Case 1 - Chicago Pathology



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IRAP Case Histories and Diagnoses

University of Chicago Medical Center

February 25, 2013

Case 1

Presenter: Allison B. Cavallo, MD

Attending: Tatjana Antic, MD

Clinical History: Patient is a 26-year-old female with a clinical history of multiple colonic tubular adenomas (2000), status post total abdominal colectomy, thyroidectomy (2005) and an abdominal mass, status post resection (2007). She now presents with a midline neck mass and undergoes fine needle aspiration biopsy.

Diagnosis: Cribriform-morular variant of papillary thyroid carcinoma occurring in a patient with Gardner’s syndrome

Differential Diagnosis:

• Thyroid Malignancies

• Follicular neoplasm

▪ Comprises both follicular adenoma and follicular carcinoma. Follicular carcinoma is defined by the presence of capsular and vascular invasion.

▪ Both entities are remarkable for a female predilection

▪ Architecturally, follicular carcinoma ranges from well-formed follicles to a solid growth pattern. Nuclei lack features observed in papillary thyroid carcinoma cells.

▪ Tumor cells are reactive for TTF-1 and thyroglobulin.

• Variant of papillary thyroid carcinoma (PTC)

▪ In general, papillary thyroid carcinoma is the most common malignancy affecting the thyroid. There is a strong female predilection. Patients typically present in early middle age.

▪ Classical PTC is characterized by numerous complex papillae with fibrovascular cores. Tumor nuclei are optically clear with irregular membranes, grooves and pseudoinclusions. Psammoma bodies are a well-known feature.

▪ Tumor cells react with TTF-1 and thyroglobulin and are non-reactive for calcitonin.

▪ There are many variants of PTC including, but not limited to, the follicular variant, cribriform-morular variant, tall cell variant, columnar cell variant and the diffuse sclerosing variant.

• Medullary carcinoma

▪ Sporadic and hereditary forms are well known. The sporadic form typically presents as a solitary mass in early middle age.

▪ Characterized by a solid to nested architecture, vascular stroma, hyalinized collagen and the presence of amyloid. Tumor cells are oval to polygonal with granular cytoplasm, neuroendocrine-type chromatin and nuclear pseudoinclusions. However, this entity is well-known for its variable appearance.

▪ Tumor cells are reactive for calcitonin, TTF-1, chromogranin and synaptophysin and non-reactive for thyroglobulin.

Discussion:

• Cribriform-morular variant of papillary thyroid carcinoma

• A rare entity that occurs sporadically or as part of an inherited cancer predisposition syndrome, Gardner's syndrome.

• Typically presents as a mass lesion in females aged 28-33 years of age.

• The tumor is characterized by a cribriform architecture, but may also have solid, trabecular or follicular growth patterns. Unique to this entity is the presence of squamous morules. Tumor nuclei are remarkable for irregular nuclear membranes, optical clarity, nuclear grooves and rare pseudoinclusions.

• Immunohistochemically, tumor cells stain positive for β-catenin and TTF-1 and negative for calcitonin. Thyroglobulin staining is variable and can be entirely absent.

• Gardner's syndrome

• Autosomal-dominantly inherited cancer predisposition syndrome.

• Variant of familial adenomatous polyposis syndrome.

• Caused by germline mutations of the adenomatous polyposis coli gene (APC) that result in permanent activation of the Wnt signaling pathway, aberrant β-catenin expression and increased cellular proliferation.

• Characterized by the development of colonic tubular adenomas and a tendency towards colorectal adenocarcinoma as well as extracolonic benign and malignant tumors.

• Affected patients have a markedly increased risk for the development of thyroid carcinoma and its incidence maybe as high as 12%.

• The cribirform-morular variant of PTC is particularly common in this syndrome.

Take home point:

• The cribriform-morular variant of papillary thyroid carcinoma is characterized by cribriform, trabecular, solid and follicular architecture, the presence of squamous morules and papillary thyroid carcinoma nuclei.

• Diagnosis of this entity should prompt work-up for Gardner's syndrome.

References:

1. Cameselle-Teijeiro, J., & Chan, J. K. (1999). Cribriform-morular variant of papillary carcinoma: a distinctive variant representing the sporadic counterpart of familial adenomatous polyposis-associated thyroid carcinoma? Mod Pathol, 12(4), 400-411.

2. Cameselle-Teijeiro, J., Menasce, L. P., Yap, B. K., Colaco, R. J., Castro, P., Celestino, R., Sobrinho-Simoes, M. (2009). Cribriform-morular variant of papillary thyroid carcinoma: molecular characterization of a case with neuroendocrine differentiation and aggressive behavior. Am J Clin Pathol, 131(1), 134-142.

3. Cetta, F., Curia, M. C., Montalto, G., Gori, M., Cama, A., Battista, P., & Barbarisi, A. (2001). Thyroid carcinoma usually occurs in patients with familial adenomatous polyposis in the absence of biallelic inactivation of the adenomatous polyposis coli gene. J Clin Endocrinol Metab, 86(1), 427-432.

4. Herraiz, M., Barbesino, G., Faquin, W., Chan-Smutko, G., Patel, D., Shannon, K. M., Chung, D. C. (2007). Prevalence of thyroid cancer in familial adenomatous polyposis syndrome and the role of screening ultrasound examinations. Clin Gastroenterol Hepatol, 5(3), 367-373.

5. Kameyama, K., Mukai, M., Takami, H., & Ito, K. (2004). Cribriform-morular variant of papillary thyroid carcinoma: ultrastructural study and somatic/germline mutation analysis of the APC gene. Ultrastruct Pathol, 28(2), 97-102.

6. Raue, F., Kotzerke, J., Reinwein, D., Schroder, S., Roher, H. D., Deckart, H., et al. (1993). Prognostic factors in medullary thyroid carcinoma: evaluation of 741 patients from the German Medullary Thyroid Carcinoma Register. Clin Investig, 71(1), 7-12.

7. Xu, B., Yoshimoto, K., Miyauchi, A., Kuma, S., Mizusawa, N., Hirokawa, M., & Sano, T. (2003). Cribriform-morular variant of papillary thyroid carcinoma: a pathological and molecular genetic study with evidence of frequent somatic mutations in exon 3 of the beta-catenin gene. J Pathol, 199(1), 58-67.

Case 2

Presenter: Jerry T. Wong, MD

Attending: Peter Pytel, MD

Clinical History: The patient is a 43 years old female who presented to the University of Chicago with increasing left thigh pain. Imaging (X-ray, MRI) of her left femur showed a subtrochanteric lesion without evidence of fracture or soft tissue extension. The patient has a remote history (30 years ago) of abdominal/pelvic soft tissue sarcoma. The exact location and classification of that tumor is not known. More recently in 2012, she was diagnosed with metastatic lesions to both lungs and left lobe of her liver.

Diagnosis: Metastatic sarcoma consistent with metastatic spread of low grade fibromyxoid sarcoma

• Microscopic features:

• Dense collagenous (highlighted by picrosirius red polarization method) and myxoid matrix with bland cells

• Giant collagen cores with surrounding epithelioid cells (giant rosettes)

• Rare mitosis and minimal pleomorphism

• Immunohistochemistry: MUC4 strongly and diffusely positive

• Cytogenetics: Positive fusion of FUS-CREB3L2 loci in 94.5% of cells

Differential:

• Osteosarcoma

• Intramedullary bone lesion

• Osteoid-like matrix

• Sclerosing epithelioid fibrosarcoma

• Dense collagenous and myxoid matrix with bland cells

• Metastatic sarcoma

• Clinical history of sarcoma

Discussion:

• Low grade fibromyxoid sarcoma

• First described by Evans 1987 (2 cases)

• Cytologically bland spindle cells with alternating fibrous and myxoid matrix

• FUS-CREB3L2/1 fusion gene and MUC4 expression highly sensitive and specific

• Indolent with late metastatic potential

• Treatment with excision but frequent recurrence

• Hyalinizing spindle cell tumor with giant rosettes

• First described by Lane in 1997 (19 cases)

• Shown to be clinically, ultra-structurally, immunohistochemically, and genetically similar to low grade fibromyxoid sarcoma

• Recognized as giant rosette variant of low grade fibromyxoid sarcoma

• Sclerosing epithelioid fibrosarcoma

• First described by Meis-Kindblom in 1995 (25 cases)

• Nests/cords of round/ovoid epithelioid cells within a dense sclerotic stroma

• Clinically more aggressive than low grade fibromyxoid sarcoma

• Subset of cases with FUS-CREB3L2 fusion (9-28%) and MUC4 expression (78%)

• A subset of sclerosing epithelioid sarcoma is a variant of low grade fibromyxoid sarcoma

References:

• Antonescu, C. R., M. K. Rosenblum, P. Pereira, A. G. Nascimento and J. M. Woodruff (2001). "Sclerosing epithelioid fibrosarcoma: a study of 16 cases and confirmation of a clinicopathologically distinct tumor." Am J Surg Pathol 25(6): 699-709.

• Bejarano, P. A., T. A. Padhya, R. Smith, R. Blough, J. J. Devitt and J. L. Gluckman (2000). "Hyalinizing spindle cell tumor with giant rosettes--a soft tissue tumor with mesenchymal and neuroendocrine features. An immunohistochemical, ultrastructural, and cytogenetic analysis." Arch Pathol Lab Med 124(8): 1179-1184.

• Doyle, L. A., E. Moller, P. Dal Cin, C. D. Fletcher, F. Mertens and J. L. Hornick (2011). "MUC4 is a highly sensitive and specific marker for low-grade fibromyxoid sarcoma." Am J Surg Pathol 35(5): 733-741.

• Doyle, L. A., W. L. Wang, P. Dal Cin, D. Lopez-Terrada, F. Mertens, A. J. Lazar, C. D. Fletcher and J. L. Hornick (2012). MUC4 is a sensitive and extremely useful marker for sclerosing epithelioid fibrosarcoma: association with FUS gene rearrangement. Am J Surg Pathol. United States. 36: 1444-1451.

• Evans, H. L. (1987). "Low-grade fibromyxoid sarcoma. A report of two metastasizing neoplasms having a deceptively benign appearance." Am J Clin Pathol 88(5): 615-619.

• Evans, H. L. (2011). "Low-grade fibromyxoid sarcoma: a clinicopathologic study of 33 cases with long-term follow-up." Am J Surg Pathol 35(10): 1450-1462.

• Folpe, A. L., K. L. Lane, G. Paull and S. W. Weiss (2000). "Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes: a clinicopathologic study of 73 cases supporting their identity and assessing the impact of high-grade areas." Am J Surg Pathol 24(10): 1353-1360.

• Guillou, L., J. Benhattar, C. Gengler, G. Gallagher, D. Ranchere-Vince, F. Collin, P. Terrier, M. J. Terrier-Lacombe, A. Leroux, B. Marques, S. Aubain Somerhausen Nde, F. Keslair, F. Pedeutour and J. M. Coindre (2007). Translocation-positive low-grade fibromyxoid sarcoma: clinicopathologic and molecular analysis of a series expanding the morphologic spectrum and suggesting potential relationship to sclerosing epithelioid fibrosarcoma: a study from the French Sarcoma Group. Am J Surg Pathol. United States. 31: 1387-1402.

• Junqueira, L. C., M. T. Assis Figueiredo, H. Torloni and G. S. Montes (1986). "Differential histologic diagnosis of osteoid. A study on human osteosarcoma collagen by the histochemical picrosirius-polarization method." J Pathol 148(2): 189-196.

• Junqueira, L. C., G. Bignolas and R. R. Brentani (1979). "Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections." Histochem J 11(4): 447-455.

• Lane, K. L., R. J. Shannon and S. W. Weiss (1997). "Hyalinizing spindle cell tumor with giant rosettes: a distinctive tumor closely resembling low-grade fibromyxoid sarcoma." Am J Surg Pathol 21(12): 1481-1488.

• Meis-Kindblom, J. M., L. G. Kindblom and F. M. Enzinger (1995). "Sclerosing epithelioid fibrosarcoma. A variant of fibrosarcoma simulating carcinoma." Am J Surg Pathol 19(9): 979-993.

• Mertens, F., C. D. Fletcher, C. R. Antonescu, J. M. Coindre, M. Colecchia, H. A. Domanski, E. Downs-Kelly, C. Fisher, J. R. Goldblum, L. Guillou, R. Reid, J. Rosai, R. Sciot, N. Mandahl and I. Panagopoulos (2005). Clinicopathologic and molecular genetic characterization of low-grade fibromyxoid sarcoma, and cloning of a novel FUS/CREB3L1 fusion gene. Lab Invest. United States. 85: 408-415.

• Panagopoulos, I., C. T. Storlazzi, C. D. Fletcher, J. A. Fletcher, A. Nascimento, H. A. Domanski, J. Wejde, O. Brosjo, A. Rydholm, M. Isaksson, N. Mandahl and F. Mertens (2004). "The chimeric FUS/CREB3l2 gene is specific for low-grade fibromyxoid sarcoma." Genes Chromosomes Cancer 40(3): 218-228.

• Wang, W. L., H. L. Evans, J. M. Meis, B. Liegl-Atzwanger, J. V. Bovee, J. R. Goldblum, S. D. Billings, B. P. Rubin, D. Lopez-Terrada and A. J. Lazar (2012). FUS rearrangements are rare in 'pure' sclerosing epithelioid fibrosarcoma. Mod Pathol. United States. 25: 846-853.

Case 3

Presenter: Nhu Thuy Can, MD

Attending: Peter Pytel, MD

Diagnosis: Niemann-Pick Disease, Type C

Findings:

• Gross: Brain tissue (cerebral cortex and white matter) with no gross abnormalities

• Microscopic: Histologic sections demonstrate enlarged swollen neurons with gray foamy cytoplasm present diffusely throughout the cortex, not associated with any reactive changes.

• Electron microsopy: Neurons with heterogeneous membrane-bound cytoplasmic granular inclusions, some of which have concentric lamellar profiles.

Differential diagnosis:

|Disease |Subtype |Enzyme deficiency |Clinical features |

|Mucopolysaccharidosis |Sanfilippo Syndrome |Multiple |Severe mental retardation |

| | | |Seizures |

| | | |Mild skeletal deformities |

| |Sly Syndrome |β-glucuronidase |Seizures |

| | | |Moderate to no mental retardation |

| | | |Mild dysmorphism |

|Neuronal Ceroid Lipofuscinosis |Jansky-Bielchowsky Type|Tripeptidyl-peptidase I |Rapidly progressive psychomotor retardation |

| | | |Intractable seizures |

| | | |Myoclonus |

| |Spielmeyer-Sjogren Type|Battenin |Slowly progressive psychomotor retardation |

| | | |Intractable seizures |

| | | |Vision loss |

|Lipid Storage Disorder |Niemann-Pick Type C/D |Abnormal intracellular |Subacute/chronic form |

| | |transport of endocytosed|Vertical supranuclear gaze palsy |

| | |cholesterol |Ataxia |

| | | |Seizures |

| | | |Dementia |

| | | |Hepatosplenomegaly |

Pathogenesis:

• Abnormal intracellular transport of endocytosed cholesterol

• Mutations in NPC1 (95%) and NPC2

o NPC1: transmembrane protein involved in endocytosis

o NPC2: lysosomal protein that binds cholesterol

• Unesterified cholesterol and glycosphingolipids accumulate in neurons, liver and spleen ( neurological deterioration and hepatosplenomegaly

Diagnosis

• Filipin test – Fibroblasts cultured from a skin biopsy demonstrate accumulation of unesterified cholesterol in lysosomes, which stain positive with filipin, a fluorescent compound that binds unesterified cholesterol.

• Gene sequencing

Treatment: Miglustat, which reduces the production of glycosphingolipids, is the only available treatment for Niemann-Pick Disease, Type C

References:

1. Agamanolis DP. Neuropathology: An illustrated interactive course for medical students and residents.

. Last updated 2012.

2. Elleder M and Jirasek A. Neuropathology of various types of Niemann-Pick disease.

Acta Neuropath. 1981(7):201-203.

3. Love S, Bridges LR and Case CP. Neurofibrillary tangles in Niemann-Pick disease

type C. Brain. 1995;188:119-29.

4. Nelson JS, Mena H, Parisi JE, et al. Principles and Practice of Neuropathology. 2nd

ed. New York, NY: Oxford University Press; 2003:197-207.

5. Patterson MC, Vecchio D, Prady H et al. Miglustat for treatment of Niemann-Pick C

disease: A randomised controlled study. Lancet Neurol. 2007;6(9):765-72.

6. Patterson M. Niemann-Pick Disease Type C. 2000 Jan 26 [Updated 2008 Jul 22]. In:

Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA):

University of Washington, Seattle; 1993-. Available from:



7. Prayson, R. Neuropathology. 2nd ed. Philadelphia, PA: Elsevier Saunders;

2012:376-407.

8. Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis. 2010;5(16).

9. Vincent I, Bitao B and Erickson RP. Understanding Niemann-Pick disease: A fat

problem. Curr Opin Neurol. 2003;16:155-161.

10. Walkley SU and Suzuki K. Consequences of NPC1 and NPC2 loss of function in

mammalian neurons. Biochim et Biophys Acta. 2004;1685:48-62.

Case 4

Presenter: Stephanie M. McGregor, MD, PhD

Attending: Katja Gwin, MD, PhD

Clinical History: The patient is a 23-year-old G2P1 female. Her first pregnancy was uncomplicated and resulted in delivery of a full-term infant. She underwent a dilatation and curettage procedure at an outside hospital for a suspected molar pregnancy 8 months ago. She now presents with abdominal pain, "morning sickness", occasional vaginal bleeding and a negative urine pregnancy test. Serum β-hCG is mildly elevated. Ultrasound demonstrates a large, hypervascular mass in the uterus. Hysterectomy is pursued in lieu of biopsy out of concern for bleeding.

Diagnosis: Placental site trophoblastic tumor (PSTT)

Differential Diagnosis:

• Epithelioid trophoblastic tumor (ETT)

• Exaggerated placental site reaction (EPS)

• Squamous cell carcinoma (SCC)

• Epithelioid leiomyosarcoma

Key morphologic and immunohistochemical features:

• Cords and sheets of tumor cells infiltrating the fibers of the myometrium

• Absence of chorionic villi

• Striking involvement of vessels, with tumor cells essentially replacing the wall

• Large, round to polyhedral cells, which are primarily mononucleated

• Occasional multinucleated cells

• Nuclear pleomorphism, ranging from small with smooth borders and pale chromatin to bizarre forms with hypercondensed chromatin

• Atypical mitoses and nuclear pseudoinclusions may be present

• Cytokeratin: strong and diffusely positive

• hPL and inhibin: positive in the majority of tumor cells

• p63: negative

Establishing the diagnosis:

• In this particular setting of even mildly elevated hCG, SCC and leiomyosarcoma are low on the differential. However, hCG is not always elevated and therefore these entities must be considered. Without clinical clues the distinction of PSTT from SCC and epithelioid leiomyosarcoma can be made easily by immunohistochemistry. While both PSTT and SCC are positive for cytokeratin, PSTT is negative for p63 and SCC is positive; similarly, desmin staining is reliable in leiomyosarcoma and is negative in PSTT.

• Distinguishing PSTT from EPS is rarely difficult on a hysterectomy specimen due to the presence of a mass lesion in PSTT, which is not present in EPS. Moreover, clinical context is useful as a concurrent gestation or molar pregnancy exists with an EPS. However, the infiltrative growth pattern of the two entities can be problematic on small biopsy specimens, especially if chorionic villi are not sampled in EPS. Additional useful tools in this setting are the presence of cytological atypia and mitoses in PSTT and staining with Ki67, which will show proliferation in more than 10% of tumor cells in PSTT but 3/50hpf) and large size (>3.0 cm) associated with decreased disease-specific survival (59% after 5 years)

• Characteristic t(1;3)(p36;q25) translocation identified in >87% of cases (including lung), with WWTR1-CAMTA1 fusion product

• Local spread by intra-organ dissemination (not multiple distinct primaries)

Pulmonary epithelioid hemangioendothelioma:

• Can mimic interstitial lung disease on imaging

• Rare (~100 reported cases)

• 80% women, mean age at presentation 36 years

• Median 5-year survival 60%

References:

1. Dail DH, Liebow AA, Gmelich JT, Friedman PJ, Miyai KK, Myer WW, Patterson SD, and Hammar SP. Intravascular, bronchiolar, and alveolar tumor of the lung (IVBAT). An analysis of twenty cases of a peculiar sclerosing endothelial tumor. Cancer 1983, 51(3), 452-464.

2. Dei Tos AP, Wagner AJ, Modena P, Comandone A, and Leyvraz S. Epithelioid soft tissue tumors. Semin Oncol 2009, 36(4), 347-357.

3. Deyrup AT, Tighiouart M, Montag AG, and Weiss SW. Epithelioid hemangioendothelioma of soft tissue: A proposal for risk stratification based on 49 cases. Am J Surg Pathol 2008, 32(6), 924-927.

4. Errani C, Zhang L, Sung YS, Hajdu M, Singer S, Maki R, Healey JH, and Antonescu CR. A novel WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites. Genes Chromosomes Cancer 2011, 50(8), 644-653.

5. Errani C, Sung YS, Zhang L, Healey JH, and Antonescu CR. Monoclonality of multifocal epithelioid hemangioendothelioma of the liver by analysis of WWTR1-CAMTA1 breakpoints. Cancer Genetics 2012, 205(1-2), 12-17.

6. Mendlick MR, Nelson M, Pickering D, Johansson SL, Seemayer TA, Neff JR, Vergara G, Rosenthal H, and Bridge JA. Translocation t(1;3)(p36.3;q25) is a nonrandom aberration in epithelioid hemangioendothelioma. Am J Surg Pathol 2001, 25(5), 684-687.

7. Tanas MR, Sboner A, Oliveira AM, Erickson-Johnson MR, Hespelt J, Hanwright PJ, Flanagan J, Luo Y, Fenwick K, Natrajan R, Mitsopoulos C, Zvelebil M, Hoch BJ, Weiss SW, Debiec-Rychter M, Sciot R, West RB, Lazar AJ, Ashworth A, Reis-Filho JS, Lord CJ, Gerstein MB, Rubin MA, and Rubin BP. Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma. Sci Transl Med 2011, 3(98), 98ra82.

8. Weiss SW and Enzinger FM. Epithelioid hemangioendothelioma: A vascular tumor often mistaken for a carcinoma. Cancer 1982, 50(5), 970-981.

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