Case 6 -
Merkel Cell Carcinoma with Pagetoid Growth Pattern
University of Indiana School of Medicine
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Merkel cell carcinoma with pagetoid growth pattern
Merkel cell carcinoma (MCC) typically occurs on sun-damaged skin of elderly patients, most commonly on
the head and neck and extremities. Rare locations include the trunk, genitalia or mucosal sites.
Clinically, MCC are not distinctive. Most commonly MCC presents as an erythematous nodule 2 cm or less
in diameter, but they may be violaceous, flesh-colored or clinically appear pigmented.
Case 6 - Slide 1
Case 6 - Figure 1
Scanning magnification demonstrated a tumor that involved both the epidermis and dermis.
Case 6 - Figure 2
The tumor had a distinctly nested growth pattern.
Case 6 - Figure 3
Within the epidermis the tumor showed prominent upward pagetoid spread of tumor nests and individual tumor cells.
Case 6 - Figure 4
The tumor cells had uniform round to oval nuclei with a granular chromatin pattern.
MCC is a primary cutaneous neuroendocrine carcinoma characterized by a proliferation of relatively
uniform round to oval tumor cells with scant cytoplasm and a stippled chromatin pattern. Mitotic
activity is usually prominent and individual apoptotic cells are frequent.
MCC has a variety of growth patterns. Most commonly MCC is a dermal tumor arranged in sheets or
nests of tumor cells. Rarely, a trabecular pattern as seen in other neuroendocrine tumors may be seen.
Involvement of the epidermis may be seen in up to 10% of cases.
In rare cases the epidermal involvement has a distinctive pagetoid growth pattern analogous to true
Paget's or extramammary Paget's disease. Within the epidermis there are small nests and single tumor
cells at various levels of the epidermis that compress adjacent keratinocytes. In nests along the basal
layer, there is usually a thin rim of basal cells separating the MCC from the underlying basement
membrane. Rarely true junctional nests are present. The majority of MCC with pagetoid growth pattern
have a significant dermal component, but the proportion between the dermal and epidermal component can be
quite variable with some cases showing predominantly intraepidermal tumor. The intraepidermal pattern
can be overemphasized in shallow shave biopsy specimens.
A component of actinic keratosis, squamous cell carcinoma, or invasive squamous cell carcinoma may be
seen in association with MCC, including pagetoid MCC. These different components may be adjacent to the
MCC or be admixed with MCC.
Immunohistochemistry is often critical in the diagnosis of MCC. The vast majority of MCC express
cytokeratin 20 (CK20). Classically this is manifested in a peri-nuclear dot-like pattern, but many cases
will show more diffuse cytoplasmic staining. Rare cases of MCC are negative for CK20. 'Pan-keratin'
stains can highlight MCC in a similar pattern as immunohistochemical stains for CK20. As expected, MCC
express specific neuroendocrine markers such as chromogranin and synaptophysin in the great majority of
cases (>80%). Some cases will only express one of these markers. Neurofilament protein is expressed
in greater than 90% of cases, often in a dot-like pattern similar to the pattern of CK20 expression. MCC
also expresses neuron specific enolase (NSE), but, with the advent of more specific neuroendocrine
markers such as chromogranin, this is largely of historic interest. MCC is negative for S100 protein and
TTF-1, as discussed in more detail below.
Metastatic Small Cell Carcinoma:
The primary entity in the differential diagnosis in the majority of cases of MCC is metastatic small
cell carcinoma of the lung. Histologically they can be essentially indistinguishable and
immunohistochemical stains are critically important in resolving this question. Both express typical
neuroendocrine markers such as synaptophysin, chromogranin, and NSE. MCC express CK20 whereas most
metastatic small cell carcinomas are negative for this marker. As a caveat, approximately 1-3% of small
cell carcinomas express CK20 and in one series up to 8% of metastatic small cell carcinomas were
positive. Expression of thyroid transcription factor-1 (TTF-1) is seen in greater than 80% of metastatic
small cell carcinomas of the lung. TTF-1 expression has not been described in MCC. Neurofilament
protein expression, present in MCC, is not seen in metastatic small cell carcinoma.
Merkel cell carcinoma vs. metastatic small cell carcinoma
|Immunohistochemical Stain ||Merkel Cell Carcinoma ||Metastatic Small Cell Carcinoma|
|CK20 ||+ ||-/+ |
(rare positive cases)
|TTF-1 ||- ||+|
|Neurofilament Protein ||+ ||-|
|Chromogranin ||+ ||+|
|Synaptophysin ||+ ||+|
In MCC with pagetoid spread, melanoma needs to be considered in the differential diagnosis. There are
subtle differences in the growth pattern. Pagetoid MCC does not typically have areas with a prominent
single cell growth pattern along the basal layer, and the epidermal nests are usually separated from the
basement membrane by compressed keratinocytes. Cytologically, MCC lack the prominent nucleoli and
intranuclear cytoplasmic inclusions often seen in melanoma. Melanin pigment, when present, also helps
distinguish melanoma from MCC. In equivocal cases immunoreactivity for S100 protein or melanocytic
specific markers (e.g. HMB45) will distinguish melanoma from MCC.
Pagetoid Squamous Cell Carcinoma in Situ/poorly Differentiated Squamous Cell Carcinoma:
Squamous cell carcinoma (SCC) can have a pagetoid growth pattern in the epidermis characterized by
small nests and single atypical squamous cells. The tumor cells have more abundant eosinophilic
cytoplasm and intercellular bridges can usually be seen with careful examination under high
magnification. The tumor cells do not have the stippled chromatin pattern of MCC. It is important to
keep in mind that MCC can have an associated SCC in situ or invasive SCC component. The MCC component
will likely drive the behavior of the neoplasm and therefore management strategies may be significantly
different with consideration of sentinel lymph node biopsy and possibly adjuvant radiation therapy. In
tumors with mixed patterns, it is probably prudent to confirm the diagnosis of MCC with
immunohistochemical stains (i.e. CK20, neuroendocrine markers, neurofilament protein).
Paget's/Extramammary Paget's disease:
The distinction of pagetoid MCC from mammary or extramammary Paget's disease is usually not difficult
owing to their distinctly different clinical settings. Mammary Paget's disease presents on the nipple
and extramammary Paget's usually presents in the anogenital region. Rare cases of Merkel cell carcinoma
have been described in these areas, however.
Mammary and extramammary Paget's disease are essentially identical from the histologic standpoint.
Both have an intraepidermal proliferation of neoplastic cells arranged in nests or individual cells
within the dermis. Either may show an underlying invasive carcinoma, but this is more common in mammary
Paget's disease. The growth pattern is similar to pagetoid MCC, but the cytologic features are distinct
from MCC. The tumor cells in Paget's disease have relatively abundant, lightly eosinophilic cytoplasm.
The nuclei are large and often have prominent nucleoli. Some tumor cells have intracytoplasmic vacuoles
imparting signet-ring morphology. In questionable cases, histochemical and immunohistochemical stains
can distinguish mammary or extramammary Paget's disease from pagetoid MCC. Mucicarmine stains can
highlight mucin production in the tumor cells of Paget's disease. By immunohistochemistry, Paget's
disease is usually immunoreactive for cytokeratin 7 (CK7) but negative for CK20. An exception is
perianal extramammary Paget's disease associated with underlying rectal carcinoma. In this setting the
Paget cells typically express CK20 and may or may not express CK7. MCC does not express CK7, but normal
Merkel cells may express this marker. Therefore it is not inconceivable that MCC could rarely express
CK7. CDX-2, a homeobox gene expressed by nuclei of gastrointestinal epithelium and neoplasms, is
positive in perianal Paget's disease associated with rectal carcinoma. CEA and EMA are expressed by
Paget cells, but expression of these markers is also seen in MCC and is therefore not useful in the
Diffuse Large Cell B-cell lymphoma:
Diffuse large cell B-cell lymphoma (DLCBCL) can sometimes be considered in the differential diagnosis
of MCC. The nuclei often have a vesicular chromatin pattern and large nucleoli. DLCBCL lack CK20
expression and do not express neuroendocrine markers while they are positive for lymphoid markers (e.g.
In rare cases of pagetoid MCC, mycosis fungoides could be considered. The tumor cells in mycosis
fungoides have more cerebriform nuclei, surrounding clear halos and lack the cohesion of the pagetoid
nests of MCC. Immunoreactivity for lymphocytic markers easily allows distinction if necessary.
Prognosis and Treatment:
MCC is well known for the risk of local recurrence and relatively high risk of metastasis. The most
comprehensive outcome study was from Memorial Sloan-Kettering Cancer center by Allen, et al in 2005.
Disease stage was the single independent predictor of survival. Stage I disease, defined as tumor <2
cm without lymph node involvement, had a 5-year survival rate of 81%. Stage II disease, defined as tumor
≥ 2 cm without lymph node involvement was 67%. Stage III disease, defined as any lymph node
involvement, had a survival rate of 52%. Stage IV disease, defined as the presence of distant
metastasis, had a very poor outcome with a 5-year survival rate of 11%. Sentinel lymph node biopsy
significantly improved staging and should be considered in all patients with MCC.
Surgery is the mainstay of therapy. Adjuvant radiation has been utilized with differing results.
Some have shown a decreased risk of local recurrence while others have demonstrated no such value when
negative surgical margins were achieved. Chemotherapy has not been shown to offer a survival advantage.
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