U of Chicago IRAP HandoutFebruary 27, 2017

Case 1Presenter: Zhen Wei Mei, MDAttending(s): Peter Pytel, MD and Aliya Husain, MBBS

Clinical History: This 3-year-old African-American male presented with breathing difficulty and abdominal pain. Other history includes asthma and partial complex seizures since 1 year of age. A CT scan found a 6.3 x 6.0 x 4.8 cm posterior mediastinal mass abutting the pleura of the right superior lower lobe, right upper lobe bronchus, and bronchus intermedius without compromising the airways. At surgery, the tumor was very adherent to the lung and did not appear to arise from the paraspinal sympathetic chain. A 2.0 x 2.0 cm sample of the mass was resected and sent for intra-operative consultation and a representative section is provided.

Diagnosis: Pleuropulmonary Blastoma, Type II

Differential Diagnosis: Rhabdomyosarcoma

Key Features:The original biopsy (represented by the provided slide) showed:

Small immature blastema-like blue cells with scattered large atypical to anaplastic cells A second population of more spindled sarcomatous cells, some with distinct eosinophilic cytoplasm Focal fragments of benign epithelium overlying the malignant-appearing cells

Discussion: Historical Background:

- This entity was first described as a distinct clinicopathologic entity in 1988. Previously cases with a similar histologic appearance were reported as pulmonary blastoma in children, among other names.

- Now, it is the most common primary malignancy of the lung in childhood. Histologic Appearance:

- The categorization of this entity depends solely on the histologic appearance, which ranges from cystic to solid patterns (see figure below).

- The malignant component is composed of primitive cells that display either an undifferentiated blastema-like appearance or sarcomatous differentiation, such as rhabdomyomatous or chondromatous lineages.

- The overlying epithelium does not display any histologic abnormality even though it directly borders the underlying malignant cells.

Proposed Pathogenesis:- Increased levels of Fibroblast Growth Factor 9 (FGF-9), due to an impaired inhibitory microRNA

maturation, induce the stromal cells to proliferate uncontrollably and accumulate secondary mutations.

Associated Molecular Alterations:- Germline DICER1 mutations, which work in concert with other cellular regulatory elements to control

levels of FGF-9 during embryonic lung development, are found in the majority of PPB cases.- DICER1 Syndrome is a constellation of a variety of other tumors that may also present in individuals

who harbor this germline mutation, including Sertoli-Leydig cell tumor of the ovary, cystic nephroma, Wilms tumor, adenomas and well-differentiated carcinoma of the thyroid gland, nasal chondro-mesenchymal hamartoma, cervical embryonal rhabdomyosarcoma, neuroblastoma, ciliary body medulloepithelioma, pituitary blastoma, and pineoblastoma.

Diagnostic Workup:- Differentiate cystic type I PPB from congenital pulmonary airway malformation type 4 (CPAM 4) by

sampling extensively to ensure there is no malignant cell component underlying the benign epithelium

- Differentiate type II and III PPB from rhabdomyosarcoma through correlation with radiographic findings and keeping in mind that pediatric primary lung tumors with rhabdomyosarcomatous differentiation is a PPB until proven otherwise

- Performing DICER1 mutation molecular analysis is helpful.References

1. Manivel JC, Priest JR, Watterson J, et al. Pleuropulmonary blastoma. The so-called pulmonary blastoma of childhood. Cancer. 1988;62:1516–1526.

2. Ritter JH, Hill DA. Pulmonary and pleural pathology: Contributions of Dr. Louis “Pepper” Dehner. Seminars in Diagnostic Pathology. 2016;33:450-461.

3. Messinger YH, Stewart DR, Priest JR, et al. Pleuropulmonary Blastoma: A Report on 350 Central Pathology–Confirmed Pleuropulmonary Blastoma Cases by the International Pleuropulmonary Blastoma Registry. Cancer. 2015;121(2):276-285. doi:10.1002/cncr.29032.

4. Pugh TJ, Yu W, Yang J, Field AL, Ambrogio L, Carter SL, Cibulskis K, Giannikopoulos P, Kiezun A, Kim J, McKenna A, Nickerson E, Getz G, Hoffher S, Messinger YH, Dehner LP, Roberts CW, Rodriguez-Galindo C, Williams GM, Rossi CT, Meyerson M, Hill DA. Oncogene. 2014 Nov 6;33(45):5295-302. doi: 10.1038/onc.2014.150.

5. Hill DA, Ivanovich J, Priest JR, Gurnett CA, Dehner LP, et al. DICER1 Mutations in Familial Pleuropulmonary Blastoma. Science. 2009;325(5923):965.

6. Schultze-Florey RE, et al. DICER1 Syndrome: A New Cancer Syndrome. Klin Padiatr. 2013; 225:177-178.

7. Doros L, Yang JD, Dehner LP, et al. DICER1 Mutations in Embryonal Rhabdomyosarcomas from Children With and Without Familial PPB-Tumor Predisposition Syndrome. Pediatr Blood Cancer. 2012 September; 59(3):558-560. doi: 10.1002/pbc.24020.

8. Wagh PK, Gardner MA, Ma X, Callahan M, Shannon JM, Wert SE, Messinger YH, Dehner LP, et al. Cell- and developmental stage-specific DICER1 ablation in the lung epithelium models cystic pleuropulmonary blastoma. Journal of Pathology 2015; 236:41-52. doi: 10.1002/path.4500.

9. Doros LA, et al. Journal of Clinical Oncology 32, no. 15_suppl (May 2014) 10060-10060. DOI: 10.1200/jco.2014.32.15_suppl.10060

10. Williams GM, et al. Journal of Clinical Oncology 30, no. 15_suppl (May 2012) 9521-9521. DOI: 10.1200/jco.2012.30.15_suppl.9521

11. Messinger YH, William GM, Priest JR, et al. Outcomes of 116 cases of pleuropulmonary blastoma type I and type Ir (regressed): A report from the International PPB Registry (IPPBR)

Case 2

Presenter: Lisa Han, MDAttendings: Nicole Cipriani, MD; Peter Pytel, MD

Clinical History: This 56-year-old female presented with a dorsal left foot mass which she had initially attributed to swelling after a foot injury. She underwent an attempted aspiration thinking there was a fluid collection, but did not obtain relief. A subsequent MRI revealed a focal T1-dark T2-bright 3 cm mass along the dorsal and lateral aspect of the foot within the area of swelling. The patient then underwent a needle biopsy, left 2nd metatarsal biopsy and partial foot amputation. A representative section of the mass in the partial foot amputation is provided.

Diagnosis: Hemosiderotic fibrolipomatous tumor with sarcomatous transformation

Differential Diagnosis:

Myxofibrosarcoma Diffuse-type Tenosynovial Giant Cell Tumor Inflammatory Myofibroblastic Tumor Pleomorphic Hyalinizing Angiectatic Tumor

T1

Myxoinflammatory fibroblastic sarcoma (MIFS)

• Low-grade slow growing tumor derived from fibroblasts

• Hands and wrists• Morphologically:

• Multinodular infiltrative tumor• Distinct myxoid, hyalized, fibrotic areas• Atypical epitheloid or spindled cells• Macronucleoli and vacuolations

(“psuedolipblasts”)• Background inflammatory infiltrate• Low proliferative index

Hemosiderotic fibrolipomatous tumor (HFLT)

• Ankle/foot mass in females• Recurrences common (50%) but no

metastases/tumor related deaths • Morphologically,

• Lobules of mature adipocytes • Bland fibroblastic spindle cells

dissecting fat in fascicles• Hemosiderin deposition• +/- Scattered giant cells• No cells with macronucleoli

Myxoinflammatory Fibroblastic SarcomaKey Features:

Discussion:

In the past decade, classical cytogenetics and molecular genetics have challenged our understanding of these two tumors as separate entities. In 2001, Lambert reported a MIFS case with the karyotype of t(1;10)(p22;q24) with loss of chromosome 3. Similarly in 2008, Wettach identified the same translocation in a HFLT case. A year later, Hallor reported that this translocation juxtaposed the TGFBR3 (transforming growth factor beta receptor 3) gene on chromosome 1 with the MGEA5 (meningioma expressed antigen 5) gene on chromosome 10, resulting in not a fusion transcript but rather, through mechanisms that are not entirely unraveled, caused an upregulation of NPM3 and FGF8, the latter of which is a growth factor pivotal in limb development. Elco subsequently reported a case of a 42 year old female with an ankle mass consistent with the even rarer, "hybrid" HLFT-MIFS which had the rearrangements in TGFBR3 and MGEA5. He proposed for the first time that the two entities may represent different morphologic manifestations of a single entity OR that MIFS may represent sarcomatous progression of HFLT.

However, this view has been challenged by the two largest case series of these disease entities to date, incorporating cytogenetics to clarify the relationship between hybrid HFLT-MIFS and MIFS. Antonescu in 2011 studied 27 cases including MIFS, HFLT and hybrid HLFT-MIFS and found that only 5 of 7 MIFS had MGEA5 and TGFBR3 rearrangements, compared to significantly more of these rearrangements in both HFLT and hybrids. Similarly in 2016, Zreik studied 46 cases and found that a substantially lower number of MIFS had either of these rearrangements. Specifically, only 2 of 31 MIFS had the MGEA5 rearrangement and the remaining 29 cases had neither the MGEA5 or TGFBR3 rearrangements. Like Antonescu, he found that these aberrations were much more common in the HFLT and hybrid cases. Of note, a thorough updated literature review has shown the overall rate of TGFBR3 and/or MGEA5 rearrangements in prospectively diagnosed MIFS is only 18%.

Thus the authors' conclusions were as follows. 1. TGFBR3 and/or MGEA5 rearrangements are much more common in hybrid HFLT-MIFS than classic solo MIFS. 2. HFLT and solo MIFS may be unrelated. 3. New nomenclature for hybrid HFLT-MIFS should be considered to highlight these differences.

In fact, a closer morphologic assessment has shown that the MIFS-like myxoid sarcomatous areas in hybrid cases appear slightly different from solo MIFS. In hybrid entities, there are less hyalinized zones and less Reed-Sternberg like cells compared to solo MIFS. This particular finding was not congruent with what we see in our case as many Reed-Sternberg cells were identified in our case. As well the authors proposed that there are well developed arborizing vasculature, reminiscent of myxofibrosarcoma, seen in hybrid cases, moreso than in solo MIFS, which was also noted in our case. More importantly, the study has shown that these tumors have a potential to progress to high grade sarcomas unlike the solo MIFS which are known to be classically indolent tumors. To date, this adverse prognostic finding in hybrid forms has been supported by a handful of case reports. Because of these clinical implications, the authors suggested "HFLT with sarcomatous progression" or "sarcoma arising in HFLT" be the final diagnosis.

Take Home Points:

Identical TGFBR3 (1p22) and MGEA5 (10q24) rearrangements were found in both MIFS and HFLT TGFBR3 and/or MGEA5 rearrangements are much more common in hybrid HFLT-MIFS than classic

MIFS “Hybrid” HFLT-MIFS may actually represent high grade sarcomatous progression rather than biphasic

components of indolent tumors New nomenclature for hybrid HFLT-MIFS should be considered to reflect their adverse prognostics

References

• Antonescu CR, Zhang L, Nielsen GP, Rosenberg AE, Dal Cin P, Fletcher CD. Consistent t(1;10) with rearrangements of TGFBR3 and MGEA5 in both myxoinflammatory fibroblastic sarcoma and hemosiderotic fibrolipomatous tumor. Genes Chromosomes Cancer. 2011 Oct;50(10):757-64.

• Elco CP, Mariño-Enríquez A, Abraham JA, Dal Cin P, Hornick JL. Hybrid myxoinflammatory fibroblastic sarcoma/hemosiderotic fibrolipomatous tumor: report of a case providing further evidence for a pathogenetic link. Am J Surg Pathol. 2010 Nov;34(11):1723-7.

• Hallor KH, Sciot R, Staaf J, Heidenblad M, Rydholm A, Bauer HC, Aström K, Domanski HA, Meis JM, Kindblom LG, Panagopoulos I, Mandahl N, Mertens F. Two genetic pathways, t(1;10) and amplification of 3p11-12, in myxoinflammatory fibroblastic sarcoma, haemosiderotic fibrolipomatous tumour, and morphologically similar lesions. J Pathol. 2009 Apr;217(5):716-27.

• Morency E, Laskin W, Lin X. Cytologic and Histologic Features of Pleomorphic Undifferentiated Sarcoma Arising in a Hybrid Hemosiderotic Fibrolipomatous Tumor and Pleomorphic Hyalinizing Angiectatic Tumor: Report of an Unusual Case with a Literature Review. Acta Cytol. 2015;59(6):493-7.

• Nishio J, Iwasaki H, Nabeshima K, Naito M. Cytogenetics and molecular genetics of myxoid soft-tissue sarcomas. Genet Res Int. 2011;2011:497148.

• Rekhi B, Adamane S. Myxoinflammatory fibroblastic sarcoma with areas resembling hemosiderotic fibrolipomatous tumor: a rare case indicating proximity between the two tumors. Indian J Pathol Microbiol. 2014 Oct-Dec;57(4):647-8.

• Wettach GR, Boyd LJ, Lawce HJ, Magenis RE, Mansoor A. Cytogenetic analysis of a hemosiderotic fibrolipomatous tumor. Cancer Genet Cytogenet. 2008 Apr 15;182(2):140-3.

• Zreik RT, et al. TGFBR3 and MGEA5 rearrangements are much more common in "hybrid“ hemosiderotic fibrolipomatous tumor-myxoinflammatory fibroblastic sarcomas than in classical myxoinflammatory fibroblastic sarcomas: a morphological and fluorescence in situ hybridization study. Hum Pathol. 2016 Jul;53:14-24.

Case 3Presenter: David Byron Chapel, M.D.Attending: Aliya Noor Husain, M.D.

Clinical History: A 13-year-old boy with a history of multiple laryngoscopic procedures for resection of benign squamous papillomas presents with worsening shortness of breath and stridor. Laryngoscopy reveals multiple papillary lesions, partly obstructing the airway at the level of the false vocal cord. A laryngoscopic excision is performed without complications.

Diagnosis: Invasive squamous cell carcinoma of the lung, arising in the context of juvenile-onset recurrent respiratory papillomatosis (JoRRP) with dysplasia and pulmonary spread

Differential diagnosis: The diagnosis of juvenile-onset recurrent respiratory papillomatosis is well established by the patient’s clinical history and pathologic findings. In cases with pulmonary involvement, distinguishing benign papillomatosis involving alveoli from invasive carcinoma may be a diagnostic challenge, particularly in small biopsy specimens.

Key features:- Multiple biopsies over the course of months reveal recurrent squamous papillomas with acute inflamed fibrovascular cores. Some papillomas contain foci of hypercellularity, increased nuclear-to-cytoplasmic ratio, irregular nuclear contours, and abundant superficial mitotic figures, consistent with squamous dysplasia.

- In one biopsy, the pulmonary parenchyma is involved by benign papillomatous growth, which fills and distends the alveolar spaces, mimicking invasive carcinoma.

- Multifocal invasive squamous cell carcinoma involves the right lung at the time of palliative pneumonectomy. Invasive carcinoma cells are positive for HPV-6/11 by in situ hybridization, and negative for HPV-16.

Discussion:- JoRRP is defined by recurrent laryngeal, tracheal, or pulmonary papillomas, requiring at least two

resection procedures, and first presenting before age 14.- Pulmonary involvement is a rare complication of JoRRP, developing in 3-4% of cases.- Dysplasia and invasive carcinoma are additional rare complications of JoRRP. Dysplasia develops in

approximately 5% of patients, and invasive carcinoma in <1%. - Young age at diagnosis and infection with HPV-11 constitute risk factors for an aggressive course in

JoRRP, including progression to pulmonary involvement and development of invasive squamous cell carcinoma. Because of its prognostic value, specific HPV typing information (i.e., distinguishing HPV-6 from HPV-11 involvement) should be provided in the pathology report, when possible.

- The molecular determinants (viral and host alike) that portend an aggressive disease course generally, and malignant transformation specifically, remain poorly understood. The majority of cases progressing to carcinoma are involved by “low-risk” HPV alone.

Key References:1. Buchinsky, F.J., et al., Age of child, more than HPV type, is associated with clinical course in recurrent

respiratory papillomatosis. PLoS One, 2008. 3(5): p. e2263.2. Cook, J.R., et al., Squamous cell carcinoma arising in recurrent respiratory papillomatosis with

pulmonary involvement: emerging common pattern of clinical features and human papillomavirus serotype association. Mod Pathol, 2000. 13(8): p. 914-8.

3. Gelinas, J.F., et al, Lung involvement in juvenile onset recurrent respiratory papillomatosis: a systematic review of the literature. Int J Pediatr Otorhinolaryngol, 2008. 72(4): p. 433-52.

4. Karatayli-Ozgursoy, S., et al., Risk Factors for Dysplasia in Recurrent Respiratory Papillomatosis in an Adult and Pediatric Population. Ann Otol Rhinol Laryngol, 2016. 125(3): p. 235-41.

5. Lele, S.M., et al., Molecular events in the progression of recurrent respiratory papillomatosis to carcinoma. Arch Pathol Lab Med, 2002. 126(10): p. 1184-8.

6. Maloney, E.M., et al., Longitudinal measures of human papillomavirus 6 and 11 viral loads and antibody response in children with recurrent respiratory papillomatosis. Arch Otolaryngol Head Neck Surg, 2006. 132(7): p. 711-5.

7. Measso do Bonfim, C., et al., Differences in Transcriptional Activity of Human Papillomavirus Type 6 Molecular Variants in Recurrent Respiratory Papillomatosis. PLoS One, 2015. 10(7): p. e0132325.

8. Omland, T., et al., Risk factors for aggressive recurrent respiratory papillomatosis in adults and juveniles. PLoS One, 2014. 9(11): p. e113584.

9. Shah, K.V., A case for immunization of human papillomavirus (HPV) 6/11-infected pregnant women with the quadrivalent HPV vaccine to prevent juvenile-onset laryngeal papilloma. J Infect Dis, 2014. 209(9): p. 1307-9.

10. Silverberg, M.J., et al., Clinical course of recurrent respiratory papillomatosis in Danish children. Arch Otolaryngol Head Neck Surg, 2004. 130(6): p. 711-6.

Case 4Presenter: Aaron Miller, MDAttending: Ricardo Lastra, MD

Clinical History: The patient is a 68-year-old female (G3P3003) with history of colorectal cancer status post partial colectomy presented with one month of vaginal bleeding and left lower quadrant abdominal pain. CT scan showed a 9.0 x 9.0 cm calcified uterine mass with gaseous foci. Transvaginal ultrasound showed a complex left adnexal mass, diffusely calcified uterus without normal myometrium, and the endometrium could not be visualized. She underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy

Diagnosis: Epithelioid trophoblastic tumor (ETT)

Differential Diagnosis: Given the patient’s age and the histologic features outlined below, the main differential diagnoses were uterine clear cell adenocarcinoma and perivascular epithelioid cell tumor (PEComa). Though the histomorphology was not consistent with colorectal adenocarcinoma, we considered this entity given the patient’s recent history of this malignancy. A poorly differentiated cervical squamous cell carcinoma would also be a remote possibility. Mesenchymal tumors were also included in the differential and though the microscopic appearance was not spindle-celled or sarcomatous, the epithelioid variant of leiomyosarcoma needed to be ruled out. Lastly, though very uncommon in post-menopausal females, malignant gestational trophoblastic tumors (i.e. epithelioid trophoblastic tumor and placental site trophoblastic tumor) clearly deserved attention as the final diagnosis was an ETT.

Key Morphologic Features:- Sheets of epithelioid cells with eosinophilic to clear cytoplasm and well-defined cell borders- Nodular growth pattern at edge of tumor and at interface with necrotic areas- Prominent perivascular distribution of tumor cells- Abundant geographic necrosis

Genetic Findings:DNA microsatellite analysis with tri-allelic pattern in microdissected tumor tissue is consistent with the presence of paternal DNA in the intermediate trophoblastic tumor cells. This pattern was absent in non-neoplastic tissue from our patient.

DiscussionGestational trophoblastic tumors comprise a collection of different entities derived from the various placental trophoblastic cell populations. The three distinct trophoblast populations are cytotrophoblasts, intermediate trophoblasts, and syncytiotrophoblasts which can be further characterized as either villous or extravillous trophoblasts based on their anatomic locations. The cytotrophoblast serves as the cell of origin for all others while syncytiotrophoblasts are terminally differentiated and represent fused villous cytotrophoblastic stem cells. As the name implies, intermediate trophoblasts have morphologic and functional properties of both. These can also be further classified by their anatomic location as either placental site or chorionic-type intermediate trophoblasts. Placental site intermediate trophoblasts are those which invade the maternal decidua into the spiral arteries to establish the maternal-fetal circulation. Chorionic-type intermediate trophoblasts eventually migrate into the fetal membranes forming part of the chorion laeve.

A review article (Kurman and Shih. Int J Gynecol Pathol. 2001 Jan;20(1):31-47) nicely summarizes the histomorphologic properties of the various trophoblastic populations:

The gestational trophoblastic tumors themselves vary in terms of the cell (or cells) from which they derive, as well as their morphologic appearance, immunohistochemical profiles, and clinical behavior.

Choriocarcinoma is comprised of highly proliferative cytotrophoblasts and syncytiotrophoblasts, and is indeed the only trophoblastic lesion known to be comprised of more than one cell type. They also differ from those discussed below in that they are significantly more aggressive, strongly express beta-human chorionic gonadotropin (β-hCG) due to the presence of syncytiotrophoblasts, and typically have very high Ki-67 indices.

The group of intermediate trophoblastic tumors can be characterized as being of either placental-site or chorionic-type. Each of these two categories contain both benign and malignant counterpart lesions and there is evidence to suggest that the former may transform to the latter. To begin with, the chorionic-type tumors include the placental site nodule and the epithelioid trophoblastic tumor and in addition to having the morphologic characteristics in the table above, have an immunoprofile (i.e. p63+, hPL- with possible weak, focal positivity) that can be used to distinguish both from the corresponding implantation site lesions (i.e. exaggerated placental site and placental site trophoblastic tumor) which are p63-, hPL+. These findings were reported by the same authors as those above as follows (Am J Surg Pathol. 2004 Sep;28(9):1177-83):

Notice that all trophoblastic lesions are positive for human leukocyte antigen G (HLA-G), a class Ib HLA molecule expressed on trophoblasts and involved in the immune tolerance of these cells by the maternal immune system during gestation. Also recall that choriocarcinoma is not a tumor of intermediate trophoblasts and can be distinguished from all others by both morphology (i.e. prominent syncytiotrophoblasts) and strong expression of β-hCG. Distinguishing benign from malignant within each category of intermediate trophoblast tumors relies on the Ki-67 index, with a threshold of 10% for chorionic-type and 1% for implantation site tumors. The reason for the different Ki-67 index cutoffs lies in the proliferative activity of the cells of origin (i.e. implantation site intermediate trophoblasts are minimally proliferative while those of chorionic-type do retain some of this ability).

In terms of the outcomes of these various entities, all carry a relatively favorable prognosis. Though choriocarcinoma frequently presents with metastasis and was formerly highly lethal, the prognosis has improved significantly with overall survival in excess of 90%. Likewise, both epithelioid and placental site trophoblastic tumors have similar outcomes with rates of metastasis and mortality of approximately 20% and 10% respectively.

References 1. Shih IM, Kurman RJ. p63 expression is useful in the distinction of epithelioid trophoblastic and placental

site trophoblastic tumors by profiling trophoblastic subpopulations. Am J Surg Pathol. 2004 Sep;28(9):1177-83.

2. Kurman RJ, Shih IeM. Discovery of a cell: reflections on the checkered history of intermediate trophoblast and update on its nature and pathologic manifestations. Int J Gynecol Pathol. 2014 Jul;33(4):339-47.

3. Ngan HY, Kohorn EI, Cole LA, Kurman RJ, Kim SJ, Lurain JR, Seckl MJ, Sasaki S, Soper JT. Trophoblastic Disease. Int J Gynaecol Obstet. 2012 Oct;119 Suppl 2:S130-6.

4. Shih IM, Kurman RJ. The pathology of intermediate trophoblastic tumors and tumor-like lesions. Int J Gynecol Pathol. 2001 Jan;20(1):31-47.

5. Singer G, Kurman RJ, McMaster MT, Shih IeM. HLA-G immunoreactivity is specific for intermediate trophoblast in gestational trophoblastic disease and can serve as a useful marker in differential diagnosis. Am J Surg Pathol. 2002 Jul;26(7):914-20.

6. Shih IeM, Kurman RJ. Molecular basis of gestational trophoblastic diseases. Curr Mol Med. 2002 Feb;2(1):1-12.

7. Almarzooqi S, Ahmad Al-Safi R, Fahad Al-Jassar W, Akhter SM, Chiab-Rassou Y, Albawardi A. Epithelioid trophoblastic tumor: report of two cases in postmenopausal women with literature review and emphasis on cytological findings. Acta Cytol. 2014;58(2):198-210.

8. Yap KL, Hafez MJ, Mao TL, Kurman RJ, Murphy KM, Shih IeM. Lack of a y-chromosomal complement in the majority of gestational trophoblastic neoplasm. J Oncol. 2010

9. Kaur B, Short D, Fisher RA, Savage PM, Seckl MJ, Sebire NJ. Atypical placental site nodule (APSN) and association with malignant gestational trophoblastic disease; a clinicopat5hological study of 21 cases. Int J Gynecol Pathol. 2015 Mar;34(2):152-8.

Case 5Presenter: Megan Parilla, MDAttending: Girish Venkataraman, MD

Clinical History: The patient is a 57-year-old woman with autosomal dominant polycystic kidney disease, status post liver and kidney transplant 2 years ago. She returned to clinic for a routine follow-up with some mild left upper abdominal discomfort but she is otherwise asymptomatic. Complete blood count demonstrates a leukocytosis to 40.2K/uL with an absolute monocytosis at 6.4K/uL. Her platelets are adequate at 234 K/uL and hemoglobin and hematocrit are within the normal range at 12.6g/dL and 38.9% respectively.

Diagnosis: Chronic phase chronic myelogenous leukemia (CML) with p190 BCR-ABL

Differential Diagnosis:

Her history of solid organ transplant raises the possibility of a PTLPD or PT-AML, however, the morphologic findings are incongruent with these diagnoses. However, given the history of immunosuppressive therapy, infection is a distinct possibility which could lead to the granulocytic and monocytic response seen. This could also represent a neoplastic process such as a CML or CMML.

Key Morphologic Features:

Peripheral blood:- Leukocytosis with an absolute monocytosis- “Myelocyte buldge”- Absent thrombocytopenia and absent anemia.- No granulocytic dysplasia

Bone marrow:- Hypercellular marrow with a granulocytic/ neutrophilic predominance and monocytosis.- Generally unremarkable megakaryocytes, except possibly very rare dwarf forms- No increased blast count or a predominance of lymphocytes.

Genetic Findings:-The BCR-ABL assay detected the P190 fusion variant instead of the classic P210 form

Discussion

The peripheral blood shows leukocytosis with increased numbers of circulating bands, metamyelocytes and myelocytes but without circulating blasts. Granulocytes are without significant dysplasia. Basophils are present at approximately 2% of the total circulating cellularity and there is an absolute monocytosis. A bone marrow biopsy is hypercellular with marked granulocytic expansion comprised predominately of mature neutrophils.

The myeloid to erythroid ratio is >6:1. There is no increase in blasts. The megakaryocytes are generally morphologically unremarkable but there are regenerative forms as well as some smaller forms, possibly consistent with dwarf megakaryocytes.

The diagnosis of CML has classically relied on detection a hypercellular marrow with granulocytic predominance and dwarf megakaryocytes. Dwarf megakaryocytes are not easily apparent in this case. Additionally, monocytosis is not a typical presentation for CML, and the leukocytosis with marked monocytosis in this case makes CMML a diagnostic consideration. However, the normal platelet counts and lack of dysplasia are unusual for CMML. A BCR-ABL assay performed on peripheral blood detected the P190 BCR-ABL fusion variant, leading to the diagnosis of chronic phase CML. The classic P210 BCR-ABL form was not detected.

Chronic myeloid leukemia is a clonal hematopoietic neoplasm characterized by neutrophilic leukocytosis often with splenic enlargement. Interestingly, this disease was the first malignancy associated with a recurrent chromosomal abnormality. The abnormally, a shortened chromosome 22, was first identified by two researchers in Philadelphia, PA at the time and thus the short chromosome 22 was named the Philadelphia chromosome. It took another 13 years before Janet Rowley at the University of Chicago discovered that the Philadelphia chromosome arises as a reciprocal translocation between chromosomes 9 and 22. The translocation involves the proto-oncogene and tyrosine kinase, ABL, which is normally located on chromosome 9 and a previously unknown gene on chromosome 22, which was termed the breakpoint cluster region/ BCR. The fusion gene creates a shortened ABL protein which is composed of just its tyrosine kinase domain without the regulatory domain. The constitutively active ABL tyrosine kinase activates downstream proteins via the MAPK pathway and ultimately leads to the malignant phenotype.

This deregulated ABL protein, created as a result of this fusion, comes in a variety of different sizes. The protein size is predominantly dependent on the distance within the BCR gene that the break-point occurs and the most common fusion genes are 190kD, 210kD and 230kD in size and so termed p190, p210 and p230 respectively. The p210 form is the most common form in CML. The P190 form, isolated and without P210 expression, is rare in CML and occurs as in approximately 1-2% of all cases. The morphology is unique in that when it does occur it often resembles a “proliferative” CMML due to the associated marked monocytosis. The p230 transcript is also rare and phenotypically presents with neutrophilia and thrombocytosis. The case highlights the need to exclude presence of BCR-ABL rearrangements before one makes a diagnosis of CMML by morphology.

Additionally, the different transcripts of BCR-ABL fusion genes may have prognostic and treatment implications. Imantinib/Gleevac is a tyrosine kinase inhibitor (TKI) which has been remarkably successful and has turned CML from a fatal disorder into a chronic disease with a normal lifespan all while maintaining minimal side effects. It was designed through the knowledge that the BCR-ABL fusion is required for the pathogenesis of CML. A 2009 analysis at M.D. Anderson Cancer Center demonstrated that while p210 BCR-ABL CML has an outstanding response to TKI therapy, p190 BCR-ABL has an inferior outcome and has only short-lived response with an increased likelihood of resistance to imatinib treatment. The suggestion following this study is if a p190 BCR-ABL mutation is discovered, closer monitoring is need, and these patients should be offered stem cell transplant early if they are eligible [1].

Finally, a recent case report and review of literature published in Berlin in 2014 suggests that CML can be considered a secondary malignancy following solid organ transplantation, as was seen in this case [2]. Malignancy following solid organ transplant has been well described with hematologic conditions such as posttransplant lymphoproliferative disorder and myeloid dysplastic disorder as well as acute myeloid leukemia known to result following the intensive immunosuppressive therapy. The comprehensive literature review in this paper suggests that CML is also specifically linked to solid organ transplantation and likely the required immunosuppression and can be considered a post-transplant secondary malignancy just as PTLD, MDS and AML.

References

1. Verma, D., Kantarjian, H. M., Jones, D., Luthra, R., Borthakur, G., Verstovsek, S., ... & Cortes, J. (2009). Chronic myeloid leukemia (CML) with P190BCR-ABL: analysis of characteristics, outcomes, and prognostic significance. Blood, 114(11), 2232-2235.

2. Oberender, C., Kleeberg, L., Nienhues, N., Gresse, M., Dörken, B., Riess, H., & le Coutre, P. (2014). Clinical Lessons to Be Learned from Patients Developing Chronic Myeloid Leukemia While on Immunosuppressive Therapy after Solid Organ Transplantation: Yet Another Case after Orthotopic Heart Transplantation. Case reports in hematology, 2014.

3. Swerdlow, S. H., Campo, E., Pileri, S. A., Harris, N. L., Stein, H., Siebert, R., ... & Jaffe, E. S. (2016). The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood, 127(20), 2375-2390.

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5. Apperley, J. F. (2015). Chronic myeloid leukaemia. The Lancet, 385(9976), 1447-1459.6. Ren, R. (2005). Mechanisms of BCR–ABL in the pathogenesis of chronic myelogenous

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Case 6Presenter: David Byron Chapel, M.D.Attending: Aliya Noor Husain, M.D.

Clinical History: A 25-year-old man with a history of acute-onset heart failure, initially diagnosed in July 2015, remains inotrope-dependent with a left ventricular ejection fraction of 20%, despite placement of a left ventricular assist device. He is now undergoing an orthotopic heart transplant, sixteen months after his initial presentation.

Diagnosis: Cocaine-induced cardiomyopathy

Differential Diagnosis: The differential diagnosis includes clinical causes of global myocardial hypoxia, including history of severe shock, variant angina, endogenous or exogenous catecholamine-induced injury, and cocaine-induced cardiomyopathy. Furthermore, amyloidosis, Fabry disease, and glycogen storage disease are diagnostic considerations, but are effectively ruled out morphologically and histochemically.

Key Features:- Diffuse, moderate to severe interstitial fibrosis, with accentuation in the inner half of the myocardium, implicates chronic global hypoxemic injury. Subepicardial fibrosis, however, is also focally advanced, indicating a coincident toxic injury.

- These features, although not specific, are consistent with cocaine-induced cardiomyopathy, which is confirmed by clinical inquiry.

- Acute changes of cocaine-induced cardiotoxicity, including edema and contraction band necrosis, were absent from the explant specimen, consistent with long-term abstinence from cocaine use. Acute cocaine-induced changes were identified on review of the left ventricular core from the time of LVAD placement.

Discussion:- Cocaine-induced cardiac injury comprises both ischemic and toxic mechanisms.

- Ischemia is induced by excess stimulation of catecholaminergic G protein-coupled receptors, producing coronary arterial vasoconstriction while simultaneously increasing myocardial work and oxygen demand.

- Toxic injury is mediated by reactive oxygen species and oxidized metabolites of catecholamines (aminochromes). Myocyte death results from permeabilization of the mitochondrial membranes, which allows release of pro-apoptotic (and, in severe cases, pro-necrotic) mediators.

- Ultrastructural studies have implicated toxic injury as the primary mediator of myocyte death in cocaine-induced cardiac injury, with ischemic injury playing a secondary role.

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