Presenter: Lily Marsden, MD History: The patient is a 4-day-old female who was transferred on day of life 1 from an outside hospital because of a large facial mass and numerous, variably-sized, red-purple nodules covering the body. The mass was identified prenatally and fetal MRI suggested that the mass was arising from the left frontal lobe through a defect in the cribriform plate. No other fetal anomalies were identified. She was born to a G1P0 mother without any known medical comorbidities, and other than continuous growth of the mass in utero, the pregnancy was unremarkable with regular prenatal care. Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. Upon admission, repeat imaging with brain MRI showed a mass measuring 10.3 x 7.0 x 4.5 cm with peripheral enhancement arising from the subcutaneous soft tissues of the midline face with no calvarial defect or intracranial extension. Imaging also showed innumerable subcutaneous masses throughout the body, within the paraspinal musculature, throughout the retroperitoneum and replacing the pancreas. A skin biopsy was performed.
Diagnosis: Congenital rhabdomyosarcoma, favor alveolar subtype
PNET/Ewing’s sarcoma family of tumors
Key Microscopic Features:
Non-cohesive, large, predominantly uniform, hyperchromatic tumor cells, most with prominent nucleoli
Usually scant cytoplasm but can see some cells with moderate to abundant eosinophilic cytoplasm
Transcripts for t(2;13) and t(1;13) can be negative in cases of congenital alveolar RMS
Neonatal/congenital RMS, defined as neoplasm presenting at less than 1 month of age, is extremely rare
It represent ~1% of all childhood RMS
Less than 50 cases have been reported in the literature
In larger studies, the majority are categorized as embryonal
Most case reports discuss the alveolar subtype
Alveolar subtype is distinct from alveolar RMS in older children
>50% of cases present as cutaneous/subcutaneous primary lesions
Must be on the differential diagnosis in “blueberry muffin baby” with:
Extramedullary hematopoiesis due to infection (TORCH organisms)
Hemolytic disease of the newborn
Congenital vascular malformations
Langerhans cell histiocytosis
Leukemia/lymphoma manifesting as leukemia cutis
Many reported cases in the literature do not have t(1;13) or t(2;13) translocations characteristic of alveolar RMS in older patients
Congenital alveolar RMS is a highly malignant tumor
The longest survival that has been reported is 27 months of age
Alamo L, Beck-Popovic M, Gudinchet F, Meuli R. Congenital tumors: imaging when life just begins. Insights into Imaging. 2011;2(3):297-308.
Bresters D, Reus ACW, Veerman AJP, van Wering ER, van der Does-van den Berg A, Kaspers GJL. Congenital leukaemia: the Dutch experience and review of the literature. Br J Hematol. 2002;117:513-524.
Goyal S, Biswas A, Gupta R, Mohanti BK. Congenital peripheral primitive neuroectodermal tumor: a case treated successfully with multimodality treatment. J Egypt Natl Canc Inst. 2014 Dec;26(4):219-224.
Pavlidis NA. Coexistence of pregnancy and malignancy. Oncologist. 2002 Aug;7(4):279-287.
Grundy R, Anderson J, Gaze M, Gerrard M, Glaser A, Gordon A, Malone M, Pritchard-Jones K, Michalski A. Congenital alveolar rhabdomyosarcoma: clinical and molecular distinction from alveolar rhabdomyosarcoma in older children. Cancer. 2001;91:606-612.
Brecher AR, Reyes-Mugica M, Kamino H, Wu Chang, M. Congenital primary cutaneous rhabdomyosarcoma in a neonate. Ped Derm. 2003:20(4):335-338.
Godambe SV, Rawal J. Blueberry muffin rash as a presentation of alveolar cell rhabdomyosarcoma in a neonate. Acta Paediatr. 2000;89:115-119.
Rodriguez-Galindo C, Hill DA, Onyekwere O, Pin N, Rao BN, Hoffer FA, Kun LE, Pappo AS, Santana VM. Neonatal alveolar rhabdomyosarcoma with skin and brain metastases. Cancer. 2001;92(6):1613-1620.
Mehta V, Balachandran C, Lonikar V. Blueberry muffin baby: a pictoral differential diagnosis. Dermatol Online J. 2008 Feb;14(2):8.
Presenter: Shunyou Gong, MD, PhD
Clinical history: 3 year-old boy presented with a firm subcutaneous nodule on the right side of his neck, measuring 4 cm in greatest dimension. Mom noted this nodule approximately 6 weeks ago and it was slowly growing. He was otherwise asymptomatic and CBC was normal. A biopsy was performed.
Diagnosis: B-lymphoblastic lymphoma/leukemia.
Histology: H&E stained sections reveal skin with dense dermal lymphocytic infiltrate extending to subcutaneous fat. There is no significant epidermotropism. The infiltrate is composed of predominantly medium-sized atypical cells with oval nuclei, fine chromatin and small nucleoli. Rare residual follicles and scattered small mature lymphocytes are seen in the background. Frequent mitotic figures are noted.
Immunohistochemical stains for CD20, CD3, CD79a, PAX-5, CD34, TdT, BCL-2, BCL-6, CD10, CD21, MPO, and Ki-67 were performed. The malignant cell are uniformly strongly positive for TdT and CD10, positive for PAX-5, CD79a, BCL-2, and weakly positive for CD20, negative for CD34, CD3, MPO, and BCL-6. A few
residual follicles are composed of CD20-strongly positive B cells and with follicular dendritic cell meshwork highlighted by CD21. The diffuse areas with leukemic infiltrate have no FDC meshwork. CD3 shows scattered background small T cells.Ki-67 shows a high proliferation index (approximately 80% of lymphoma cells are positive).
Cutaneous low grade B-cell lymphomas (cutaneous marginal zone lymphoma or primary cutaneous follicle center cell lymphoma)
B-lymphoblastic lymphoma/leukemia (B-ALL) is a neoplasm of immature B cells which is postulated to arise from precursor B cells in the bone marrow. About 80% of precursor B-cell neoplasms present as acute leukemias, with bone marrow and peripheral blood involvement. By definition, the term “lymphoma” is used in cases exhibiting a bulky lesion in tissue, with no or minimal evidence of peripheral blood and bone marrow involvement, with a threshold of <25% blasts in the bone marrow.
Cases exceeding this number of blasts in the bone marrow or with significant peripheral blood involvement are designated leukaemia, but there is a significant biological and clinical overlap between neoplasms diagnosed as lymphoblastic lymphoma and acute lymphoblastic leukaemia. The most up-to-date WHO tumor classification now names this neoplasm as B-lymphoblastic leukemia/lymphoma.
Although very rare, skin may be the primary presenting site of B-ALL, particularly in children. In reality, B-lymphoblastic lymphoma/leukemia is the third most common cutaneous lymphoproliferative disease in children, after mycosis fungoides (MF) and CD30+ lymphoproliferative disorder (LPD). The most common anatomic site is head and neck region, involved in 80% of cases. Cutaneous involvement by B-lymphoblastic lymphoma/leukemia occurs twice as common in girls as in boys, with a median age at diagnosis of 5 years. About 20% of patients present with multiple cutaneous lesions. In half of the patients, extracutaneous disease is evident at presentation. Histologically, the tumor cells often display artificial changes due to high fragility, making histopathological diagnosis difficult. A large battery of immunohistochemical stains may be necessary to render an accurate diagnosis.
Boccara O et al. Cutaneous B-cell lymphoblastic lymphoma in children: a rare diagnosis. J Am Acad Dermatol 2012; 66: 51–57.
Muljono A, Graf NS, Arbuckle S. Primary cutaneous lymphoblastic lymphoma in children: series of eight cases with review of the literature. Pathology 2009; 41: 223–228.
Millot F et al. Cutaneous involvement in children with acute lymphoblastic leukemia or lymphoblastic lymphoma. The Children’s Leukemia Cooperative Group of the European Organization of Research and Treatment of Cancer (EORTC). Pediatrics 1997; 100:60–64.
Lin P et al. Precursor B-cell lymphoblastic lymphoma: a predominantly extranodal tumor with low propensity for leukemic involvement. Am J Surg Pathol 2000; 24: 1480–1490.
Zachariadis V, Gauffin F, Kuchinskaya E, et al. The frequency and prognostic impact of dic(9;20)(p13.2;q11.2) in childhood B-cell precursor acute lymphoblastic leukemia: results from the NOPHO ALL-2000 trial. Leukemia, 2011; 25(4): 622-8
Bomken S, Haigh S, Bown N, et al. Cutaneous B-lymphoblastic lymphoma with IL3/IgH translocation presenting with hypereosinophilia and acute endocarditis. Pediatr Blood Cancer. 2015 Jun;62(6):1055-7.
CASE # 3 Nicoleta Arva, MD/PhD
Pediatric pathologist, Ann & Robert H. Lurie Children’s Hospital of Chicago
Assistant Professor of Pathology, Feinberg School of Medicine, Northwestern University
Clinical history: The patient is a previously healthy 13 year old male who presented with left leg pain for the past two months.
Physical Exam: No palpable mass; left leg with intact sensation and motor function; adequate circulation.
Radiology: MRI of the pelvis revealed a large (9.7 cm), lobular left pelvic mass which appeared to be centered at the left sacrum with extension across the sacroiliac joint and into the adjacent soft tissues.
Pathology: Patient underwent an open biopsy of the lesion. Sections revealed a malignant neoplasm composed of oval/spindle cells with a storiform/fascicular arrangement. The cells were uniform, with oval nuclei, fine chromatin pattern and fair amount of eosinophilic cytoplasm. Nucleoli were inconspicuous. No osteoid or chondroid material was appreciated. Numerous small, thin-walled, compressed vascular channels were seen between the tumor cells. Immunohistochemical studies revealed positivity for vimentin, CD99 (both cytoplasmic and membranous pattern), Bcl-2 (cytoplasmic); lesional cells were negative for S-100, SMA, EMA, desmin, CD68 and CD31.
Molecular studies were performed and demonstrated negative EWSR1-FLI1, EWSR1-ERG, SYT-SSX, CIC-DUX4 fusion transcripts (by RT-PCR). EWSR1 and FUS FISH studies did not reveal rearrangements of these genes.
RT-PCR for BCOR- CCNB3 was positive.
FINAL DIAGNOSIS: UNDIFFERENTIATED SARCOMA WITH BCOR-CCNB3 TRANSLOCATION.
UNDIFFERENTIATED SARCOMA WITH BCOR-CCNB3 TRANSLOCATION
Localized to bone, preferentially long bones, the spine, and pelvis
Occurs in adolescents or young adults, ranging from 6 to 26 years with a median age of 13 years
Male to female ratio of 2:1
A review by Peters TL et al. (Peters TL et al. BCOR-CCNB3 fusions are frequent in undifferentiated sarcomas of male children. Mod Pathol. 2015 Apr;28(4):575-86) of the pre-treatment diagnostic biopsy specimens from the six BCOR-CCNB3 positive cases showed tumors of variable cellularity. The tumors were comprised of areas with high cellularity alternating with less cellular areas in which discohesive neoplastic cells were embedded, often in an edematous and myxoid stroma containing occasionally angulated thin-walled vessels. Tumor cells had scant to moderate amounts of eosinophilic cytoplasm, and irregular nuclear contours. Nuclei were vesicular with finely dispersed chromatin and occasional indistinct to small nucleoli. None of the tumors showed bizarre nuclear pleomorphism that would be more compatible with a diagnosis of undifferentiated pleomorphic sarcoma. Areas of necrosis were seen in three tumors, ranging from focal to 50% of the tumor area. Mitotic activity was often brisk in the pre-treatment tumors, with a median of 30 mitoses per 10 high-power fields (ranging from 1 to 40).
Immunohistochemistry can show expression of CCNB3 (100%), bcl2 (90%), CD99 (60%), and CD117 (60%).
The tumor is characterized by paracentric inversion on chromosome X resulting in a BCOR-CCNB3 fusion gene. The pathogenic role of BCOR-CCNB3 fusions in sarcomas remains to be determined. Whereas CCNB3 is thought to be a meiotic cyclin restricted to spermatocytes, the BCOR gene, originally discovered to encode a nuclear corepressor of BCL6, regulates mesenchymal stem cell function through epigenetic modification of histone methylation. The expression of the BCOR-CCNB3 fusion gene in undifferentiated unclassified sarcomas is therefore consistent with the presumed activity of the BCOR promoter in putative mesenchymal progenitor cells.
The clinical outcomes for patients with BCOR-CCNB3 are currently unclear, given the small number of such patients reported to date and the heterogeneity of treatment regimens administered. In a study by Puls F. et al. (Puls F. et al. BCOR-CCNB3 (Ewing-like) sarcoma: a clinicopathologic analysis of 10 cases, in comparison with conventional Ewing sarcoma. Am J Surg Pathol. 2014 Oct;38(10):1307-18) the overall survival of BCOR-CCNB3 sarcoma (75% at 5 y) was not statistically different from a large series of classic Ewing sarcoma (54% at 5 y).
Can have similar clinical features
Histologic features can be comparable, although Ewing sarcoma may exhibit peri-vascular or Homer-Wright pseudorosettes; CD99 has a characteristic membranous staining pattern
Classical fusion transcripts; gene re-arrangement can be demonstrated by EWSR1 or FUS FISH studies using break-apart probes
Small cell osteosarcoma
Comprises approximately 1.5% of all osteosarcoma
More commonly seen in the second decade of life (slightly later than conventional osteosarcoma)
Usually involved metaphysis of the long bones
Radiologically, it has mixed lytic and blastic pattern and can destroy the cortex often extending into the soft tissue; mineralized matrix is present in most of the tumors
Composed of hyperchromatic cells with round to oval nuclei and scanty cytoplasm
No specific immunophenotype; tumor cells may variably express CD99
No recurrent molecular genetic abnormalities have been detected
Malignant mesenchymal neoplasm with partial epithelial differentiation
Accounts for 5% to 10% of all soft tissue sarcomas
Encountered predominantly in older children and young adults
Occurs at almost any anatomic site
2 major histologic subtypes (biphasic and monophasic)
Defined by the presence of the t(X;18)(p11.2;q11.2) translocation, involving the SS18 gene on chromosome 18 and one of several synovial sarcoma X (SSX) genes on chromosome X
Rare but highly malignant tumor, accounting for <3% of all primary chondrosarcomas
May occur at any age, with a peak incidence in the second and third decades of life
Shows a widespread skeletal distribution but more commonly arises in the axial skeleton, including craniofacial bones, ribs, ilium, and vertebrae
Radiologically, presents as lytic and destructive lesions; calcified matrix, poor margination, and cortical destruction with an accompanying soft-tissue mass are frequently seen
Biphasic appearance with sheets of primitive small, round, blue cells admixed with variable amount of well-differentiated hyaline cartilage islands
A hemangiopericytoma-like vascular pattern is common in the hypercellular, small cell zones
The small cell component is variably positive for CD99
SOX9 is positive in both small cell and cartilaginous components
A recurrent HEY1-NCOA2 fusion has recently been identified
IDH1/2 mutations were not detected
Accounts for 4%–5% of all childhood malignancies and nearly half of pediatric soft tissue sarcomas
WHO 2013 classification:
Spindle cell sclerosing
Represents 80% of all RMS
Composed of cells resembling fetal skeletal muscle
Most frequently in the 1st decade of life
Most commonly seen in the head and neck area and GU tract
Comprises 15%–20% of all RMS
More common in the extremities
Occurs in older children and teenagers
About 75% of ARMSs harbor the gene fusion between PAX3/PAX7 and FOXO1
Undifferentiated sarcoma with CIC-DUX4 translocation
In 2006, 2 cases of “Ewing-like sarcoma” were found to harbor a recurrent chromosomal translocation t(4;19)(q35;q13), which resulted in fusion between CIC, a human homolog of Drosophila capicua, which encodes a high mobility group box transcription factor, and DUX4, a double homeodomain gene
34 cases are reported to date: the age distribution ranges from 5 to 62 years, with an equal sex distribution; all reported cases are soft tissue based, except 1 with peritonsillar and mandible involvement and another involving bone by direct extension
The vast majority of cases show CD99 immunoreactivity, ranging from focal and/or weak to diffuse and/or strong; most tumors are focally positive for S-100 protein; desmin, myogenin, cytokeratin, and EMA reactivity was found in rare cases
Pierron G et al. A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat Genet. 2012 Mar 4;44(4):461-6.
Peters TL et al. BCOR-CCNB3 fusions are frequent in undifferentiated sarcomas of male children. Mod Pathol. 2015 Apr;28(4):575-86.
Puls F. et al. BCOR-CCNB3 (Ewing-like) sarcoma: a clinicopathologic analysis of 10 cases, in comparison with conventional Ewing sarcoma. Am J Surg Pathol. 2014 Oct;38(10):1307-18.
Wei, Shi; Siegal, Gene Round Cell Tumors of Bone: An Update on Recent Molecular Genetic Advances. Advances in Anatomic Pathology. 21(5):359-372, September 2014.
Thway K, Fisher C. Synovial sarcoma: defining features and diagnostic evolution. Ann Diagn Pathol. 2014 Dec;18(6):369-80.
Case 4: Acute Villitis
Presenter: Lily Marsden, MD History: The patient is a 23 year-old G1P0 female at 40 and 3/7 weeks gestation who presented to Labor and Delivery with spontaneous contractions. Six days before admission she presented to clinic with vaginal burning with vesicles and was prescribed acyclovir for presumed herpes simplex virus. Upon admission she was afebrile but had a fever to 100.4 F during delivery. The infant had Apgars of 8 and 9 a 1 and 5 minutes, respectively. Amniotic fluid was slightly meconium stained. The infant appeared healthy until day 2 of life when he began experiencing fevers, poor feeding and increased irritability. Placental examination was performed.
Diagnosis: Acute villitis secondary to Listeria infection
Herpes Simplex Virus
Varicella Zoster Virus
Normal enteric/vaginal flora:
Group B Streptococcus
Key Microscopic Features:
Acute villitis with micro and macroabscesses
Predominantly neutrophils and histiocytes
Chorionamnionitis with large numbers of organisms
Gram stain will highlights numerous gram positive coccobacilli
There are a limited number of organisms that result in an acute villitis
Listeria is the most well-known because of its characteristic micro- and macroabscesses
Mother infected through consumption of contaminated food products (unpasteurized milk products, deli meats, vegetables)
Infection is 20X more common in pregnant women that in the general population
Diagnosis is difficult to make unless suspected
Mother will often only have mild flu-like symptoms
Neonatal infection can result in intrauterine fetal demise, pneumonia, sepsis and meningitis
If infant presents with sepsis symptoms soon after birth, clinicians should be advised to perform bacterial cultures as well as viral cultures and possibly cultures for M. tuberculosis based on maternal risk factors
Placental examination is important and can provide answers before cultures come back
Can often distinguish bacteria by Gram stain
Listeria: Gram positive coccobacilli
GBS: Gram positive cocci in pairs and chains
E. coli: Gram negative bacilli
Immunohistochemistry can be used if HSV or VZV suspected based on patient history
Mycobacterium tuberculosis is a rare entity that is often forgotten
Usually placenta will be heavily colonized and special stains can be used
Brown ZA, Gardella C, Wald A, Morrow RA, Corey L. Genital herpes complicating pregnancy. Obstet Gynecol. 2005 Oct;106(4):845-856.
Finger-Jardim F, Teixeifa LO, de Oliveira GR, Barral MF, da Hora VP, Gonclaves CV, Soares MA, de Martinez AM. Herpes Simplex Virus: prevalence in placental tissue and incidence in neonates cord blood samples. J Med Virol. 2014 Mar;86(3):519-524.
Sheikh SS, Amr SS, Lage JM. Acute placental infection due to Klebsiella pneumoniae: report of a unique case. Infect Dis Obstet Gynecol. 2005 Mar;13(1):49-52.
Sauerbrei A, Wutzler P. Herpes simplex and varicella-zoster infections during pregnancy: current concepts of prevention, diagnosis and therapy. Part 2: varicella-zoster virus infections. Med Microbiol Immunol. 2007 Jun;196(2):95-102.
CDC. Reported Tuberculosis in the United States, 2014. Atlanta, GA: U.S. Department of Health and Human Services, CDC, October 2015. Available at http://www.cdc.gov/tb/statistics/reports/2014
Abramowsky CR, Gutman J, Hillnski JA. Mycobacterium tuberculosis infection of the placenta: a study of the early (innate) inflammatory response in two cases. Pediatr Dev Pathol. 2012;15(2):132-136.
Bae GE, Yoon N, Hwang S, Choi M, Hwang H, Kim JS. Acute placental villitis as evidence of fetal sepsis: an autopsy case report. Pediatr Dev Pathol. 2015 Oct 12. [Epub ahead of print].
Janakiraman V. Listeriosis in pregnancy: diagnosis, treatment and prevention. Rev Obstet Gynecol. 2008;1(4):179-185.
Heerema-McKenney A, De Paepe ME, Popek, EJ. Diagnostic Pathology: Placenta. Salt Lake City, UT. Amirsys Publishing, Inc. 2014.
Presenter/Attending: Nitin Wadhwani, MD
Clinical History: This is an infant male born at 39 and 2/7 weeks' gestational age via cesarean for failure to progress at a hospital across the state lines. Past medical history is remarkable for an abnormal prenatal ultrasound for which the patient underwent an MRI after he was delivered. Physical exam was remarkable for cleft lip and palate. The MRI is below.
There is a large cyst in the extra-axial space of the left anterior cranial fossa, extending slightly across midline, with associated cerebral compression and displacement of the left frontal and temporal lobes. There is also a solid mass with apparent lateral dural base near the displaced left frontal and temporal lobes, with slight peripheral enhancement. Sections from the solid mass are submitted for your review.
Key Features/Discussion: Heterotopic brain tissue can occur anywhere in the CNS. The earliest reports were of tissue located in the dura and occipital scalp, but IEGH can also be seen in the face, spine, and thoracic cavity. It will anchor to normally developed cortical tissue or the dura. Components of the telencephalon most likely will resemble normal developing cortical tissue and should be called Intracranial Extracerebral Glioneuronal Heterotopia. Anomalies occurring earlier than 28 days gestation can occur and may contain more portions of the neural tube resulting in variations of what we are seeing. For example cerebrum, brainstem, cerebellum (call it Intracranial Extracerebral Brain Heterotopia).
WHO Classification of Tumors of the Central Nervous System.
Moore, Keith. The Developing Human: Clinically Oriented Embryology. 7th Edition.
Cho et al. Intracranial extracerebral glioneuronal heterotopia with adipose tissue and a glioependymal cyst: A case report and review of the literature. The Korean Journal of Pathology. 48: 254-257, 2014.