Department of Pathology

IRAP Case Presentation HandoutsChicago Pathology Society

November 20, 2017

Case 1

Presenter: Farres Obeidin, MD

Clinical History: This is a 56-year-old male who presented with recent difficulty breathing, right-sided nasal obstruction, and trouble sleeping at night. The patient has tried saline rinses, oral steroids, nasal steroids, and antibiotics with no relief. He has a history of a nasal tumor over 10 years prior. Physical examination revealed a large, vascular mass in the right nasal cavity that obstructed nearly the entire airway. MRI showed a 5.5 cm polypoid mass in the right nasal cavity extending into the right ethmoid sinus, maxillary sinus, and nasopharynx. An endoscopic surgical removal was performed and submitted for pathology.

Final Diagnosis: Sinonasal Glomangiopericytoma

Histologic Findings: Histologic sections show multiple fragments of unremarkable respiratory mucosa with a subepithelial spindle cell proliferation growing in short fascicles and whorls. The background shows focal myxoid change and prominent staghorn vasculature with perivascular hyalinization. The nuclei are monotonous and show minimal atypia with rare mitotic figures.

Differential Diagnosis:

1. Cellular Schwannoma: Schwannomas are the most common nerve sheath tumor in the sinonasal tract and feature spindle cells arranged in fascicles with a neurofibrillary background. A classic finding in schwannomas is the presence of hypercellular (Antoni A) and hypocellular (Antoni B) areas, which are not seen in this tumor. However, the cellular variant has scarce or absent Antoni B areas. In addition, the blood vessels often have thickly hyalinized walls as we see in this case. A hemangiopericytic pattern to the vasculature is not appreciated.IHC: S100+, SOX10+

2. Biphenotypic sinonasal sarcoma: These tumors are low grade sarcomas that are unique to the sinonasal tract. The appear as polypoid masses composed of uniform spindle cells in a fascicular or herringbone growth and can show dilated branching vasculature. However, hyalinization of the vessels is not typical, and a simultaneous proliferation of the overlying respiratory epithelium is observed in up to 70% of cases. The epithelium in this case was not involved. Biphenotypic sinonasal sarcomas harbor a consistent PAX3-MAML3 t(2;4)(q35;q31.1) translocation, and have a hybrid neural and myogenic staining pattern.IHC: S100+, SMA+, MSA+, desmin+

3. Malignant peripheral nerve sheath tumor: MPNST’s are very rare tumors in the sinonasal tract and are composed of spindle cells in fascicles and various patterns. There are often alternating areas of hypercellularity and hypocellularity, imparting a “marbled” appearance. Some tumors may show concentric perivascular growth; however, hemangiopericytic vessels and perivascular hyalinization are not usually seen. Mitotic activity is present.IHC: Variable S100 and SOX10 positivity

4. Spindle cell melanoma: Melanoma can demonstrate many different morphologies, including spindle cell type. This tumor is composed of atypical melanocytes but can frequently appear amelanotic on histology. Melanomas can occur anywhere in the body and often present initially with widespread

metastatic disease. In contrast to our tumor, spindle cell melanomas will often demonstrate nuclear atypia and large, cherry red nucleoli.IHC: SOX10+, S100+, HMB45+, MelanA+, MITF+

5. Solitary fibrous tumor: SFT’s encompass approximately 1% of all sinonasal tumors. Histologically, they appear as a proliferation of spindled cells in a “patternless” pattern and with characteristic hemangiopericytic, staghorn vessels. Of note, perivascular hyalinization is not typical for these tumors. The background stroma can show prominent, coarse, and ropy collagen. SFT’s have an NAB2-STAT6 inv(12) abnormality.IHC: CD34+ (diffuse), CD99+, BCL2+, STAT6+

6. Monophasic synovial sarcoma: Synovial sarcomas are a malignant class of soft tissue tumor that may occur anywhere in the body. It is postulated that the cell of origin for these tumors is a multipotent mesenchymal stem cell. The monophasic form is a spindle cell lesion comprised of fascicles of tightly packed, often touching, nuclei. The nuclei are characteristically monotonous with inconspicuous nucleoli. Mitotic activity may be brisk. Some synovial sarcomas show staghorn vasculature; however, perivascular hyalinization is not typical. They harbor an SS18-SSX t(X;18)(p11.2;q11.2) translocation.IHC: Patchy positivity for cytokeratins and EMA, CD99+, BCL2+, TLE1+, β-catenin+

7. Lobular capillary hemangioma: Lobular capillary hemangiomas, also known as pyogenic granulomas, are relatively common tumors in the sinonasal tract. They typically arise on the septum and are composed of lobules of proliferating, variably sized blood vessels. Often found is a centrally located, larger “feeder” vessel. The background can show granulation tissue and inflammation, leading to reactive changes in the endothelial cells that can mimic a more solid lesion. The capillaries in these tumors will not show a predominant hemangiopericytic pattern or hyalinization.IHC: Typical endothelial markers (CD34+, CD31+, ERG+, Fli-1+, D2-40+, FVIII+, vWF+, GLUT1+)

8. Sinonasal glomangiopericytoma: These are tumors unique to the sinonasal tract and are made up of spindle cells in a variety of patterns, including fascicular, whorling, or storiform. The lesion is subepithelial, often with a distinct Grenz zone. The vascular pattern is hemangiopericytic, with prominent perivascular hyalinization. The nuclei are typically monotonous with rare mitotic activity. Sinonasal glomangiopericytomas have been reclassified due to immunohistochemical studies as a perivascular myoid cell tumor.IHC: SMA+, β-catenin, Cyclin D1+

Immunohistochemistry from our case

Positive NegativeSMA AE1/AE3β-catenin EMACD34 (patchy) Desmin

S100SOX10D2-40CD99TLE1Fli-1

Summary:

The clinical, macroscopic, histologic, and immunohistochemical are consistent with a sinonasal glomangioperictyoma. These tumors have historically been known “hemangiopericytoma-like intranasal tumor” and “sinonasal hemangiopericytoma” due to the hemangiopericytic vascular pattern observed on histology. Studies with immunohistochemical stains demonstrate a perivascular myoid phenotype, so they have been renamed to “glomangiopericytoma” to reflect this. Although most tumors are indolent, local recurrences can occur in 17 – 40% of cases and rare reports of malignant features have been noted. The WHO classifies these tumors as borderline with low malignant potential.

Sinonasal glomangiopericytomas all harbor a mutation in the CTNNB1 gene, and as such, have nuclear expression of β-catenin. β-catenin is involved in the cadherin protein complex that acts as a signal transducer in the Wnt signaling pathway. This pathway aids in regulation of cell-cell adhesion and cell growth. In the “Off state”, Wnt1 is unbound to its transmembrane receptor, leading to constitutive ubiquitination of β-catenin. This leads to the degradation of the β-catenin protein. When Wnt1 binds, it promotes formation of the cadherin complex, of which β-catenin is a part of, and migrates to the nucleus to regulate cell growth. Mutations in any gene in this pathway leads to deregulation of cell growth as a result. β-catenin nuclear and/or cytoplasmic activity is detectable by immunohistochemistry in these tumors and many others listed below:

Desmoid-type fibromatosisWilms tumorColonic adenocarcinomaHepatocellular carcinomaEndometrial carcinomaMedulloblastomaPulmonary lymphangioleiomyomatosisPEComaPilomatrixomaIntranodal palisaded myofibroblastoma

Solid pseudopapillary tumor of the pancreasMicrocystic stromal tumor of the ovaryPulmonary sclerosing hemangiomaCalcifying nested stromal-epithelial tumor of the liverSynovial sarcomaSolitary fibrous tumorNasopharyngeal angiofibromaSalivary basal cell adenoma

Treatment: Surgical only. Radiation has not been shown to reduce recurrence rates.

References:

Thompson, LD, Miettinen, M, Wenig BM. “Sinonasal-type hemangiopericytoma: A clinicopathologic and immunophenotypic analysis of 104 cases showing perivascular myoid differentiation.” Am J Surg Pathol. 2003 Jun; 27(6): 737-49

Jo, VY. “Nuclear Beta Catenin Expression is Frequent in Sinonasal Hemangiopericytoma and Its Mimics.” Head Neck Pathol. 2017 Jun; 11(2): 119-123

Weiss, S. W., & Goldblum, J. R. (2007). Enzinger and Weiss' soft tissue tumors. St. Louis, Mo: Mosby.

Case 2

Presenter: David Waters, MD

Clinical History: The patient is a 64-year-old male with a 3 month history of a painless parotid swelling. Past medical history was significant for prostate adenocarcinoma status post resection, ampullary adenocarcinoma status post resection, and kidney transplant secondary to adult polycystic kidney disease. Social history revealed no tobacco or alcohol use. Exam found a palpable 3.5 x 2.0 cm mass in the left parotid gland. Ultrasound showed a mixed solid and cystic lesion. MRI found a 3.9 cm well-circumscribed mass in the superior aspect of the left superficial parotid. No pathologic lymph nodes were seen. A fine needle aspiration was performed and diagnosed as “favor oncocytic lesion” and a differential was described. A superficial parotidectomy was then performed.

Final Diagnosis: Oncocytic Papillary Cystadenoma with Prominent Mucinous Differentiation of the Parotid Gland

Gross and Histologic Findings: The mass was opened to reveal copious brown-mucoid material within a large cystic cavity. Additionally, within the cavity was a red-brown polypoid solid mass measuring 1.9 cm. Histologically the tumor showed a multicystic and papillary architecture. The tumor was well defined but not encapsulated. Within the papillary structures multiple multicystic spaces were visualized containing copious bubbly eosinophillic secretions. On highest power the cells appeared polygonal with finely granular eosinophillic cytoplasm consistent with oncocytes. Dispersed throughout the tumor were also multiple mucocytes. Overall there was no atypia or overt invasion noted.

Differential Diagnosis:

1. Mammary Analog Secretory Carcinoma (MASC): MASC is a low-grade malignant entity that was historically considered a variant of acinic cell carcinoma. It is analogous to secretory carcinoma of the breast. It is histologically defined as a well-circumscribed mass divided by fibrous septae into lobules composed of various architecture including tubular, glandular and multicystic. Within the tumor spaces bubbly eosinophilic secretions are hallmark. These tumors may also present as a large dominant cyst with an apocrine or hobnail like epithelial giving it a similar appearance to our case. These tumors are typically positive for S100, Mammaglobin, SOX10, GATA3, and MUC4. Staining is typically negative for DOG1. These tumors, like their breast counterparts contain a hallmark gene rearrangement (ETV6-NTRK3 fusion, t(12;15)(p15,q25)).

2. Low Grade Intraductal/Salivary Ductal Carcinoma: These tumors are rare and mostly found within the parotid gland. Histology resembles that of ductal carcinoma in situ (DCIS) of the breast. It is characterized by multiple prominent cysts with an intraluminal proliferation of bland eosinophillic ductal cells with frequent associated secretions. Architectures, like DCIS, varies and may appear papillary, micropapillary, cribriform or tufted. Given our cystic tumor with prominent papillary architecture this entity was considered. These tumor are typically positive for S100, Mammaglobin, and p63 in a complete basal cell layer. Androgen receptor may be positive. Estrogen and progesterone receptors are negative.

3. Acinic Cell Carcinoma, Papilary Cystic Variant: Acinic cell carcinoma is a low-grade malignant entity most commonly found in the parotid. The papillary cystic variant is a much rare form and is considered a high grade morphology with a much worse 10 year prognosis. Histology shows a multicystic mass with papillary architecture composed of polygonal cells that range from the

traditional basophilic to pale eosinophillic. The cytoplasm also contains granules, however, they are composed of zymogens and appear larger and coarser than typical oncocytes. Some cells may also show vacuolation. These tumor stain positively for DOG1, SOX10 and PAS in the granules.

4. Low Grade Oncocytic Mucoepidermoid Carcinoma (OMEC): This variant of mucoepidermoid carcinoma is well defined and represents a very small percentage of mucoepidermoid tumors. There is no defined cutoff of oncocytic change to place a tumor in this category. Histology shows variably sized cysts line predominantly by oncocytes with few intervening mucocytes. These tumor typically have a multinodular growth but can be deceptively bland. Definitive foci of invasion may also be difficult to locate. These tumor typically stain positive for cytokeratin 5/6 and p63 diffusely. They are also defined by a hallmark genetic translocation. About 70% of tumor show a CRTC1-MAML2 fusion gene (t(11;19)(q21;p13)). In the additional 30% a different rearrangement involving the MAML2 gene is often found.

5. Oncocytoma/Oncocytic Carcinoma: These tumors enter the differential whenever an oncocytic lesion is seen. However, grossly they appear as solid masses with a light brown or mahogany color, unlike our tumor. Histologically they show a solid growth pattern of monomorphic oncocytes. While microcystic change is rare, papillary and mucinous differentiation is not described. Carcinoma typically shows obvious invasion, is multifocal in nature, and has higher grade nuclear features.

6. Oncocytic Papillary Cystadenoma/Cystadenocarcinoma: Cystadenomas are extremely rare in the major salivary glands but show a circumscribed mass with multicystic spaces. Lining cells are bland but range from flat to columnar. They have been noted to have oncocytic, epidermoid, mucinous, or apocrine changes. Immunohistochemical profile is poorly defined but they are often positive for cytokeratin 7, Mammaglobin, and negative for S100 and p63. Cystadenocarcinoma is typically directly invasive with high-grade nuclear features (S100 is also positive).

7. Intraductal Papilloma: Benign growth, typically seen in minor salivary glands. Histology shows complex branching papillary fronds within a cystically dilated duct. These lesions are lined by a single layer of cells on the fibrovascular cores. These cells are typically flat or cuboidal and can have interspersed mucocytes.

8. Sialadenoma Papilliferum, Inverted Pattern: Extremely rare benign growth, most commonly found in minor salivary glands, especially in the palate. Characterized most commonly by exophytic growth, that in some cases may be inverted and grow down a duct. Histology shows numerous papillary infoldings with a classic bilayered epithelium composed of columnar luminal cells and basal cells. The luminal cells stain positively for EMA, and the basal cells for p63 and p40.

Summary:

Although this tumor was low grade in appearance, the mucinous differentiation and abundant secretions warranted further evaluation for a possibly malignancy. Numerous immunohistochemical stains showed positivity for CK7, CK5/6, MUC4, BRST2, Mammaglobin, Vimentin, p40 in the cytoplasm, PAS and Mucicarmine within cytoplasmic mucin and secretions, and a Ki-67 index of 5%. All other stains performed were negative. Although this staining pattern most supported a cystadenoma, definitive exclusion of MASC and OMEC was performed using molecular testing. Reverse transcriptase PCR for an ETV6-NRTK3 fusion gene was negative ruling out MASC. FISH for MAML2 rearrangement was negative

ruling out OMEC. Our final diagnosis was “Oncocytic Papillary Cystadenoma with Prominent Mucinous Features”.

Cystadenomas are rare tumors of salivary glands, and are far more common in minor salivary glands comprising 0.9-2.0% of all minor gland tumors. They are extremely rare within the major salivary glands. Cystadenomas have two distinct types, papillary and mucinous. Both have been described with prominent oncocytic change, however, there is no cutoff describing how much is necessary to make the diagnosis. Due to their rarity immunohistochemical and molecular features are largely unknown. An exhaustive review of the literature revealed very few cases of oncocytic papillary cystadenomas within major salivary glands (less than 20). No published case described mucinous differentiation within the tumor, which further complicated our case. In all cases of cystadenoma resection is the definitive treatment with rare recurrences thought to be related to incomplete initial resection.

References:

Alexiev, B et al. “Oncocytic papillary cystadenoma with prominent mucinous differentiation of parotid gland: A case report”. Pathology Research and Practice. 2017, ePub ahead of print.

S. Budnick, R.H.W. Simpson, Cystadenoma, in: A.K. El-Naggar, J.K.C. Chan, J.R. Grandis, T. Takata, P.J. Slootweg (Eds.), World Health Organization Classification of Head and Neck Tumours, IARC Press, Lyon, 2017, p.191.

Fujimaki, M et al. “Oncocytic mucoepidermoid carcinoma of the parotid gland with CRTC1-MAML2 fusion transcript: report of a case with review of the literature”. Human Pathology. 2011; 42, 2052-2055.

Kuo, Y, Weinreb, I, and Perez-Ordonez, B. “Low-Grade Salivary Duct Carcinoma or Low-Grade Intraductal Carcinoma? Review of the Literature”. Head and Neck Pathology. 2013; 7, S59-S67.

Fowler, CB and Damm, DD. “Sialadenoma Papilliferum: Analysis of Seven New Cases and Review of the Literature”. Head and Neck Pathology. 2017, ePub ahead of print.

Skalova, A et al. “Newly Described Entities in Salivary Gland Pathology”. American Journal of Surgical Pathology. 2017; 41(8), e33-e44.

Din, NU, Fatima, S, and Kayani, N. “ Mammary analogue secretory carcinoma of salivary glands: a clinicopathologic study of 11 cases”. Annals of Diagnostic Pathology. 2016; 22, 49-53.

Case 3

Presenter: Jean Victoria Fischer, MD

Clinical History: The patient is a 37-year-old female presenting to the ER with vaginal bleeding and abdominal cramping. She reports having a miscarriage two months prior, and her last menstrual period was 6 weeks ago. Physical exam is notable for mild bleeding coming from the cervix with no adnexal or cervical tenderness. Laboratory results show an elevated serum hCG of 17,681.0 mIU/M. Ultrasound demonstrates a closed internal os with a 2cm gestational sac containing a live fetal pole and yolk sac within the endocervical canal. The patient received systemic methotrexate, but the bleeding continued. At this time, the patient underwent uterine artery embolization followed by hysterectomy and bilateral salpingectomy.

Final Diagnosis: Cervical ectopic pregnancy

Gross and Histologic Findings:

A previously opened uterus was received which showed a 2.1 cm hemorrhagic lesion within the endocervical canal and a detached gestational sac containing an intact fetus. Histologic sections of the endocervical lesion show infiltrating polygonal to ovoid cells within the endocervical canal with abundant eosinophilic cytoplasm, large eccentrically placed nuclei with pleomorphism, prominent nucleoli, and no readily identified mitotic figures.

Differential Diagnosis (if chorionic elements and/or fetal parts were not present):

1. Perivascular epithelioid cell tumor (PEComa): PEComa is a mesenchymal tumor with hybrid myo-melanocytic differentiation. It is a heterogeneous tumor occurring throughout the body with the most common sites including the kidneys, liver, lungs, and uterus. The majority of tumors are associated with the tuberous sclerosis complex; however, a subset of PEComas harbor translocations involving TFE3. Transcription factor E3 (TFE3) gene is a member of the MiTF family of transcription factors, and it is located on chromosome Xp11.2. Distinctive pathologic features for tumors harboring this translocation include relatively younger patient age, lack of tuberous sclerosis, epithelioid cytology with nested-alveolar architecture, minimal to no expression of actin or desmin, and strong TFE3 immunoreactivity. There has been one reported primary case in the cervix. Histology of conventional PEComa demonstrates epithelioid to spindled cells with clear to granular eosinophilic cytoplasm and round nuclei which are arranged in nests and separated by a vascular stroma. Immunohistochemical stains show positivity for HMB45, SMA, Melan-A, and desmin and negativity for cytokeratin.

2. Epithelioid leiomyosarcoma: Leiomyosarcomas account for 1-2% of uterine malignancies. The epithelioid and myxoid variants are rare and may be difficult to recognize as the nuclear atypia is usually mild and the mitotic rate is often lower. Histology demonstrates sheets of round to polygonal cells with eosinophilic and vacuolated cytoplasm and vesicular nuclei. Immunohistochemical stains show positivity for SMA, desmin, and vimentin. HMB45 may also be positive, so a second melanocytic marker (Melan-A) should be used to differentiate epithelioid leiomyosarcoma from PEComa.

3. Cellular pseudosarcomatous fibroepithelial stromal polyp: Fibroepithelial stromal polyps (FSP) are benign lesions of the lower female genital tract which show a wide range of histologic appearances. The cellular pseudosarcomatous variant demonstrates stromal hypercellularity, cytologic atypia, and increased and atypical mitoses. Many of the reported cases of cellular pseudosarcomatous FSPs were associated with pregnancy, suggesting a hormonal drive, Immunohistochemical stains show positivity for vimentin, desmin, CD10, and sometimes ER and PR.

4. Embryonal rhabdomyosarcoma: Embryonal rhabdomyosarcoma is a primitive soft tissue sarcoma comprised of small blue cells that resemble embryonic skeletal muscle. It is the most common rhabdomyosarcoma subtype, comprising 65% if cases. Histology demonstrates sheets of small, spindled or moderate to poorly differentiated round cells with scant or deeply eosinophilic cytoplasm, eccentric and small oval nuclei, scattered elongated cells with abundant eosinophilic cytoplasm and cross striations (rhabdomyoblasts), and condensation of tumor cells beneath the epithelium (cambium layer). Immunohistochemical stains show positivity for desmin, MyoD1, and myogenin.

5. Epithelioid trophoblastic tumor (ETT): ETT is a rare form of gestational trophoblastic disease. It is thought to occur due to neoplastic transformation of cytotrophoblast that differentiate into chorionic-type intermediate trophoblast. Histology demonstrates a well circumscribed lesion with nests and cords of infiltrating cells with clear to eosinophilic cytoplasm, prominent cellular necrosis in a hyalinizing stroma, and a lymphocytic infiltrate at the periphery. Immunohistochemical stains show positivity for AE1/AE3, CAM 5.2, and p63 and focal positivity for hCG and hPL.

6. Placental site trophoblastic tumor (PSTT): PSTT is a rare form of gestational trophoblastic disease, representing 3% of cases. It is thought to occur due to neoplastic transformation of cytotrophoblast that differentiate into implantation site intermediate trophoblast. PSTT can be diagnosed years after the last known pregnancy. Histology demonstrates large infiltrating polygonal cells in sheets or nests, scattered multinucleated cells, and invasion of the muscular wall of vessels by intermediate trophoblasts with fibrinoid material deposition (“transformed” blood vessels). Immunohistochemical stains show positivity for hPL, a Ki-67 proliferation index >10%, and negativity for p63.

Summary:

Implantation site is comprised of infiltrating implantation site intermediate trophoblastic cells which will stain positively for hPL, negatively for p63 and hCG, and have a Ki-67 proliferation index of <1%. The trophoblastic cells can show significant pleomorphism, so when chorionic elements and/or fetal parts are not present, implantation site histology may mimic a variety of lesions.

Cervical ectopic pregnancies are rare, accounting for less than 0.1% of all pregnancies and less than 1% of all ectopic pregnancies. Predisposing factors that are implicated in the pathogenesis of cervical ectopic pregnancies include endometrial damage after curettage or chronic endometritis, leiomyoma, intrauterine devices, in vitro fertilization, and primary embryo anomaly. The association of cervical ectopic pregnancy with these factors is weak as retrospective studies have not been possible due to the rarity of the condition.

Since a significant risk of hemorrhage is associated with cervical ectopic pregnancy, the condition in the past was treated presumptively with hysterectomy. However, improved ultrasound resolution and earlier detection has led to the development of more conservative management. The five treatment categories for cervical ectopic pregnancy include intra-amniotic feticide with potassium chloride and/or methotrexate, systemic chemotherapy with methotrexate, surgical excision by curettage or hysterectomy, tamponade with Foley catheter, and reduction of blood supply by ligation or embolization of cervical, uterine, or internal iliac arteries. The most effective method of management is still under investigation. Hysterectomy is still the preferred treatment in cases of intractable hemorrhage and second or third trimester diagnosis, with one review finding that all cases of cervical ectopic pregnancy beyond 12 weeks eventually required hysterectomy.

References:

Agaram NP, Sung Y-S, Zhang L, et al. Dichotomy of Genetic Abnormalities in PEComas with Therapeutic Implications. The American journal of surgical pathology. 2015;39(6):813-825.

Crum CP, Nucci MR, Lee KR. Diagnostic Gynecologic and Obstetric Pathology. 2nd Edition. Philadelphia, PA: Elsevier; 2011.

Fadare O. Uterine PEComa: appraisal of a controversial and increasingly reported mesenchymal neoplasm. International seminars in surgical oncology : ISSO. 2008;5:7.

Kurman RJ, Hedrick Ellenson L, Ronnett BM. Blaustein's Pathology of the Female Genital Tract. 6th ed. New York, NY: Springer; 2011.

Li RF, Gupta M, McCluggage WG, Ronnett BM. Embryonal rhabdomyosarcoma (botryoid type) of the uterine corpus and cervix in adult women: report of a case series and review of the literature. Am J Surg Pathol. 2013 Mar;37(3):344-55.

Liu R, Jia W, Zou H, et al. Expression of CD44 and CD29 by PEComa cells suggests their possible origin of mesenchymal stem cells. International Journal of Clinical and Experimental Pathology. 2015;8(10):13023-13033.

Nucci MR, Young RH, Fletcher CD. Cellular pseudosarcomatous fibroepithelial stromal polyps of the lower female genital tract: an underrecognized lesion often misdiagnosed as sarcoma. Am J Surg Pathol. 2000 Feb;24(2):231-40.

Samal SK, Rathod S. Cervical ectopic pregnancy. Journal of Natural Science, Biology, and Medicine. 2015;6(1):257-260. Schoolmeester JK, Dao LN, Sukov WR, et al. TFE3 Translocation Associated Perivascular Epithelioid Cell Neoplasm (PEComa) of the Gynecologic Tract: Morphology, Immunophenotype, Differential Diagnosis. The American journal of surgical pathology. 2015;39(3):394-404.

Setia A, Kanotra S, Aggarwal R, Bhavthankar DP. Epithelioid leiomyosarcoma of uterus. BMJ Case Reports. 2012;2012:bcr1120115144.

Singh S. Diagnosis and management of cervical ectopic pregnancy. Journal of Human Reproductive Sciences. 2013;6(4):273-276.

Song JS, Song DE, Kim KR, Ro JY. Cellular pseudosarcomatous fibroepithelial stromal polyp of the vagina during pregnancy: a lesion that is overdiagnosed as a malignant tumor. Korean J Pathol. 2012 Oct;46(5):494-8.

Williams JW and Hoffman BL. Williams Gynecology. 2nd ed. New York, N.Y.: McGraw-Hill Education LLC.; 2012.

Case 4

Presenter: Claire Sorensen, MD

Clinical History: The patient is a 52 year old female with a past medical history of diabetes, but no other relevant health problems. She presented to the Emergency department with four days of epigastric pain radiating to the back and to the right upper quadrant. On physical exam, she was found to have nausea and a positive Murphy’s sign. However, the patient had no fever or elevated white blood cell count, and denied emesis or food association with her pain. US and MRI revealed cholelithiasis and gallbladder wall thickening, with an adjacent abnormality of the hepatic parenchyma. The patient underwent an open cholecystectomy, during which surgeons discovered a firm, palpable area at the top of the gallbladder, and removed a segment of liver as well.

Final Diagnosis: Adenocarcinoma of the Gallbladder with Enteroblastic Differentiation

Gross and Histologic Findings: Opening of the gallbladder and attached segment of liver revealed a tan, well-demarcated 4 cm mass in the liver parenchyma, as well as gallbladder wall thickening. Grossly, the margins of the resection appeared to be free of tumor.

Microscopic examination of the mass on low power showed infiltrating glands on a background of necrosis. In addition to the glandular architecture, multiple other architectural patterns were present in other parts of the tumor, including areas of poorly differentiated tubular architecture, and papillary architecture. On high power, the cells were shown to have large pleomorphic nuclei with brisk mitotic activity. The majority of the cells showed a distinctive clear cytoplasm, which was caused by vacuoles located either above or below the nuclei.

Differential Diagnosis: The chief differential in this case is a primary tumor of the gallbladder versus a metastasis. The patient has no known history of any other tumor and clinical workup at the time of presentation was negative, so a metastasis was excluded by clinical history.

The question becomes, if this is a primary carcinoma of the gallbladder, how can we further classify it?

Gallbladder carcinoma can be classified by cellular phenotype, such as intestinal, pancreatobiliary, or gastric foveolar type. It can also be classified by architecture, including papillary adenocarcinoma, mucinous adenocarcinoma, tubular adenocarcinoma, clear cell carcinoma, adenocarcinoma NOS, adenosquamous carcinoma, squamous cell carcinoma, small cell carcinoma, and undifferentiated carcinoma.

Because our tumor has tubular, glandular, papillary, and clear cell features, we obtained stains to further clarify the subtype.

Stains:

PAS Diffusely positivePAS-D NegativeCDX2 Diffusely positiveAFP Focally positiveSALL4 Diffusely positiveGPC3 Focally positive

The fact that PAS is positive but PAS-D is negative indicates that the clear vacuoles in the cells of this tumor contain glycogen, not mucin. CDX2 stains the nuclei of intestinal epithelial cells, which helps us to narrow down the cellular phenotype of the tumor. AFP and GPC3 are fetal oncoproteins, and SALL4 is an embryonic stem cell marker reported to represent fetal gut-like differentiation.

AFP is a marker for a number of tumors, including hepatocellular carcinoma, yolk sac tumors, squamous cell carcinoma of the lung, fetal-type adenocarcinoma of the lung, esophageal adenocarcinoma, adenocarcinoma of the small bowel, colon, and appendix, and adenocarcinoma with enteroblastic differentiation.

SALL4, GPC3, and AFP are enteroblastic lineage markers.

Enteroblastic Differentiation: Neoplasms with enteroblastic differentiation closely resemble fetal gut. They can have solid, papillary, or tubular features, and their glands are lined by columnar cells with prominent clear cytoplasm, containing both supranuclear and infranuclear vacuoles. These vacuoles do not contain mucin, only glycogen.

Adenocarcinoma with enteroblastic differentiation has a worse overall prognosis than conventional gallbladder adenocarcinoma. Lymphatic and vascular permeation is increased, and there is a higher incidence of lymph node and liver metastases.

Conventional Gallbladder Carcinoma: This is an uncommon tumor, with an incidence in the US of about 3 per 100,000 people per year. It occurs twice as often in females than males, and usually occurs in the seventh and eighth decades of life. Risk factors include obesity, chronic cholecystitis and cholelithiasis, as well as chronic typhoid infection of the gallbladder. For reasons which are unclear, the incidence of gallbladder carcinoma is elevated in South America, Eastern Europe, Northern India, and Japan. Certain ethnic groups, such as Hispanics and Native Americans, are also at greater risk.

Gallbladder carcinoma is often asymptomatic; when symptoms occur, they include right upper quadrant pain, indigestion, weight loss, jaundice, and emesis with bile. Gallbladder carcinoma can be cured by resection if it is caught early enough; however, the prognosis is poor once the patient is already symptomatic.

Patient Follow-Up: The patient had a straightforward hospital course after her surgery and was discharged on PO pain medications. Plans are being made for a close post-operative follow-up, since her cancer is more aggressive and has the potential for a worse prognosis.

References:

Morita, Shigeki et al. “High-grade Lung Adenocarcinoma with Fetal Lung-like Morphology.” American Journal of Surgical Pathology 37.6 (2013): 924-929.

Mitsuma, Koko et al. “A case of adenocarcinoma with enteroblastic differentiation of the ampulla of Vater.” Pathology International 2016; 66: 230-235.

Matsumoto, K. et al. “Gastric cancer with enteroblastic differentiation.” World Journal of Gastroenterology 22.36 (2016): 8206-8208.

Murakami, Takashi et al. “Clinicopathologic and immunohistochemical characteristics of gastric adenocarcinoma with enteroblastic differentiation: a study of 29 cases.” Gastric Cancer 19 (2016): 503-505.

Ferreccio, C. (2012). "Salmonella typhi and Gallbladder Cancer". Bacteria and Cancer. p. 117.

Case 5

Presenter: Carissa LaBoy, MD

Clinical History: The patient is a 71 year old male with a 48 pack year smoking history who presents for a screening low dose computed tomography scan. Past medical history includes radiation for enlarged tonsils as a child and Warthin’s tumor in left parotid gland status post resection. He denies any symptoms of chest pain, shortness of breath, cough, numbness, weakness, muscle fatigue, drooping eyelids, or unexpected weight loss. His physical examination is unremarkable. On the low dose CT, a homogeneous, well circumscribed mass was seen located in the anterior mediastinum, abutting the right lung measuring approximately 4 cm. There was no evidence of infiltration or vascular involvement and no enlargement of mediastinal lymph nodes. At this time, the patient underwent a right video assisted thorascopic surgery (VATS) thymectomy.

Final Diagnosis: Micronodular Thymoma with Lymphoid Hyperplasia

Gross and Histologic Findings: The specimen weighed 103 grams and was 19 cm in greatest dimension with a centrally located nodular mass that measured 4.5 cm in greatest dimension. On cut section, the mass was seen to be encapsulated with a yellow, lobulated, solid surface with pink-tan and cystic areas that range in size from 0.3 to 2.0 cm in greatest dimension. Histologic sections showed multiple nodules, some discrete, some anastomosing, within a lymphoid background with follicles and germinal centers. The nodules contained epithelial cells that were bland with oval to spindle nuclei with open chromatin and inconspicuous nucleoli. No cytologic atypia, mitosis, or necrosis were appreciated.

Differential Diagnosis:

1. Type A thymoma: This type of thymoma comprises 4-19% of all thymomas and 24% of cases are associated with myasthenia gravis. Grossly, the mass is well circumscribed and encapsulated. Microscopically, the epithelial cells present have bland spindle to oval nuclei with dispersed chromatin and inconspicuous nucleoli that grow in a sheet like or storiform pattern with few or no immature T lymphocytes present in the background. Thus, the bland nature of the epithelial cells present on histologic sections resembled Type A thymoma, but the lack of micronodules or a dense population of immature T lymphocytes precluded the diagnosis.

2. Type AB thymoma: This type of thymoma comprises 15-43% of all thymomas and 14% of cases are associated with myasthenia gravis. Grossly, the mass is encapsulated with multiple nodules separated by white fibrous bands. Microscopically, there is a lymphocyte poor Type A thymoma component admixed with a lymphocyte rich Type B like component. The Type B like component has small polygonal epithelial cells with oval to spindle pale nuclei with dispersed chromatin and inconspicuous nucleoli that are dispersed within a background of scattered lymphocytes. The bland nature of the epithelial cells present on histologic sections resembled Type AB thymoma, but the lack of micronodules or a dense population of immature T lymphocytes precluded the diagnosis.

3. Type B2 thymoma: This type of thymoma comprises 18-42% of all thymomas and 30-82% of cases are associated with myasthenia gravis. Grossly, the mass is encapsulated with multiple nodules separated by white fibrous bands. Microscopically, large coarse lobules are present separated by delicate septa within a moderately dense population of lymphocytes. The epithelial cells are large

and polygonal with vesicular nuclei and distinct nucleoli and form a network that palisades around perivascular spaces. The nodular growth pattern of epithelial cells within a dense lymphocyte background resembled Type B2 thymoma, but the presence of large cells with distinct nucleoli palisading around perivascular spaces precluded the diagnosis.

4. Micronodular thymic carcinoma with lymphoid hyperplasia: This entity is rare and comprises <5% of thymic tumors. Patients rarely have a history of myasthenia gravis or any other autoimmune disorders. Grossly, the masses are infiltrative and often invade into adjacent structures and prominent cystic changes are not present. Microscopically, there are micronodules of epithelial cells set within a lymphoid background. The epithelial cells in the nodules are large, round to oval, with vesicular nuclei and conspicuous nucleoli. These cells have frankly malignant features consisting of atypia, increased mitosis, and necrosis. A background of lymphoid hyperplasia with germinal centers is observed with a mixed B and T cell lineage. The nodular growth pattern within a background of lymphoid hyperplasia resembles micronodular thymic carcinoma with lymphoid hyperplasia, but the presence of frankly malignant features of the epithelial cells precludes the diagnosis.

Summary:

Micronodular thymoma with lymphoid hyperplasia was first described by Suster and Moran in 1999. They are rare tumor, comprising only 1-5% of all thymomas. Patients with this diagnosis rarely have a history of myasthenia gravis or other autoimmune disorders. The entity often presents in patients older than 40 years of age with a slight male predominance. The majority of patients are asymptomatic and masses are often discovered incidentally. Grossly, the mass is well circumscribed, encapsulated and minimally invasive and ranged from 3-15 cm in greatest dimension. Cystic areas of various sizes are commonly present. Microscopically, multiple small nodules of thymic epithelial cells are seen within a background of lymphoid hyperplasia. The nodules are composed of oval to spindle cells containing oval nuclei without atypia or increased mitotic activity with a few scattered lymphocytes. The epithelial cells are strongly and diffusely positive for cytokeratin. The lymphoid component is composed of mature CD20+ B cells and diffusely positive CD99+ immature T lymphocytes in a perinodular distribution.

In the thymus, lymphoid hyperplasia with germinal center formation is usually seen in patients with myasthenia gravis or other autoimmune disorders. However, patients with micronodular thymomas rarely have myasthenia gravis or autoimmune disorders. Thus, it has been speculated that the lymphoid hyperplasia is either a host response to tumor antigens or tissue response to unrelated intrathymic antigens.

Zhu et. al. found CD1a+, S100+ cells present within the micronodules that also expressed langerin delineating them as Langerhans cells (LCs) or antigen presenting cells. LCs reside mainly within the epithelial component and progressively mature to dendritic cells (DCs). As they migrate towards the stroma, they form clusters with mature T lymphocytes, thus activating them resulting in lymphoid follicle formation.

Ishikawa et. al. compared numbers of LCs and DCs between micronodular thymomas and Type A and Type AB thymomas using antibodies specific to each cell. The results showed that the number of LCs in the tumor epithelium and the number of mature DCs in the tumor stroma were significantly higher in micronodular thymoma than in Type A and Type AB thymomas.

Thus, the immune reaction is believed to be beneficial leading to overall improved survival in these patients, such as seen in some other lymphoid rich neoplasms. The prognosis in micronodular thymoma is excellent with no recorded reports of tumor metastasis or tumor related deaths.

References:

Mneimneh, Wadad S. et al. Micronodular thymic neoplasms: case series and literature review with emphasis on the spectrum of differentiation. Modern Pathology (2015) 28, 1415-1427

Den Bakker, Michael A. et al. Histologic Classification of Thymoma: A Practical Guide for Routine Cases. Journal of Thoracic Oncology. Volume 9, Number 9, Supplement 2, September 2014

Ishikawa, Yoshinori. et al. Micronodular thymoma with lymphoid stroma: an immunohistochemical study of distribution of Langerhans cells and mature dendritic cells in six patients. Histopathology 2015. 66, 300-307

Zhu, Pengcheng et al. Langerhans cells proliferation in ectopic micronodular thymoma with lymphoid stroma: a case report. Int J Exp Pathology 2014; 7(10); 7262-7267

Suster, Saul and Moran, Cesar. Micronodular Thymoma with Lymphoid B-cell Hyperplasia: Cinicopathologic and Immunohistochemical Study of Eighteen Cases of a Distinctive Morphologic Variant of Thymic Epithelial Neoplasm. The American Journal of Surgical Pathology. Volume 23 (8), August 1999, 955

Case 6

Presenter: Katrina Krogh, MD

Clinical history: The patient is a 56-year-old male with a history of polycystic kidney disease with end-stage renal disease, on hemodialysis for 10 years. Pre-kidney transplant workup showed a small hiatal hernia and a prominent paraesophageal lymph node. The patient reported no symptoms at that time, including heartburn, dysphagia, or gastritis. His last colonoscopy was in 2011. At GI clinic, an upper endoscopy was performed. Biopsies were taken.

Final Diagnosis: Gastric and Duodenal Lanthanosis

Gross and Histologic Findings:

EGD showed Barrett’s esophagus, stomach with discolored, erythematous, and texture-changed mucosa, and duodenum with mucosal changes. Biopsies of the stomach and duodenum showed expansion of the lamina propria by histiocytes filled with eosinophilic, refractile material. The histiocytes were CD68+, Iron+, PAS+, PAS-D+, and AFB-.

Differential Diagnosis:

1. Mycobacterial infection: In end-stage AIDS patients, nontuberculous mycobacteria are a cause of gastrointestinal lamina propria expansion by granular and eosinophilic histiocytes. The histiocytes are packed with bacilli, evident from acid fast staining. Histiocytes are PAS+. In our case, no bacilli were identified in the histiocytes.

2. Whipple disease: Infection by bacterium Tropheryma whipplei (Whipple bacillus) can cause malabsorption, arthritis, lymphadenopathy, endocarditis, and neuropsychiatric manifestations. In the small bowel, histology demonstrates massive infiltration of lamina propria by foamy macrophages. The Whipple bacillus is acid fast negative, and PAS+.

3. Gastric xanthoma: EGD showed whitish lesions in the stomach, and gastric xanthoma must be considered from this finding. These mucosal polyps or plaques are characterized by infiltration of the lamina propria by lipid-laden, foamy macrophages. Histology demonstrates bland foamy histiocytes with finely bubbly cytoplasm and round, inconspicuous nuclei. In our case, morphology is not consistent with this diagnosis.

4. Drug-induced injury (iron gastropathy): Exogenous and endogenous iron accumulation in gastric mucosa can alter it to cause destruction, in addition to deposition of 3 patterns: 1) accumulation in macrophages, endothelial and stromal cells; 2) extracellular golden brown deposits; and 3) epithelial deposits. The iron is highlighted with Prussian blue stain.

Summary:

After noting the patient’s history of lanthanum carbonate therapy, we diagnosed him with gastric and duodenal lanthanosis. Lanthanum carbonate (LaC) is a non-aluminum and non-calcium phosphate binder used to prevent hyperphosphatemia in dialysis patients. Hyperphosphatemia can lead to hypercalcemia, and dystrophic calcifications in various organs. Use of LaC is a new therapy, and began in 2005 in the US and 2009 in Japan. It is commonly believed that little is absorbed into gastrointestinal mucosa (<0.002%); however, there are numerous reports of deposits in multiple tissues (and reports of

end-organ damage). Gastrointestinal symptoms from lanthanosis include abdominal discomfort, vomiting, and diarrhea.

On endoscopy, lanthanosis appears as whitish lesions on EGD, and can accompany gastric erosions, and polyps. On histology, background mucosa usually shows chronic inflammation, and characteristic large eosinophilic histiocytes can be identified in the mucosa (and occasionally the lamina muscularis mucosae). These histiocytes can be multinucleated, and can contain phagocytized foreign bodies, including transparent crystalloids and eosinophilic to brownish, coarsely to finely granular, or string-like substances. Lanthanosis deposits can be found with calcium and iron deposition, but interestingly, is not associated with cancer or H. pylori. Furthermore, lanthanosis is rarer in the duodenum and distally, presumably due to a more alkaline mucosal environment.

Diagnostically, the pathologist must consider various histiocytic inflammatory conditions. Generally, infectious and non-infectious nodular granulomatous lesions can be ruled out. In addition, the degree of lanthanum accumulation not strictly related to duration. If X-ray diffraction is performed, chemical analysis will show equal parts lanthanum to phosphorus. It is important to also consider endoscopic differential diagnosis for whitish lesions. These include gastric xanthoma, extranodal marginal zone lymphoma, and MALT lymphoma. Overall, there seem to be two diagnostic criteria: 1) eosinophilic histiocytes, and 2) history of dialysis in patient treated with LaC.

Importantly, further studies are needed regarding lanthanosis, as little is known clinically or prognostically about the short and long term effects of this finding.

References:

Ban S, Suzuki S, Kubota K et al. Gastric mucosal status susceptible to lanthanum deposition in patients treated with dialysis and lanthanum carbonate. Ann Diagn Pathol 2017; 26: 6–9.

Haratake J, Yasunaga C, Ootani A, Shimajiri S, Matsuyama A, Hisaoka M. Peculiar histiocytic lesions with massive lanthanum deposition in dialysis patients treated with lanthanum carbonate. Am J Surg Pathol 39: 767-771, 2015.

Hattori, K., Maeda, T., Nishida, S., Imanishi, M., Sakaguchi, M., Amari, Y., Moriya, T. and Hirose, Y. (2017), Correlation of lanthanum dosage with lanthanum deposition in the gastroduodenal mucosa of dialysis patients. Pathol Int, 67: 447–452. doi:10.1111/pin.12564

Hoda R S, Sanyal S, Abraham J L, Everett J M, Hundemer G L, Yee E, Lauwers G Y, Tolkoff-Rubin N & Misdraji J (2017) Histopathology 70, 1072–1078. DOI: 10.1111/his.13178 Lanthanum deposition from oral lanthanum carbonate in the upper gastrointestinal tract

Murakami, N., Yoshioka, M., Iwamuro, M., Nasu, J., Nose, S., Shiode, J., … Yamamoto, K. (2017). Clinical Characteristics of Seven Patients with Lanthanum Phosphate Deposition in the Stomach. Internal Medicine, 56(16), 2089–2095. http://doi.org/10.2169/internalmedicine.8720-16

Shitomi, Y., Nishida, H., Kusaba, T., Daa, T., Yano, S., Arakane, M., Kondo, Y., Nagai, T., Abe, T., Gamachi, A., Murakami, K., Etoh, T., Shiraishi, N., Inomata, M. and Yokoyama, S. (2017), Gastric lanthanosis (lanthanum deposition) in dialysis patients treated with lanthanum carbonate. Pathol Int, 67: 389–397. doi:10.1111/pin.12558

Yabuki K, Shiba E, Harada H, et al Lanthanum deposition in the gastrointestinal mucosa and regional lymph nodes in dialysis patients: analysis of surgically excised specimens and review of the literature. Pathol Res Pract. 2016;212:919-926.