically significant findings may
not be truly accurate.

\textbf{CONCLUSION}

Biological and psychosocial factors may contribute to the delayed
diagnosis of HNCs. The high rate of cancer-related deaths in postmortem
diagnosis of non-thyroid HNCs reveals the need for health care
professionals to increase vigilance in detecting these cancers in order
to prevent misdiagnoses. Our study demonstrates that it is imperative
the medical community improves awareness of asymptomatic HNC patients
and emphasizes the need to improve screening in those who may be high
risk for disease development.

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\textbf{Figure 1.} Age distribution of head and neck cancers diagnosed
at autopsy. Grey: thyroid carcinoma, black: non-thyroid head and neck
carcinoma. x-axis: age group.

\textbf{Figure 2.} Causes of deaths of patients with non-thyroid adult
head and neck cancers diagnosed at autopsy from 2000 to 2017.

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