Keywords
human papillomavirus related multiphenotypic sinonasal carcinoma - HPV type 16 - sinonasal
carcinoma - adenoid cystic carcinoma - HPV-related carcinoma with adenoid cystic-like
features
Introduction
Malignant neoplasms of the sinonasal tract are uncommon. These tumors are diverse
and include a variety of histopathologies such as squamous cell carcinoma (SCC) and
adenoid cystic carcinoma (ACC).[1] Human papillomavirus (HPV) related multiphenotypic sinonasal carcinoma (HMSC), also
known as HPV-related carcinoma with adenoid cystic-like features, is a recently described
neoplasm restricted to the sinonasal tract, with histological features of high-grade,
solid-type ACC, with HPV positivity and paradoxically indolent behavior.[2]
[3]
[4]
HMSC was provisionally included in the 2017 World Health Organization classification
of head and neck tumors as a candidate to be a separate tumor entity, different from
ACC and SCC.[5] In contrast to ACC, HMSC (1) is associated with HPV, most commonly type 33, (2)
may have overlying squamous dysplasia/SCC of the surface epithelium, (3) fails to
demonstrate the MYB gene fusions, and (4) has a more indolent clinical behavior.[3]
[6]
The largest case series of HMSC is described by Bishop et al, who first suggested
that these tumors have a favorable outcome. Most reports published since this series
have followed this trend.[1]
[3]
[4]
[6]
[7]
[8]
[9]
[10] To our knowledge, only a few recorded cases have documented locally aggressive tumors
or very late distant metastasis, and there have been no reported tumor-related deaths.[3]
[11]
[12] Here, we present a case of HMSC with early and progressive metastatic disease. With
this report, we aim to add to the understanding of the behavior of this new clinical
entity.
Case Report
A 65-year-old man was referred to the Department of Otolaryngology with unilateral
nasal congestion and epistaxis. Anterior rhinoscopy revealed a large mass occupying
the entire left nasal cavity. The tumor was biopsied and initially diagnosed as nonkeratinizing
HPV-related SCC. The patient underwent an endoscopic-assisted medial maxillectomy,
achieving a gross total resection with negative margins.
Pathology revealed a basaloid tumor consisting of solid nests with multiple foci of
cribriform architecture ([Fig. 1]). There was no overt squamous differentiation identified within the tumor, but surface
epithelial squamous dysplasia was present. HPV testing by real-time polymerase chain
reaction (Roche cobas 4800 HR-HPV analysis, Roche, Basel, Switzerland) was positive
for HPV-16 and was confirmed by HPV-16/18 RNA in situ hybridization (RNAscope ACD
HR16/18, Advanced Cell Diagnostics Inc., Newark, California, United States), showing
positive staining within the carcinoma ([Fig. 2]), thus supporting the diagnosis of HMSC. Immunohistochemical staining showed diffuse
positivity for p16. In addition, the carcinoma was positive for p63 and CK7 and showed
focal positivity for S100, calponin, and smooth muscle actin ([Fig. 2]).
Fig. 1 Hematoxylin and eosin staining at (A) low and (B) high power showing solid nests with multiple foci of cribriform architecture.
Fig. 2 On immunohistochemistry stainings, the tumor was positive for (A) p16 and displayed focal positivity for (B) MYB. (C) Smooth muscle actin, along with other myoepithelial markers, was focally positive.
(D) RNA in situ hybridization was positive for high-risk human papillomavirus within
the tumor.
Two months postoperatively, the patient underwent three-dimensional proton therapy
to the paranasal sinuses to a total dose of 66.6 Gy. Twenty-three months after the
surgical resection, he developed enlarging pulmonary nodules that had histological
features consistent with metastasis from the primary sinonasal tumor. He was treated
with three cycles of chemotherapy (carboplatin/taxol), with initial partial response
but subsequent progression. He was then treated with immunotherapy (pembrolizumab)
for eight cycles, but it was discontinued because of evidence of progressive disease
on the PET-CT (positron emission tomography–computed tomography). He remains on palliative
chemotherapy (fluorouracil/cetuximab).
Discussion
HMSC is a newly identified pathological entity that has been suggested to be indolent
despite a high-grade appearance on histopathology. Given the limited number of reported
cases, the clinical behavior and consensus treatment guidelines have not yet been
established. However, in view of the typically indolent behavior, it has been suggested
that surgery with close monitoring has resulted in a good prognosis.[1]
[9] This management is in direct contrast with most sinonasal malignancies that are
treated with adjuvant therapy. Our case, however, is one with early and progressive
metastatic disease despite gross total resection and adjuvant radiation therapy, highlighting
an aggressive subset of this disease and the need to properly stratify patients to
determine the need for adjuvant radiation or chemoradiation therapy.
Most HMSC cases reported have positive outcomes following surgical removal alone or
accompanied by radiotherapy. In the limited cases that recur, the tumors are slow
growing, with the timing of recurrence ranging widely: the earliest local recurrence
previously reported occurred 23 months posttreatment, and the latest recurrence previously
reported occurred after a 30-year disease-free interval.[1]
[3]
[4]
[6]
[7]
[8]
[9]
[10]
[11] Most previously reported recurrences responded well to treatment, achieving long
disease-free intervals. Only two cases previously reported progressed to distal metastasis
after 96 and 144 months following their initial treatment.[3] Our case differs from others reported in the literature due to the very early development
of distal metastasis in less than 2 years following the initial treatment. Furthermore,
our patient's recurrence progressed even after chemotherapy and immunotherapy. We
were not able to find reports of another HMSC tumor with such aggressive behavior,
leading us to speculate that there may be a relation between its odd clinical and
molecular characteristics.
In the past, HMSC cases have frequently carried the diagnosis of ACC. As previously
mentioned, several characteristics differentiate HMSC from ACC. Yet, another important
diagnostic entity in the differential is basaloid SCC. Morphologically, it is difficult
to distinguish HMSC from ACC or basaloid SCC due to the presence of solid and cribriform
architecture and highly cellular lesions composed of basaloid and ductal cells.[1] Immunohistochemistry can help distinguish HMSC from HPV-related basaloid SCC, as
the latter lacks the myoepithelial cells (often positive for cytokeratin, S100, actin,
calponin, and p63) that make up salivary gland neoplasms.[13]
From a molecular standpoint, the case we report herein is unique due to its association
with high-risk HPV type 16, which, to the best of our knowledge, has only been reported
twice previously, and in neither of these reports were the clinical outcomes specifically
highlighted.[3]
[6] Most HPV-positive head and neck carcinomas arise from the oropharynx, with the sinonasal
tract now recognized as another anatomic “hotspot” for HPV-related neoplasms.[3]
[10]
[14] Sinonasal tract HMSC is most often associated with HPV type 33.[4] Here, we describe the case of an HMSC with HPV-16 identified by both RT-PCR (reverse
transcription polymerase chain reaction) and HPV-16/18 RNA in situ hybridization associated
with an aggressive clinical course. Although anecdotal, the relationship between HPV
subtype and clinical behavior in HMSC is the one that needs to be better delineated,
as it may have important implications for patient stratification.
Conclusion
Here, we present an HPV16-associated case of HMSC with early and progressive metastatic
disease. As more HMSC cases are identified, the clinical management of this entity
may be better defined. We propose that HPV subtype may have prognostic importance
and that the relationship between subtype and clinical behavior warrants further investigation.
