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Pigmented Extraadrenal Paragangliomas
A Clinicopathologic and Immunohistochemical Study of Five Cases
Cesar A. Moran, M.D.1
Jorge Albores-Saavedra,
Bruce M. Wenig, M.D.3
Hernando Mena, M.D.4
BACKGROUND. Pigmented extraadrenal paragangliomas are unusual neoplasms
that have rarely been reported in the literature.
METHODS. The clinical, pathologic, and immunohistochemical features of five cases
of pigmented extraadrenal paragangliomas were reviewed.
RESULTS. The patients were 2 women and 3 men within the ages of 17 and 56
Department of Pulmonary and Mediastinal Pathology, Armed Forces Institute of Pathology,
Washington, DC.
Division of Anatomic Pathology, University of
Texas Southwestern Medical Center, Dallas,
Department of ENT-Endocrine Pathology,
Armed Forces Institute of Pathology, Washington, DC.
Department of Neuropathology, Armed Forces
Institute of Pathology, Washington, DC.
years (mean age: 36.5). Two neoplasms were located in the lumbar spine, one in the
urinary bladder, one in the anterior mediastinum, and one in the retroperitoneum.
Clinically, one patient with spinal paraganglioma presented with symptoms of
numbness and weakness of the lower extremities whereas the second patient had
low back pain of several weeks’ duration. The paraganglioma of the bladder occurred in a pregnant woman who had symptoms of dysuria and microscopic hematuria whereas the patient with an anterior mediastinal tumor presented with chest
pain. No clinical history was obtained from the patient with the retroperitoneal
tumor. None of the patients had a history of hypertension. Grossly, the tumors
were described as well-circumscribed, soft, and slightly hemorrhagic, and measured from 2 to 9 cm in greatest dimension. Histologically, the five tumors displayed characteristics similar to those described in these tumors, mainly the presence of an organoid or zellballen growth pattern. In addition, they contained
moderate amounts of intracellular melanin pigment that focally obscured the true
nature of the lesion. Immunohistochemically, four cases were positive for chromogranin whereas S-100 protein was detected in the sustentacular cells in four
cases. Follow-up information ranging from 6 months to 18 years for 3 patients
revealed that the patients were alive and well without recurrence or metastasis.
One patient with spinal paraganglioma was lost to follow-up, and the patient with
mediastinal paraganglioma was a recent case and therefore the behavior of the
paraganglioma could not be assessed.
CONCLUSIONS. The current study expands the morphologic spectrum of extraadrenal paragangliomas and emphasizes the need to consider these tumors in the
differential diagnosis of pigmented neoplasms. These findings suggest that the
presence of melanin pigment does not alter the behavior of these neoplasms.
Cancer 1997; 79:398–402. q 1997 American Cancer Society.
The opinions or assertions expressed herein are
the private views of the authors and are not to
be construed as official or as reflecting the
views of the Department of the Army, Air Force,
or the Department of Defense.
Address for reprints: Cesar A. Moran, M.D., Department of Pulmonary and Mediastinal Pathology, Room 3017, Armed Forces Institute of Pathology, Washington, DC 20306-6000.
Received March 22, 1996; revision received July
31, 1996; accepted September 9, 1996.
KEYWORDS: melanotic, paraganglioma, extraadrenal, bladder, spinal cord.
xtraadrenal paragangliomas are unusual neoplasms that have been
described in many anatomic sites. The extraadrenal locations include the head and neck area, mediastinum, retroperitoneum, gallbladder and extrahepatic bile ducts, urinary bladder, and spinal region.1 – 12 Although the microscopic features of paragangliomas are
well established and are essentially similar, regardless of the anatomic
site, some differences have been noted according to the location of
the tumor. The presence of melanin pigment in extraadrenal paragangliomas has been described in only a few cases.13,14 Tavassoli13 re-
q 1997 American Cancer Society
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Pigmented Paragangliomas/Moran et al.
Clinical Features of Five Patients With Pigmented Paragangliomas
Case no.
A&W 6 mo
Pregnant, dysuria,
microscopic hematuria
Weakness, numbness of legs
Low back pain
Chest pain
Anterior mediastinum
Lost to follow-up
A&W 18 yrs
A&W 1 mo
A&W 7 yrs
F: female; M: male; NA: not available; A&W: alive and well.
ported two unusual cases occurring in the uteri of
adult females. However, in both cases, the paraganglioma was an incidental finding. The case reported by
Paulus et al.14 was a tumor of the orbit occurring in a
young woman who presented with a decrease in visual
acuity. In addition, examples of melanin-producing
adrenal paragangliomas (pheochromocytomas) also
have been recorded in the medical literature.15 The
authors report five cases of melanin-containing extraadrenal paragangliomas occurring in unusual anatomic locations. These cases expand the morphologic
spectrum of extraadrenal paragangliomas and emphasize the need to include melanin-containing extraadrenal paragangliomas in the differential diagnosis of
pigmented neoplasms.
Five cases of pigmented paragangliomas (two involving the lumbar spine, one located in the urinary bladder, one in the anterior mediastinum, and one in the
retroperitoneum) form the basis of this study. The
cases were identified from the files of the Departments
of Pulmonary and Mediastinal Pathology, Neuropathology, and Endocrine Pathology at the Armed Forces
Institute of Pathology in Washington, DC and the University of Texas Southwestern Medical School in Dallas, Texas.
Paraffin sections stained with hematoxylin and eosin, Fontana-Masson stain for melanin pigment, and
iron stains were available for review. For immunohistochemical studies, formalin fixed, paraffin embedded
tissue sections were incubated with antibodies against
broad-spectrum keratin (Dako Co., Carpenteria, CA;
1:800), S-100 protein (Enzo, Syosset, NY; 1:800), chromogranin (Enzo; 1:800), synaptophysin (Dako; 1:200),
and HMB-45 (Dako; 1:100), by the avidin-biotin complex technique.16 Nonimmune rabbit and mouse serum were substituted for the antibody as negative controls. Appropriate positive controls were run concurrently for every antibody tested.
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Clinical follow-up was obtained by contacting the
referring physician.
Clinical Features
The clinical features of the five patients are summarized in Table 1. The patient’s ages ranged from 17 to
56 (mean, 36.5 years). There were two women and
three men. Two paragangliomas involved the lumbar
spine, one was located in the urinary bladder, one in
the anterior mediastinum, and one in the retroperitoneum. No history of systemic symptoms, such as hypertension, was given by any of the patients. Surgical
resection was accomplished in all five patients.
Gross Findings
The tumors from the spinal region were described as
soft, hemorrhagic lesions, measuring between 2 and
2.5 cm in greatest dimension. The lesion in the urinary
bladder was described as a well demarcated, soft, pigmented nodule measuring 1.5 cm in greatest dimension, and the mediastinal lesion was described as a
soft, tan, slightly hemorrhagic tumor of approximately
2.5 cm in greatest dimension. The retroperitoneal tumor was described as a cystic, well circumscribed, dark
mass measuring approximately 9 cm in greatest dimension.
Histopathologic Features
The bladder tumor was partially covered by a rim of
normal transitional epithelium. Underneath the epithelium were nests of large cells (Fig. 1) with abundant
eosinophilic or clear cytoplasm. The cells had large
round nuclei with occasional prominent nucleoli.
However, many cells contained abundant melanin
pigment that obscured the cytoplasmic and nuclear
features (Fig. 2). No mitoses were identified. One of
the tumors from the spinal canal, the mediastinal neoplasm, and the retroperitoneal tumor showed the classic zellballen pattern. The cells were large, had abun-
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CANCER January 15, 1997 / Volume 79 / Number 2
FIGURE 1. Paraganglioma of the urinary bladder showing a proliferation
FIGURE 2. Closer view of a paraganglioma of the bladder showing large
of larger cells with pale cytoplasm and scattered pigmented cells with
areas of inflammatory infiltrate (H & E, 175).
cells, some with abundant melanin pigment (H & E, 1100).
FIGURE 4. S-100 protein staining sustentacular cells in a paraganglioma
FIGURE 3. Mediastinal paraganglioma showing more conventional areas
(H & E, 1150).
and focal extracellular clumps of melanin pigment (H & E, 175).
dant eosinophilic cytoplasm and round large nuclei
with visible nucleoli. Although many cells showed macronuclei, no mitotic figures were present. Intra- and
extracellular melanin pigment was observed (Fig. 3).
The other spinal tumor had abundant melanin pigment, making it more difficult to discern the nature
of the lesion. However, focally, the characteristic organoid pattern was recognized. There were round,
polygonal, and spindle-shaped cells admixed with a
few clear cells, but the nuclear morphology was bland
and there were no mitotic figures. The pigment was
positive for Fontana-Masson and negative for the iron
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Immunohistochemical Features
The spinal paragangliomas showed focal positivity for
synaptophysin and chromogranin whereas the S-100
protein stain delineated the sustentacular cells (Fig.
4). Conversely, the neuroendocrine markers were negative in the bladder lesion whereas S-100 protein highlighted some sustentacular cells. Both neuroendocrine
markers and S-100 protein were positive in the mediastinal tumor. The retroperitoneal tumor showed positive staining with chromogranin and negative staining
with S-100 protein. Keratin and HMB-45 antibodies
were negative in all tumors.
Clinical follow-up ranging from 1 month to 18 years
was obtained in 4 patients. These patients were found
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Pigmented Paragangliomas/Moran et al.
to be alive and well without evidence of recurrence
or metastases. One patient with spinal paraganglioma
was lost to follow-up. In the patient with mediastinal
paraganglioma, the follow-up was too short to assess
proper clinical behavior of the paraganglioma.
Although unusual, extraadrenal paragangliomas occurring in the urinary bladder, spinal canal, mediastinum, and retroperitoneum have been recognized for
many years. These four sites are among the most unusual locations for paragangliomas. Although there are
no specific data regarding the incidence of spinal paragangliomas, it is estimated that urinary bladder paragangliomas comprise õ1% of all sympathoadrenal
paragangliomas.17 Leestma and Price from the Armed
Forces Institute of Pathology18 reported a large series
of urinary bladder paragangliomas and concluded that
these tumors can be observed in any age group with
no predilection for males or females. Clinically, hypertension and headaches during or after voiding in association with hematuria are classic symptoms of functioning urinary bladder paragangliomas.17 Conversely,
spinal paragangliomas do not give rise to systemic
manifestations and are commonly associated with
back pain and sensory/motor deficit.12
To the authors’ knowledge, pigmented paragangliomas occurring in the sites herein described have not
been reported previously. However, melanin pigment
is relatively common in paragangliomas (pheochromocytomas) of the adrenal gland. Landas et al.15 found
melanin-like pigment in 6 of 19 paragangliomas of
the adrenal gland. Ultrastructurally, melanosomes and
neurosecretory granules were found within the tumor
cells of three cases. Melanin pigment has also been
recognized in a variety of nonmelanocytic tumors, especially those with an neuroendocrine phenotype
such as carcinoids of the lung and thymus, and medullary thyroid carcinomas.19 – 21
The presence of melanin pigment in paragangliomas may pose a difficult diagnostic problem. The possibility of malignant melanoma must be excluded. In
heavily pigmented areas containing abundant melanin
pigment, the diagnostic areas may be overlooked.
Complete clinical history is helpful in arriving at the
correct diagnosis. However, a reliable clinical history
of melanoma is often difficult to obtain. Recognition of
the characteristic nesting growth pattern and cytologic
features of paraganglioma permit the diagnosis. In addition, paragangliomas are comprised of chief cells
and sustentacular cells that have a characteristic immunohistochemical profile. Therefore, the use of neuroendocrine markers such as chromogranin and synaptophysin and the S-100 protein stain play an im-
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portant role in confirming the diagnosis. It is
important to remember that melanomas are tumors
that, in addition to cellular pleomorphism, also demonstrate increased mitotic activity. Conversely, the
negativity for neuroendocrine markers such as chromogranin and synaptophysin should aid clinicians in
arriving at a more specific diagnosis. Nevertheless, it
should be noted that in one of the cases in the current
study the tumor cells did not stain with any of the
neuroendocrine markers. However, the S-100 protein
stain delineated the sustentacular cells. Likewise, the
lack of reactivity for HMB-45 and S-100 protein militated against the diagnosis of melanoma. Sustentacular cells, commonly observed in paragangliomas, are
absent in melanomas. It has been suggested that cells
from pigmented paragangliomas may produce melanin pigment13 rather than neuroendocrine granules,
thus explaining the absence of reactivity for neuroendocrine markers.
One other consideration, mainly for tumors in the
mediastinal location, is a carcinoid tumor. Although
both tumors share similar histopathologic features, a
positive staining for cytokeratin would favor a carcinoid tumor.4 With regard to retroperitoneal pigmented
paragangliomas, the main differential diagnosis would
be with a metastatic melanoma.
The presence of melanin pigment, although a pitfall in diagnosis, does not appear to alter the biologic
behavior of paragangliomas. In the current study, follow-up demonstrated that complete surgical resection
appears to be the treatment of choice and if it is accomplished the patients follow an uneventful clinical
course. Two of the study patients in whom a clinical
follow-up of between 6 months and 18 years was obtained were both without evidence of recurrence or
metastases. The difficulty of predicting clinical outcome in patients with paragangliomas based on morphologic grounds alone has long been recognized.
In synthesis, the authors have presented five cases
of pigmented extraadrenal paragangliomas that expand the morphologic spectrum of these lesions. This
study highlights the ubiquitous distribution of these
tumors and the importance in separating them from
other more aggressive tumors such as malignant melanoma.
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