An 80-year-old man presented with a subcutaneous hard mass. The patient reported the mass developed over a period of 6-8 weeks. Imaging showed a 2 cm mass superficial to the gracilis and involving the greater saphenous vein. The patient underwent surgical resection. Representative images from the resection are shown below.

Figure 1
Figure 2
Figure 3

What is the diagnosis?

  • Lipoma
  • Leiomyosarcoma
  • Malignant peripheral nerve sheath tumor
  • Leiomyoma

The correct answer is ...

The correct answer is: Leiomyosarcoma.

Leiomyosarcomas are malignant neoplasms of smooth-muscle cells that typically occur from middle age to older individuals. While the most common site of origin is in the retroperitoneum, leiomyosarcomas often arise from blood vessels, as was seen in this case. A key histologic feature of leiomyosarcomas are intersecting fascicles of spindle cells with abundant eosinophilic cytoplasm. In addition, larger tumors typically demonstrate areas of coagulative tumor necrosis and hyalinized tissue. At the nuclear level, elongated, blunt-ended, cigar-shaped nuclei are readily identified. Nuclear atypia and mitosis are also appreciated with close examination. SMA and desmin stains are positive in most well-differentiated leiomyosarcomas; however, de-differentiated tumors demonstrate focal loss of both stains.  

Leiomyomas also demonstrate intersecting fascicles and blunt-ended cigar-shaped nuclei. Important histologic differences that can be used to differentiate leiomyomas from leiomyosarcomas is the lack of nuclear atypia, necrosis, or mitosis, all of which were observed in this case. The presence of any of these features should prompt careful further examination of the specimen, including additional levels, if possible. 

Lipomas are benign tumors of mature adipocytes. Grossly, the cut surface of lipomas appears homogenously yellow. Leiomyosarcomas demonstrate a white to tan cut surface and typically will have whorls. The histologic appearance of lipomas is that of mature adipocytes with eccentrically located nuclei.

Malignant peripheral nerve sheath tumors are neoplasms involving the peripheral nerve. These lesions can be sporadic but are often associated with disorder neurofibromatosis type 1. Imaging can be useful in identifying if the lesion is arising from or is associated with a peripheral nerve, unlike the vein, as was seen in this case. Microscopically malignant peripheral nerve sheath tumors demonstrate uniform spindle cells with areas of hyper and hypocellularity.  


  1. The WHO Classification of Tumours Editorial Board. WHO Classification of Tumours Soft Tissue and Bone Tumours, 5th ed. Lyon: IARC Press; 2020.
  2. Farshid G, Pradhan M, Goldblum J, Weiss SW. Leiomyosarcoma of somatic soft tissues: a tumor of vascular origin with multivariate analysis of outcome in 42 cases. Am J Surg Pathol. 2002 Jan;26(1):14-24. 
  3. Muratori F, Greto D, Cenatiempo M, Mazzei G, Frenos F, Roselli G, Livi L, Capanna R, Baldi G, Campanacci DA. Leiomyosarcoma: Clinicopathological study and retrospective analysis of prognostic factors in a series of 100 patients. J Orthop. 2019 Mar 25;16(4):303-307. 
  4. George S, Serrano C, Hensley ML, Ray-Coquard I. Soft Tissue and Uterine Leiomyosarcoma. J Clin Oncol. 2018 Jan 10;36(2):144-150.

Blake Ebner, M.D., Ph.D.

Resident, Anatomic Pathology and Neuropathology
Mayo Clinic

Jorge Torres-Mora, M.D.

Consultant, Anatomic Pathology
Mayo Clinic

Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

A 29-year-old man presents with abdominal pain and is found to have a 5 cm presacral mass and vertebral metastasis.

Figure 1: BM-20X H&E Histologic sections of the metastatic vertebral lesion
Figure 2: BM-40X CD99 x2 Immunostaining for CD99

What genetic alteration is most characteristic for this malignancy?

  • BRAF v600e mutation
  • FUS-DDIT3 fusion
  • SS18-SSX1 fusion
  • EWSR1-FLI1 fusion

The correct answer is ...

The correct answer is: EWSR1-FLI1 fusion.

The histologic sections show a monotonous, small, round, blue cell neoplasm that is characteristic of Ewing’s sarcoma. The most common genetic alteration of Ewing’s sarcoma is EWSR1-FLI1 gene fusion, although alternative fusions between FET family genes and genes encoding for ETS-transcription factors have been described. The SS18-SSX1 gene fusion is found in synovial sarcoma. BRAF v600e mutations are found in a multitude of malignancies, including melanoma and papillary thyroid carcinoma, among others. FUS-DDIT3 gene fusion is found in myxoid liposarcoma.

Jeremy Molligan, M.D.

Senior Associate Consultant, Anatomic Pathology
Mayo Clinic

Jorge Torres-Mora, M.D.

Consultant, Anatomic Pathology
Mayo Clinic

Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

The patient is a 4-month-old Arabic male with persistent, severe diarrhea. No other significant clinical history. 

Figure 1: H&E low power
Figure 2: H&E intermediate power
Figure 3: IHC BerEp4

Based on the histology and immunohistochemistry, what is your most likely diagnosis?

  • Congenital tufting enteropathy
  • Autoimmune enteropathy
  • Infectious enteropathy
  • Microvillus inclusion disease

The correct answer is ...

The correct answer is: Congenital tufting enteropathy.

  • Congenital tufting enteropathy (CTE), which is the correct answer, also known as intestinal epithelial dysplasia, is a rare autosomal recessive disorder, first described in 1994 by Reifen et al. Prevalence is 1/50,000-100,000 live births in Western Europe, but is higher in areas with a high degree of consanguinity and in patients of Arabic origin.

    Patients present in the first few months of life with chronic, watery diarrhea and may have choanal, rectal or esophageal atresia and nonspecific punctuated keratitis.

    Associated genetic mutations include: epithelial cell adhesion molecule (EPCAM) gene (chromosome 2p21), constituting 73% of CTE (isolated form) or the SPINT2 gene (chromosome 19q13.2), constituting 21% of CTE (syndromic form).

    Biopsies from small bowel show various degrees of villus atrophy, crypt hyperplasia, disorganization of surface enterocytes with focal crowding resembling tufts and absence of significant of inflammation.

    Negative staining for BerEP4 (EPCAM) immunohistochemical stain is integral for a correct diagnosis. Molecular genetic testing can help confirm the diagnosis.
  • Microvillus inclusion disease (MID) is an important differential diagnosis, a very rare autosomal recessive disorder of intestinal brush border (at least 200 cases have been reported in Europe).

    Affected infants often have failure to thrive, developmental delay and osteoporosis.

    The disease is caused by MYO5B gene mutation resulting in enterocytes' inability to properly form microvilli. Affected enterocytes form intracellular small clumps of abnormal microvilli mix (microvillus inclusions) that can be seen by electron microscopy. These intracellular inclusions are an important finding that help in differentiating it from. On light microscopy, severe atrophy of microvilli, crypt hyperplasia, and bubbly vacuolated apical cytoplasm with extensive or patchy absence of brush border (usually heighted by PAS and CD10) can be seen.
  • Autoimmune enteropathy is another consideration. The disease is due to autoimmune antibodies directed against the intestinal epithelial cells and affects 1 in 100,000 infants.

    It can be part of IPEX syndrome, an X-linked recessive disorder due to mutations in FOXP3. Patients do not respond to dietary restriction and treatment by immunosuppressive agents is needed. The most important finding on light microscopy is the absence of goblet and/or Paneth cells. Other histologic features include villus atrophy, crypt hyperplasia, expansion of lamina propria by a lymphoplasmacytic infiltrate, increased intraepithelial lymphocytes (IELs), and crypt apoptosis.
  • Infectious enteropathy is unlikely given the absence of significant inflammation and an identifiable offending microorganism.


  1. AlMahamed S, Hammo A. New mutations of EpCAM gene for tufting enteropathy in Saudi Arabia. Saudi J Gastroenterol. 2017;23(2):123-126.
  2. W. Overeem, Arend & Posovszky, Carsten & H. M. M. Rings, Edmond & Giepmans, Ben & C. D. van IJzendoorn, Sven. (2016). The role of enterocyte defects in the pathogenesis of congenital diarrheal disorders. Disease Models & Mechanisms. 9. 1-12. 10.1242/dmm.022269. 
  3. Salomon, J., Goulet, O., Canioni, D. et al. Genetic characterization of congenital tufting enteropathy: epcam associated phenotype and involvement of SPINT2 in the syndromic form. Hum Genet (2014) 133: 299. 
  4. Masia R, Peyton S, Lauwers GY, Brown I. Gastrointestinal biopsy findings of autoimmune enteropathy: a review of 25 cases. Am J Surg Pathol. 2014;38(10):1319-29.
Photo of Farah Baban, M.B., Ch.B.

Baban Farah, M.B.Ch.B.

Resident, Anatomic Pathology
Mayo Clinic


Samar Said, M.D.

Consultant, Anatomic Pathology
Mayo Clinic

Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

A 50-year-old woman presents with lower abdominal pain and heavy vaginal bleeding. She has not had a Pap test for 20 years. CT scan reveals a 7 cm cervical mass with metastatic disease. Concurrent cervical and endometrial biopsies show sheets of malignant cells with scant cytoplasm, irregular hyperchromatic nuclei with conspicuous nucleoli. Crush artifact, nuclear molding, brisk mitotic activity and apoptotic cells are seen. Tumor cells stain with synaptophysin, chromogranin, keratin AE1/AE3 and P16. HPV RNA ISH is positive.

Figure 1: NEC

Based on the immunomorphologic findings, what is the diagnosis?

  • Metastatic small cell carcinoma
  • Poorly differentiated squamous cell carcinoma
  • Endometrioid carcinoma, FIGO grade III
  • High-grade neuroendocrine carcinoma, large cell type

The correct answer is ...

The correct answer is: High-grade neuroendocrine carcinoma, large cell type.

Neuroendocrine carcinoma (NEC) is a rarely encountered entity in the cervix, comprising less than 5 percent of diagnosed cervical cancer. Like the more commonly seen cervical squamous cell carcinoma and adenocarcinoma, most of these tumors are driven by human papillomavirus (HPV), particularly HPV18. However, NEC carries a much poorer prognosis due to its aggressive behavior and propensity for metastatic spread. Because NEC is uncommon and has no specific morphologic features to suggest the site of origin, it can be misdiagnosed as metastatic carcinoma, leading to an unnecessary work up in search of the primary site. In this case the endometrial metastases can erroneously point to an endometrial cancer with involvement of the cervix. As a surrogate marker for an HPV-mediated process, P16 immunohistochemical stain can aid in making the correct diagnosis, which can then be confirmed by in situ hybridization. Although NEC has no precursor lesion that would allow diagnosis of preinvasive disease during screening procedures, HPV-driven NEC can be prevented with the available vaccine. 


  1. Castle PE, Pierz A, Stoler MH. A systematic review and meta-analysis on the attribution of human papillomavirus (HPV) in neuroendocrine cancers of the cervix. Gynecol Oncol. 2018 Feb;148(2):422-429. 
  2. Alejo M, et al; RIS HPV TT study group. Contribution of Human papillomavirus in neuroendocrine tumors from a series of 10,575 invasive cervical cancer cases. Papillomavirus Res. 2018 Jun;5:134-142. 
Maria Zayko profile

Maria Zayko, D.O.

Fellow, Surgical Pathology
Mayo Clinic

Michael Henry, M.D.

Emeritus Consultant, Anatomic and Clinical Pathology
Mayo Clinic

Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

A 59-year-old HIV positive man developed worsening shortness of breath over the previous six months. Chest radiography revealed a left-sided pleural effusion on which thoracentesis was performed. The aspirate and cell block demonstrated discohesive sheets of large cells with pleomorphic nuclei and abundant pale to basophilic cytoplasm that was often vacuolated (see Figures 1 and 2). There were frequent reactive histiocytes associated with abundant apoptotic debris.

Figure 1: H&E 20x
Figure 2: H&E 400x
Figure 3

Initial workup demonstrated the pleomorphic cells lacking staining for CD3, CD5, CD10, CD19, CD20, CD21, CD30, CD45, CD79a, CD138, BCL2, BCL6, Cyclin-D1, Pan-Keratin, S100, EBV-LMP1, OCT2, MPO, and PAX5. The pleomorphic cells were positive for EMA, MUM1, HHV8, CD38 (Figure 3), and EBV-ish. 

What is the best diagnosis?

  1. Plasmablastic lymphoma 
  2. Primary effusion lymphoma 
  3. Diffuse large B-cell lymphoma
  4. Anaplastic large cell lymphoma 

The correct answer is ...

The correct answer is: Primary effusion lymphoma (PEL).

Primary effusion lymphoma (PEL) is a rare form of lymphoma which usually occurs within the body cavities of individuals with AIDS. It usually does not form a solid tumor mass. The neoplastic cells in PEL are large and pleomorphic/anaplastic, often with plasmacytoid cytology. The neoplastic cells are infected with HHV8, which is the virus culpable for Kaposi sarcoma (not usually seen in these individuals). Staining for HHV8 is necessary for a diagnosis of PEL. Additionally, these neoplastic cells are often infected with EBV, as are many lymphomas in patients with AIDS. The prognosis is poor for individuals with PEL; survival is usually around one year. The neoplastic cells are technically B-cells based on molecular studies and usually express the common leukocyte antigen, CD45, and lack B-cell markers like PAX-5, CD20, and CD19. They do, however, stain like terminally differentiated B-cells with positivity for CD138, CD38, and MUM-1 as well as EMA. Rarely PEL can occur in sites outside of body cavities, termed extracavitary PEL, and have a similar morphology and immunophenotype, except they are more likely to express pan-B cell markers.

Incorrect answers:

Plasmablastic lymphoma can resemble PEL in terms of cytology but will have a more consistent plasmacytoid appearance. In contrast, PEL can demonstrate plasmacytoid morphology, but will be more varied in appearance with more anaplastic appearing morphology than plasmablastic lymphoma. Plasmablastic lymphomas will stain for plasma cell antigens like CD138 and CD38 similar to PEL, but will be negative for HHV8. This is another rare lymphoma that arises also in AIDS patients and can also be associated with EBV, but again will be HHV-8 (-). These lymphomas are often seen in the oral cavity and can involve lymph nodes, but are less likely to involve body cavities. Similar to PEL, they weakly stain for pan B-cell antigens like CD20 and the common leukocyte antigen, CD45.

DLBCL’s make up a significant proportion of AIDS-related lymphomas and retain a similar morphology to their immunocompetent-related counterparts. Similar to other lymphomas in immunodeficient individuals, EBV can be frequently identified, specifically in DLBCLs of the CNS. However, in contrast to PEL, they stain with both EBV-ISH and LMP-1, while PEL characteristically does not stain for EBV-LMP-1. This is why in the above case EBV-ISH was positive but EBV-LMP-1 was negative. Similar to other variants of DLBCL, they stain with pan-B cell markers, including CD19, CD20, CD79a, PAX-5; conversely PEL do not stain for B-cell markers and will more consistently stain more for postgerminal center markers.

Peripheral T-cell lymphomas including ALCL are much less common in immunodeficient conditions. ALCL can be ALK (+) or ALK (-), but ALCL consistently stains for CD30 regardless of ALK reactivity. As a T-cell lymphoma they will stain for T-cell markers, but commonly lose CD3, CD5, CD7 and CD8. CD4 and CD43 are more likely to retain reactivity in ALCL. A lack of CD30 staining effectively rules out ALCL in this case. ALCL is most likely to show up in a seroma in the case of breast-implant associated ALCL. Like the name implies, it usually (not always) occurs in individuals with breast implants and is diagnosed in a peri-implant effusion. These cases are usually negative for ALK. These patients have a better prognosis than systemic or nodal ALCL.


  1. Patel S, Xiao P. Primary effusion lymphoma. Arch Pathol Lab Med. 2013 Aug;137(8):1152-4. doi: 10.5858/arpa.2012-0294-RS. PMID: 23899073
  2. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, WHO Classification of Tumours, Revised 4th Edition, Volume 2. Edited by Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J
Photo of Caseu Gleue

Casey Gleue, M.D.

Resident, Anatomic and Clinical Pathology
Mayo Clinic

William Macon, M.D.

Consultant, Pathology
Mayo Clinic

Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

Microarray and Fragile X testing were ordered for a 6-year-old boy with autism. The microarray result was normal. Triplet repeat primed PCR analysis showed CGG repeat sizes of 31 (normal) and >200 (full mutation) in the 5’UTR of the FMR1 gene. The >200 repeat was fully methylated. Fragile X testing of the patient’s mother revealed FMR1 CGG repeat sizes of 30 (normal) and 105 (premutation). 

Figure 1: Submission

What is the correct diagnosis of the patient and the patient’s mother? 

  • Normal; Normal
  • Normal; Risk of passing on an expanded allele
  • Fragile X syndrome; Risk for primary ovarian insufficiency
  • Fragile X syndrome; Fragile X syndrome

The correct answer is ...

The correct answer is: Fragile X syndrome; Risk for primary ovarian insufficiency.

Fragile X syndrome is a repeat expansion disorder. The 5’UTR and promoter region of the FMR1 gene become methylated once the number of CGG repeats in the 5’UTR reaches a threshold of around 200 repeats. This shuts down FMR1 gene expression and a subsequent absence of the FMR1 protein, which plays a central role in neuronal development and synaptic plasticity.

The patient is mosaic for a normal allele and a methylated, full mutation allele. Fragile X syndrome is X-linked, meaning that he has a diagnosis for fragile X syndrome. The severity of mosaic fragile X syndrome can range from mild to severe, depending on the proportion of normal to full mutation alleles in tissues important for fragile X pathogenesis like the brain (1). 

The patient’s mother is at risk of for primary ovarian insufficiency as well as fragile X-associated tremor and ataxia syndrome because she has a premutation allele. She also has a risk of passing on a full mutation allele to her children because of the relative instability of the premutation allele. 

The combination of the normal and full mutation alleles seen in the patient is quite rare (2). Males with mosaic fragile X syndrome typically have a combination of the premutation allele and the full mutation allele. This is because of the premutation allele’s propensity to expand to the full mutation during embryogenesis. The mechanism behind a mosaic of normal and full mutation alleles is thought to be both the contraction and expansion of the unstable premutation allele (3). Therefore, the most likely explanation for the patient’s mosaicism is that he inherited the premutation allele from his mother, which then expanded to the full mutation in a subset of cells and contracted to the normal allele in others.


  • Pretto et al. Clinical and molecular implications of mosaicism in FMR1 full mutations. Front. Genet. 2014; 5:318. PMID: 25278957
  • Bonarrigo et al. J Child Neurol. Think about it: FMR1 gene mosaicism. 2014;29(9):NP74-7. PMID: 24065579
  • Schmucker and Seidel. Mosaicism for a full mutation and a normal size allele in two fragile X males. Am J Med Genet. 1999;84(3):221-5. PMID: 10331596
Lauren Choate

Lauren Choate, Ph.D.

Resident, Laboratory Genetics and Genomics
Mayo Clinic

Wei Shen

Wei Shen, Ph.D.

Senior Associate Consultant, Laboratory Genetics and Genomics
Mayo Clinic

Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

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