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The International Journal on Orbital Disorders, Oculoplastic and Lacrimal Surgery
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Merkel Cell Palpebral Tumors: Three Cases
B. Arnaud, L. Navarre, K. Zaghloul, C. Malrieu, G. Barneon & B. Machayekhi
To cite this article: B. Arnaud, L. Navarre, K. Zaghloul, C. Malrieu, G. Barneon & B.
Machayekhi (1989) Merkel Cell Palpebral Tumors: Three Cases, Orbit, 8:3, 157-166, DOI:
10.3109/01676838909087645
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Published online: 08 Jul 2009.
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(Accepted 20 October 1988)
Merkel cell palpebral tumors
Three cases
B. ARNAUD1*, L. NAVARRE', K. ZAGHLOUL', C. MALRIEU', G. BARNEON2 and B. MACHAYEKH12
'Ophthalmological Clinic, 2Department of Pathology, Hdpital St Eloi, Montpellier, France
ABSTRACT. The Merkel cell tumor was recently recognized (1972) as an individual malignant skin tumor. On the basis of a review of the literature and of three personal observations, the authors have defined the clinical, pathological and evolutional characteristics of palpebral localizations.
Its frequency is evaluated at 7.8%.
The Merkel cell tumor is mainly located in the upper eyelid. Its clinical symptomatology is not very specific. The aspect is nodular and angiomatous.
The diagnosis is made on the pathology. It concerns an intra-dermal proliferation of small regular cells, with a large nucleus and reduced cytoplasm and arranged in sheets. A positive reaction with the antineuronic specific antibodies, enolase, anticytokeratin, antineurofilament, epithelial mem- brane anti-antigen and antiprotein S100, is revealed by the immunohistochemical study. A negative reaction is observed with the anti-antigen antibodies common to leucocytes. The evidence of neu- rosecretory granules and paranuclear intermediate filaments by electron microscopy is suggestive of a Merkel cell tumor. The development of this essentially local malignant tumor is often combined with lymph node or visceral metastases. Because of the relatively favorable prognosis, early diagno- sis and full surgical management are required. This tumor is included by most authors in the field of apudoma.
Key words: palpebral tumor ;
Merkel cell tumor
;neuroendocrine carcinoma
;skin apudoma
;neurosecretory granulomas
INTRODUCTION
In 1972 Toker30 reported for the first time about a particular skin tumor that he was unable to differentiate from a metastasis of anaplastic car- cinoma. He followed five patients, one of them for ten years, and despite his sophisticated inves- tigation the primary tumor was not found.
Histochemical research also remained unsuc-
cessful. This led him to consider the existence of a skin tumor of unknown nature. He suggested that it might be a sudoriparous tumor because:
1. In the midst of the cellular trabecular arrange- ment he found fissures that he thought were primitive acini, and
2. These tumors were localized in the skin. No ultrastructural study was made.
In collaboration with Tong he studied three more cases in 1978, followed by a group of 17
0 Correspondence
to: Dr, B. Ar,.,aud,
1102rue Ro- cases in 1979. An ultrastructural analysis was done. This study evidenced the presence of in-
queturibre, 34090 Montpellier, France
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Vol. 8, No. 3, pp. 157-1640
Aeolus Press Amsterdam 1989157
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B. Arnaud et al.
Fig. 1.
Massive dermal infiltration by round cells, giving a lymphoma-type aspect. HE
x40.
tracytoplasmic granules resembling those found in the Merkel cell, which led him to come forward with the hypothesis that these tumors are Merkel cell tumors.
T H E MERKEL CELL
This cell was reported by Merkel in 187514. It was an epidermic cell with an irregular nucleus and a clear cytoplasma. Extensions were observed and it was closely connected to a nerve end. However, at that time, microscopy techniques were unable to give a satisfactory definition. It was only after electron microscopy was introduced that progress started.
These cells are localized in the epidermis, in large quantities in the outer sheath of hair folli- cles and on the palmar face of fingers. They are also found in the oral mucosa, gum, palate and at the edge of lips. Its quantities are lower in the
adult than in the child. Lastly, they are found in various corpuscular nerve ends such as the Mer- kel discs and Pinkus corpuscles, which are found in the form of discs in human skin.
Electron microscopy revealed two categories of cytoplasmic extensions, some are wide and thread through the keratinocytes, the others deform these keratinocytes where the cell is attached by desmosomes. They contain thin filaments in groups or tracts. They seem to originate in the plasmic membranes and then disperse and thick- en in the cytoplasma. However, the cytoplasma of the Merkel cell is characterized mainly by the presence of Merkel granulations, specific gran- ules of 80 to 200 A in diameter, occasionally con- tained in a small vacuole with a dense center, sur- rounded by a clear space separating the core from the limiting membrane. Their role is unknown but because of their preferential localization at the cell pole and in contact with the terminal
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Merkel cell palpebral tumors
Fig. 2.
Round monomorphic cells with regular nuclear cores and thin cytoplasmic crowns. Numerous mitoses. HE
x 640.axon, they are considered as presynaptic vesicles.
The nucleus is notched by extensive folds of the membrane. Sometimes the nucleolus is absent but, here again, the presence of extremely partic- ular intranuclear inclusions is the main charac- teristic of this nucleus. These inclusions are of two types :
1. Either rod inclusions whose width is 3000 to 5000 A and whose length is sometimes equal to that of the nucleus.
2. Multilayer inclusions resembling a plate of variable size.
Merkel cell relations with the terminal axon are not constant. This axon completely covers the cell or penetrates between it and the basal membrane.
Labelling of Merkel cells has been obtained by immunofluorescence with specific antibodies.
The presence of a specific neuronic enolase has been established in the isolated as well as in the innervated cells. A positive reaction is observed with antiserum anti-Met-enkephaline. However,
other epidermic structures also possess this property.
It is also important to study the intermediate filaments. Indeed, it is one of the best ways of tracing the origin of a cell.
The epithelial cells are cytokeratin positive, a property equally presented by the Merkel cell which consequently is of epithelial origin. This may seem contradictory to the neuroendocrine properties of the Merkel cell. However, cytokera- tin is known to be also present in the insulin secre- tory cells of the pancreas.
The origin of the Merkel cell is much debated.
The existence of intra-nuclear granules indicates that the Merkel cell should be classified within the APUD system. This cell could originate from the neural crest and migrate into the epidermis.
The functions of the Merkel cell are not known. Merkel, who first found the cell, thought of a cutaneous mechano-receptive function be- cause of its localization, in contact with a nerve
159
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ending. From the present state of physiological, histochemical and immunological research it cannot be concluded that there is a neurotrans- mitting function and indeed the Merkel cell may only be an auxiliary cell.
THE MERKEL CELL TUMOR
About a hundred cases have been described in the literature. As already stated, the tumor was dis- covered recently and only since 1980 have these le- sions been drawing the attention of pathologists.
In fact, the tumor undoubtedly occurs much more frequently. In eyelids, we found seven cases reported in one year. We operated on three pa- tients with a palpebral tumor of this type which implies that the frequency is greater than that reported in the literature.
The mean age is generally high and the tumor seems to develop more frequently on the uncov-
ered parts of the body, head, legs, arms. In 50%
of cases, the localization occurs on the face, in particular on the cheeks, on the eyelids, on the scalp and exceptionally, on the lips. There are no known promoting factors and it usually concerns only one single lesion. However, in 10% of cases there are several nodules but these nodules remain close to one another.
The tumor itself is a protruding subcutaneous nodule. The epidermis is intact and the color is of a purplish red. Some of these tumors develop in depth but these cases are exceptional. Occa- sionally, the occurrence of a central ulceration or pigmentation is suggestive of a melanoma.
Deep metastases are unusual (10Vo of cases) and occur in the lungs or in the testicles, like in one of our cases. On the other hand, invasion via regional lymph nodes is frequently reported (50% of cases). In addition, there are also many cases of local recurrence (1/3 of cases).
Fig. 3. Clear looking cells with intracytoplasmatic granulations. Presence of intercellular junctions (Case 1).
Orbit 1989.8:157-166.
Merkel cell palpebral tumors CASE REPORTS
First
CaseMrs De ... : F, 82 years of age, had lost the sight of her rigfit eye due to myopia. Five months prior to surgery a subcutaneous mass had gradually invaded the internal canthus of the right eye. The skin was raised and hypervascularized, without modifica- tion of color or texture. When palpated, a nodule was perceived that seemed elastic and small in size.
It was not adherent to the bone or to the eye-ball.
Because of the age and localization, biopsy was realized under local anesthesia. The tumor was pushing back the internal rectus muscle and was pressing against the medial wall of the orbit that was nevertheless intact. The limits of the tumor were quite clear, the posterior pole was beyond the equator of the globe.
Pathological examination (Prof. Pages, Dr. Bar- neon) revealed that it concerned a Merkel cell tumor : ‘The tumor consisted of small round, regu- larly shaped, monomorphic cells’. The structure represents large lobules in some places and small in-
filtrating protrusions in others. The outer limit is not very distinct, but upon removal, it can be distin- guished from healthy tissues. Electronmicroscopy reveals a few intercellular junctions (Fig. 3). In the cytoplasm of cells there are scattered membrane- bound, round, dense-core granules, 120 nm to 200 nm in diameter (Fig. 4).
Secondary radiotherapy was immediately real- ized under protection of the eye. It proved to be in- sufficient. Indeed, it was already within two months that the tumor recurred at the same spot showing a red protruding formation with lymph- adenopathy under the right maxillary bone. Anoth- er biopsy was performed for lymph node aspiration cytology. It proved to be a relapse of the Merkel cell tumor.
In the preceding history it was of interest that one year earlier, in October 1983, a lesion of the apex of the right eyebrow was discovered. By that time it was labeled as an undifferentiated carcinoma. A pathological study was done again. It was equally a Merkel cell carcinoma. An immunohistochemical study was realized on the initial palpebral samples
Fig.
4.Membrane bound, round, dense core-granulae with clear halo,
120nm to
200nm in diameter (Case
1).161
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B. Arnaud et al.
siderable, the reconstruction could be realized by simply connecting the edges of the wound.
The histopathological examination (Prof. Bal- det) revealed : ‘malignant tumor, massively in- filtrating the epidermis, consisting of extremely basophilic monomorphic cells with rounded and regular nuclei. The lesion is infiltrating into the stri- ated muscle and surrounds the pilosebaceous ap- pendices. Diagnosis : ‘anaplastic epithelioma, or Merkel cell tumor’.
Three months later, right cervical lymph- adenopathies appeared. After extirpation, ex- amination confirmed the malignancy of a jugal sub-digastric adenopathy. A 50 Gray radiation ser- ies focussed on the right laterocervical region was given.
Six months after this second episode, a large right testicle developed. An orchidectomy was per- formed evidencing a testicular metastasis of the Merkel cell tumor. No other tumoral localizations were found by the tomodensitometric extension test. Sequential polychemotherapy was instituted with Vindesine; VP 16. Three years after discovery of the palpebral lesion the patient was free from metastases.
An ultrastructural study was done on the metastatic lymphadenopathy : ‘A neoformation is noted consisting of monomorphic, globular look- ing cells with surface microvilli, and junctions. The cytoplasm includes small, osmiophilic, neurosecre- tory granulations, surrounded by a single mem- brane. These ultrastructural aspects are sufficient to confirm a diagnosis of Merkel cell tumor’.
An immunohistochemical study was realized on a paraffin section. The usual elements of this type of tumor were found in the palpebral ganglionic and testicular swabs : anticytokeratin (CK) + ;
anti-neurofilament (NF) + : antiprotein SlOO (PS100) + ; epithelial membrane anti-antigen (E.M.A.) + ; anti-antigen common to leucocytes (L.C.) -.
Fig.
5.Case 2 before extirpation.
and the following elements were revealed : CK + ;
The patient died one year after removal of the or- bital tumor following a retentional icterus of pan- creatic origin. The etiology remained unknown.
N F + ; E.M.A. + ; LC
-; PS 100 +.
Second case (Fig.
5)M. S....M, 60years of age, had a small red, protrud- ing tumor 4 mm in diameter that occupied the cen- tral part of the upper eyelid of the right eye. A biop- sy of the tumor was performed. The pathological diagnosis of basocellular carcinoma was recorded.
This patient was referred to us. The tumor was en- tirely removed. Because the tissue laxity was con-
Fig. 6. Case 3 before extirpation.
Third
caseMr. F....R., 65 years of age.
’Ikomonths previously his ophthalmologist had operated on a ‘chalazion’
that recurred. No histological analysis was done at that time. The tumor was localized at the center of the upper eyelid of the left eye. It was red wine- colored, 18 mm long, and protruded 3 mm. No
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Merkel cell palpebral tumors
lymphadenopathies were found upon palpation.
The tumor was removed completely. Reconstruc- tion of the defect was realized by taking a graft 1 cm in, length from the internal part of the lower eyelid according to Hubner’s technique.
The pathological examination (Dr. Pignodel, Dr.
Barneon) revealed: ‘Throughout the dermis as far as the deep muscle there is a tumoral proliferation consisting of monomorphic dusty cells with fine chromatin. These cells are forming layers separated in a few places by fine conjunctival shelves. On the peripheral part of the specimen several associated inflammatory elements are noted. The aspects strongly suggest the diagnosis of a Merkel cell tumor’.
The tumor was removed entirely. One year later there was no local recurrence or metastasis. The im- munohistochemical study of paraffin sections re- vealed the tumor cells to be positive for CK, NF, E.M.A., PS 100, and to be negative for the anti L.C.
antibodies.
HISTOLOGICAL STUDY
The tumor always develops within the dermis and spreads from there. The cutaneous appendices are never invaded. The tumor itself, although its borders are quite distinct, does not have a cap- sule. The layout is most often trabecular. The cells are separated from each other by conjunctival septa. Several authors have described pictures in the form of a rosette, the center of which being occupied by collagenous material or a vessel. In the event of degeneration or melting of the cen- tral collagen, the formation of a central cavity was observed. It was this particular aspect of the figure that led Toker to the suggestion of the pos- sibility of sudoriparous tumors developing round pseudo acini. The presence of globes similar to those found in the spinocellular epitheliomas has been reported by S i d h ~ ~ ~ and Silva et al.26.
Viewed through a light microscope, the tumor cells are small, badly defined, rounded and meas- ure approximately 15 pm. The nucleus occupies
almost the entire cell. Often it contains a fine chromatin pattern. The ring of outer cytoplasm is thin, basophilic or eosinophilic. Staining with Giemsa reveals an extremely large nucleus with a non-specific cytoplasm collar.
Electron microscopic study revealed in some cases inclusions consisting of fasciculi of shreds in the shape of rods. The most characteristic elements are revealed by the cytoplasm study : granules, 100 to 200 nm in diameter, the center of which is opaque; these granules appear sometimes to be contained in small vacuoles.
Moreover, microfilaments, a small endoplasmic reticulum and a variable number of hairy looking cytoplasmic extensions are noted. Lastly, the cells are attached to each other and to the neighboring keratinocytes by desmosomal Immunohistochemical research of specific neuronal enolase was done in certain cases : the result was positive, This property together with the presence of large quantities of neurosecretory type granules in the cytoplasm strongly suggest a neuro-endocrine origin of the tumor. The cell is cytokeratin +, it is also neurofilament + (neu- ronal characteristic) ; epithelial membrane anti- antigen +, antiprotein SlOO +, with a negativity formations2.
11.23.24, 31.Fig.
7. Case 3 after extirpation and reconstruction
byfull depth palpebral graft.
163
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B. Arnaud et al.
for the anti-antigen antibodies common to leu- cocytes.
COMPARISON OF MERKEL CELL AND MERKEL CELL TUMOR
Both the Merkel cell and the Merkel cell tumor have been described. The question is whether it is possible to establish a direct link between the two. In fact, there is a discordance between these two formations :
- - The Merkel cell is localized in the cutaneous epidermis.
The Merkel cell tumor is always localized 1
within the dermis itself.
The Merkel cell is cytokeratin + , therefore of epithelial nature.
The cell that constitutes the Merkel cell tumor is also cytokeratin + but it is in addition, neu- rofilament + . Therefore it is both of epithelial and of nervous origin. This would suggest that it may originate from the neural crest like car- cinoids of the digestive tract. Rather than referring to a Merkel cell tumor, one should therefore speak in terms of a cutaneous neu- roendocrine carcinoma, originating from a neuroendocrine cell of the dermis.
In the literature Merkel cell tumors are also described under the following names :
- Neuroendocrine carcinoma of the - Small cell epithelial tumor of the skin18.
- Small cell carcinoma of the skin29.
- Apudoma of the skin36.
skin73
8, 16, 17, 22, 34.DIFFERENTIAL DIAGNOSIS
There are several differential diagnoses that should in particular be mentioned in presence of neuroendocrine carcinoma of the skin.
- The non Hodgkin cutaneous lymphoma, but
light microscopy shows that the cells are smaller in size. The nucleus is either very regu- lar, or in some cases more irregular. The ar- rangement is often less trabecular with a lower cell density. Electron microscopy shows no in- tracytoplasmic granules or desmosomal at- tachments.
The cutaneous metastasis of a small cell car- cinoma.
There exists a primary pulmonary or digestive tract tumor. Microscopy shows extensive zones of necrosis with nuclear hyper- chromatism. The cells are less monomorphic.
The neuroblastoma of the adult is undoubted- ly the most difficult diagnosis to eliminate since the ultrastructural study can reveal the presence of neurosecretory granules in the cytoplasm. But in these cases there are nervous fibers with microtubules and no keratinocyte type differentiation.
The round cell sarcoma is extremely unusual.
Here the same aspect may be observed by light microscopy.
Basal cell carcinoma develops out of the epidermis into the dermis. The cytoplasm of cells is small and clear. The nucleus is either egg-shaped or round. The cells are arranged in clusters. The peripheral cells of the tumor are arranged in the form of a hedgerow round the tumor.
Glandular carcinoma: the tumor has the lay- out of a gland with lobuli grouped around a central cavity. Lipidic deposits observed in the cells characterize the disease.
TREATMENT
1. Surgical treatment with excision of a wide margin around the tumor is the treatment of choice for these lesions ; it avoids local relapses.
When lymph node metastases have been noted,
Orbit 1989.8:157-166.
Merkel cell palpebral tumors which, as we have said, is often the case, wide sur-
gical excision of the area concerned must be realized.
2. The treatment of Merkel cell tumors by chemotherapy has seldom been reported in the literature.
According to Kessingerg who treated 11 cases of apudoma, the results after three months were the following : one case had total regression, two cases with partial regression, six cases with un- changed condition and one case with develop- ment of the tumor.
According to S ~ - i d h a r ~ ~ , out of 12 inoperable cases of apudoma treated with Doscorbicin to- gether with Asplatin, regression was observed in 50% of the treated tumors. These results were evaluated after six months but the series included tumors other than the Merkel cell tumor.
To our knowledge no cases of palpebral tumors treated with chemotherapy have been reported in the literature. Nine cases of Merkel cell tumors localized outside the eyelid were submitted to chemotherapy in addition to surgical or radio- therapeutic treatment. Visceral localizations were reported in all series5.
17, 18, 29.3. Radiotherapy has been used6,
8, 2 5 .Cases of
secondary localizations and recurrence were reported. According to Illy6 this treatment does not seem to improve the prognosis.
CONCLUSIONS
Palpebral Merkel cell tumors are rarely reported although they probably occur quite frequently.
They are often mistaken for lymphomas or small cell carcinomas. The prognosis and treatment of these tumors differ considerably. After surgical removal, which is in fact the only appropriate treatment, local recurrence often occurs when the extirpation was not done sufficiently wide around the tumor. In nearly 50% of cases lymph node metastases are observed. Radiotherapy is in- efficient.
The origin of these tumors is probably neu- roendocrine. Indeed, the granules observed in their cytoplasm by electron microscopy are ex- tremely characteristic. As regards cutaneous Mer- kel cells, there is much doubt as to their origin and one should speak of a cutaneous neuro- endocrine carcinoma.
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