Key-words:
Elderly - merkel cell carcinoma - spinal metastasis
Introduction
Merkel cell carcinoma (MCC) is an aggressive skin neoplasm, neuroendocrine in origin,
also known as small cell carcinoma of the skin. Classically, MCC occurs on the chronically
exposed, sun-damaged skin of the face, neck, and the upper and lower extremities in
the elderly,[[1]] but it has occurred in younger populations, especially those that are immunocompromised.[[2]],[[3]],[[4]],[[5]],[[6]],[[7]],[[8]] Pathogenesis has been related to many factors, more recently being the Merkel cell
polyomavirus.[[2]],[[3]],[[4]],[[5]],[[6]],[[9]] The common cutaneous manifestation includes a violaceous papule or nodule with
a smooth, shiny surface.[[1]] Although variations of the cutaneous manifestations of MCC include pedunculated
masses, chalazions, and granulation tissue.[[10]],[[11]],[[12]] The incidence in the United States is projected around 1500 cases each year[[2]] with increases seen, in part, to diagnostic and staining techniques. Even with
early recognition, MCC has a dismal prognosis given the high rate of recurrence and
early metastasis. While literature has evaluated many of the common and unique metastatic
sites, there is limited information regarding involvement of the spinal column and
surrounding tissue. In this case, we offer a look into the unique clinical presentation
of metastatic disease to a lymph node and spinal column without a known primary cutaneous
tumor.
Case Report
In February of 2015, a 75-year-old man was evaluated by his primary care physician
for an asymptomatic left neck nodule that would “move around.” There did not appear
to be any overlying skin changes, but the patient was concerned given the rapid increase
in size over a couple of weeks' duration. A thorough history and physical examination
did not reveal any acute abnormalities. The patient was referred to surgery where
a lymphadenectomy was performed. The specimen removed measured 1.3 cm and was submitted
for flow cytometry, histology, and immunohistochemical staining. The pathology revealed
small blue cells 2–3 times the size of nearby lymphocytes, arranged in nests [[Figure 1]] with a staining pattern most consistent with MCC, thyroid transcription factor-1
negative, AE1/AE1 positive, synaptophysin strongly positive, and cytokeratin 20 strongly
positive [[Figure 2]].
Figure 1: Microscopic section showing a lymph node with near replacement by coalescing nests
of malignant cells. The individual tumor cells have hyperchromatic nuclei and surrounding
scant cytoplasm with abundant mitotic activity
Figure 2: Cytokeratin 20 staining is strongly positive
After a negative positron emission tomography–computed tomography (PET/CT) scan, the
patient was evaluated using the National Comprehensive Cancer Network (NCCN) guidelines
and labeled Stage 1. The patient was offered chemotherapy but declined due to concerns
about quality of life. His treatment included adjuvant radiotherapy (RT) postlymphadenectomy.
This was completed on May 27, 2016. Shortly after, however, the patient began experiencing
bilateral shoulder, cervical neck, and lower back pain. This was evaluated with multiple
X-rays and an open-air MRI which came back negative. After failure of medical therapy
by orthopedics for pain, the patient was eventually referred to neurosurgery. The
physical evaluation revealed diminished sensation in the distal right upper extremity
and asymmetric reflexes among the right and left arms. There was also significantly
diminished muscle strength in the right deltoid labeled a 1 of 5. An MRI was then
ordered and completed in August. The results showed multiple areas of tumor in the
cervical, thoracic, and lumbar spine. In the cervical spine, there was a diffuse abnormal
signal in the C5 vertebra with epidural extensions posterior to the C4 vertebra and
C5 causing canal stenosis. There was also tumor in the neural foramina on the right
of C5 with extension to the inferior aspect of C6. The thoracic level yielded an anterolateral
paraspinous tumor up to 35 mm at the level of T3, with minimal involvement of the
T4 vertebra. There was also a paraspinous mass noted on the left at the level of L4–L5
measuring up to 57 mm. This involved the L4–L5 L5–S1 foramina with destruction of
the lateral bony elements. There was a 64 mm tumor abutting the lumbosacral plexus
at the right side of vertebral level S2. This was also evaluated using a PET/CT [[Figure 3]], [[Figure 4]].
Figure 3: Whole-body positron emission tomography-computed tomography with contrast revealing
hypermetabolic activity in the C5 vertebral body, in the left anterolateral soft tissue,
as well as in the left foramen with a standardized uptake value of 5. There is also
some suggestion of asymmetric soft-tissue attenuation of concern for a paraspinous
mass
Figure 4: Pictured is a hypermetabolic paraspinous soft-tissue mass at the level of L4 that
extends caudally. The mass is posterior to the left psoas muscle and measures 3.5
cm x 4.8 cm. This may be contiguous with another portion extending into the left paraspinous
muscle measuring 3.9 cm x 4 cm. There is also an extension into the foramen at the
L4-L5 and the L5-S1 levels, with some probable bony destruction of the L5 transverse
process
The patient was treated with a combination of chemo-radiation therapy consisting of
carboplatin/etoposide. Unfortunately, he was unable to complete therapy due to a significant
decline in function from bilateral deep venous thrombosis and an episode of cardiac
arrest. The patient and his family ultimately decided to retire to hospice care given
the poor prognosis and inability to handle the treatment regimen.
Discussion
The MCC case presented here represents a very unique clinical manifestation given
its primary isolated lymph node involvement and later spinal column metastasis. At
presentation, most cases of MCC develop as a rapidly growing, painless, violaceous,
or skin-colored papule or nodule.[[1]],[[6]],[[7]],[[8]],[[13]],[[14]] This is typically seen in the elderly Caucasian male population, most commonly
observed on the skin of the face (27%), the upper limbs, and the shoulders (22%),
followed by the lower limbs and hips (15%), according to a study by Albores-Saavedra
et al.[[7]] Notably, the study also addressed common sites of extracutaneous isolated tumor
involvement, such as lymph nodes. Indeed, studies have shown as much as 14% of those
with nodal disease to have no associated cutaneous finding.[[7]],[[8]],[[10]],[[11]],[[13]],[[14]]
With MCC's lack of distinctive characteristics and assorted presentations, clinical
suspicion is often underutilized. That is why past studies have suggested the use
of the AEIOU system – asymptomatic/lack of tenderness, expanding rapidly, immune suppression,
older than 50 years of age, and ultraviolet (UV) exposure-for initial evaluation.[[7]],[[8]],[[13]] When applied to this case, the patient characteristics meet four of the five criteria,
thereby demonstrating its possible utility. This is unsurprising given that the system's
formulation resulted from the five most common clinical features that were observed
among the MCC group studied. While this system may be beneficial for increasing the
clinical threshold of suspicion, definitive evaluation with histology and staining
is necessary.[[4]] This is due to the somewhat broad clinical differential of similar appearing conditions
such as basal cell carcinoma, amelanotic melanoma, and epidermoid cyst.[[15]]
MCC is described as one of the “small blue cell tumors” that is neuroendocrine in
origin. It is thought to arise from mechanoreceptors at the dermal-epidermal junction,
with about 10% arising from the epidermis.[[6]] Histological evaluation presents in three main architectural patterns: trabecular,
intermediate, and small cell. The primary distinguishing factor of MCC from other
cancers, namely other small blue cell tumors, is its unique immunohistochemical staining
pattern. This is due to the presence of both epithelial and neuroendocrine components
that can be targeted for identification. The two markers commonly used, as done in
this case, are synaptophysin and cytokeratin 20.[[14]],[[16]]
Several factors have been implicated in the pathogenesis of MCC without any single
etiology being identified. Increased risk has classically been associated with chronically
damaged sun-exposed skin. This becomes evident with the increased rates of MCC seen
among Caucasians, with very few cases seen in the African American population.[[7]] In addition, nearly 81% of MCC develops on the sun-exposed areas of the body.[[1]] An increased incidence has also been seen in psoriatic patients receiving psoralen
and UVA phototherapy.[[3]] Other likely contributing factors include the Merkel cell polyomavirus, which has
been identified in up to 80% of MCC cases[[9]],[[16]],[[17]],[[18]],[[19]] and immunosuppression with MCC reported in younger populations secondary to conditions
such as organ transplant.[[18]]
The natural course of MCC often results in rapid growth and early metastasis. Some
of the common sites described are the lymph nodes, distant skin, bones, liver, and
lung.[[8]],[[13]],[[14]] While distant metastasis is common, there is limited information regarding metastasis
to the spinal column, especially in the setting of nerve complication. With the symptoms
of back pain, dermatomal sensory loss in the upper right extremity, weakness, and
asymmetric reflexes, the patient's presentation in this case was consistent with radiculopathy.
This presentation has rarely been seen in the literature. These findings underscore
the need for prompt diagnostic evaluation of new-onset radicular pain in those patients
with a history of MCC.
For staging and comprehensive therapeutic approaches, current practices use the NCCN
for guidelines. Each treatment plan employed is dependent on the stage at diagnosis.
The current approach for localized disease is resection with negative margins and
RT.[[20]] Although, RT may be the sole option for treatment for those who are poor surgical
candidates. In advanced disease, a combination of RT and etoposide with platinum-containing
agents is the accepted management.[[17]],[[20]],[[21]] Even with the common use of these agents, outcomes have shown high rates of morbidity
and mortality,[[19]] and despite the radiosensitive nature of MCC, the prognosis is poor with the stage
of the disease at diagnosis being the best predictor of overall survival.[[1]],[[5]],[[6]],[[7]]
Declaration of patient consent
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images and other clinical information to be reported in the journal. The patients
understand that their names and initials will not be published and due efforts will
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