Interactive Microscopy Session:

Second Edition: Modern Surgical

Pathology Through the Expert Eyes of
APSS-USCAP: Challenging Head and Neck
Tumors
Handout

Jeffrey F. Krane, MD, PhD

Professor of Pathology
Department of Pathology and Laboratory Medicine
David Geffen School of Medicine at UCLA
Los Angeles, CA

Course Dates: October 27-30, 2019

Interactive Microscopy Session | Second Edition: Modern Surgical Pathology Through the Expert Eyes
of APSS-USCAP: Challenging Head and Neck Tumors | Jeffrey F. Krane, MD, PhD (Oct. 27-30, 2019)

Overview

The cases presented for this topic represent a bit of a potpourri, so inevitably the handout
is similarly so. The discussion is divided into 2 main topics: 1. Selected challenges in
thyroid pathology and 2. Basaloid tumors of the head and neck including HPV-associated
tumors of the head and neck. The scope of these topics is such that this handout can only
serve as a broad overview of each topic.

CHALLENGING THYROID TUMORS

While the diagnosis of classic type papillary thyroid carcinoma is generally straightforward,
there are a number of other variants that are important to recognize. Several of these
should be recognized for their potentially more aggressive clinical behavior: columnar, tall
cell, hobnail, and diffuse sclerosing variants all fall into this category. Cribriform morular
variant should be recognized for its association with familial adenomatous polyposis.
Then there is the follicular variant of papillary carcinoma and the closely related, new
classification of non-invasive follicular thyroid tumor with papillary-like nuclear features
(NIFTP).

NIFTP

The NIFTP terminology grew out of recognition that encapsulated or circumscribed

tumors that had been called follicular variants of papillary carcinoma behave in an indolent
fashion that does not seem to warrant classification as a malignancy.1-3 Furthermore, the
TCGA sequencing project demonstrated that papillary carcinomas broadly fall into two
categories – those with BRAF-like genetic profiles (including classic and tall cell variants)
and those with a RAS-like genetic profile, more akin to the molecular alterations seen in
follicular neoplasms, including those encapsulated/circumscribed follicular variants of
papillary carcinoma.4-6 The NIFTP terminology is, therefore, a recognition of the clinically
and genetically distinct nature of these tumors compared to papillary carcinomas. The
original NIFTP proposal7 includes the following criteria: 1) Encapsulated/circumscribed
tumor 2) Follicular growth pattern with <1% papillary growth, no psammoma bodies and
<30% solid/insular/trabecular growth 3) Nuclear score 2-3 4) No vascular or capsular
invasion (entire capsule must be examined) 5) No necrosis or mitoses of 3 or more per
10 HPF. After the initial NIFTP proposal, there were some limited reports of spread of
tumors termed NIFTP and stricter criteria were proposed precluding any papillary growth
(entire tumor examination recommended) and using BRAF V600E and other high-risk
mutations such as TERT and TP53 as exclusionary criteria.8 There are still unresolved
issues with the NIFTP terminology. What should be done with follicular patterned
encapsulated/circumscribed tumors with papillary-like nuclear features that are <1 cm in
size? It seems counterintuitive to call smaller tumors carcinoma, but not larger ones, but
at some point it becomes difficult to morphologically distinguish the NIFTP morphology
from small classic type papillary microcarcinomas or to assess infiltrative growth. Where
should this lower limit be? There is as yet no consensus around this question but 0.2 cm

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Interactive Microscopy Session | Second Edition: Modern Surgical Pathology Through the Expert Eyes
of APSS-USCAP: Challenging Head and Neck Tumors | Jeffrey F. Krane, MD, PhD (Oct. 27-30, 2019)

may be a reasonable lower threshold with liberal use of BRAFV600E

immunohistochemistry to exclude small BRAF mutated tumors from classification as
NIFTP.9

Tall Cell Variant

The tall cell variant is an aggressive variant of papillary carcinoma characterized by cells
that are 2-3X as tall as they are wide with abundant eosinophilic cytoplasm. This variant
has prominent elongate follicles and intranuclear pseudoinclusions are usually readily
appreciated. At least 30% of the tumor should have tall cell morphology before calling a
tumor a tall cell variant.10 Less clear is the significance of lesser degrees of tall cell
features, but as little as 10% tall cell features has been reported to behave more
aggressively.11 Therefore, it is recommended that if the presence of tall cell features (<30%
of total tumor) is noted then the percentage of tall cell features should be specified.

Columnar Cell Variant

This is a rare variant of papillary carcinoma resembling colonic or endometrioid

adenocarcinoma.12 The cells are elongate, sometimes with clear cytoplasm and nuclei
are typically hyperchromatic in contrast to the fine chromatin of most papillary carcinomas.
The nuclear contour irregularities of papillary carcinoma (inclusions and grooves) are also
less apparent. This variant must be distinguished from metastatic disease. Behavior is
largely dictated by whether the tumor is circumscribed or infiltrative.13

Cribriform-Morular Variant

This variant occurs mostly in women sporadically (usually solitary) but may also be
associated with APC gene germline mutations in the autosomal dominant disorder familial
adenomatous polyposis (FAP), particularly when present as multiple nodules. This variant
is characterized by cribriform architecture and focal squamous morules.14 Typically
cytologic features of papillary carcinoma are also present but the nuclei tend to be more
hyperchromatic. Of note, the cribriform structures are devoid of colloid. Beta-catenin
immunohistochemistry characteristically shows strong nuclear and cytoplasmic staining
with this entity. Since the thyroid tumor(s) may represent the initial manifestation of FAP,
recognition of this variant can be an invaluable clue to the clinical syndrome.

Diffuse Sclerosing Variant

This uncommon variant is seen in younger patients and the diagnosis is suggested by the
clinical presentation of a mass encompassing an entire lobe or the entire thyroid. 15 These
tumors have numerous psammoma bodies, well-developed cytologic and architectural
features of papillary carcinoma, and prominent squamous morules and/or squamoid
cytologic features. Lymphoid cells are often prominent in association with the tumor and
extensive lymphovascular invasion is common. Despite the propensity of these tumors to

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Interactive Microscopy Session | Second Edition: Modern Surgical Pathology Through the Expert Eyes
of APSS-USCAP: Challenging Head and Neck Tumors | Jeffrey F. Krane, MD, PhD (Oct. 27-30, 2019)

spread to lymph nodes and distantly, prognosis remains favorable perhaps due to the
tendency to treat patients aggressively. RET/PTC translocations are most common.

Hobnail Variant

This rare variant has >30% of cells with hobnail features with papillary and micropapillary
growth and cells with apically oriented nuclei, high N:C ratio, and a loss of cohesion.
Increased p53 expression >25% of nuclei may be seen and the tumors behave in an
aggressive clinical fashion.16

Poorly Differentiated Thyroid Carcinoma

As outlined by the Turin proposal, poorly differentiated thyroid carcinoma (PDTC) has
solid/trabecular or insular growth; lacks PTC nuclear features; and has at least one of
necrosis, convoluted nuclei or mitoses of at least 3 per 10 hpf.17 As little as 10% of these
features in a tumor may be associated with more aggressive clinical behavior and should
be noted in the pathology report.18 The Memorial Sloan-Kettering group reports different
criteria for PDTC requiring tumor necrosis or mitoses of at least 5 per 10 hpf regardless
of tumor growth pattern or PTC nuclear features.19 Although not recognized by the WHO,
many pathologists call PTC with these features PTC with high-grade features and note
that the behavior is similar to PDTC.

Cowden Syndrome

Autosomal germline mutation of PTEN is responsible for Cowden syndrome.

Manifestations include carcinomas and hamartomas in the thyroid, breast, and uterus. In
patients with numerous adenomatous nodules, particularly those in which carcinoma is
present in at least one nodule, PTEN immunohistochemistry should be performed to
assess the possibility of Cowden syndrome.20 Complete or heterogeneous loss of PTEN
expression should lead to further evaluation.

BASALOID HEAD AND NECK NEOPLASMS

Basaloid neoplasms are diagnostically challenging lesions frequently encountered in

Head and Neck specimens. The term basaloid refers to the immature basal cell-like
phenotype shared by these lesions. A basaloid morphology essentially means that the
cells have high N:C ratios with scanty cytoplasm. Since it is the features of the cytoplasm
that frequently allow us to recognize the lineage of cell differentiation, the paucity of
cytoplasm makes these lesions closely resemble one another. In order to classify such
lesions, we must look at other features including chromatin quality, extracellular elements
and, most helpfully when present, co-existing non-basaloid cellular morphologies that
allow us to recognize the underlying nature of the lesion. Nevertheless, a significant
number of these lesions remain difficult to distinguish by morphology alone requiring
special studies such as immunocytochemistry or genetic analysis to ultimately make the
diagnosis.

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Interactive Microscopy Session | Second Edition: Modern Surgical Pathology Through the Expert Eyes
of APSS-USCAP: Challenging Head and Neck Tumors | Jeffrey F. Krane, MD, PhD (Oct. 27-30, 2019)

Some of the more commonly encountered basaloid neoplasms and their mimics are
discussed below.

• Basal cell adenoma/basal cell adenocarcinoma of salivary gland

• Adenoid cystic carcinoma of salivary gland
• High-grade neuroendocrine carcinoma (including Merkel cell carcinoma,
metastatic small cell carcinoma, and neuroendocrine carcinoma of salivary gland)
• Basaloid squamous cell carcinoma
• HPV-associated squamous cell carcinoma
• Nasopharyngeal carcinoma, non-keratinizing, undifferentiated type
• Sinonasal undifferentiated carcinoma
• NUT carcinoma
• SMARCB1 (INI1) deficient carcinoma
• Sarcomas, especially rhabdomyosarcoma and synovial sarcoma
• Lymphoma

Discussion of salivary gland tumors is covered in the handout for that session. HPV-
associated carcinomas are the main focus of the discussion below.

HPV-Mediated Oropharyngeal Carcinoma

HPV infection has been described in association with a variety of head and neck tumors
including both benign (squamous papillomas) and malignant tumors. The most significant
in the latter category are HPV-mediated oropharyngeal carcinomas.21

While smoking and smoking related SCC is on the decline in the US, there has been a
corresponding increase in SCC associated with HPV infection such that these tumors
currently account for 20-25% of all head and neck SCCs. These tumors primarily occur
in men (M:F 4:1) who are slightly younger than those with smoking related SCC (<60
vs >60). The tumors arise predominantly in the oropharynx (especially the tonsil and base
of tongue). Viral transmission is through sexual contact. >90% of tumors are associated
with HPV type 16. Importantly, HPV-associated SCC is associated with an improved
prognosis relative to conventional SCC. Clinical trials are now focused on deintensified
radiation therapy for appropriately selected patients with HPV-mediated oropharyngeal
SCC.

A variety of histologic patterns have been described in association with HPV infection
including papillary SCC and lymphoepithelial carcinoma like tumors, but the most
common morphology is that of a basaloid SCC. Realistically, the differential diagnosis is
most commonly with a high-grade neuroendocrine carcinoma (small cell carcinoma,
Merkel cell carcinoma) as well as a high-grade lymphoma or melanoma. Rare HPV-
mediated oropharyngeal high-grade neuroendocrine carcinomas have been reported; like

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Interactive Microscopy Session | Second Edition: Modern Surgical Pathology Through the Expert Eyes
of APSS-USCAP: Challenging Head and Neck Tumors | Jeffrey F. Krane, MD, PhD (Oct. 27-30, 2019)

other tumors with this morphology they behave aggressively and should therefore not be
confused with HPV-mediated SCC.22,23

HPV-mediated oropharyngeal SCC and EBV-associated nasopharyngeal carcinoma

frequently present with a small, clinically occult primary and bulky neck nodal metastasis.
Once the diagnosis of SCC has been established, the question of primary site arises.
HPV-associated SCC (along with EBV-associated nasopharyngeal carcinoma [NPC])
provides one of the few opportunities to localize the primary site of an SCC (to the
oropharynx) based on the detection of high-risk [HR] HPV in the metastasis.

CAP testing guidelines for HPV testing have been published recently.24 P16
immunohistochemistry testing (with a positive threshold of at least 70% nuclear and
cytoplasmic staining) should be performed on oropharyngeal primary squamous cell
carcinomas and neck metastases in levels 2 or 3 with no known primary.

Other HPV-Associated Head and Tumors

HPV has been inconsistently associated with a variety of other head and neck tumors
including sinonasal (schneiderian) papillomas and various sinonasal carcinomas. 25 HPV-
related multiphenotypic sinonasal carcinoma is important to recognize as it may have
areas mimicking other tumors (most commonly adenoid cystic carcinoma), but is usually
recognizable by the presence of an in situ squamous component and/or squamous
differentiation. Such tumors are associated with high-risk HPV viral types, most frequently
HPV type 33 and usually behave in an indolent manner.26

Neuroendocrine Tumors

Neuroendocrine tumors detected in the neck may represent a number of morphologically

overlapping entities. Included in this differential diagnosis are the following:

1. Paraganglioma

a. Primary paraganglioma may present as a neck mass potentially mimicking

a lymph node metastasis.

b. As with the other tumors discussed in this context, neuroendocrine

markers are positive. Additionally, S100 staining of sustentacular type

cells may be seen. Keratin stains are negative.

2. Moderately differentiated neuroendocrine carcinomas

a. Most commonly these are medullary thyroid carcinoma

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Interactive Microscopy Session | Second Edition: Modern Surgical Pathology Through the Expert Eyes
of APSS-USCAP: Challenging Head and Neck Tumors | Jeffrey F. Krane, MD, PhD (Oct. 27-30, 2019)

b. Differential diagnosis includes moderately differentiated neuroendocrine

carcinoma of the larynx (atypical carcinoid)

c. Both tumors may be calcitonin positive by immunohistochemistry

d. Distinction can be based on the following:

i. Serum calcitonin levels are markedly elevated in medullary

carcinoma, but not the laryngeal primary

ii. TTF-1 is positive in medullary carcinoma and usually negative in

laryngeal primary27

3. High-grade neuroendocrine carcinoma

a. Metastatic small cell carcinoma is most common

i. TTF-1 lacks specificity for the lung in this context (but is positive

in 75-90% of lung small cell carcinomas)

b. Merkel cell carcinoma

i. Dot-like CK20 staining, TTF-1 negative

ii. Merkel cell polyoma virus association

c. HPV-associated small cell carcinoma

i. Extremely rare

ii. Does not have favorable prognosis of HPV-associated SCC

Nasopharyngeal Carcinoma

NPC may be a variant of conventional SCC (keratinizing type) or EBV-associated (non-

keratinizing type). The EBV-associated non-keratinizing types have differentiated and
undifferentiated subtypes that may co-exist. The differentiated subtype has the
appearance of a non-keratinizing SCC, while the undifferentiated type is the variant
classically described as lymphoepithelial carcinoma. Undifferentiated NPC exhibits an
intimate admixture of malignant cells with lymphocytes. The malignant cells have scant

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Interactive Microscopy Session | Second Edition: Modern Surgical Pathology Through the Expert Eyes
of APSS-USCAP: Challenging Head and Neck Tumors | Jeffrey F. Krane, MD, PhD (Oct. 27-30, 2019)

cytoplasm with large vesicular nuclei having a single prominent nucleolus. The tumor is
generally readily recognized as carcinoma when the cells form syncytial aggregates, but
when present singly distinction from lymphoma, particularly Hodgkin’s disease, may be
challenging. When presenting as metastatic disease, keratin immunostains and the
detection of EBV encoded early mRNAs (EBER) by in situ hybridization support a
nasopharyngeal primary. Similar appearing undifferentiated carcinomas (with variable
EBV association) have been described at other sites (including salivary gland), but with
the classic presentation of cervical adenopathy a nasopharyngeal primary is most
probable. As mentioned above, HPV-associated SCC may also resemble undifferentiated
NPC so that initial evaluation of an undifferentiated carcinoma in the neck should include
testing for both EBV and HPV.

Sinonasal Undifferentiated Carcinoma

Sinonasal undifferentiated carcinoma is an undifferentiated carcinoma of the sinonasal

tract that is essentially a diagnosis of exclusion with regard to many other high-grade,
poorly differentiated entities including many of those mentioned above. Of note, a
significant subset of these tumors have recently been identified as harboring IDH1/2
mutations.28

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Interactive Microscopy Session | Second Edition: Modern Surgical Pathology Through the Expert Eyes
of APSS-USCAP: Challenging Head and Neck Tumors | Jeffrey F. Krane, MD, PhD (Oct. 27-30, 2019)

References

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Interactive Microscopy Session | Second Edition: Modern Surgical Pathology Through the Expert Eyes
of APSS-USCAP: Challenging Head and Neck Tumors | Jeffrey F. Krane, MD, PhD (Oct. 27-30, 2019)

16. Asioli S, Erickson LA, Sebo TJ, Zhang J, Jin L, Thompson GB, Lloyd RV.
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