IRAP Case Histories and Diagnoses
University of Chicago Medical Center
February 27, 2012
1
Case 1
Presenter: Mei Lin Z. Bissonnette, MD, PhD
Attending: Jerome Taxy, MD
Clinical History: The patient is a previously healthy 17 year-old female who presented with acute onset of
heavy vaginal bleeding. On physical exam, a 10 cm hemorrhagic mass was found protruding from the introitus,
and the mass was emergently excised.
Diagnosis: Translocation negative rhabdomyosarcoma with alveolar and embryonal patterns
Differential Diagnosis:
 Classic embryonal rhabdomyosarcoma (ERMS), botryoid variant
 Occurs in children <5 years old, and most common sites are genitourinary and head and neck
 ERMS is a morphologic spectrum. Typically presents as sheets of spindled cells in a myxoid
matrix with loose and dense areas recapitulating embryonic muscle. Scattered rhabdomyoblasts
are also present. Cells stain positive for desmin.
 Botryoid variant characterized by a cambium layer composed of tumor cells condensing under
an epithelial layer
 Classic alveolar rhabdomyosarcoma (ARMS)
 Occurs in adolescents, and most common site in the extremities
 Typical ARMS shows nests of polygonal cells separated by fibrovascular septa. The cells in
these nests show loss of cohesion and line the septa in a picket fence pattern. Giant cells are
also common
 ARMS can also present as a solid variant, which lack nests
 Cells are desmin positive, and show strong, diffuse myogenin staining
 Majority characterized by PAX-FOXO1 translocations (see discussion below)
Discussion:
 Determining ERMS versus ARMS histology can be a diagnostic challenge
 Distinguishing ERMS and ARMS is necessary because ARMS is more aggressive, and histologic
subtype is a component of patient risk stratification, a prognostic indicator for survival, and a factor in
determining the treatment regimen
 Alveolar histology is associated with a poorer prognosis. Alveolar histology, regardless of tumor stage
and grade, places the patient in either intermediate or high risk groups which correlates with 55-76%
and 33% 3 year failure-free survival rates, respectively
 ARMS is associated with two translocations: t(2;13) and t(1;13) resulting in the fusion genes PAX3FOXO1 and PAX7-FOXO1, respectively. 55% of all alveolar RMS are t(2;13) positive, 22% are t(1;13)
positive, and 25% are translocation negative
 There is no characteristic histological feature of ARMS translocation status
 Gene expression analysis suggests translocation negative ARMS is genetically indistinguishable from
ERMS, and these two entities are distinct from translocation positive ARMS
 Overall survival is similar for translocation negative ARMS and ERMS, and is greater than survival of
translocation positive ARMS patients
References:
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5.
Davicioni E, et al. Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the
prognosis of alveolar rhabdomyosarcomas. Cancer Res 2006;66(14):6936-6946.
Davicioni E, et al. Gene expression profiling for survival prediction in pediatric rhabdomyosarcomas: a report from the
Children’s Oncology Group. J Clin Oncol 2010;28(7):1240-1246.
Hayes-Jordan A, Andrassy R. Rhabdomyosarcoma in children. Curr Opin Pediatr 2009;21:373-378.
Parham DM, et al. Correlation between histology and PAX/FKHR fusion status in alveolar rhabdomyosarcoma: a report from
the Children’s Oncology Group. Am J Surg Pathol 2007;31(6):895-901.
Raney RB, et al. Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: a selective review of
Intergroup Rhabdomyosarcoma Study Group experience and rationale for Intergroup Rhabdomyosarcoma Study V. J Pediatr
Hematol Oncol 2001;23(4):215-220.
2
6.
7.
Sorensen PHB, et al. PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a
report from the Children’s Oncology Group. J Clin Oncol 2002;20(11):2672-2679.
Williamson D, et al. Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from
embryonal rhabdomyosarcoma. J Clin Oncol 2010;28(13):2151-2158.
Case 2
Presenter: Charles van Slambrouck MD
Attending: Elizabeth Hyjek MD
Clinical History:
The patient is a 43 year-old male with a past medical history significant for EBV+ B-cell lymphoma of the right
cheek which was treated with CHOP in 1999. In addition, the patient has multifocal recurrent squamous cell
carcinomas of the head and neck which have been complicated by multiple post-operative bacterial infections
including a recent osteomyelitis of the maxilla.
Diagnosis: WHIM syndrome
Key Morphologic Features:
 Myelokathexis (myelo=marrow, kathexis=retention)
o Peripheral neutropenia
o Hypercellular bone marrow with granulocytic hyperplasia
o Hypermature neutrophils: Vacuolated cytoplasm, condensed nuclei, long/thin intrasegmental
filaments.
Differential Diagnosis (Hypercellular marrow with granulocytic hyperplasia):
 Reactive conditions
o Osteomyelitis, bone marrow response to chronic systemic infection
o Treatment with G-CSF or high-dose steroids
o Neoplasm secreting G-CSF-like molecule
 Hematopoietic malignancy
o Myeloproliferative neoplasms:
 Chronic myelogenous leukemia, chronic neutrophilic leukemia
o Therapy-related myeloid neoplasm (t-MDS)
Discussion:
 WHIM Syndrome1,2,3
o Rare, autosomal dominant disorder due to a mutation in the chemokine receptor CXCR4
resulting in altered leukocyte localization.
o Incidence is unknown, however since 1964 approximately 40 cases have been reported in the
literature
o Pan-ethnic distribution: Cases described from USA, Italy, Japan, and Slovenia
 WHIM
o Warts4,5: Patients have widespread, therapy-resistant, cutaneous warts, cervical dysplasia,
squamous carcinomas of the cervix and head/neck due to an increased susceptibility to
common HPV serotypes
o Hypogammaglobulinemia6,12: Degree is variable amongst WHIM patients. A recent proposed
mechanism is that: B-cells require the ability to down-regulate CXCR4 in order to transition to
from the dark to light zone in the germinal center. In WHIM, the mutation causes inability to
downregulate CXCR4 and thus B-cell differentiation is hindered. Patients with WHIM still have
normal CD4/CD8 ratios, and preserved proliferative responses to mitogens.
o Infections7: Peripheral neutropenia + hypogammaglobulinemia  increased susceptibility to
common bacterial infections including otitis, sinusitis, pneumonia, and cellulitis. Their infections
respond normally to antibiotics. They do not develop infections to opportunistic organisms or
fungal pathogens.
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Myelokathexis8: Neutrophils are retained in the marrow and eventually undergo apoptosis after
their normal lifespan. Absolute neutrophil counts in untreated WHIM syndrome generally <
300/uL
EBV+ Lymphomas in WHIM Syndrome9,10
o Well-established association of malignancy with immune deficiency disorders
o Lymphomagenesis in WHIM syndrome is thought to result from defective immune surveillance
making them vulnerable to EBV infection and subsequent B-cell lymphomas (similar to risk seen
in other disorders such as Wiskott-Aldrich syndrome and ataxia-telangiectasia)
Pathogenesis of WHIM syndrome11
o WHIM syndrome results from one of four, heterozygous, gain-of-function mutations in CXCR4
which always result in truncation of it’s intracytoplasmic carboxy-terminus
o This results in an inability to down-regulate CXCR4 expression
o In the presence of its ligand (CXCL12), CXCR4 promotes chemotaxis toward higher CXCL12
gradients.
o Leukocytes with CXCR4 mutations are unable to modulate the surface expression of CXCR4
and thus cannot leave the marrow and eventually undergo apoptosis
References:
1.
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6.
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8.
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10.
11.
12.
13.
Zueler W, et al, “Myelokathexis” – A new Form of Chronic Granulocytopenia. Report of a Case, The New England Journal of
Medicine 1964: 270(14) 699-704.
Wetzler et al, A new familial immunodeficiency disorder characterized by severe neutropenia, a defective marrow release
mechanism, and hypogammaglobulinemia, Am J Med 1990;89:663-72
Nortarangelo L, WHIM syndrome (Warts Hypogammaglobulinemia Infections Myelokathexis), Orphanet encyclopedia, 2004
Cipriani N et al, WHIM syndrome and oral squamous cell carcinoma, Oral Surg Med Oral Pathol Oral Radiol Endod, 2010;
109:105-108
European Society for Immunodeficiencies, Clinical Diagnostic Criteria, 2004
Gulino A et al, Altered leukocyte response to CXCL12 in patients with warts, hypogammaglobulinemia, infections, myelokathexis
(WHIM) syndrome, 2004; 104:444-452
Rezaei N et al, Primary immunodeficiency diseases associated with increased susceptibility to viral infections and malignancies; J
Allergy Clin Immunol, 2011; 127(6): 1329-1341
Gulino A, WHIM syndrome: a genetic disorder of leukocyte trafficking, Curr Opinion in Allergy and Clinical Immunology, 2003,
3:443-450
Chae KM, Ertle JO, Tharp MD. B-cell lymphoma in a patient with WHIM syndrome. J Am Acad Dermatol 2001;44:124-8.
Imashuku S, Miyagawa A, Chiyonobu T, Ishida H, Yoshihara T, Teramura T, et al. Epstein-Barr virus-associated Tlymphoproliferative disease with hemophagocytic syndrome, followed by fatal intestinal B lymphoma in a young adult female with
WHIM syndrome. Warts, hypogammaglobulinemia, infections, and myelokathexis. Ann Hematol 2002;81:470-3.
Hernandez PA, Gorlin RJ, Lukens JN, Taniuchi S, Bohinjec J, Francois F, et al. Mutations in the chemokine receptor gene CXCR4
are associated with WHIM syndrome, a combined mmunodeficiency disease. Nat Genet 2003;34:70-4.
McGuire Et al.. Oligoclonality, impaired class switch and B-cell memory responses in WHIM syndrome, Clinical Immunology. 2010
McDermott DH et al, The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome, Blood, 2011;
118:4957-4962
Case 3
Presenter: Emma Whitcomb, MD
Attending: Shu-Yuan Xiao, MD
Diagnosis: Small bowel adenocarcinoma with gastric differentiation arising in Crohn’s enteritis
Morphology:
This patient’s adenocarcinoma has spectrum of well-differentiated glands to poorly differentiated
infiltrating single cells. The glands are composed of cells with finely granular, eosinophilic cytoplasm and large,
round, pleomorphic nuclei with occasional prominent nucleoli. The tumor is primarily located in the mucosa and
submucosa with invasion through the muscularis propria and penetration of the visceral peritoneum. Adjacent
to the mass are areas of mucosal surface dysplasia with similar-appearing epithelial cells with eosinophilic
cytoplasm and atypical nuclei. This lesion arises in a background of Crohn’s enteritis, demonstrating a range of
quiescent disease, with branching crypts and extensive pyloric metaplasia, to severely active disease with
ulceration.
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Discussion:
Small bowel adenocarcinomas are rare, comprising only 2% of primary gastrointestinal tumors. De
novo small bowel adenocarcinomas are histologically similar to colonic adenocarcinoma and are thought to
arise out of a similar adenoma-carcinoma sequence. In the setting of Crohn’s disease, small bowel
adenocarcinoma has a few unique characteristics. It typically occurs at a younger age, is more often located in
the ileum rather than the duodenum, arises out of dysplasia with infiltrative growth, and has a greater incidence
of poorly differentiated tumors. There are features of this case that are typical of small bowel adenocarcinoma
arising in Crohn’s disease, such as the patient’s relatively young age of 47, presence of dysplasia, and a poorly
differentiated component. The morphology of this tumor, however, is unique and suggestive of a gastric type
adenocarcinoma arising in the small bowel. The immunophenotype of this tumor is also consistent with gastric
rather than intestinal differentiation. Intestinal markers such as mucicarmine, CDX2, MUC2, and CD10 are
negative. Gastric markers such as MUC5AC, MUC6, and Hepar-1 are positive. In addition, the presence of
extensive pyloric gland metaplasia in the background of this lesion raised the possibility that this
adenocarcinoma with gastric differentiation developed out of pyloric gland metaplasia.
Pyloric glands are neutral mucin secreting glands normally located in the gastric cardia, antrum, and
pylorus. Pyloric gland metaplasia is seen in the setting of mucosal injury and is most frequently described in
Crohn’s enteritis. The presence of normal pyloric glands in hostile environments such as the stomach and
metaplastic pyloric glands in areas of injury as well as their secretion of reparative substances such as
epidermal growth factor and trefoil peptides suggest they are part of an adaptive response to injury.
Most discussions of pyloric gland dysplasia and progression to carcinoma are in the setting of pyloric
adenomas, a rare tumor most commonly located in the stomach, duodenum, and gallbladder. In a recent
series of 41 cases of pyloric adenoma, dysplasia, defined as elongated nuclei, pseudostratification, enlarged
nucleoli, pleomorphism, and irregular glands was present in 64% of cases. Adjacent adenocarcinoma was
present in 12% of cases. These findings suggest pyloric gland adenocarcinoma can arise out of a dysplasiacarcinoma sequence; however the molecular details of this transition have not been established. To our
knowledge, there is only one report in the literature of pyloric gland metaplasia with dysplasia and associated
poorly differentiated adenocarcinoma in the small intestine of a patient with Crohn’s disease.
References:
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Delaunoit T, Neczyporenko F, Limburg PJ, Erlichman C. Pathogenesis and risk factors of small bowel adenocarcinoma: A
colorectal cancer sibling? Am J Gastroenterol, 2005; 100:703-710
Palascak-Juif V, Bouvier AM, et al. Small bowel adenocarcinoma in patients with Crohn’s disease compared with small bowel
adenocarcinoma de novo. Inflamm Bowel Dis, 2005 v11n9:828-832
Hanby AM, Wright NA. The ulcer-associated cell lineage: The gastrointestinal repair kit. J Pathol, 1993; vol171:3-4
Lee FD. Pyloric metaplasia in the small intestine. J Path Bact, 1964; vol87:267-277
Zong-Ming C, Scudiere JR. Abraham SC, Montgomery E. Pyloric gland adenoma. Am J Surg Pathol, 2009;33:186-193
Simpson S, Traube J, Riddell RH. The histologic appearance of dysplasia (precarcinomatous change) in Crohn’s disease of
the small and large intestine. Gastroenterology, 1981;81:492-501
Case 4
Presenter: Kristen M. Paral, MD
Attending: Anthony G. Montag, MD
History: This is a 44-year-old female with a left buttock mass first noted 4 months ago. She presents with
sciatic pain associated with sitting. Past medical history is significant for a previous mass excision from the
same location 10 years ago. Physical exam is notable for a scar in the left buttock overlying a palpable mass,
which, when compressed, reproduces the sciatic pain.
Pathology: The lesion has both solid and cystic components. The periphery is characterized by a fibrous rim
with lymphoid aggregates, creating a pseudocapsule. The solid areas consist of pale-staining sheets of mainly
histiocytoid cells. The cystic areas are composed of irregular, blood-filled spaces. The neoplastic cells range
from oval to plump-spindly, and focally there is hobnailing into the blood-filled spaces.
Differential: Vasoformative lesions.
 Benign: glomangioma is a consideration at low power, but high power shows more compact,
uniform, rounded cells in glomangioma compared to our lesion. Epithelioid hemangioma has a
lymphoid cuff and sheets of epithelioid cells in common with our lesion, albeit focally.
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Intermediate: Kaposi and our lesion both display interstitial hemorrhage, spindled cells, and
minimal pleomorphism, but our case lacks hyaline globules. Kaposiform
hemangioendothelioma is possible given the occasional appearance of slit-like vessels blending
with spindly cells. Dabska tumor is a consideration due to intraluminal tufting with hobnail
morphology. Angiomatoid fibrous histiocytoma has 3 features in common with our lesion: 1)
pseudocapsule, 2) blood-filled spaces, 3) histiocytoid cells.
Malignant: epithelioid angiosarcoma demonstrates greater pleomorphism and hyperchromasia
than our lesion. Epithelioid hemangioendothelioma and our lesion have the appearance of
intracytoplasmic lumen formation, but our lesion does not have a myxohyaline background.
Immunohistochemistry: Positive vimentin, desmin, CD99, and calponin (focal). Negative CD31, CD34,
SMA. These findings are non-diagnostic but rule out vascular neoplasms, leaving us with angiomatoid fibrous
histiocytoma (AFH). In order to confirm this diagnosis, we need cytogenetics.
Cytogenetics: FISH results show EWSR1-ATF1 in 93% of cells. There are 3 fusions that have been reported
in AFH: EWSR1-CREB1 > EWSR1-ATF1 > FUS-ATF1. The fusion partner must be noted, as the finding of
EWSR1 rearrangement alone can lead to a misdiagnosis of Ewing sarcoma when the AFH has a round-cell
morphology (50% of cases) and CD99 positivity.
Diagnosis: Angiomatoid fibrous histiocytoma, recurrent.
Discussion: The non-diagnostic immunoprofile of AFH reflects its uncertain differentiation. The entity was first
described in 1979 by Enzinger, who coined the term “angiomatoid malignant fibrous histiocytoma.” He
considered it a variant of MFH owing to its fibroblast- and histiocyte-like morphology. Following his paper,
several studies sought to characterize the neoplastic cells using mainly electron microscopy, but no consensus
was reached. In 1999, Fanburg-Smith focused on immunohistochemistry to support a myoid phenotype,
mainly myofibroblastic. They also drew a connection to the desmin-positive stromal cells of lymph nodes.
Fanburg-Smith and others called for removal of “malignant” from the name, as only 1% of AFH were reported
to metastasize. In 2002, the WHO concedes this point and AFH is down-graded into the intermediate
category. In addition to rarely metastasizing, AFH rarely recurs (2% recurrence). Other than our patient’s
recurrence, her case was typical, both clinically and histologically. Notwithstanding, this case serves to
underscore the diagnostic pitfalls associated with this lesion as well as to review this rare entity.
Cytogenetic studies are key in clinching the diagnosis of AFH. However, the results must be interpreted within
the context of morphological and immunohistochemical findings, as the same gene fusions are found in clear
cell sarcoma. The explanation behind the development of two clearly different phenotypes is not yet known,
but one possibility is that the phenotype depends on the affected precursor cell rather than on the specific gene
fusion.
References
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Antonescu CR et al. 2007. EWSR1-CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma. Genes,
Chromosomes, & Cancer 46: 1051-1060.
Chen, G et al. 2011. Angiomatoid fibrous histiocytoma: unusual sites and unusual morphology. Modern Pathology 24: 15601570.
Enzinger FM. 1979. Angiomatoid malignant fibrous histiocytoma: A distinct fibrohistiocytic tumor of children and young adults
simulating a vascular neoplasm. Cancer 44: 2147-2157.
Fanburg-Smith JC, Miettinen M. 1999. Angiomatoid “malignant” fibrous histiocytoma: A clinicopathologic study of 158 cases
and further exploration of the myoid phenotype. Hum Pathol 30: 1336-1343.
Fisher C and Montgomery E. 2011. Biopsy interpretation of soft tissue tumors. Lippincott Williams & Wilkins. Philadelphia,
PA.
Matsumura T et al. 2010. Angiomatoid fibrous histiocytoma including cases with pleomorphic features analyzed by
fluorescence in situ hybridization. J Clin Pathol 63(2): 124-8.
Qian X et al. 2011. Angiomatoid fibrous histiocytoma: a series of five cytologic cases with literature review and emphasis on
diagnostic pitfalls. Diagn Cytopathol. PMID 22045622.
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8.
Tanas MR et al. Utility of FISH in the diagnosis of angiomatoid fibrous histiocytoma: a series of 18 cases. Modern Pathology
23: 93-97.
9. Wegmann W and Heitz P U. 1985. Angiomatoid malignant fibrous histiocytoma: evidence for the histiocytic origin of tumor
cells. Virchows Arch (Pathol Anat) 206: 59-66.
10. Weiss SS and Goldblum JR. Soft tissue tumors. Fifth edition. 2008. Mosby.
Case 5
Presenter:
Attendings:
Becca Wolsky, MD
Chad El-Zayaty, MD, John Hart, MD, Thomas Krausz, MD
Diagnosis: Clear cell sarcoma, located in the gastrointestinal (GI) tract
Important Differential Diagnosis: Malignant melanoma
Clinical Features of Clear Cell Sarcoma of Tendons and Aponeuroses (Malignant Melanoma of Soft
Parts)
 <1% of all soft tissue tumors
 Approximately 500 cases reported
 Young to middle aged adults
 Presents as a slow-growing mass
 Most often in the extremities, especially foot and ankle
 Unusual sites reported: GI tract, ear, abdominal wall, chest wall, pleura, penis
Key Morphologic Features
 Nests, fascicles or diffuse architecture
 Epithelioid or fusiform cells
 Clear, pale or eosinophilic cytoplasm
 Uniform nuclei with prominent nucleoli
 Few mitotic figures
 Occasionally melanin
 Multinucleated tumor giant cells frequently present
Immunohistochemical Features
 Vimentin: 96%
 S-100: 75-100%
 HMB-45: 90-97%
 MiTF: 71-81%
 Melan A: 71%
 Synaptophysin: 43%
Genetics
 EWSR1-ATF1 (most common)
 EWSR1-CREB1
 Neither has ever been identified in melanoma
Discussion
 The combination of morphology, IHC and genetic studies are key in diagnosing clear cell sarcoma.
 If melanoma with an unknown primary is on the differential, consider clear cell sarcoma even if the
tumor is negative for melanocytic markers other than S-100, and even if the tumor is located in the GI
tract.
 Both EWSR1-ATF1 and EWSR1-CREB1 have been found in both clear cell sarcoma located in soft
parts and clear cell sarcoma located in the GI tract. Importantly, neither has ever been reported in
melanoma.
 In 2003, Zambrano & Rosai described 6 cases of the GI tract with features similar to clear cell sarcoma
of tendons and aponeuroses. In all 6 cases, melanocytic markers other than S-100, such as Melan A,
HMB-45, and MiTF, were negative. Additionally, all 6 cases exhibited osteoclast-like giant cells (in
contrast to multinucleated tumor giant cells). One of six cases tested cytogenetically was positive for
the EWSR1-ATF1 fusion gene. They proposed that this entity may be an entity distinct from classic
clear cell sarcoma of tendons and aponeuroses, and the terms “osteoclast-rich CCS-like tumors of the
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GI tract” or “osteoclast-rich tumor of the GI tract with features resembling CCS of tendons and
aponeuroses” have variably been used in the literature since.
A review of all clear cell sarcomas in the GI tract (33 cases) revealed that these cases may or may not
have osteoclast-like giant cells and may or may not be positive for melanocytic markers other than S100 (Melan A, HMB-45 or MiTF), suggesting that “osteoclast-rich CCS-like tumor of the GI tract” may
be best regarded as part of a spectrum, rather than a distinct entity.
Based on this review, clear cells sarcomas in the GI tract are positive for melanocytic markers other
than S-100 (Melan A, HMB-45 or MiTF) only 40% of the time, in contrast to 90-97% of clear cell
sarcomas overall. This suggests that the spectrum of presentation of clear cell sarcoma in the GI tract
is broader than that of clear cell sarcoma in soft parts.
References
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Antonescu CR, Nafa K, Segal NH, Dal Cin P, Ladanyi M. EWS-CREB1: a recurrent variant fusion in clear cell sarcoma-association with gastrointestinal location and absence of melanocytic differentiation. Clin Cancer Res. 2006 Sep
15;12(18):5356-62.
Chung EB, Enzinger FM. Malignant melanoma of soft parts. A reassessment of clear cell sarcoma. Am J Surg Pathol. 1983
Jul;7(5):405-13.
Comin CE, Novelli L, Tornaboni D, Messerini L. Clear cell sarcoma of the ileum: report of a case and review of literature.
Virchows Arch. 2007 Oct;451(4):839-45.
Dim DC, Cooley LD, Miranda RN. Clear cell sarcoma of tendons and aponeuroses: a review. Arch Pathol Lab Med. 2007
Jan;131(1):152-6.
Donner LR, Trompler RA, Dobin S. Clear cell sarcoma of the ileum: the crucial role of cytogenetics for the diagnosis. Am J
Surg Pathol. 1998 Jan;22(1):121-4.
Ekfors TO, Kujari H, Isomäki M. Clear cell sarcoma of tendons and aponeuroses (malignant melanoma of soft parts) in the
duodenum: the first visceral case. Histopathology. 1993 Mar;22(3):255-9.
Enzinger FM. Clear-cell sarcoma of tendons and aponeuroses: an analysis of 21 cases. Cancer. 1965 Sep;18:1163-74.
Fukuda T, Kakihara T, Baba K, Yamaki T, Yamaguchi T, Suzuki T. Clear cell sarcoma arising in the transverse colon. Pathol
Int. 2000 May;50(5):412-6.
Hisaoka M, Ishida T, Kuo TT, Matsuyama A, Imamura T, Nishida K, Kuroda H, Inayama Y, Oshiro H, Kobayashi H, Nakajima
T, Fukuda T, Ae K, Hashimoto H. Clear cell sarcoma of soft tissue: a clinicopathologic, immunohistochemical, and molecular
analysis of 33 cases. Am J Surg Pathol. 2008 Mar;32(3):452-60.
Kosemehmetoglu K, Folpe AL. Clear cell sarcoma of tendons and aponeuroses, and osteoclast-rich tumour of the
gastrointestinal tract with features resembling clear cell sarcoma of soft parts: a review and update. J Clin Pathol. 2010
May;63(5):416-23.
Pauwels P, Debiec-Rychter M, Sciot R, Vlasveld T, den Butter B, Hagemeijer A, Hogendoorn PC. Clear cell sarcoma of the
stomach. Histopathology. 2002 Dec;41(6):526-30.
Romeo S, Dei Tos AP. Soft tissue tumors associated with EWSR1 translocation. Virchows Arch. 2010 Feb;456(2):219-34.
Rosai J. Editorial: clear cell sarcoma and osteoclast-rich clear cell sarcoma-like tumor of the gastrointestinal tract: one tumor
type or two? Melanoma or sarcoma? Int J Surg Pathol. 2005 Oct;13(4):309-11.
Sandberg AA, Bridge JA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: clear cell
sarcoma (malignant melanoma of soft parts). Cancer Genet Cytogenet. 2001 Oct 1;130(1):1-7.
Segal NH, Pavlidis P, Noble WS, Antonescu CR, Viale A, Wesley UV, Busam K, Gallardo H, DeSantis D, Brennan MF,
Cordon-Cardo C, Wolchok JD, Houghton AN. Classification of clear-cell sarcoma as a subtype of melanoma by genomic
profiling. J Clin Oncol. 2003 May 1;21(9):1775-81.
Wang WL, Mayordomo E, Zhang W, Hernandez VS, Tuvin D, Garcia L, Lev DC, Lazar AJ, López-Terrada D. Detection and
characterization of EWSR1/ATF1 and EWSR1/CREB1 chimeric transcripts in clear cell sarcoma (melanoma of soft parts).
Mod Pathol. 2009 Sep;22(9):1201-9.
Zambrano E, Reyes-Mugica M, Franchi A, Rosai J. An osteoclast-rich tumor of the gastrointestinal tract with features
resembling clear cell sarcoma of soft parts: reports of 6 cases of a GIST simulator. Int J Surg Pathol. 2003 Apr;11(2):75-81.
Case 6
Presenter: Lei Zhao, MD PhD
Attending: John Hart, MD; Shane Meehan, MD
Diagnosis: Primary Hyperoxaluria Type 1 (PH type 1)
Gross and Microscopic Findings:
 Gross: Liver without gross abnormalities
 Microscopic: Oxalate crystals are present in the walls of small arteries within the liver. Sections of the
hilar vessels also reveal rare scattered intramural oxalate crystals. No other abnormalities are present.
Differential diagnosis:
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 Metabolic liver diseases with no hepatic histologic abnormality but cured by liver transplantation.
Disease
Enzyme or protein factor
Clinical Presentation
deficiency
Crigler-Najjar
Uridyldiphosphate glucuronosyl
Hyperbilirubinemia and
transferase
kernicterus
Urea cycle disorders a
Urea cycle enzymes
Hyperammonemia
Familial hyper- cholesterolemia
LDL receptor or ApoB
↑plasma LDL and cardiovascular
complication
Coagulation factor deficiency
Factor VIII, IX, VII, protein C or S
Bleeding disorders
Familial amyloid polyneuropathy Transthyretin
mixed polyneuropathy with
type 1
sensory, motor, and autonomic
involvement
Primary hyperoxaluria type 1
Alanine : Glyoxylate
Renal failure and systemic
Aminotransferase
oxalosis
a
except Arginosuccinate lyase deficiency: liver fibrosis
Pathogenesis:
 Type 1 PH
o Caused by a deficiency of the liver specific, peroxisomal, pyridoxal phosphate-dependent enzyme
alanine : glyoxylate amino transferase (AGT)
o Severe hyperoxaluria, leading to renal failure and systemic oxalosis (see figure below)
 Type 2 PH
o Caused by a deficiency of glyoxylate reductase/hydroxypyruvate reductase (GRHPR), a cytosolic
enzyme
o Mild hyperoxaluria
Diagnosis and Treatment
 Gene sequencing or enzyme activity measurement
 Conservative measures or liver/kidney transplantation
References:
1.
2.
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