Pediatric Oncologic Pathology
Moderators: Dr. Tony Bourne and Dr. Denis Benjamin
Case 4 -
Poorly differentiated malignant neoplasm showing a
Sara O. Vargas, M.D.
Department of Pathology, Children's Hospital
This previously healthy girl presented at age 23 months with a 3-day history of shortness of breath.
Mild subcostal and intercostal retractions were observed. There were bronchovesicular breath sounds on
the right side accompanied by inspiratory and expiratory wheezes. A 0.5-cm firm mobile subclavicular
lymph node was palpable. Chest x-rays showed complete opacification of the right hemithorax and a left
mediastinal shift, and a CT scan demonstrated a large mass in the right hemithorax and a pleural
On hospital day #2, open biopsy and debulking were performed via median sternotomy, during which the
tumor was noted to involve the right lung and encase the trachea. Within several days the patient
developed superior vena cava (SVC) syndrome and increasing respiratory and ventilatory failure. On
hospital day #9, she underwent an emergent tumor resection which included a right pneumonectomy, further
mediastinal debulking, and a right pneumonectomy. Recrudescent growth led to recurrent SVC syndrome.
Chemotherapy (ifosfamide, adriamycin, and vincristine), begun on hospital day #40, was complicated by
pancytopenia, and in the setting of worsening ventilatory failure, the patient died on hospital day #49.
An autopsy was declined.
Histologic sections showed a poorly differentiated neoplasm growing in nests, cords, and sheets with
fine fibrous septa. In some areas the cells were closely packed with overlapping nuclei, while in other
areas, there was a discohesive appearance. Nuclei were large and round with open vesicular chromatin and
conspicuous nucleoli. Cytoplasm was scant and amphophilic. Mitosis and single-cell necrosis were
frequent. Patchy confluent necrosis was also seen.
Case 4 - Slide 1
Immunostaining showed patchy positivity for desmin, faint nonmembranous positivity for CD99, and foci
of possible faint staining for EMA. The following immunostains were negative: cytokeratins (MNF116,
AE1/AE3, Cam5.2), WT-1, alk-1, PLAP, CD30, CD45, synaptophysin, chromogranin, PGP9.5, NB84, myogenin.
Cytogenetic analysis showed the following karyotype: t(10;19)(q22.3;p13.1).
FISH on paraffin sections showed a rearrangement involving the gene BRD4 (at 19p13.1), but
not NUT (at 15q13).
Poorly differentiated malignant neoplasm showing a
The case presented is that of a poorly differentiated malignant tumor with a chromosomal
translocation that is a variant of that observed in "t(15:19) carcinoma." Tumors harboring the t(15;19)
translocation have been recently identified as a particularly lethal subset of tumors affecting young
patients and usually involving the upper respiratory tract or other midline structures. There is almost
invariably a rapidly fatal clinical course, often with superior vena cava syndrome due to the tumor's
rapid and bulky local growth. The tumors generally have the histologic appearance of undifferentiated or
poorly differentiated carcinomas, often requiring ancillary techniques such as immunostaining or electron
microscopy to demonstrate epithelial differentiation. Squamous differentiation may be perceptible in
some cases and often becomes more apparent following chemotherapy. Only one case reported to date lacked
epithelial differentiation altogether; this occurred in bone and was likened histologically to Ewing
Distinguishing t(15;19) tumors from conventional carcinoma is not possible solely on
histologic means. Although the occurrence of a poorly differentiated carcinoma in a child or young adult
might raise suspicion, genetic confirmation is required; this can be done by conventional karyotype, by
FISH using probes directed at the breakpoints, or by PCR. This pediatric carcinoma is distinctive in
that it is characterized by relatively simple chromosomal rearrangements, as opposed to adult carcinomas,
which presumably arise after multiple genetic insults often related to chronic environmental exposures
and are generally characterized by extremely complex karyotypes. Pediatric tumors, most commonly
sarcomas, tend to harbor single or few genetic changes, and thus have served as excellent entry points
for uncovering genetic mechanisms of tumorogenesis. The identification of t(15;19) carcinoma is
particularly noteworthy because it is the first aggressive carcinoma to be characterized by a
The genes affected by the t(15;19) translocation have been identified as BRD4 (at 19p13)
and NUT (at 15q13). BRD4 is a member of the bromodomain gene family, known from murine models to play a
critical role in regulating cell cycle progression and cellular proliferation. Bromodomain-containing
fusions have been demonstrated in several types of leukemia, including AML with t(8;16). The normal
function of the gene NUT (named for nuclear protein in testis) is unknown. Its expression to date has been identified only in testis and
in NUT-rearranged tumors, where it is localized in the nucleus. The oncogenic mechanism of BRD4-NUT
fusion is currently a subject of intense investigation.
Three cases of carcinoma showing NUT translocated with an unknown variant partner have
been described. These may have a tendency toward better squamous differentiation and more prolonged
survival. The case presented herein is the first observation of a "BRD4-variant" tumor. It appears
similar to the spectrum of classic t(15;19) tumors in that it affected a young patient, involved the
lung/mediastinum, exhibited a poorly differentiated morphology, and rapidly led to death.
Immunostaining of the tumor presented herein helped to rule out other poorly
differentiated "round cell" neoplasms of childhood such as Ewing sarcoma, lymphoma, and rhabdoid tumor.
Another childhood neoplasm in the differential diagnosis is pleuropulmonary blastoma (PPB). PPB is an
aggressive poorly differentiated intrathoracic neoplasm that most often presents as an extremely large
mass in a child under age 5. Histologic components include primitive elements such as blastema and
rhabdomyosarcoma. Primitive or malignant-appearing cartilage as well as fibrosarcomatous areas may also
be apparent. Anaplasia is common. Benign epithelial cysts, presumed to represent maldeveloped
underlying lung tissue, may be interspersed. Since its description in 1988, PPB has been increasingly
recognized; it may now be that some pathologists are using this term as a diagnosis for a broad range of
primitive neoplasms occurring in the lung. Some authors, for example, have advocated conceiving
virtually every apparent embryonal rhabdomyosarcoma of the lung as PPB. But the spectrum of primary
intrathoracic tumors with primitive features that should be designated PPB is not well defined. The lack
of well-defined recurrent karyotypic abnormalities in tumors reported as PPB suggests that the published
cases may represent a diverse grouping. The primitive tumor reported herein lacks the morphologic
heterogeneity (i.e., rhabdomyosarcomatous elements, cartilage, anaplasia, spindled fibrosarcoma-like
pattern) typical of many PPB. Its distinctive genetics set it apart and serve to illustrate that not all
primitive primary neoplasms of the lung are PPB.
As exemplified by the case presented herein, tumor genetics are becoming an important part
of the field of pathology. This is especially true in the area of pediatric neoplasia, where
characteristic genetic aberrations are a distinguishing feature of many pediatric tumors, and where
pathologists are often confronted with primitive and poorly differentiated tumors in which genetic
testing can be of particular aid diagnostically.
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These insights would be impossible without the efforts of Chris French, M.D., of Brigham and Women's
Hospital, Boston , MA , whose outstanding laboratory work has resulted in the identification and
characterization of the BRD4-NUT fusion. Dr. French performed the FISH in this case. Thanks to the
referring pathologist, Edith F. Schmidt, M.D., of Laboratory Medicine Consultants, Las Vegas, NV for
providing material and detailed clinical records for the patient presented herein. And thanks to Stephen
J. Qualman, M.D., and the Children's Oncology Group for the opportunity to review material from primary
pediatric tumors archived in the Biopathology Center , Columbus , OH .