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****** DATA-MEDICOS **********
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EL CARCINOMA DE MERKEL 
THE MERKEL CELL CARCINOMA
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****** DERMAGIC-EXPRESS No.38 ******* 
****** 12 FEBRERO DE 1.999 ********* 
12 FEBRUARY 1.999
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EDITORIAL ESPANOL
=================
Hola amigos DERMAGICOS, el tema de hoy, el CARCINOMA DE CELULAS DE MERKEL 
tumor bastante controversial en cuanto a origen, diagnostico y tratamiento.
Estas 51 referencias bibliograficas nos detallan bien estas interrogantes. 

Dra. Hortensia Garcia, aqui tienes la respuesta a tu pregunta en DERMLIST
sobre el MERKELIOMA !!! 


Saludos a TODOS,,, 

Dr. Jose Lapenta R.,,,


EDITORIAL ENGLISH
=================
Hello DERMAGICS friends, today's topic, the MERKEL CELL CARCINOMA quite
controversial tumor as for origin, diagnose and treatment. These 51
bibliographical references detail us well these queries. 

Dr. Hortensia Garcia, here you have the answer to your question in DERMLIST
on the MERKELIOMA!!! 

Greetings to ALL, 

Dr. José Lapenta,
=======================================================================
DERMAGIC/EXPRESS(38)
======================================================================
EL CARCINOMA DE MERKEL /THE MERKEL CELL CARCINOMA
======================================================================
1.) Merkel cell carcinoma. Diagnosis and treatment.
2.) Is aggressive surgical management justified in the treatment of
3.) Merkel cell carcinoma. Histopathology, immunohistochemistry, and
cytogenetic analysis.
4.) Merkel's cell (neuroendocrine) carcinoma of the vulva.
5.) CD44 expression in Merkel cell carcinoma may correlate with risk of
metastasis.
6.) Neuroendocrine (Merkel cell) carcinoma with an intraepidermal component.
7.) The treatment of advanced Merkel cell carcinoma. A multimodality
chemotherapy and radiation therapy treatment approach.
8.) Merkel cell tumor of the head and neck. Five new cases with
literature review.
9.) Chromosomes 1, 11, and 13 are frequently involved in karyotypic
abnormalities in metastatic Merkel cell carcinoma.
10.) Merkel cell carcinoma of the labial mucosa. An immunohistochemical and
ultrastructural study with a review of the literature on oral Merkel cell
carcinomas.
11.) Neuroendocrine carcinoma within lymph nodes in the absence of a
primary tumor, with special reference to Merkel cell carcinoma [see comments]
12.) Pagetoid intraepidermal spread in Merkel cell (primary
neuroendocrine) carcinoma of the skin.
13.) Multiple hamartoma syndrome (Cowden's disease) associated with renal
cell carcinoma and primary neuroendocrine carcinoma of the skin (Merkel
cell carcinoma).
14.) Merkel cell carcinoma. Prognosis and management.
15.) Hyperthermia and radiation therapy in the treatment of recurrent
Merkel cell tumors.
16.) Merkel cell carcinoma. Improved locoregional control with
postoperative radiation therapy.
17.) Giant neuroendocrine (Merkel cell) carcinoma of the skin.
18.) Tumor lysis syndrome in a patient with metastatic Merkel cell carcinoma.
19.) Spontaneous regression in Merkel cell (neuroendocrine) carcinoma of
the skin.
20.) Merkel cell carcinoma metastatic to the testis.
21.) The use of VP16 and cisplatin in the treatment of Merkel cell carcinoma.
22.) Radiotherapy as an adjunct in the management of Merkel cell carcinoma.
23.) Neuroendocrine (Merkel cell) carcinoma of the skin: a
clinico-morphological study of 13 cases.
24.) Merkel cell carcinoma.
25.) Merkel cell carcinoma. A successful treatment with tumor necrosis
factor.
26.) Involvement of chromosome 22 in a Merkel cell carcinoma in a patient
with a previous meningioma.
27.) Clinicopathologic correlations of cutaneous neuroendocrine Merkel
cell carcinoma.
28.) Chemotherapy for metastatic Merkel cell carcinoma. Review of the M.D.
Anderson Hospital's experience.
29.) Neuroendocrine (Merkel cell) carcinoma of the skin. Its natural
history, diagnosis, and treatment.
30.) Recurrent and metastatic cutaneous neuroendocrine (Merkel cell)
carcinoma mimicking angiosarcoma.
31.) Trabecular (Merkel cell) carcinoma of the skin. Treatment of primary,
recurrent, and metastatic disease.
32.) Chemotherapy for metastatic Merkel cell carcinoma.
33.) Electron microscopy of Merkel cell carcinoma from formalin-fixed tissue.
34.) Primary neuroendocrine (Merkel cell?) carcinoma of the skin. I. A
clinicopathologic and ultrastructural study of 43 cases.
35.) Merkel cell carcinoma of the skin: the structure and origin of normal
Merkel cells.
36.) Neuroendocrine skin carcinoma associated with calcitonin production:
a Merkel cell carcinoma?
37.) Cytokeratin 20 is a general marker of cutaneous Merkel cells while
certain neuronal proteins are absent.
38.) Neuroendocrine carcinoma of the skin (Merkel cell carcinoma). An
immunoelectron-microscopic case study.
39.) Somatostatin analogue scintigraphy. A simple and sensitive method for
the in vivo visualization of Merkel cell tumors and their metastases.
40.) Cytokeratin 20 in human carcinomas. A new histodiagnostic marker
detected by monoclonal antibodies.
41.) Merkel cell tumor of the back detected during pregnancy.
42.) Immunological studies on the occurrence and properties of
chromogranin A and B and secretogranin II in endocrine tumors.
43.) [Cervicofacial neuroendocrine Merkel cell carcinoma: radiotherapy] 
44.) p53 abnormalities are rare events in neuroendocrine (Merkel cell)
carcinoma
of the skin. An immunohistochemical and SSCP analysis. 
45.) Radiotherapy for Merkel cell carcinoma of the skin of the head and neck. 
46.) Lymph node Merkel cell carcinoma with no evidence of cutaneous
tumor--report of two cases. 
47.) Presumed choroidal metastasis of Merkel cell carcinoma. 
48.) Chemotherapy for Merkel cell carcinoma with carboplatin and etoposide. 
49.) Expression of alpha subunit of guanine nucleotide-binding protein Go in
Merkel cell carcinoma. 
50.) Deletion of chromosome arm 1p in a Merkel cell carcinoma (MCC). 
51.) The role of radiation therapy and chemotherapy in the treatment of Merkel
cell carcinoma. 
=======================================================================
=======================================================================
1.) Merkel cell carcinoma. Diagnosis and treatment.
========================================================================
SO - Dermatol Surg 1995 Aug;21(8):669-83
AU - Haag ML; Glass LF; Fenske NA
AD - Division of Dermatology and Cutaneous Surgery, University of South
Florida College of Medicine, Tampa 33612, USA.
PT - JOURNAL ARTICLE; REVIEW (175 references); REVIEW, ACADEMIC
AB - BACKGROUND. Merkel cell carcinoma is an uncommon malignancy of the
skin that often portends a poor prognosis. Since its first description by
Toker in 1972, a plethora of case reports and articles regarding the
etiopathogenesis and treatment have been published spanning multiple
medical and surgical disciplines. Much confusion still exists regarding the
diagnosis and treatment of this ominous tumor. OBJECT. Through extensive
review of the medical, surgical, and pathological literature, to collate
the observations of multiple investigators and summarize these findings.
METHODS. Articles from journals of multiple subspecialties were carefully
with particular emphasis placed on epidemiology, prognosis,
histology, immunohistochemistry, electron microscopy, tumor origin,
treatment, and work-up of Merkel cell carcinoma. RESULTS. Merkel cell
carcinoma is an aggressive malignant neoplasm. Local recurrence develops in
-44% of patients despite therapy. Up to three-fourths of patients
eventually develop regional nodal metastases with distant metastases
occurring in one-third of all patients. Reported overall 5-year survival
rates range from 30% to 64%. CONCLUSION. Treatment recommendations
unfortunately are based more on anecdotal than scientific data because of
the rarity of the tumor and its recognized high risk. Most authors
recommend wide local excision of the primary lesion and regional lymph node
resection if lymph nodes are palpable followed by x-irradiation of both the
postsurgical bed and lymph node basin. The role of elective lymph node
resection in the absence of clinically positive nodes remains controversial.

========================================================================
2.) Is aggressive surgical management justified in the treatment of
========================================================================
Merkel cell carcinoma? [see comments]
CM - Comment in: Plast Reconstr Surg 1995 Jul; 96(1):237
SO - Plast Reconstr Surg 1994 Dec;94(7):970-5
AU - Shack RB; Barton RM; De Lozier J; Rees RS; Lynch JB
AD - Department of Plastic Surgery, Vanderbilt University Medical Center,
Nashville, Tenn.
PT - JOURNAL ARTICLE
AB - Since its original description in 1972, we have seen and personally
treated a group of 15 patients with Merkel cell carcinoma at the Vanderbilt
Medical Center and the Nashville VA Hospital. We will review the
demographics, management, and clinical course of this extremely lethal but
initially benign appearing cutaneous malignancy. The majority of lesions
occur on the head and neck, followed by the extremities and trunk. Location
of the primary tumor has no effect on outcome. Despite a high mortality in
our series (10 of 15), early recognition and aggressive surgical therapy
may be the only way to prolong survival. No other adjuvant therapy has
proved effective.

========================================================================
3.) Merkel cell carcinoma. Histopathology, immunohistochemistry, and
cytogenetic analysis.
========================================================================
SO - J Dermatol Surg Oncol 1994 Oct;20(10):648-52; quiz 653-4
AU - Tope WD; Sangueza OP
AD - Department of Dermatology, Oregon Health Sciences University, Portland.
PT - JOURNAL ARTICLE
AB - BACKGROUND. Merkel cell carcinoma (MCC) is a cutaneous neoplasm,
histopathologically difficult to differentiate from other small blue cell
neoplasms. Immunohistochemical and ultrastructural analyses are usually
helpful in differentiating these neoplasms. Recently, cytogenetic analysis
has emerged as a potential tool in the diagnosis of solid neoplasms,
including MCC. OBJECTIVE. To describe the immunohistochemical and
cytogenetic features of a case of primary MCC and to review the
cytogenetics literature on MCC. METHODS. Formalin-fixed tissue was
processed routinely and labeled with a battery of antibodies. Metaphase
cells from fresh tissue were prepared by Giemsa banding. RESULTS.
Histopathologically, there were irregular aggregates of pyknotic cells with
little cytoplasm. Immunohistochemically, the neoplastic cells stained
positive for neurofilament, cytokeratin, neuron-specific enolase, and
epithelial membrane antigen. Leucocyte common antigen, S-100, 013, and
chromogranin were negative. Karyotyping of neoplastic cells showed loss of
chromosome Y (-Y). CONCLUSIONS. Coexpression of cytokeratin and
neurofilament is characteristic of MCC and allows it to be differentiated
from similar neoplasms. The significance of Y chromosome loss is unclear.
Further cytogenetic analyses are warranted to identify genetic mutations
significant to the pathogenesis of MCC.

========================================================================
4.) Merkel's cell (neuroendocrine) carcinoma of the vulva.
========================================================================
SO - Cancer 1994 Apr 15;73(8):2186-91
AU - Chen KT
AD - Department of Pathology, Saint Agnes Medical Center, Fresno,
California 93720.
PT - JOURNAL ARTICLE; REVIEW (15 references); REVIEW OF REPORTED CASES
AB - BACKGROUND. Merkel's cell carcinoma rarely arises in the vulva. It is
unclear whether those cases arising in the vulva behave differently from
the usual Merkel's cell carcinomas. METHODS. A Merkel's cell carcinoma of
the vulva was studied by light microscopy, immunohistochemistry, and
electron microscopy. The clinical data of this case and of other reported
cases are summarized and compared with those of Merkel's cell carcinoma in
general. RESULTS. This tumor showed the characteristic trabecular pattern
of Merkel's cell carcinoma. The tumor cells were immunoreactive to
low-molecular-weight cytokeratin and neuron-specific enolase. This patient
was treated initially with local excision. She died 17 months later with
progressive metastatic disease unresponsive to chemotherapy. This case
study and the review of six other cases indicate that Merkel's cell
carcinoma of the vulva is universally metastatic, both to the regional
lymph nodes and distant sites, and that it invariably follows a rapidly
fatal course. CONCLUSION. Merkel's cell carcinoma of the vulva appears to
have a biologic behavior more aggressive than that of Merkel's cell
carcinoma in general. An initial modality combining chemotherapy, with or
without irradiation, with aggressive surgery should be tried in future cases.

=======================================================================
5.) CD44 expression in Merkel cell carcinoma may correlate with risk of
metastasis.
=======================================================================
SO - J Cutan Pathol 1994 Feb;21(1):22-6
AU - Penneys NS; Shapiro S
AD - Division of Dermatology, St. Louis University School of Medicine,
Missouri 63104.
PT - JOURNAL ARTICLE
AB - We retrospectively studied 25 cases of cutaneous primary, locally
recurrent or metastatic Merkel cell carcinoma to see if expression of the
cell surface marker CD44 correlated with metastatic potential. In 3 of 6
cases in which metastasis was documented, CD44 was found on membranes of
tumor cells. Three cutaneous lesions associated with local metastasis did
not express CD44. Three primary tumors expressed CD44 but had not
disseminated at the time of this report; follow-up after excision of the
primary lesion in these cases was less than 6 months. None of the primary
or locally recurrent Merkel cell carcinomas followed longer than 6 months
(14 of 19 cases) expressed CD44. We conclude that expression of CD44 in
Merkel cell carcinoma may eventually be of some value in the assessment of
prognosis of cutaneous Merkel cell carcinoma.

=======================================================================
6.) Neuroendocrine (Merkel cell) carcinoma with an intraepidermal component.
=======================================================================
SO - Am J Dermatopathol 1993 Dec;15(6):528-33
AU - Smith KJ; Skelton HG 3d; Holland TT; Morgan AM; Lupton GP
AD - Department of Dermatopathology, Armed Forces Institute of Pathology,
Washington, D.C. 20306.
PT - JOURNAL ARTICLE
AB - We present 11 cases of primary neuroendocrine (Merkel cell) carcinoma
of the skin with an intraepidermal component that were identified in a
larger review of Merkel cell carcinomas. Among these is a case with a
follow-up of over 11 years in which the primary lesion appeared as bowenoid
dysplasia, with subsequent recurrences as intraepidermal Merkel cell
carcinoma with focal tubular differentiation, and then with dermal invasion
and lymph node metastasis. In addition to immunohistochemical markers
commonly used in the identification of Merkel cell carcinomas
(neuron-specific enolase and cytokeratin), these tumors stained with
Ber-EP4, an immunohistochemical marker used to identify carcinomas. We
believe that these histopathologic and immunohistochemical features further
confirm that Merkel cell carcinomas represent an epithelial tumor with the
potential for neuroendocrine and adnexal differentiation.

=======================================================================
7.) The treatment of advanced Merkel cell carcinoma. A multimodality
chemotherapy and radiation therapy treatment approach.
=======================================================================
SO - J Dermatol Surg Oncol 1993 Sep;19(9):860-4
AU - Fenig E; Lurie H; Klein B; Sulkes A
AD - Institute of Oncology, Beilinson Medical Center, Petah Tiqva, Israel.
PT - JOURNAL ARTICLE
AB - BACKGROUND. The optimal management of Merkel cell carcinoma has not
been clearly defined. OBJECTIVE. To describe the treatment of eight
patients who presented with Merkel cell carcinoma. METHODS. Eight patients
with advanced locoregional Merkel cell carcinoma were seen in our institute
over a 7-year period. Four patients were successfully treated by induction
chemotherapy after excisional biopsy, followed by radiotherapy. Three
patients died from widespread metastases and one from neutropenic sepsis
induced by chemotherapy. RESULTS. These cases demonstrate the potential
lethality and aggressive nature of this rare skin tumor despite its
chemosensitive and radioresponsive character. In all four patients who are
alive and disease-free, chemotherapy was given first and radiotherapy was
given as consolidation. CONCLUSION. We suggest that a multimodality
treatment approach--chemotherapy followed by radiotherapy--is indicated in
patients with advanced Merkel cell carcinoma.

=======================================================================
8.) Merkel cell tumor of the head and neck. Five new cases with
literature review.
======================================================================
SO - Arch Otolaryngol Head Neck Surg 1993 Jul;119(7):782-6
AU - Rice RD Jr; Chonkich GD; Thompson KS; Chase DR
AD - Department of Surgery (Head and Neck Division), Loma Linda University
School of Medicine, CA.
PT - JOURNAL ARTICLE; REVIEW (29 references); REVIEW, TUTORIAL
AB - Merkel cell carcinoma (MCC) of the skin is an uncommon, but highly
aggressive neoplasm with a marked propensity for local and distant
metastasis. Despite the fact that more than half of the 600 cases of MCC
reported in the literature involved primary sites in the head and neck, MCC
has rarely been discussed in otolaryngology publications. We present five
new cases of MCC of the head and neck and summarize 89 additional cases
from the literature in which detailed treatment and survival data were
given. Our findings again emphasize the difficulty in making the initial
histopathologic diagnosis of MCC and demonstrate the necessity of early
diagnosis and multimodality treatment.

======================================================================
9.) Chromosomes 1, 11, and 13 are frequently involved in karyotypic
abnormalities in metastatic Merkel cell carcinoma.
======================================================================
SO - Cancer Genet Cytogenet 1993 May;67(1):65-70
AU - Leonard JH; Leonard P; Kearsley JH
AD - Queensland Radium Institute Laboratory, Queensland Institute of
Medical Research, Brisbane, Australia.
PT - JOURNAL ARTICLE
AB - We report a cytogenetic study of six Merkel cell carcinomas (MCC) in
which rearrangement of chromosome 1 was noted in four cases: two cases were
trisomic, in one case there was a reciprocal translocation between
chromosomes 1 and 5 [t(1; 5)(p36; p13)], and in the fourth case all cells
had a normal chromosome 1 and three derivatives, a del(1)(p22) and
del(1)(q21), and a translocation involving material of unknown origin to
the long arm, t(1; ?)(q21; ?). Four cases demonstrated loss of chromosome
13; in two of these, both copies were lost, and the survival for these two
patients was much longer than is common for MCC patients. Partial trisomy
of chromosome 11 was noted in two cases, and two patients demonstrated loss
of chromosome 22 in all cells examined. Although no consistent chromosome
change was noted in our cases, our data and those of previously published
reports, show that abnormalities of chromosomes 1, 11, and 13 occur in
30-47% of cytogenetic reports of this rare malignancy.

======================================================================
10.) Merkel cell carcinoma of the labial mucosa. An immunohistochemical and
ultrastructural study with a review of the literature on oral Merkel cell
carcinomas.
======================================================================
SO - Oral Surg Oral Med Oral Pathol 1992 Aug;74(2):193-200
AU - Vigneswaran N; Muller S; Lense E; Stacey B; Hewan-Lowe K; Weathers DR
AD - Department of Oral Pathology, Emory University School of Medicine,
Atlanta, GA.
PT - JOURNAL ARTICLE; REVIEW (32 references); REVIEW OF REPORTED CASES
AB - Merkel cell carcinoma is a rare cutaneous neuroendocrine tumor that
occurs predominantly in the head and neck region of older patients. An
88-year-old white man had an erythematous, umbilicated tumor on his lower
lip, which on histopathologic examination showed solid sheets of
infiltrating basaloid round cells with a high mitotic index. Globular,
paranuclear immunostaining for low-molecular-weight cytokeratins (Nos. 8,
18, and 19) and neurofilament was observed. On ultrastructural examination,
the tumor cells demonstrated paranuclear whorls of intermediate filament
aggregates and occasional electron-dense granules. This unique cytokeratin-
and neurofilament-staining pattern with coexpression enabled the Merkel
cell carcinoma to be differentiated from other small cell malignant tumors
that included metastatic neuroendocrine carcinomas from other regions. The
follow-up 1 year after surgery and radiation showed that the patient
remained disease free. Review of the literature revealed 11 cases of oral
Merkel cell carcinomas with a predilection for the labial mucosa of older
men. The mode of treatment and the clinical course of these cases are also
presented, with an update on therapeutic management of Merkel cell carcinomas.

======================================================================
11.) Neuroendocrine carcinoma within lymph nodes in the absence of a
primary tumor, with special reference to Merkel cell carcinoma [see comments]
======================================================================
CM - Comment in: Am J Surg Pathol 1993 Jul; 17(7):746; discussion 747-8;
Comment in: Am J Surg Pathol 1993 Jul; 17(7):747; discussion 747-8; Comment
in: Am J Surg Pathol 1993 Sep; 17(9):954
SO - Am J Surg Pathol 1992 Jul;16(7):658-66
AU - Eusebi V; Capella C; Cossu A; Rosai J
AD - Istituti di Anatomia e Istologia Patologica, Bologna, Italy.
PT - JOURNAL ARTICLE
AB - We report eight cases of neuroendocrine carcinomas found within
inguinal (five cases), axillary (two cases), and submandibular (one case)
lymph nodes. The patients underwent extensive investigations, but no
primary tumor was found in any case. Although the existence of an occult or
regressed primary cannot be ruled out, the possibility of a lymph node
origin should be considered on the basis of epithelial inclusions or
anomalous carcinomatous differentiation of stem cells of the
lymphoreticular system.

======================================================================
12.) Pagetoid intraepidermal spread in Merkel cell (primary
neuroendocrine) carcinoma of the skin.
======================================================================
SO - Am J Surg Pathol 1992 Jun;16(6):584-92
AU - Le Boit PE; Crutcher WA; Shapiro PE
AD - Department of Pathology, University of California, San Francisco
94143-0506.
PT - JOURNAL ARTICLE
AB - Pagetoid intraepidermal spread of neoplastic cells was noted in six
cases of Merkel (primary neuroendocrine) cell carcinoma of the skin. In two
cases, the volume of the intraepidermal portion of the neoplasm was either
equal to or more extensive than the dermal component. The intraepidermal
component in all six cases was remarkable because of the following
findings: the presence of cells with scant cytoplasm arranged both
individually and as nests, sometimes along the dermoepidermal junction;
splaying of the apical portions of basal keratinocytes by solitary
neoplastic cells; incomplete rims of compressed basal keratinocytes at the
peripheries of some junctional nests; and occasional contiguity of
neuroendocrine carcinoma cells with those of Bowen's disease or solar
keratosis. These features can be used to distinguish these Merkel cell
carcinomas from other lesions that have a pagetoid pattern, even in
superficial biopsies, and immunohistochemistry can confirm the diagnosis or
resolve problematic cases. The occurrence of cutaneous neuroendocrine
carcinoma situated largely in the epidermis raises the possibility that
some of these tumors may arise from intraepidermal Merkel cells.

======================================================================
13.) Multiple hamartoma syndrome (Cowden's disease) associated with renal
cell carcinoma and primary neuroendocrine carcinoma of the skin (Merkel
cell carcinoma).
======================================================================
SO - Am J Clin Pathol 1992 May;97(5):705-12
AU - Haibach H; Burns TW; Carlson HE; Burman KD; Deftos LJ
AD - Department of Pathology, University of Missouri-Columbia.
PT - JOURNAL ARTICLE
AB - A case of multiple hamartoma syndrome (Cowden's disease) associated
with renal cell adenocarcinoma and primary neuroendocrine carcinoma of the
skin is described. Neither of these neoplasms has been documented
previously in association with this genodermatosis. A search for epidermal
growth factor receptor (c-erb-B protooncogene) gene abnormalities in the
kidney, liver, and thyroid, as well as in tissue of the primary
neuroendocrine carcinoma, was negative. Serum obtained from the patient
before his death contained elevated levels of both chromogranin A (2641
ng/mL; normal level, less than 20 ng/mL) and calcitonin (517 pg/mL; normal
level, less than 200 pg/mL), suggesting that the patient's principal tumor
was neuroendocrine in origin.

======================================================================
14.) Merkel cell carcinoma. Prognosis and management.
======================================================================
SO - Arch Surg 1991 Dec;126(12):1514-9
AU - Yiengpruksawan A; Coit DG; Thaler HT; Urmacher C; Knapper WK
AD - Department of Surgery, Memorial Sloan-Kettering Cancer Center, New
York, NY 10021.
PT - JOURNAL ARTICLE
AB - Seventy patients with Merkel cell carcinoma were treated at Memorial
Sloan-kettering Cancer Center between 1969 and 1989. The overall estimated
5-year survival rate was 64%. Factors predictive of improved survival
included head and neck site and negative lymph nodes at presentation. Local
recurrence was seen in 18 patients (26%) and did not correlate with
patient-, tumor-, or treatment-related variables. Nine patients with local
recurrence (50%) were free of disease following aggressive reoperation.
Regional nodes were involved at some point during the course of the disease
in forty-six patients (66%). Regional lymph node involvement was apparent
within 2 years of diagnosis in 40 (87%) of 46 patients in whom it occurred.
Systemic disease was nearly uniformly preceded by the appearance of nodal
metastases and was uniformly fatal regardless of subsequent therapy. This
suggests an orderly "cascade" pattern of spread for this tumor, in which
elective regional lymph node dissection may be justified. Our
recommendations for treatment include a wide excision of the primary tumor
and either elective or early therapeutic regional node dissection. The role
of adjuvant radiotherapy or chemotherapy remains unproven.

======================================================================
15.) Hyperthermia and radiation therapy in the treatment of recurrent
Merkel cell tumors.
======================================================================
SO - Cancer 1988 Oct 15;62(8):1479-86
AU - Knox SJ; Kapp DS
AD - Department of Radiation Oncology, Stanford University, School of
Medicine, California 94305.
PT - JOURNAL ARTICLE; REVIEW (33 references); REVIEW OF REPORTED CASES
AB - A high incidence of local recurrence, spread to regional lymph nodes,
and distant metastases has been reported after surgical excision of Merkel
cell tumors (MCT). The use of postoperative radiation therapy and/or
chemotherapy is reviewed from the literature. Despite adjuvant treatment,
local tumor recurrences frequently develop. Two patients are presented with
metastatic MCT recurrent in previously irradiated sites who had excellent
clinical responses and local control following retreatment with local
hyperthermia in conjunction with low to moderate dose radiation therapy.
These patients represent the first reported use of hyperthermia in the
management of MCT. The encouraging local responses described suggest a
potential role for the use of hyperthermia and concomitant radiation
therapy in the treatment of recurrent MCT.

======================================================================
16.) Merkel cell carcinoma. Improved locoregional control with
postoperative radiation therapy.
======================================================================
SO - Cancer 1991 Sep 1;68(5):1004-8
AU - Wilder RB; Harari PM; Graham AR; Shimm DS; Cassady JR
AD - Department of Radiation Oncology, University Medical Center, Tucson,
Arizona 85724.
PT - JOURNAL ARTICLE; REVIEW (23 references); REVIEW LITERATURE
AB - Between April 1981 and May 1990, 11 patients with Merkel cell
carcinoma were treated with radiation therapy in Tucson, Arizona. The
length of follow-up time from the time of irradiation ranged from 6 to 64
months. Locoregional control was maintained in seven of eight patients
treated with surgery and postoperative radiation therapy for primary or
recurrent cancer. The other three patients had bulky metastatic disease at
the time of referral. Palliation was achieved in all three patients with
radiation therapy. Hyperthermia also appeared to be beneficial in the one
patient in which it was used, and chemotherapy achieved responses in two of
four patients. These results, combined with a review of the literature,
suggest that the administration of radiation therapy postoperatively to
both the surgical bed and the draining lymph nodes improves locoregional
control and may result in long-term disease-free survival when administered
after the initial surgical resection.

======================================================================
17.) Giant neuroendocrine (Merkel cell) carcinoma of the skin.
======================================================================
SO - J Am Acad Dermatol 1991 May;24(5 Pt 2):827-31
AU - Tada J; Toi Y; Yamada T; Yasutomi H; Nagao Y; Arakawa K; Arata J
AD - Department of Dermatology, Okayama University Medical School, Japan.
PT - JOURNAL ARTICLE
AB - An 82-year-old woman had a dark red to purple tumor on the left
buttock that had gradually enlarged during the last 5 years. Although
routine histologic examination was not sufficient for diagnosis,
neuroendocrine carcinoma was diagnosed by immunohistochemical and
ultrastructural studies. Immunohistochemical-positive reactions to
neurofilament, cytokeratin, neuron-specific enolase, and epithelial
membrane antigen were noted. Electron microscopically, membrane-bound,
dense core granules that yielded a positive uranaffin reaction and
intermediate filaments in the perinuclear area were observed in the
cytoplasm of most tumor cells. Desmosome-like structure between them was
also found. Approximately 6 months after local excision, metastatic lesions
developed in the regional lymph nodes and liver.

======================================================================
18.) Tumor lysis syndrome in a patient with metastatic Merkel cell carcinoma.
======================================================================
SO - Cancer 1991 Apr 15;67(8):2207-10
AU - Dirix LY; Prove A; Becquart D; Wouters E; Vermeulen P; Van Oosterom A
AD - Department of Medical Oncology, University Hospital Antwerp, Edegem,
Belgium.
PT - JOURNAL ARTICLE
AB - A first course of combination chemotherapy for large volume
metastatic disease in a patient with Merkel cell carcinoma resulted in a
tumor lysis syndrome. After this course a nearly complete response was
documented. This case report extends further the chemosensitivity of Merkel
cell carcinoma and demonstrates the need for tumor lysis syndrome
prophylaxis in patients with bulky disease or fast-growing tumors.

======================================================================
19.) Spontaneous regression in Merkel cell (neuroendocrine) carcinoma of
the skin.
======================================================================
SO - Arch Dermatol 1991 Apr;127(4):550-3
AU - Kayashima K; Ono T; Johno M; Kojo Y; Yamashita N; Matsunaga W
AD - Department of Dermatology, Kumamoto University Medical School, Japan.
PT - JOURNAL ARTICLE
AB - In two Japanese women, 68 and 88 years old, Merkel cell
(neuroendocrine) carcinoma of the face developed. Their tumors regressed
after biopsy was performed, a rare occurrence. Histological and electron
microscopic examination showed apoptosis, cellular necrosis, and an
infiltration composed mainly of lymphocytes in the tumors. These changes
may have been related to the mechanism of regression. It is interesting
that our two patients were women, as was another patient described with
Merkel cell carcinoma regression, in light of the fact that the prognosis
of this tumor is sex dependent.

======================================================================
20.) Merkel cell carcinoma metastatic to the testis.
======================================================================
SO - Am J Clin Pathol 1990 Oct;94(4):384-9
AU - Ro JY; Ayala AG; Tetu B; Ordonez NG; el-Naggar A; Grignon DJ; Mackay B
AD - Department of Pathology, University of Texas M. D. Anderson Cancer
Center, Houston 77030.
PT - JOURNAL ARTICLE
AB - Tumor metastases to the testes are rare and are usually found
incidentally at autopsy or after orchiectomy for prostatic carcinoma. It is
even more unusual for testicular metastases to be clinically detected or
symptomatic. The authors report two cases of clinically detected testicular
metastases from Merkel cell carcinoma of the skin. Merkel cell carcinoma
metastatic to the testes has not been reported previously. The two tumors,
to some degree, resembled testicular lymphomas and the interstitial type of
seminoma.

======================================================================
21.) The use of VP16 and cisplatin in the treatment of Merkel cell carcinoma.
======================================================================
SO - J Dermatol Surg Oncol 1990 Mar;16(3):276-8
AU - Davis MP; Miller EM; Rau RC; Johnson OE; Naille RA; Crnkovich MJ
AD - Riverside Regional Cancer Institute, Columbus, Ohio.
PT - JOURNAL ARTICLE
AB - A 70-year-old male with regionally recurrent Merkel cell cancer
obtained a complete remission with three cycles of VP16 and cisplatin. His
response was consolidated with local radiation therapy. Two additional
patients have been reported to have responded to the same combination.
Chemotherapy consisting of either cyclophosphamide, vincristine, and
doxorubicin or VP16 and cisplatin should be considered in locally recurrent
Merkel cell cancer.

======================================================================
22.) Radiotherapy as an adjunct in the management of Merkel cell carcinoma.
======================================================================
SO - Cancer 1990 Jan 1;65(1):60-4
AU - Marks ME; Kim RY; Salter MM
AD - Department of Radiation Oncology, University of Alabama, Birmingham
35233.
PT - JOURNAL ARTICLE
AB - Four patients with a diagnosis of Merkel cell carcinoma initially
underwent surgery followed by radiotherapy. Recurrent disease prompted use
of radiation in three cases. The three cases of recurrent disease
illustrate the aggressiveness of Merkel cell carcinoma and also provide
further documentation of the radiosensitivity of this tumor. Additionally,
these cases suggest that surgery alone frequently is inadequate to achieve
local control of disease.

======================================================================
23.) Neuroendocrine (Merkel cell) carcinoma of the skin: a
clinico-morphological study of 13 cases.
======================================================================
SO - Histopathology 1989 Nov;15(5):483-93
AU - Szadowska A; Wozniak L; Lasota J; Giryn I; Mirecka B; Wolska H
AD - Department of Oncology, Medical Academy of Lodz, Poland.
PT - JOURNAL ARTICLE
AB - The clinico-morphological features in 13 patients (nine female) with
neuroendocrine carcinoma of the skin are presented. The mean age was 64.9
years. The limbs were the most common site of primary tumour, followed by
the face. The clinical course was characterized by a high incidence of
regional lymph node metastases (69%) and recurrences (46%). Seven of the
patients died of tumour, with a mean survival time of 13 months.
Histologically, a solid pattern of tumour growth was most common. The cells
were usually small and uniform. Squamous cell differentiation was found in
one tumour. The cell of all tumours reacted positively for cytokeratins and
neuron-specific enolase. The positive reaction frequently had a ball-like
globular pattern, corresponding to inclusion-like bodies seen on light
microscopy and to paranuclear whorls of intermediate filaments observed on
electron microscopy. Neurosecretory granules were seen on electron
microscopy in the 11 cases examined and in one case a 'Luse body' was found
in the intercellular space.

======================================================================
24.) Merkel cell carcinoma.
======================================================================
SO - Arch Dermatol 1989 Aug;125(8):1096-100
AU - Hanke WC; Conner AC; Temofeew RK; Lingeman RE
AD - Department of Dermatology, Indiana University School of Medicine,
Indianapolis.
PT - JOURNAL ARTICLE
AB - Merkel cell carcinoma is an unusual primary cutaneous tumor with an
aggressive biologic nature. Following surgical treatment, 40% of patients
have local recurrences develop, 55% have regional lymph node metastases
develop, and 49% have distant metastases develop. We have treated four
patients with Merkel cell carcinoma; only one of the four patients was
alive and well after 2 years. Two patients died of metastatic disease, one
at 11 months following initial treatment and one at 39 months. The fourth
patient had a rapid recurrence following initial treatment and is currently
in remission following chemotherapy for regional metastases. Recent reports
indicate that chemotherapy may be helpful in treating patients with
recurrent or metastatic Merkel cell carcinoma.

======================================================================
25.) Merkel cell carcinoma. A successful treatment with tumor necrosis
factor.
======================================================================
SO - Arch Dermatol 1989 Aug;125(8):1093-5
AU - Ito Y; Kawamura K; Miura T; Ueda K; Onodera H; Takahashi H; Horikoshi
T; Sugiyama S; Takahashi M
AD - Department of Dermatology, Sapporo Medical College, Japan.
PT - JOURNAL ARTICLE
AB - A Merkel cell carcinoma of the mandibular area in a 78-year-old woman
was treated successfully by direct intratumoral administration of
recombinant human tumor necrosis factor. The patient received 2.5 x 10(5)
U/d of recombinant human tumor necrosis factor every other day. A total of
six injections (total dose, 1.5 x 10(6) U, 0.52 mg of protein) were
administered over a period of 12 days. Soon after the therapy ended, the
lesion softened and decreased in size. After 1 month, only erythema was
visible. The lesion had completely disappeared clinically and
histologically 5 months after the local injection of recombinant human
tumor necrosis factor. Neither recurrence nor metastasis has been observed
for at least 12 months following the treatment. Recombinant human tumor
necrosis factor is suggested to be effective for the treatment of Merkel
cell carcinoma.

======================================================================
26.) Involvement of chromosome 22 in a Merkel cell carcinoma in a patient
with a previous meningioma.
======================================================================
SO - Cancer Genet Cytogenet 1989 Mar;38(1):43-8
AU - Shabtai F; Sternberg A; Klar D; Reiss R; Halbrecht I
AD - B. Gattegno Research Institute, Hasharon Hospital, Golda Medical
Center, Petach Tikva, Israel.
PT - JOURNAL ARTICLE
AB - The relatively simple cytogenetic findings in an aggressive
metastatic Merkel cell carcinoma are reported. Deletion 2p was found in
100% of the cells. Nevertheless, this was considered a secondary
(metastatic?) change because the same aberration has been found in several
other kinds of malignancy. The involvement of chromosome 22 [del(22q) and
-22] in 85% of the cells seemed more intriguing, considering the fact that
the Merkel cell carcinoma followed a previous meningioma.

======================================================================
27.) Clinicopathologic correlations of cutaneous neuroendocrine Merkel
cell carcinoma.
======================================================================
SO - J Clin Oncol 1988 Dec;6(12):1863-73
AU - Pilotti S; Rilke F; Bartoli C; Grisotti A
AD - Division of Anatomic Pathology, Istituto Nazionale per lo Studio e la
Cura del Tumori, Milan, Italy.
PT - JOURNAL ARTICLE
AB - A study of 50 consecutive cases (22 men, 28 women; age range, 39 to
84 years; mean age, 65 years) of cutaneous neuroendocrine Merkel cell
carcinoma (CNC), 39 of whom had a mean follow-up of 34 months, revealed
that the prognostic significance of the histopathologic subtyping in
trabecular, solid, and diffuse variants of CNC was not as important as the
pathologic postsurgical staging in localized, regional, and extraregional
disease. The overall mortality was 23.5%. None of the 19 patients with
localized disease died of CNC, while 11% of the 24 patients with regional
disease and all seven patients with extraregional disease at presentation
died of CNC. A second primary malignancy was found to be associated with
the CNC in 15% of the cases. The clinical course in patients with localized
disease was favorable in spite of the high number of local recurrences.
Also, the presence of regional metastases was not related to an unfavorable
prognosis. In 68% of the cases the disease involved the lower limbs or
girdle. In ten cases the overt exophytic presentation of primary CNC was
replaced by the presence of tumor masses infiltrating the inguinal soft
tissues with or without nodal involvement.

======================================================================
28.) Chemotherapy for metastatic Merkel cell carcinoma. Review of the M.D.
Anderson Hospital's experience.
======================================================================
SO - Cancer 1988 Aug 15;62(4):683-5
AU - Feun LG; Savaraj N; Legha SS; Silva EG; Benjamin RS; Burgess MA
AD - Division of Medicine, M. D. Anderson Hospital and Tumor Institute,
Houston, Texas.
PT - JOURNAL ARTICLE; REVIEW (10 references); REVIEW, TUTORIAL
AB - Thirteen patients with regional or distant metastases from Merkel
cell carcinoma were treated with combination chemotherapy. Three patients
had a complete response to therapy. In two patients with nodal disease the
duration of response was 10+ and 4+ years. In addition, three patients had
a partial response, and six patients had minor responses. Chemotherapy
using a combination of drugs that are active against small cell carcinoma
of the lung is recommended in the treatment of unresectable disease in
patients with Merkel cell carcinoma; it may produce prolonged responses.
While tumor regressions as a result of chemotherapy were often dramatic,
once the disease progressed, the course of the disease often moved rapidly
downhill and proved to be fatal.

======================================================================
29.) Neuroendocrine (Merkel cell) carcinoma of the skin. Its natural
history, diagnosis, and treatment.
======================================================================
SO - Ann Surg 1988 Feb;207(2):201-7
AU - Hitchcock CL; Bland KI; Laney RG 3d; Franzini D; Harris B; Copeland
EM 3d
AD - Department of Pathology, University of Florida College of Medicine,
Gainesville.
PT - JOURNAL ARTICLE; REVIEW (66 references); REVIEW, TUTORIAL
AB - Over 400 cases of neuroendocrine (Merkel cell) carcinoma of the skin
(NCS) have been reported. This tumor continues to pose problems in
diagnosis and effective treatment for physicians unfamiliar with its
biological characteristics. Reported here are five additional cases of NCS
and the literature for this rare neoplasm is comprehensively reviewed. An
early and accurate diagnosis is made possible by combining clinical
presentation with results of histologic study, immunoperoxidase staining
for neuron-specific enolase (NSE), epithelial membrane antigen (EMA),
cytokeratins, and electron microscopy. NCS is an aggressive tumor.
Depending on the length of follow-up, up to 40% of tumors locally recur,
55% develop regional nodal metastases, and 36% undergo distant metastasis.
Survival is sex, but not age, dependent, with an overall 2-year survival
rate of 72% (males 58% vs. females 79%). No standard procedure for initial
and/or follow-up treatment for NCS exists. The authors recommend that NCS
be treated, whenever possible, using the same rationale as applied for the
treatment of squamous cell carcinoma of the skin.

======================================================================
30.) Recurrent and metastatic cutaneous neuroendocrine (Merkel cell)
carcinoma mimicking angiosarcoma.
======================================================================
SO - Arch Dermatol 1987 Oct;123(10):1368-70
AU - Tyring SK; Lee PC; Omura EF; Green LK; Merot Y
AD - Department of Dermatology, University of Alabama at Birmingham.
PT - JOURNAL ARTICLE
AB - An elderly man presented with bright red-to-purple confluent nodules
and plaques of the scalp that appeared clinically consistent with
angiosarcoma. He had undergone surgical removal of a similar lesion from
his left temple seven months before this presentation. Although routine
histologic examination was not sufficient for diagnosis, Merkel cell
carcinoma was diagnosed by immunohistochemical studies and electron
microscopy. In addition, oat cell carcinoma of the lung was excluded with a
computed tomographic scan of his chest. With chemotherapy, the recurrent
and metastatic lesions of Merkel cell carcinoma completely resolved,
rapidly recurred, and resolved a second time with chemotherapy. Eight
months following the fourth course of chemotherapy, the patient again
developed widespread cutaneous lesions. He committed suicide within one
month of this last recurrence. An autopsy revealed no primary tumor other
than of the skin.

======================================================================
31.) Trabecular (Merkel cell) carcinoma of the skin. Treatment of primary,
recurrent, and metastatic disease.
======================================================================
SO - Cancer 1986 Jan 1;57(1):178-82
AU - Raaf JH; Urmacher C; Knapper WK; Shiu MH; Cheng EW
PT - JOURNAL ARTICLE
AB - Four new patients with trabecular (Merkel cell) carcinoma of the skin
are described, and an additional 76 patients from the literature are
reviewed. The mean age of the combined group of patients was 68; 84% were
60 years or older. Primary tumors appeared most frequently on the head and
neck (44%), leg (28%), arm (16%), or buttock (9%). No primary tumor
appeared on the trunk. The rate of local recurrence was 36%, regional
metastatic disease, 53%; distant metastases, 28%; and death due to
metastatic tumor (minimally), 25%. It appears that trabecular carcinoma of
the skin is more aggressive and lethal than previously thought. The authors
recommend that patients with this tumor undergo wide resection of the
primary site and, in healthy patients, prophylactic regional node
dissection. Both radiation therapy and chemotherapy are effective in
palliating unresectable disease.

======================================================================
32.) Chemotherapy for metastatic Merkel cell carcinoma.
======================================================================
SO - Cancer 1985 Sep 1;56(5):1034-8
AU - George TK; di Sant'agnese PA; Bennett JM
PT - JOURNAL ARTICLE
AB - Merkel cell carcinomas (also known as trabecular carcinomas) are
primary cutaneous small cell neuroendocrine neoplasms with the potential to
metastasize. Control of disseminated disease is therefore important. A case
of metastatic Merkel cell carcinoma with an excellent response to
chemotherapy is presented. The regimen chosen for this case is similar to
that used for bronchogenic small cell anaplastic carcinoma. The reason for
selecting this regimen was the common neuroendocrine differentiation and
the similar histopathologic features of these two tumors. Only a few
reports have described chemotherapy for Merkel cell carcinoma and similar
agents were used. These cases are reviewed and critically analyzed.

======================================================================
33.) Electron microscopy of Merkel cell carcinoma from formalin-fixed tissue.
======================================================================
SO - J Am Acad Dermatol 1985 Mar;12(3):487-92
AU - Haneke E
PT - JOURNAL ARTICLE
AB - Merkel cell carcinomas have characteristic, but not pathognomonic,
histomorphologic features. The diagnosis can be confirmed by
immunohistochemistry studies and electron microscopy. However, differential
diagnostic problems often occur only after all tumor material has been
fixed in formalin and embedded in paraffin, which gives poor tissue
preservation for electron microscopy. Therefore, in addition to histologic
and immunohistochemical studies, parallel ultrastructural investigations
were performed on tumor specimens fixed in glutaraldehyde and routinely
processed, for electron microscopy, on formalin-fixed tissue and on
formalin-fixed paraffin blocks. Formalin fixation led to an almost complete
loss of neurosecretory granules and cell membranes; however, the
characteristic paranuclear whorls of intermediate filaments were retained
in all tumors. Merkel cell carcinomas are immunoreactive for
neuron-specific enolase (NSE), but NSE-antisera have only recently become
commercially available. Cytokeratin is demonstrable as a paranuclear clump,
and this feature was found in four out of six tumors. Thus histologic,
immunohistochemical, and electron microscopy studies of formalin-fixed
tissue are able to confirm the diagnosis of neuroendocrine Merkel cell
carcinoma.

======================================================================
34.) Primary neuroendocrine (Merkel cell?) carcinoma of the skin. I. A
clinicopathologic and ultrastructural study of 43 cases.
======================================================================
SO - Am J Surg Pathol 1985 Feb;9(2):95-108
AU - Sibley RK; Dehner LP; Rosai J
PT - JOURNAL ARTICLE
AB - The clinical and pathologic features of 43 cases of primary
neuroendocrine carcinoma of the skin are reported. These tumors arise in
the dermis and subcutaneous tissues of elderly individuals. The head and
neck are the most common primary sites followed by the lower and upper
extremities and trunk. Characteristic histologic features include round
cells with scanty amphophilic cytoplasm and vesicular nuclei with multiple
small nucleoli. The cells are arranged in sheets, solid nests, or
anastomosing trabeculae. Collections of perinuclear intermediate filaments,
cytoplasmic dense-core membrane-bound secretory granules, complex
intercellular junctions, and cytoplasmic spinous processes are the
principal fine structural features. These ultrastructural findings are
similar to those of the normal cutaneous Merkel cell. The natural history
of this neoplasm is characterized by local recurrence in 30% of cases,
regional lymph node metastases in 65% of cases, and distant metastases in
40%. One-third of the patients were dead because of their tumors. Treatment
of extensive local or distant metastatic disease with chemotherapy or
radiotherapy resulted in only short-term palliative response.

======================================================================
35.) Merkel cell carcinoma of the skin: the structure and origin of normal
Merkel cells.
======================================================================
SO - Histopathology 1983 Mar;7(2):229-49
AU - Frigerio B; Capella C; Eusebi V; Tenti P; Azzopardi JG
PT - JOURNAL ARTICLE
AB - A series of 15 Merkel cell tumours of skin is reported. They occur
dominantly on the head and neck and on the extremities of elderly women,
frequently presenting as a reddish nodule. Three cases were associated with
squamous carcinoma at the same site, an association deserving further
study. There are two main patterns: the commoner one takes the form of a
trabecular carcinoma in the dermis mimicking metastatic carcinoma,
including oat-cell carcinoma and neuroblastoma: a dissociated-cell form
mimicks malignant lymphoma. The triad of vesicular nuclei with very small
nucleoli, abundant mitotic activity and apoptosis is so characteristic as
to be virtually pathognomonic in conjunction with structural features.
Argyrophilia is common, but Bouin fixation is necessary to demonstrate it
regularly. Small round secretory granules (89 +/- 18 nm) with narrow
haloes, and an abundance of intermediate size filaments are among the
ultrastructural hallmarks. There is a close similarity between better
differentiated tumour cells and normal Merkel cells. The neural crest
origin of MC is in doubt both on the basis of studies of the development
and regeneration of MC and from the study of Merkel cell tumours.

======================================================================
36.) Neuroendocrine skin carcinoma associated with calcitonin production:
a Merkel cell carcinoma?
======================================================================
SO - Hum Pathol 1980 Sep;11(5 Suppl):586-8
AU - Johannessen JV; Gould VE
PT - JOURNAL ARTICLE
AB - An elderly woman presented with an ulcerating skin carcinoma located
over the right parietal area. It healed after local radiotherapy but
recurred locally and metastasized to the subcutaneous tissue and one
regional lymph node. Neurosecretory granules were demonstrated
ultrastructurally, and blood levels of calcitonin were repeatedly elevated.
A metastasizing medullary carcinoma of the thyroid was suspected, and a
total thyroidectomy was performed; however, no medullary carcinoma or C
cell hyperplasia could be identified. Furthermore, the calcitonin levels
remained unchanged following thyroidectomy, whereas they decreased twice
after the skin tumor or its metastases were ablated. Clinical follow-up for
over seven years revealed no other lesion that could have been responsible
for the overproduction of calcitonin. The ultrastructural features of this
skin carcinoma and its metastases, particularly the neurosecretory
granules, were reminiscent of those of the so-called Merkel cell. We
conclude that this skin carcinoma might indeed produce calcitonin, that
this tumor may be derived from Merkel cells, and that Merkel cells may
belong within the APUD system.

======================================================================
37.) Cytokeratin 20 is a general marker of cutaneous Merkel cells while
certain neuronal proteins are absent.
======================================================================
SO - J Invest Dermatol 1995 Jun;104(6):910-5
AU - Moll I; Kuhn C; Moll R
AD - Department of Dermatology, Mannheim Medical School, University of
Heidelberg, Germany.
PT - JOURNAL ARTICLE
AB - Merkel cells are difficult to identify in tissue sections. Previous
studies have used cytokeratins (CK) 8, 18, and 19 as histologic markers of
Merkel cells. However, these CKs are also expressed in some outer root
sheath keratinocytes and some early fetal epidermal cells and thus are not
truly specific of Merkel cells in general. Using selective antibodies
against a newly described CK, number 20--originally found in intestinal
epithelium and Merkel cell carcinomas--in comparison to a key protein of
neuroendocrine cells, chromogranin A, we established CK 20 as a specific
Merkel cell marker in skin of humans, pigs, and mice. CK 20 seems to be an
even more general and sensitive Merkel cell marker as compared to CgA. In
double-labeling experiments with stratified-squamous epithelial CK (numbers
5 and 13-17) and simple epithelial CK (numbers 8, 18, and 20) antibodies
evaluated by confocal laser scanning microscopy, no cell expressing CKs of
both types (i.e., no cell of so-called "transitional" character between
Merkel cells and keratinocytes) was identified in human skin. In addition,
various neuronal markers present in Merkel cell carcinomas including
neurofilaments, peripherin, nerve growth factor receptor, and neuronal cell
adhesion molecule appear to be absent in normal Merkel cells. Thus, Merkel
cells exhibit a distinct and unique marker profile, with CK 20 being of
particularly high value in various species.

======================================================================
39.) Somatostatin analogue scintigraphy. A simple and sensitive method for
the in vivo visualization of Merkel cell tumors and their metastases.
======================================================================
SO - Arch Dermatol 1992 Jun;128(6):818-21
AU - Kwekkeboom DJ; Hoff AM; Lamberts SW; Oei HY; Krenning EP
AD - Department of Medicine, University Hospital Dijkzigt, The Netherlands.
PT - JOURNAL ARTICLE
AB - BACKGROUND--Trabecular carcinomas of the skin, or Merkel cell tumors,
are aggressive neoplasms that tend to occur in sun-exposed skin. These
tumors frequently metastasize and, despite therapy, the number of
disease-related deaths is high. Ultrastructurally and immunocytochemically,
the majority of these tumors have neuroendocrine characteristics. Recently,
we described the in vivo visualization of various neuroendocrine tumors
after injection of a radiolabeled somatostatin analogue (octreotide). In
this study, we report the results of scintigraphy with radioactive-labeled
somatostatin analogues in five patients with Merkel cell tumors.
OBSERVATIONS--In all four patients in whom tumor was detected using
computed tomographic scanning and ultrasound, the tumor sites were also
demonstrated on octreotide scintigrams. In one patient, a tumor with a
diameter that was smaller than 0.5 cm could not be detected with octreotide
scintigraphy, computed tomography, or ultrasound. Using octreotide
scintigraphy we found presumed tumor spots in two patients that were not
evident when other techniques were used. CONCLUSIONS--Octreotide
scintigraphy has an equal or even greater sensitivity than computed
tomography and ultrasound for detecting Merkel cell tumors and their
metastases. Establishing the spread of the disease in this way may ensure
an optimal choice of treatment in patients with this type of tumor.

======================================================================
40.) Cytokeratin 20 in human carcinomas. A new histodiagnostic marker
detected by monoclonal antibodies.
======================================================================
SO - Am J Pathol 1992 Feb;140(2):427-47
AU - Moll R; Lowe A; Laufer J; Franke WW
AD - Institute of Pathology, University of Mainz Medical School, Federal
Republic of Germany.
PT - JOURNAL ARTICLE
AB - The authors have recently identified a new cytokeratin (CK)
polypeptide, CK 20, whose expression is almost entirely confined to the
gastric and intestinal epithelium, urothelium, and Merkel cells. Seven
monoclonal antibodies (MAbs) specific for CK 20 were raised and
characterized by applying immunoblotting and immunocytochemical screening.
All of them reacted on frozen tissue sections. A further MAb, IT-Ks20.8,
recognized CK 20 in sections of formalin-fixed, paraffin-embedded tissue
samples. A total of 711 cases of primary and metastatic cancer, mostly
carcinomas, were analyzed immunohistochemically for CK-20 expression, using
CK-20 specific guinea-pig antibodies and MAbs. The expression spectrum of
CK 20 in carcinomas resembled that seen in the corresponding normal
epithelia of origin. CK-20 positivity was seen in the vast majority of
adenocarcinomas of the colon (89/93 cases), mucinous ovarian tumors,
transitional-cell and Merkel-cell carcinomas and frequently also in
adenocarcinomas of the stomach, bile system, and pancreas. Most squamous
cell carcinomas in general and most adenocarcinomas from other sites
(breast, lung, endometrium), nonmucinous tumors of the ovary, and
small-cell lung carcinomas were essentially or completely negative. The
authors propose to use CK 20 as a diagnostic marker valuable in
distinguishing different types of carcinomas, notably when presenting as
metastases.

======================================================================
41.) Merkel cell tumor of the back detected during pregnancy.
======================================================================
SO - Plast Reconstr Surg 1990 Aug;86(2):347-51
AU - Chao TC; Park JM; Rhee H; Greager JA
AD - Department of Surgery, University of Illinois College of Medicine,
Chicago.
PT - JOURNAL ARTICLE
AB - Merkel cell tumor is an unusual, aggressive malignancy of skin that
has been considered to be derived from cutaneous Merkel cells. We are
reporting a case of Merkel cell tumor overlying the left scapula with
metastases to the thoracic spine and pleura. The tumor was found
incidentally in a 23-year-old pregnant black woman. The tumor recurred
locally 5 months after initial wide excision. Subsequently, a second wide
excision of the recurrent tumor with ipsilateral axillary dissection was
performed. The course of the disease was complicated by local recurrence
and formation of distant metastases to pleura and spine. At the end-stage
of the disease, the patient was found to have a cardiac murmur, and
echocardiography revealed a mass in the anterior wall of the right
ventricle that was suspicious for a metastatic lesion. The patient expired
from extensive distant metastases 23 months after diagnosis.

======================================================================
42.) Immunological studies on the occurrence and properties of
chromogranin A and B and secretogranin II in endocrine tumors.
======================================================================
SO - Am J Surg Pathol 1988 Nov;12(11):877-84
AU - Weiler R; Fischer-Colbrie R; Schmid KW; Feichtinger H; Bussolati G;
Grimelius L; Krisch K; Kerl H; O'Connor D; Winkler H
AD - Department of Pharmacology, University of Innsbruck, Austria.
PT - JOURNAL ARTICLE
AB - We investigated a variety of endocrine tumors for the presence of
chromogranins A and B and secretogranin II. These antigens were identified
by one- and two-dimensional immunoblotting and in some cases by
immunohistochemistry. An antigen corresponding in electrophoretic behavior
to adrenal chromogranin A was present in all types of tumors, including
insulinomas, oat cell carcinomas, and Merkel cell tumors of the skin.
Chromogranin B had a much more limited distribution. This antigen could not
be detected in parathyroid adenomas, oat cell carcinomas, or Merkel cell
tumors, either by immunoblotting and immunohistochemistry. The occurrence
of secretogranin II was similar to that of chromogranin B, with the
exception of a positive reaction in Merkel cell tumors. In benign
pheochromocytomas, all three antigens were found consistently; whereas in
two of three malignant pheochromocytomas, chromogranin B was absent. Our
study establishes that in most cases chromogranins and secretogranin in
tumors are identical to the adrenal antigens, but that these antigens are
not always stored together. Chromogranin A is the most widely distributed
marker for endocrine tumors.

======================================================================
43.) [Cervicofacial neuroendocrine Merkel cell carcinoma: radiotherapy] 
======================================================================
Author 
Volino F; Galera F; Catalano E; Di Gennaro D; Russo R 
Address 
Divisione di Otorinolaringoiatria, Ospedali Riuniti, Salerno. 
Source 
Acta Otorhinolaryngol Ital, 14(6):651-7 1994 Nov-Dec 
Abstract 
The Authors report a case of Merkel cell carcinoma of the cervicofacial
district, particular due to its clinical and evolutive characteristics. The
Merkel cell carcinoma was first identified by Toker in 1972 and is also
known as a primary neuroendocrine the or trabecular carcinoma of the skin.
The Merkel cell carcinoma is a rare aggressive skin cancer most frequently
localized in the cervicofacial district. Although in earlier reports on the
clinical history of these tumors primary emphasis was placed on their local
aggressive behaviour, it has recently become evident that these neoplasms
have a marked propensity for early dissemination. Distant metastases are
often responsible for disease-related mortality. Merkel cell carcinoma have
classically been managed with surgery alone or surgery followed by
radiation therapy. Treatment of Merkel cell carcinoma with radiation
therapy alone has usually been reserved for advanced unresectable tumors. 

======================================================================
44.) p53 abnormalities are rare events in neuroendocrine (Merkel cell)
carcinoma
of the skin. An immunohistochemical and SSCP analysis. 
======================================================================
Author 
Schmid M; Janssen K; Dockhorn-Dworniczak B; Metze D; Zelger BW; Luger TA;
Schmid KW 
Address 
Clinic of Dermatology, University of M¨unster, Germany. 
Source 
Virchows Arch, 430(3):233-7 1997 Mar 
Abstract 
The aim of the present study was to assess a possible role of the tumour
suppressor gene p53 in neuroendocrine (Merkel cell) carcinoma of the skin
with regard to tumour development and tumour progression. p53 was
investigated in a series of routinely processed Merkel cell carcinomas,
with application of four different p53 antibodies (CM-1, PAb1801, DO7, and
PAb240) to 25 carcinomas and screening for p53 mutations of exons 4-8 by
single-strand conformation polymorphism (SSCP) analysis in 9 cases. All 25
tumours in the present series showed the characteristic microscopic and
immunohistochemical features of Merkel cell carcinoma of the skin. In 5 of
the 25 Merkel cell carcinomas investigated 5-10% of tumour cell nuclei
showed a positive p53 reaction with at least one anti-p53 antibody. A few
scattered p53 positive nuclei were found in an additional 9 cases. The
remaining 11 cases completely lacked p53 immunostaining. SSCP analysis of
exons 4-8 revealed no significant alterations in the mobility shift of the
single strand DNAs in the five cases with 5-10% p53-immunoreactive tumour
nuclei or in five cases lacking p53 accumulation significant. Our results
suggest that alterations of the p53 gene play only a minor part in the
development or progression of Merkel cell carcinoma of the skin. 

======================================================================
45.) Radiotherapy for Merkel cell carcinoma of the skin of the head and neck. 
======================================================================
Author 
Suntharalingam M; Rudoltz MS; Mendenhall WM; Parsons JT; Stringer SP;
Million RR 
Address 
Department of Radiation Oncology, University of Florida College of
Medicine, Gainesville, USA. 
Source 
Head Neck, 17(2):96-101 1995 Mar-Apr 
Abstract 
BACKGROUND. Merkel cell carcinoma is a relatively rare neuroendocrine
carcinoma of the skin. It arises in the head and neck region in
approximately 50% of cases. Its aggressive behavior predisposes patients to
local-regional recurrence and distant metastases after surgical excision
alone. In this article, we describe our experience with Merkel cell
carcinoma of the head and neck. METHODS. Of 18 patients with Merkel cell
carcinoma treated in the Department of Radiation Oncology at the University
of Florida, 12 patients who had primary tumors in the head and neck region
are reported. Eight patients were treated at initial diagnosis (group A),
and four were treated at the time of local-regional recurrence (group B).
RESULTS. Local-regional control was achieved in seven of eight patients in
group A and all four patients in group B. One patient in group A and all
patients in group B developed distant metastases and eventually died of
their disease. Bone exposure developed in one patient, requiring surgical
debridement and hyperbaric oxygen treatment. CONCLUSION. Patients with
Merkel cell carcinoma of the head and neck should be treated aggressively.
Our data suggest that local-regional recurrence is a harbinger of distant
metastases. We recommend that these patients receive treatment to both the
primary site and draining lymphatics at initial presentation. The role of
chemotherapy remains unclear. 

======================================================================
46.) Lymph node Merkel cell carcinoma with no evidence of cutaneous
tumor--report of two cases. 
======================================================================
Author 
Ferrara G; Ianniello GP; Di Vizio D; Nappi O 
Address 
Servizio di Anatomia Patologica, Azienda Ospedaliera G. Rummo, Benevento,
Italy. 
Source 
Tumori, 83(5):868-72 1997 Sep-Oct 
Abstract 
We report two cases of Merkel cell carcinoma within inguinal and axillary
lymph nodes, respectively, showing no clinico-pathologic evidence of a
primary (extranodal) tumor; one of our patients was alive with no evidence
of disease five years and ten months after the surgical excision of the
neoplasm with no postoperative chemotherapy. The diagnosis of nodal Merkel
cell carcinoma needs to be supported by a careful immunohistochemical
study: in fact, cytokeratin- and neurofilament-positive paranuclear "dots",
as well as epithelial antigens and neuroendocrine markers may be variably
expressed in tumor cells, thus requiring the application of a complete
antibody panel. In the presence of a nodal Merkel cell tumor, an exhaustive
clinico-radiologic search for a primary tumor must be carried out. After
the exclusion of any reasonable starting point of the neoplasm, a
provisional diagnosis of "primary" nodal Merkel cell carcinoma may be
acceptable; since a primary extracutaneous tumor is expected to follow a
less aggressive course than a metastatic one, follow-up data may provide
indications as to the truly extracutaneous origin of Merkel cell carcinoma. 

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47.) Presumed choroidal metastasis of Merkel cell carcinoma. 
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Author 
Small KW; Rosenwasser GO; Alexander E 3d; Rossitch G; Dutton JJ 
Address 
Duke University Medical Center, Durham, NC 27712. 
Source 
Ann Ophthalmol, 22(5):187-90 1990 May 
Abstract 
Merkel cell carcinoma is a rare skin tumor of neural crest origin and is
part of the amine precursor uptake and decarboxylase system. It typically
occurs on the face of elderly people. Distant metastasis is almost
uniformly fatal. Choroidal metastasis, to our knowledge, has not been
described. We report a patient with Merkel cell carcinoma who had a
synchronous solid choroidal tumor and a biopsy-proven brain metastasis. Our
56-year-old patient presented with a rapidly growing, violaceous
preauricular skin tumor. Computed tomography of the head disclosed
incidental brain and choroidal tumors. Light and electron microscopy of
biopsy specimens of both the skin and the brain lesions showed Merkel cell
carcinoma. Ophthalmoscopy, fluorescein angiography, and A and B echography
revealed a solid choroidal mass. The brain and skin tumors responded well
to irradiation. A radioactive episcleral plaque was applied subsequently to
the choroidal tumor. All tumors regressed, and the patient was doing well
28 months later. To our knowledge this is the first case of presumed
choroidal metastasis of Merkel cell carcinoma. 

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48.) Chemotherapy for Merkel cell carcinoma with carboplatin and etoposide. 
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Author 
Pectasides D; Moutzourides G; Dimitriadis M; Varthalitis J; Athanassiou A 
Address 
1st Department of Medical Oncology, Metaxas Memorial Cancer Hospital,
Piraeus, Greece. 
Source 
Am J Clin Oncol, 18(5):418-20 1995 Oct 
Abstract 
Merkel cell carcinoma is a rare malignant tumor of the skin. We treated
three patients with Merkel call carcinoma with the combination of
carboplatin and etoposide, which have been mostly used in the treatment of
small cell lung carcinoma. Two patients experienced partial remission of
short duration. The third patient received the combination on an adjuvant
basis but relapse occurred briefly. Two of these patients failed to respond
to second-line chemotherapy with cisplatin, ifosfamide, and epirubicin. The
patient who had the first-line treatment on an adjuvant basis, responded
completely with the second-line chemotherapy plus radiotherapy and remains
disease-free for 5+months. Merkel cell carcinoma appears to be a sensitive
tumor to chemotherapeutic regimens used for small cell lung carcinoma, but
the responses are often brief. 

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49.) Expression of alpha subunit of guanine nucleotide-binding protein Go in
Merkel cell carcinoma. 
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Author 
Uhara H; Wang YL; Matsumoto S; Kawachi S; Saida T 
Address 
Department of Dermatology, Shinshu University School of Medicine, Nagano,
Japan. 
Source 
J Cutan Pathol, 22(2):146-8 1995 Apr 
Abstract 
The alpha subunit of guanine nucleotide-binding protein Go (Go alpha),
which was initially isolated from bovine brain, interacts with muscarinic
cholinergic receptors and regulates neuronal calcium channels. Go alpha is
known to be localized in neural tissues, some endocrine cells, and
neuroendocrine tumors. We have immunohistochemically investigated the
expression of Go alpha in 4 cases of Merkel cell carcinoma using the method
of microwave treatment. In all cases of Merkel cell carcinoma, Go alpha was
consistently detected on the plasma membrane and cytoplasm of the tumor
cells. Nerve fibers in the skin were also positive for Go alpha, but other
epidermal or dermal components such as keratinocytes, melanocytes,
fibroblasts, or lymphoid cells were negative. Tumor cells of squamous cell
carcinoma, cutaneous lymphoma, sweat gland carcinoma, and malignant
melanoma were negative for Go alpha. The present study indicates that Go
alpha may be a useful immunohistochemical marker of Merkel cell carcinoma. 

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50.) Deletion of chromosome arm 1p in a Merkel cell carcinoma (MCC).
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Author 
Gibas Z; Weil S; Chen ST; McCue PA 
Address 
Department of Pathology and Cell Biology, Thomas Jefferson University,
Philadelphia, Pennsylvania. 
Source 
Genes Chromosomes Cancer, 9(3):216-20 1994 Mar 
Abstract 
A case of neuroendocrine skin carcinoma (Merkel cell carcinoma) with a
deletion of the short arm of chromosome 1 (1p) as the sole chromosomal
abnormality was examined. The tumor originated in the skin of the left knee
of a 67-year-old man. Histopathologic study showed an undifferentiated
small cell tumor which expressed neuron-specific enolase, chromogranin, and
cytokeratin (CAM 5.2). Cytogenetic analysis of a lymph node metastasis from
the groin showed a pseudodiploid cell population with a deletion of the
short arm of chromosome 1 as the only abnormality: 46,XY,del(1)(p36.1). In
situ hybridization with the D1Z2 probe specific for the terminal band of 1p
confirmed the terminal deletion. This is the first case of Merkel cell
carcinoma in which only one chromosomal abnormality has been observed. Loss
of the terminal portion of 1p suggests that a tumor suppressor gene on 1p
plays a role in the pathogenesis of Merkel cell carcinoma. 

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51.) The role of radiation therapy and chemotherapy in the treatment of Merkel
cell carcinoma. 
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Author 
Fenig E; Brenner B; Katz A; Rakovsky E; Hana MB; Sulkes A 
Address 
Institute of Oncology, Rabin Medical Center, Beilinson Campus, Petah Tiqva
and Sackler School of Medicine, Tel Aviv University, Israel. 
Source 
Cancer, 80(5):881-5 1997 Sep 1 
Abstract 
BACKGROUND: Merkel cell carcinoma is a rare and highly aggressive skin
tumor. The purpose of this study was to determine the role of radiation
therapy and chemotherapy in the treatment of patients with Merkel cell
carcinoma. METHODS: A retrospective analysis of 27 patients treated at
Rabin Medical Center in Israel is presented, focusing on the treatment
details. Data for 40 patients (the authors' 27 patients and an additional
13 patients from the Israeli Cancer Registry), were analyzed for prognostic
factors using univariate and multivariate analyses. RESULTS: Univariate
analyses revealed regional lymph node involvement and the coexistence of a
second primary tumor as unfavorable prognostic factors. On multivariate
analysis, only lymph node involvement showed borderline statistical
significance. Radiation therapy was highly effective when given as
consolidation after surgery or chemotherapy. In 11 patients irradiated
effectively, only 1 (9%) in-field recurrence occurred. Radiation therapy
yielded responses in 15 of 15 measurable sites (5 complete responses and 10
partial responses). Chemotherapy produced responses in 18 of 26 patients
(69%), mostly complete (41%). However, in the absence of radiation therapy,
the responses were short lived. CONCLUSIONS: These data support the use of
combined treatment with chemotherapy followed by radiation therapy for
patients with advanced locoregional Merkel cell carcinoma. In patients with
metastatic disease, chemotherapy as well as radiotherapy can provide
effective palliation. Further large scale investigations are warranted to
confirm this approach. 
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DATA-MEDICOS/DERMAGIC-EXPRESS No (38) 12/02/99 DR. JOSE LAPENTA R. 
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