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Abdomen/retroperitoneum

A 71-year-old woman presents with a three-month history of vague abdominal pain and an abdominal mass. She has experienced hematuria and bloody stools in the past month with a 10-pound weight loss in the past two months. Physical exam reveals a mobile large mass in her left abdomen. A computed tomography scan demonstrates a 32.0 cm solid mass involving the left kidney, spleen, pancreas, colon, and extending deep into the retroperitoneum. The tumor superficially involves the uterus. The tumor is resected and the microscopic slide represents the tumor. The tumor expresses smooth muscle actin, desmin, and p16. Tumor cells do not express CD10, AE1/AE3, TLE1, caldesmon, CD117, DOG-1, CD34, estrogen receptors, progesterone receptors, HMB-45, or smoothelin.

Master List of Diagnoses

  • Angiomyolipoma
  • Gastrointestinal stromal tumor
  • Leiomyosarcoma
  • Symplastic leiomyoma
  • Synovial sarcoma
View slide image with DigitalScope

This case first appeared as Performance Improvement Program Critique 2017- Case 01, Leiomyosarcoma of the abdomen/retroperitoneum involving the abdomen, left colon, uterus, pancreas, left kidney, and retroperitoneum.

Criteria for Diagnosis and Comments

Sections reveal a spindle cell neoplasm forming intertwining fascicles with foci of necrosis. There are also sections in which there is an epithelioid component to the neoplasm with marked areas of necrosis. The spindle cells are elongated with variable pink to strongly eosinophilic staining cytoplasm and regionally clear cytoplasm. Nuclei are enlarged, elongated, with some being cigar-shaped and hyperchromatic. On cross section in well-differentiated regions, there is peri-nuclear cytoplasmic clearing around a centrally located nucleus. There are many areas in which there is marked nuclear pleomorphism including multi-lobated nuclei. Mitotic figures with atypical forms are easily identified. There is no evidence of intra-tumoral adipose tissue or a vascular component to this neoplasm. There is no evidence of palisading, or an epithelial component (biphasic pattern). The histology and immunohistochemical profile supports an interpretation as a high-grade leiomyosarcoma (LMS). Several blocks of this tumor contain areas that show low-grade LMS, as well as other higher-grade regions, suggesting that this tumor has become a pleomorphic LMS.

Abdominal/retroperitoneal LMS represents approximately two-thirds of all extra-uterine soft tissue LMS with a higher incidence in women (2:1 F:M). They are usually seen in the elderly with a peak incidence in the seventh decade. Some of these tumors in females are of uterine origin, and can be found expressing estrogen and/or progesterone receptors supporting interpretation that they are metastases from a gynecologic origin. Most tumors are strikingly large at time of presentation exceeding 10.0 cm in maximum dimensions, and usually involving multiple abdominal organs and the vertebral column. Lower grade tumors may resemble the benign form grossly with a whorled, white to grey appearance on cut section, while higher grade tumors will exhibit a softer fleshy appearance with areas of hemorrhage and necrosis. A small number of these tumors will have anaplastic features mimicking an undifferentiated pleomorphic sarcoma (malignant fibrous histiocytoma pattern), while some may appear to be high-grade tumors arising in a pre-existing lower grade LMS, and are known as pleomorphic LMS. There are variants including myxoid LMS that have a hypocellular pattern with spindle cells separated by small lakes of hyaluronic acid. Because of the hypocellularity, mitotic activity may appear deceptively low to the pathologist. The threshold for mitotic activity is lower in these tumors when differentiating a benign tumor from a malignant one. Myxoid LMS tend to behave as lower-grade tumors clinically. Inflammatory LMS is a rare variant containing an infiltrate of lipophages, lymphocytes and occasionally neutrophils, in addition to conventional leiomyosarcoma.

Criteria to differentiate a malignant smooth muscle tumor from a benign one in deep soft tissues are dependent on the presence or absence of nuclear atypia, necrosis and mitotic activity. In retroperitoneal tumors where there is absence of nuclear atypia and necrosis, the mitotic count should be no greater than 5 per 50 high-power fields (HPF) to classify as a benign leiomyoma. In deep somatic soft tissue (extremities), a tumor with no necrosis and no atypia should have fewer than 1 mitotic figure per 50 HPF to be classified as a leiomyoma. To interpret a retroperitoneal tumor as a smooth muscle tumor of uncertain malignant potential (SMT-UMP) there should be no necrosis or atypia and the mitotic count should be greater than 5 per 50 HPF. In a retroperitoneal smooth muscle tumor containing atypia, low mitotic counts of 5 mitoses per 50 HPF is all that is needed to make a diagnosis of LMS.

LMS typically express desmin and actins with variable expression of caldesmon. Studies have shown that 30%-40% of LMS do not express caldesmon. Smoothelin, a mature cytoskeletal protein in differentiated smooth muscle cells, is a new smooth muscle marker. However, studies have shown that it is expressed diffusely in all leiomyomas, with only a small number (less than 5%) of low-grade, intermediate-grade and high-grade LMS expressing smoothelin, mostly weakly or focally. It is important to note that while less than 5% of LMS show cytoplasmic only smoothelin expression, a slightly higher percentage can show focal nuclear expression (11% in soft tissue LMS), but the nuclear staining does not occur in leiomyomas. This pattern is aberrant because the protein is normally located in the cytoplasm. Approximately 80% of all LMS also express p16 with high-grade tumors being significantly more likely to express p16.

Leiomyomas of the retroperitoneum and deep soft tissue are extremely rare to the degree that some question if the entity exists. However, there are strict criteria (above) to diagnose deep soft tissue leiomyomas. The criteria are based on absence of atypia and necrosis. In uterine symplastic leiomyomas there is variable nuclear atypia present without necrosis or mitotic activity. The atypia in these tumors is a degenerative change in the cell and nucleus. There have been no reported cases of symplastic leiomyomas of the retroperitoneum or deep soft tissue. Until data is published on deep soft tissue symplastic leiomyomas, it is recommended that in the absence of necrosis and mitotic activity, deep soft tissue symplastic leiomyomas should be classified as at least SMT-UMP. The tumor in this case has necrosis, significant atypia, significant mitotic activity and absence of smoothelin expression not seen in benign leiomyoma. Smoothelin (and usually desmin) is always diffusely expressed in leiomyomas.

Angiomyolipoma (AML) is a triphasic tumor usually arising in a kidney and belongs to the family of tumors known as perivascular epithelioid cell tumors (PEComa). Large tumors may be attached to other organs in the abdomen, and about one-third of tumors are seen in patients with tuberous sclerosis complex. PEComas can also occur in the uterus and metastasize to soft tissue reinforcing the need to obtain HMB-45, and hormone receptors in cases with features suggestive of PEComa. Histologically, the tumor is composed of thick-walled intermediate sized vessels containing perivascular epithelioid myoid cells and adipocytes. Some tumors contain a spindle cell component of myoid cells. Myoid cells may sometimes exhibit significant atypia with hyperchromatic, and pleomorphic nuclei. Lesional cells express smooth muscle actin, HMB-45 and Melan-A. A significant number of tumors may also express progesterone receptors and CD117. Biologically, these tumors usually behave in a benign fashion; however, ones with markedly atypical epithelioid histology with necrosis have metastatic potential. There are also reported cases of sarcomatous transformation of both the spindle cell and epithelioid myoid cell types of AML. The histologic features and immunohistochemical features of this tumor do not support the interpretation of AML in this case.

Gastrointestinal stromal tumors (GISTs) arise from the interstitial cell of Cajal. They may occur at any age, but three-fourths occur in patients greater than 50 years of age. Most are located in the GI tract, including the stomach, jejunum, ileum, duodenum and colorectum in descending order of incidence; however, they can also occur in the retroperitoneum, mesentery and omentum where they are known as extra-gastrointestinal stromal tumors. Grossly, these tumors may have areas of necrosis, cystic change and hemorrhage, features that do not predict malignancy. Histologically, the tumors have three patterns, spindle cells, epithelioid cells and a combination of both spindle and epithelioid cells. The histology varies significantly but gastric GISTs usually have epithelioid or mixed spindle/epithelioid pattern. Spindle cell gastric GISTs sometimes have perinuclear vacuoles that are prominent due to fixation artifact, and spindle cell small intestinal GIST sometimes have collagen fibrils known as so-called “skeinoid fibers.”

Epithelioid GISTs have large epithelioid cells with eosinophilic to clear cytoplasm. Nuclei can be bland or atypical and it is not unusual to find an occasional multinucleated form. Immunohistochemically, GISTs express CD117 (95%), DOG-1 (95%), CD34 (70%), smooth muscle actin (25%), and rarely desmin (2%). GISTs should not express cytoplasmic smoothelin; however, it has been reported that a subset of cases can aberrantly express nuclear smoothelin, the phenomenon seen in a small number of leiomyosarcoma cases. The Miettinen criterion for risk of metastatic disease or tumor-related death is based on the size, mitotic rate and the anatomic location (generally gastric tumors have a more favorable prognosis than intestinal GISTs). Tumors larger than 10.0 cm and having a mitotic rate of greater than 5 per 5 cubic millimeters, regardless of where the tumor arises, have a high risk of developing progressive disease. This tumor had a spindle cell component with a high mitotic rate but does not express CD34, CD117 or DOG-1 and is not diagnostic of a GIST.

Synovial sarcomas are rare tumors found in the abdomen and retroperitoneum, and they can take four forms – biphasic, monophasic fibrous, monophasic epithelial and poorly differentiated types that arises from monophasic or biphasic types. This tumor would fall in the monophasic fibrous type if it was a synovial sarcoma. Synovial sarcomas of the abdomen and retroperitoneum represent less than 2%-4% of all synovial sarcomas. Grossly, a large percentage of abdominal/retroperitoneal tumors have cystic qualities not present in this case. Histologically, the monophasic fibrous type is composed of uniform spindle cells containing scant cytoplasm and resembling fibrosarcoma but lacking the classic herringbone pattern. The spindle cells form irregular nodules. Mitotic activity is usually not high except in the poorly differentiated areas of the tumor. There may be nuclear palisading, calcification, ossification, cartilage formation, myxoid change, and hyalinization in some tumors. Some tumors may exhibit a hemangiopericytoma like vascular pattern. Mast cells may be easily identified in the spindle cell component of most synovial sarcomas. These tumors usually exhibit, at least regionally, expression of keratins, especially CK7, and EMA. Other antigens that are expressed often include TLE1 (97%), Bcl-2 (90%), CD99 (65%) and S100 (30%). Tumors typically do not express CD34. Most of these tumors, cytogenetically, exhibit a t(X;18)(p11;q11) balanced reciprocal translocation resulting in the SYT-SSX fusion gene, which can be detected by FISH. Histologically and immunophenotypically, this tumor does not have features of a synovial sarcoma, monophasic fibrous type.

  1. A 4.0 cm retroperitoneal myoid neoplasm that exhibits minimal cytologic atypia, no necrosis, and mitotic activity of fewer than 1 per 50 HPF and expresses both desmin and HMB45 would best be classified as which of the following?
    1. Leiomyoma of deep soft tissue
    2. Myxoid leiomyosarcoma
    3. PEComa
    4. Pleomorphic leiomyosarcoma
    5. Rhabdomyosarcoma
  2. A 45-year-old man presents with an abdominal mass that is resected. Histologically, the tumor is a high-grade malignant spindle cell neoplasm containing cystic change, myxoid change, hyalinization, and calcification with ossification. No epithelial component is present. Tumor cells express focally epithelial membrane antigen and pancytokeratin, CK7, and strongly express Bcl-2, TLE1 and CD99. Tumor cells do not express CD117, smoothelin, desmin, or S100. Which of the following is the best diagnosis?
    1. Gastrointestinal stromal tumor
    2. Myxoid leiomyosarcoma
    3. PEComa
    4. Pleomorphic leiomyosarcoma
    5. Synovial sarcoma, monophasic fibrous type
  3. An 11.8 cm gastrointestinal stromal tumor with a mitotic count of 15 mitoses per 50 high-power fields (HPF) has a high risk of progressive disease.
    1. True
    2. False

References

  1. Billings SD, Folpe AL, Weiss SW. Do leiomyomas of deep soft tissue exist? An analysis of highly differentiated smooth muscle tumors of deep soft tissue supporting two distinct subtypes. Am J Surg Pathol. 2001;25(9):1134-1142.
  2. Fetch JF, Meis JM. Synovial sarcoma of the abdominal wall. Cancer. 1993;72(2):469-477.
  3. Gannon BR, Manduch M, Childs TJ. Differential immunoreactivity of p16 in leiomyosarcomas and leiomyoma variants. Int J Gynecol Pathol. 2008:27(1):68-73.
  4. Goldblum JR, Folpe AL, Weiss SW. Enzinger & Weiss’s Soft Tissue Tumors, 6th edition. Philadelphia, PA: Elsevier Saunders; 2014:524-568,897-901,1052-1070.
  5. Mayhall K, Lewin E, Lebeau H, et al. Evaluation of Immunohistochemical markers smoothelin, DOG-1, caldesmon and p16 in leiomyosarcomas of different grades and anatomical sites of origin. Mod Pathol, 2015;28(2):22A.
  6. Nese N, Martignoni G, Fletcher CD, et al. Pure epithelioid PEComas (so-called epithelioid angiomyolipoma) of the kidney: a clinicopathologic study of 41 cases: detailed assessment of morphology and risk stratification. Am J Surg Pathol. 2011;35(2):161-176.
  7. Odze RD, Goldblum JR. Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas. 3rd edition. Philadelphia, PA: Elsevier Saunders; 2015:822-829.
  8. Weiss SW. Smooth muscle tumors of soft tissue. Adv Anat Pathol. 2002;9(6):351-359.

Authors

Greg Mayhall, MD
Surgical Pathology Fellow
Medical College of Wisconsin
Milwaukee, Wisconsin

Byron Crawford, MD
CAP Surgical Pathology Committee
Tulane University School of Medicine
New Orleans, Louisiana


Answer Key

  1. PEComa (c)
  2. Synovial sarcoma, monophasic fibrous type (e)
  3. True (a)