Background: Immune suppression secondary to Human Immunodeficiency Virus (HIV) infection is associated with an
increased risk of head and neck cancer (HNC) and poorer tumor-related survival. In this article, the authors focused on the outcome of a specific subgroup of HIV-HNC patients with undetectable HIV load at cancer diagnosis.
Case Presentation: We report of 4 HIV patients with head and neck cancer. The first patient showed an incidental finding of synchronous papillary thyroid carcinoma in the cervical lymph nodes after neck dissection. The second patient developed multiple local and regional recurrences of a nasal carcinoma. The third patient could not receive treatment for nasopharyngeal carcinoma due to multiple comorbidities. The fourth patient showed a long disease free survival after aggressive treatment
of an oropharyngeal carcinoma. The patients reported developed synchronous HNC and local recurrences. Moreover, local control was not always easy to achieve. Multiple comorbidities, psychological factors and complications often led to treatment delay.
Conclusions: The authors suggest consideration of early aggressive treatment and intensive follow up for HIV-HNC patients
despite undetectable HIV load; since other parameters, such as immunosuppression, inflammation and direct viral oncogenic
effect, could have already accelerate the natural course of the disease and affect the outcome.
Keywords: Head and Neck Neoplasms; HIV; Immunology; Prognosis
Immune suppression secondary to Human Immunodeficiency
Virus (HIV) infection is associated with an two to
five fold risk of head and neck cancer (HNC) . In one case
series with 94 HIV patients with head and neck cancer (HIVHNC),
patients with lower CD4 cell count at time of cancer
diagnosis (< 200 cells/μL) had significantly poorer survival. All
but one patient had detectable HIV viremia at diagnosis .
In this article, the authors focused on the outcome of a specific
subgroup of HIV–HNC patients with undetectable HIV load
at cancer diagnosis. We report 4 HIV-HNC patients (Table 1,
2 and 3) who received cancer treatment from 2007 until 2017
at the Department of Otorhinolaryngology of the Medical
University of Innsbruck, Austria. Data were obtained in a retrospective
way from medical records. Diagnostic and therapeutic
procedures were accorded in a multidisciplinary tumor
board (MDT). HIV load and CD4 cell count at highly active
combination anti-retroviral therapy (cART) initiation and at
cancer diagnosis are described in table 1.
Case 1: A 52-year-old non-smoking male homosexual patient
was diagnosed with HIV infection in March 2014, stage C3. At
that time, the patient had been treated with primary chemoradiotherapy
due to an anal carcinoma cT2N1M0. After developing
seborrhoic dermatitis, serologic tests revealed infection
from HIV-1, subtype B.
In December 2015, the patient was subjected to total laryngectomy
with bilateral selective neck dissection due to a Human
papilloma virus (HPV)-negative cT3N0M0 laryngeal squamous
cell carcinoma of the glottis (Figure. 1). In the surgical
neck specimens, no cervical metastases from the SCC were
found. However, there was an incidental finding of papillary
thyroid carcinoma metastasis in 3 neck lymph nodes. The patient
underwent total thyroidectomy 2 weeks later. The surgical
specimen revealed a pT1a multifocal, papillary micro carcinoma
of the thyroid gland. No complications were observed
in the postoperative follow-up. Currently, the patient is free of
Case 2: A 47-year-old smoking male homosexual patient was
diagnosed with HIV infection in February 1992. In March
1999, he developed esophageal candidiasis. At that time, his
HIV infection stage was C3. In October 2014, the patient was
subjected to partial right nasal ablation due to an HPV-negative
cT2N0M0 nasal squamous cell carcinoma. Because margins
were not tumor-free, 4 further quite extensive resections
in the midface (Figure. 2; left) of clinically uninvolved, but histologically
positive tissue were performed.
To cope with histologic perineural spread and lymphovascular
invasion, the patient underwent percutaneous hyperfractionated
radiotherapy of the primary tumor region with 70.2
Gy from April 2015 until June 2015. During radiotherapy the
patient developed a right cheek in transit metastasis as well
as lymph node metastasis in the right level Ib and the radiation
field was expanded accordingly. Following treatment, CT
scans did not reveal any local or regional residual disease.
Case 3: A 54-year-old smoking female patient was diagnosed
with HIV infection in June 1986, stage C3. The virus was
transmitted through intravenous drug use. In June 2015, the
patient was diagnosed with a cT4N1M0 nasopharyngeal squamous
cell carcinoma (Figure. 3). HPV status was unavailable.
The patient could not receive primary chemoradiotherapy due
to multiple comorbidities, such as liver cirrhosis, hepatitis C,
cardiac arrhythmia, renal insufficiency, marasm (BMI 11.7)
and bipolar disorder. Thus, primary radiotherapy was recommended
in an attempt to obtain local tumor control. The patient
refused to undergo radiotherapy, considering the possible
complications. The patient deceased in October 2016.
Case 4: A 50-year-old smoking male homosexual patient was
diagnosed with HIV infection in October 2003, stage C3. In
July 2007, the patient was diagnosed with an HPV-negative
cT4aN2bM0 oropharyngeal squamous cell carcinoma (Figure.
4). In August 2007, the patient was subjected to primary tumor
resection. Margins were not tumor free. However, the patient
developed acute abdomen due to appendicitis postoperatively.
A right hemicolectomy was performed due to toxic megacolon
and intestinal pneumatosis. Three weeks later, the patient
underwent left modified and right selective neck dissection.
TNM stage was pT4aN0M0R1. Further resection of the primary
tumor was not possible. The patient underwent adjuvant
chemoradiotherapy. In November 2007, there was no histologic
or radiologic sign of malignancy or residual disease.
In January 2010, he developed pleural metastases. Palliative
chemotherapy with cetuximab and cisplatin was performed.
The patient deceased in May 2010.
Discussion and Conclusions
This case series describes the unfavorable course of 4
HIV-HNC patients with undetectable HIV load. The patients
reported here developed synchronous HNC and local recurrences.
Moreover, local control was not always easy to achieve
due to tumor positive margins and the existence of clinically
uninvolved, but histologically positive tissue. Multiple comorbidities,
psychological factors and complications often led to
treatment delay. HIV-infected individuals have increased exposure
to tobacco, alcohol and HPV infection, the three primary
HNC risk factors . Interestingly, 3/4 patients reported
here were HPV-negative; HPV status was unavailable for 1/4
patient. 3/4 patients were smokers.
Immune suppression secondary to HIV infection is
associated with an two to five fold risk of HNC . Brickman
and coauthors suggested that this increased risk could be attributed
to immunosuppression, systemic inflammation and
direct oncogenic effects . Impaired lymphocyte function
due to HIV infection results in decreased tumor surveillance
and increased risk of malignancy. This link is stronger in Acquired
immunodeficiency syndrome (AIDS) defining malignancies.
The relationship between immunosuppression and
the risk for non-AIDS defining malignancies (NADMs) such
as HNC is less clear. Recent studies have detected an association
between increased risk for NADMs and low CD4 count at
cancer diagnosis, CD4 nadir and duration of low CD4 count
[4, 5]. Particularly, patients with less than 200 CD4 cells/μL
at initiation of cART and less than 250 CD4 cells/μL 2 years
after cART had an increased risk for NADM and death due to
NADM . Bruyand and coauthors observed that a higher incidence
of NADMs was independently associated with longer
and current exposure to less than 500 CD4 cells/μL, but not to
plasma HIV RNA level . Also, in a case series with 94 HIVHNC
patients, patients with lower CD4 cell count at diagnosis
(<200 cells/μL) had significantly poorer survival. All but one
patient had detectable HIV viremia at diagnosis . In our
case series, all but one case had less than 150 CD4 cells/μL and
higher than 3.50 log10 copies/ml HIV RNA at cART initiation
(table I). Also, all cases had undetectable HIV RNA and all but
one case less than 250 CD4 cells/μL at cancer diagnosis (table
During treatment, one patient also had less than 200 CD4 cells/
μL and undetectable HIV RNA (case 2). It’s already mentioned
that HIV-associated immunosuppression could lead to initial
carcinogenesis. Perhaps, long exposure to low CD4 cell count
(<250 cells/μL) before cancer diagnosis could better describe
the term immunosuppression and its importance on poor outcome.
It’s possible that HIV-associated immunosuppression
may result in initial viral carcinogenesis (through infection or
mutations) that cannot be reversed by immune reconstitution.
Moreover, increased risk for NADMs due to long-lasting immunosuppression
may not be detectable by CD4 count alone.
Smoking could also lead to poorer outcome, as well as HIVrelated
comorbidities . The role of HIV load on outcome
People living with HIV have been linked to elevated
inflammatory markers compared to HIV-non-infected individuals
even after years of detectable immune suppression .
In a large longitudinal cohort, Borges and coauthors detected
a small but statistically significant association between interleukin-
6, C-reactive protein and D-dimer and the hazard of
developing infection-related and infection-unrelated malignancies
Direct oncogenic effects have been linked to the HIV
transactivator protein tat. This protein is secreted from HIVinfected
cells and taken up by adjacent cells; it is involved in
the activation of viral and cellular genes and in downregulation
of DNA repair pathways, cell-cycle stimulation and inhibition
of apoptosis . The protein tat also appears to enhance the
transformation and infectious potential of oncogenic viruses;
it upregulates the expression of the HPV oncogenic proteins
E6 and E7, thus enhancing the oncogenic potential of HPV
. Thus they may develop NADMs, including HNC .
Concluding, the authors suggest consideration of
early aggressive treatment, increased vigilance and intensive
follow up of HIV-HNC patients despite undetectable HIV
viremia; since other parameters, such as immunosuppression,
inflammation and direct viral oncogenic effect, could have already
accelerate the natural course of the disease and affect the
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