TITLE: Merkel Cell Carcinoma
SOURCE: Grand Rounds Presentation, University of Texas Medical Branch
(UTMB Health), Dept. of
Otolaryngology
DATE: February 24, 2012
RESIDENT PHYSICIAN: Naren Venkatesan, MD
FACULTY PHYSICIAN: Susan McCammon, MD
DISCUSSANT: Vicente Resto, MD, PhD
SERIES EDITOR: Francis B. Quinn, Jr., MD
ARCHIVIST: Melinda Stoner Qui=
nn,
MSICS
"This material was
prepared by resident physicians in partial fulfillment of educational
requirements established for the Postgraduate Training Program of the UTMB
Department of Otolaryngology/Head and Neck Surgery and was not intended for
clinical use in its present form. It was prepared for the purpose of
stimulating group discussion in a conference setting. No warranties, either
express or implied, are made with respect to its accuracy, completeness, or
timeliness. The material does not necessarily reflect the current or past
opinions of members of the UTMB faculty and should not be used for purposes=
of
diagnosis or treatment without consulting appropriate literature sources and
informed professional opinion."
Editor’s note:
images cannot be seen in all views of Microsoft Word. Images can be =
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Introduction
This talk will focus on the understanding of Merkel Ce= ll Carcinoma, a rare but lethal form of skin cancer. Due to its predilection f= or the head and neck, this cancer is often encountered in the Otolaryngologist practice. Also, its rapid progression makes it a disease that requires a hi= gh level of suspicion. When identified early, there is a much greater 5 year prognosis which due to the disease’s spread makes a significant difference.
History
This disease is a relatively new diagnosis. In 1875, t= he Merkel cell was first described by Friedrich Merkel when isolated in the sk= in of ducks and geese. In 1972, Cyril Toker described the first case of Merkel Cell Carcinoma. It has been described under various aliases, trabecular carcinoma of the skin, neuroendocrine cancer of the skin, and small cell carcinoma of the skin. Due to its recently relative description, much remai= ns to be known regarding Merkel cell carcinoma. Further, its rarity prevents l= arge case studies or reports.
Incidence
In the United States, the age-adjusted incidence has b= een increasing. In 1986, the incidence was 0.15 in 100,000 which has now risen = to 0.44 per 100,000 as of 2001. As with skin cancers, there is an increased incidence amongst lighter skinned individuals. The incidence amongst Caucas= ians in the US is 0.23 per 100,000 when compared to 0.01 per 100,000 amongst African-Americans. When compared to other skin cancers, Merkel cell carcino= ma is the most lethal. Fatality rates for Merkel cell carcinoma reach nearly 1= in every 3 patients while melanoma is only 1 in every 6. These diagnoses carry= an obviously significantly worse prognosis than squamous cell carcinoma (1 in = 50) and basal cell carcinoma (less than 1 per 10,000).
For an Otolaryngologist, Merkel cell carcinoma is an important diagnosis to note due to its frequency in the head and neck regio= n. Nearly 47% of all primary Merkel cell carcinoma is found in the head and ne= ck region. In the head and neck, the mot common sites are perioral and periocu= lar. While mucosal presentations are rare, only 4.5%, this number should be taken with a grain of salt as the low incidence of this disease makes any percent= age somewhat uncertain.
Merkel cell carcinoma most often presents in a p= atient greater than 65 years of age. While there are a few studies stating a 1 to 1 ratio between genders, most studies demonstrate a significant male predilection, nearly 1.5-2.5 to 1. Risk factors for Merkel cell are much li= ke those for other skin cancers. These include fair skin, prolonged sun exposu= re, UVA therapy, and immunosuppressed individuals. Immunosuppressed individuals have a significantly increased risk, especially noted with HIV, Organ Transplant patients, and patients with chronic diseases like leukemia. The = risk for individuals with HIV to develop Merkel Cell carcinoma is nearly 13.4 ti= mes increased. Similarly, patients with a history of an organ transplant are at= a 10-fold increased risk.
Basics of Merkel Cells
Merkel cells are Type I mechanoreceptors. They provide= the sense of fine touch as well as sensation of hair movement. Thus, they may operate independently or in conjunction with a tactile hair disc. They are typically located in the basal layer of the epidermis – located at the dermal-epidermal junction. They arise from neural crest cells and as such a= rise in the same lineage of cells which are capable of amine precursor uptake and decarboxylation. As a reminder, neural crest cells constitute a vast group = of specialized cells. Some examples include odontoblasts, enterochromaffin cel= ls, parafollicular thyroid cells, carotid body/glomus cells, adrenal medulla ce= lls, Merkel cells, satellite glial cells, Schwann cells, Melanocytes, and Iris pigment cells. It is important and interesting to note that both Merkel cel= ls and Melanocytes arise from the same lineage as melanoma is an important differential diagnosis for Merkel cell carcinoma.
Typical Presentation
An example of a typical patient would be a 70-year-old= male patient who presents to the clinic with a rapidly enlarging mass near the u= pper lip. He is likely a fair-skinned individual who lives on a farm or in a sun-exposed profession. When asked about sun-protection, he would likely de= ny the use of sunscreen or wearing sun-protective clothing. When describing the mass, he notes that it has been steadily increasing in size since it was fi= rst noted nearly 2 months prior. He denies any pain from the mass or noting any bleeding from the mass. A variety of past medical history may be noted from none or include a chronic disease placing the patient in an immunocompromis= ed state. Social history may include a long history of smoking tobacco or alco= hol use. However, the patient’s profession and any cause of sun exposure = is the most important history needed.
The physical exam typically reveals a firm, red, non-t= ender papule in the upper lip. On initial presentation, Merkel cell carcinomas are usually from 1-1.5 cm with no ulceration, no cervical lymphadenopathy, and = no synchronous lesions. As stated earlier, these lesions are typically peri-or= al or peri-ocular but also present on the cheek, nose, forehead, and other frequent sun-exposed areas – neck, upper back, and shoulders. While nearly ½ the presentations of this disease are in the head and neck region, the extremities are another common site for presentation.
Cytopathology
One of the most perplexing aspects of this disease is = the cytopathology. Despite being visible on the skin and often initially detect= ed in early stages, the outcome for a patient is poor. One of the key reasons = why this discontinuity exists is the difficulty in obtaining a diagnosis from initial biopsies. When viewing the pathology with a typical hematoxylin and eosin stain, it is extremely challenging to identify the Merkel cells which typically arise as individual cells and at times clusters. Therefore, it is important to have Merkel cell carcinoma as a differential diagnosis to alert the pathologist to stain for this disease. Remembering this fact is further important when observing the pathology from a lymph node where it is further challenging to identify the Merkel cells which also appear as small blue ce= lls among the lymphocytes.
Cytopathology typically reveals predominantly single c= ells with round, vesicular nuclei and scant neoplasm. They show scan to absent molding and have numerous mitoses. Within each cells, there are small vesic= les which appear attached to the nucleus and are termed “perinuclear button-like inclusions.” Finally, of utmost importance, these cells s= tain specifically for cytokeratin 20, neurofilament, and neuron-specific enolase= . On high power microscopy, the nuclei are round and surrounded by a thin rim of cytoplasm. The chromatin is fine to dark with one or more inconspicuous nucleoli. Little or no molding is present, and numerous mitoses are seen. S= ome authors have described “paranuclear button-like inclusions” consisting of 2- to 3-μm crescentic shaped or discoid globules located= in the cytoplasm adjacent to the nucleus. These are best seen in hematoxylin a= nd eosin preparations.
The importance of learning these cytopathologic featur= es is to maintain a high index of suspicion. In a series by Dr. Paul Nghiem of a = 100 patients, the initial biopsy results only correctly diagnosed a non-melanoma skin cancer is 14% of patients. His table of results is shown below.
![](3D"merkel-cell-ca-2012-02_files/image002.gif")
There are three main histologic patterns noted which i= nclude the intermediate type, small cell type, and trabecular type. The Intermedia= te type is the most common type and must be distinguished from small blue cell tumors, melanoma, and lymphoma. The small cell type must be distinguished f= rom a metastasis of small cell lung cancer. The trabecular type should be distinguished from metastatic carcinoid in its differential diagnosis. Howe= ver, regardless of the type, the prognosis remains roughly the same and is poor.=
Neuroendocrine Role
While this tumor has the potential to secrete hormones= , it is rarely the case that it does. Most information on this topic exists as c= ase reports or small case series. Case reports often show an association with adrenocorticotropic hormone or anti-diuretic hormone.
Adrenocorticotropic hormone is normally secreted by the anterior pituitary gland but is a fairly common hormone to be secreted in p= araneoplastic syndromes especially with lung cancer. Its principal effects are increased production and release of cortisol. It acts on the adrenal cortex and is se= en in small cell lung cancer which is a key differential diagnosis. Excess adr= enocorticotropic hormone causes Cushing’s disease which typically presents with increa= sed weight gain, central obesity, moon facies, hirsutism, purple striae due to thinning of skin, polyuria, hypertension, and hyperpigmentation.
Anti-diuretic hormone is made in the posterior pituita= ry gland and acts on the distal renal tubule and collecting duct in the nephro= n. It results in water retention without retaining the solute – thus lowering the serum concentration of the electrolytes. Similar to ACTH, it is also secreted in paraneoplastic syndromes and most often seen with small ce= ll lung cancer. Excess anti-diuretic hormone results in symptoms which are predominantly reflective of hyponatremia. Early findings include headache, nausea, and vomiting. If the hyponatremia worsens, the patient may have irritability, confusion, seizures, or even a coma. Severe symptoms start to present once the sodium level drops below 120.
Staging
Staging was originally started in 2002 with the initial AJCC system. The system was based on size with 2 cm being the differentiation and nodal/metastatic involvement deciding the remainder of = the stages.
![](3D"merkel-cell-ca-2012-02_files/image004.gif")
The updated 2009 staging criteria involve the individu= al TNM staging as seen with other cancers. The T score is based on the size of the tumor with 2 cm and 5 cm being the cutoffs. The N score is based on differentiation micrometastasis and macrometastasis as well as placing importance on differentiating between a clinically and pathologically negat= ive neck for lymph nodes.
![](3D"merkel-cell-ca-2012-02_files/image006.gif")
![](3D"merkel-cell-ca-2012-02_files/image008.gif")
Staging therefore proceeds as follows with a pathologi= cally negative neck getting a better stage when compared to a clinically negative neck. This importance will be touched on shortly.
![](3D"merkel-cell-ca-2012-02_files/image010.gif")
The differences between each stage in this disease are drastic. Stage I disease carries an 81% rate of survival while stage II only carries 67%. Stage III carries 52% while stage IV has a drastic decrease to 11%. Studies that help understand survival for patients with Merkel cell carcinoma state that disease stage in the only independent predictor of survival. Graphs reflecting percent relative survival to years from diagnos= is show a nearly 20% difference between Stage IA and Stage IB. This is a remarkable difference in survival when realizing that both Stage IA and Sta= ge IB have T1 disease but are only differentiated by a clinically negative neck versus a pathologically negative neck. This large gap only places more emph= asis on the importance of lymph node evaluation in patients with Merkel cell carcinoma despite clinical exam.
Returning back to our thoughts on the initial presenta= tion, the average size of a Merkel cell carcinoma presenting in the head and neck region is 1.59 cm along with a clinically negative neck. This places patien= ts at a T1 and cN0 which is a Stage IB. Despite this early presentation, survi= val rates and prognosis remains poor for this disease. One of these reasons was= the delay in diagnosis secondary to difficulty in identification with biopsies. When treating the neck for other head and neck cancers, CT scans typically = help in predicting nodal disease. However, this is not the case for Merkel cell carcinoma as the sensitivity for a CT Neck is only 20% while the specificit= y is better but still not great at 87%. For distant spread, CT still shows benef= it with good sensitivity.
In order to better treat these patients, the pathologic diagnosis must be made as soon as possible. As stated above, it is integral= to ask for the specific stains including neuron-specific enolase, cytokeratin = 20, and neurofilament. After obtaining an accurate diagnosis, the uncertainty t= hat currently exists regarding treatment of the neck leads to worse outcomes. In one study, nearly 50% of patients had microscopic evidence of disease in a clinically negative neck. Such a finding mandates the need for evaluation of nodal disease in all patients. Finally, the disease carries a poor prognosi= s as the disease spreads fast and a significant percentage of patients present l= ate. Nearly 6% of patients present after distal metastasis. Further, studies estimate anywhere from 10-30% of patients present with nodal involvement at initial presentation. These three factors provide much of the reason for the poor prognosis for patients with this disease.
Treatment
Treatment for Merkel Cell carcinoma consists of wide l= ocal excision of the mass followed by a selective lymph node biopsy or regional lymph node. Following surgical treatment, radiation therapy, chemotherapy, = or a combined therapy are also options. For primary resection, wide local excisi= on is mandated. The uncertainty is the amount of margins needed. While some authors suggest upto 3 cm, this amount may be and often is unfeasible in the head and neck region where a 1 cm lesion would require 7 cm of excision. Several studies report a range of negative margins from 1 cm – 3 cm. = The only note to gather here is that the wider the margin that may be safely performed and closed should be done.
Next, unlike Squamous cell carcinoma and basal c= ell carcinoma, Merkel cell carcinoma has a high propensity for early spread to lymph nodes. It tends to have nearly 30% lymph node involvement which is the greatest among all skin cancers. For perspective, melanoma is the second mo= st common at 5%. Approximately 75% of patients with Merkel cell carcinoma pres= ent with evidence of nodal metastasis. A study by Dr. Schmalbach where a select= ive lymph node biopsy was performed in patients with Stage I Merkel Cell carcin= oma showed nodal metastasis in 2 patients. Further, a literature review showed a 12% false-negative rate when a selective lymph node biopsy was negative. Du= e to the importance of lymph node involvement, current practice guidelines by the National Comprehensive Cancer Network recommend a selective lymph node biop= sy for untreated, localized, stage I disease. When performing selective lymph = node biopsies, it is important to remind once more that the pathologist should be made aware of the diagnosis of Merkel cell carcinoma. Among the lymphocytes, identifying the individual Merkel cells is difficult but can be made easy w= ith staining – typically cytokeratin 20.
Radiation therapy and its role remain uncertain at thi= s time with more data needed. Several case series and retrospective reviews have s= hown a role for radiation, but this is an area that requires further evaluation. Currently, the National Comprehensive Cancer Network recommends radiation therapy for the primary tumor site post-operatively, in-transit lymphatics,= and for the draining nodal basin in patients who only undergo a wide local excision. The argument against post-operative XRT is highlighted by a study= by Allen et al. They showed that the combination of a wide local excision with negative margins and a selective neck dissection results in only an 8% local recurrence rate. On the other hand, there are also those that argue in favo= r of post-surgical XRT. A study by Medina-Franco et al. reviewed 11 case series = and determined that the local recurrence rate was decreased from 52.6% to 10.5%= in those patients who underwent post-operative radiation therapy. Other similar studies tend to also demonstrate a nearly 4 fold decrease in local recurren= ce and nearly 20% greater 1-year and 5-year event-free survival when post-operative radiation therapy is used. Post-operative radiation therapy = also lower regional recurrence nearly 3 fold and improves event-free survival by= 20% and 30% at 1-year and 5-year intervals, respectively.
Some authors have also suggested the use of radiation therapy as a primary treatment. Pape et al. compared the treatment of Stage= I Merkel cell carcinoma patients with primary radiation therapy versus those treated with wide local excision and radiation therapy and found comparable rates of recurrence. Further, Mortier et al. treated a small patient group = with primary radiation therapy and found no recurrence in 3 years. While these findings suggest that a role does exist for primary radiation therapy, furt= her studies are needed to better clarify if radiation therapy as a primary opti= on may be seriously considered or only used in those individuals who cannot tolerate surgical intervention. Currently, it is endorsed as a possible treatment option in the elderly who cannot tolerate surgery or if the disea= se presents a location that does not allow for wide local excision with margin= s.
Chemotherapy is currently not employed in the treatmen= t of Merkel Cell carcinoma. Chemotherapy is not typically used as it suppresses immune function – something often already seen in patients with Merke= l cell carcinoma. Chemotherapy also causes a decreased quality of life, especially= in the elderly, as it causes fatigue, hair loss, nausea, and vomiting. Neutrop= enic fever and sepsis are also complications of treatment. Due to the myriad of = side effects and the fact that the typical patient with Merkel cell carcinoma is= an elderly patient, chemotherapy has not been endorsed in treatment of this disease.
A suggested treatment protocol is shown below fr= om the dermatology journals.
![](3D"merkel-cell-ca-2012-02_files/image012.gif")
Conclusion/Highlights
The disease is a devastating one which requires a high= index of suspicion and early, aggressive management. Its clinical presentation is best characterized by the acronym, “AEIOU.” The letters stand f= or Asymptomatic or non-tender, Expanding rapidly, Immunosuppressed patients, O= lder than 65 years of age, and UV exposure in fair skinned individuals. It is important to look for per-nuclear inclusions on H&E staining. Cytokerat= in 20 is necessary to differentiate the disease from small cell lung cancer, melanoma, and lymphoma. Early treatment in stage I, which is less than 2 cm, has a fairly good prognosis of nearly 80%. Finally, regardless of treatment= , it is imperative to rule out lymph node metastasis, ideally through a selective lymph node biopsy.
DISCUSSION: Remarks by Vicente Resto, MD, PhD
First of all there is going to be a bias between specialties from an open surgical specialty such as ours and Dermatology in which they do a lot more minimally invasive approaches and I think that rea= lly from a very high level perspective that already begins to explain some of t= he biases in each of the literature bodies.&n= bsp; They have merits and weaknesses no matter which approach you choose. The first thing to recognize that only a sentinel node bias is only as good as the technical prowess of the surgeon performing it as the pathologic assessment. In its best applied form it should= be highly effective in identifying the relevant draining lymph node and a bene= fit is that the pathology assessment of those few earlier lymph nodes can be a = lot more precise and in depth than it would be for a larger specimen. That's when you really slice speci= mens every five millimeters and every so number of sections with immuno-histochemical stains. As you saw, this tends to be singl= e cell presence in a lymph node so would expect that kind of analysis likely would= be a lot more sensitive at identifying those single cells.
Now again, the weakness is that if you're given the = wrong lymph node no matter how well prepared, you're not going to find them.
The other approach, is where you do the selective ei= ther single or multilevel dissection which takes away some of the operator variability from a surgical perspective.&n= bsp; Chances are that you're going to get the relevant lymph node in there for pathologic assessment but no pathologist is going to do five millimeter sectioning and immunochemistry on the entirety of a mega-section specimen.<= span style=3D'mso-spacerun:yes'> So if you happen to have experience doing signal sentinel lymph node mapping and you have great comfort, not a little comfort, with that technique then probably sentinel lymph node mapping is the preferred approach to go after this issue. Now, even in a sentinel lymph node negative setting I think you have to be hig= hly committed to surveillance in these patients. In PET CT, where your mortal= ity numbers are so impacted by such a low volume of single cell lymph nodes and= the like, PET CT is never going to be as sensitive- it's not a microscopic technique.
My second comment is that the idea of using radiation therapy as the primary modality for "elderly and infirm patients" whom you cannot operate on, all I will do is remind you what all surgeons do, so who is really sufficie= ntly infirm not to cut out a skin tumor in fact short of something that is truly massive in size in which case it really doesn't matter how you treat that patient for that patient is probably not going to have a good outcome.
The question is what to do with a large primary in an
advanced stage and what to do with the neck even if it's a negative neck.
Again, back to the question of sentinel lymph node biopsy in a T3, you really have to sit down and th= ink about lymph node mapping and how it's done. More often than not what you do is= you basically inject dye in quadrants around your tumor. While if your tumor is very large = the likelihood of getting a truly circumferential drainage of your radio tracer= is low, and the larger it is the= less representative and the less accurate it is in particular for large lesions.
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21.AJCC 2009 Cancer Staginig Guidelines