An 82-year-old man with past medical history of recurrent deep vein thrombosis, factor V Leiden mutation and diabetes mellitus was found to have an incidental, 3 cm mass in the anterior compartment of his right leg. FDG-PET scan showed the lesion to be metabolically active, and surgical resection was performed. A well-encapsulated yellow-to-pink tan mass was received. Representative H&E sections and immunohistochemical studies are depicted below. 

Figure 1: H&E 4X
Figure 2: H&E 10X
Figure 3: H&E 20X
Figure 4: IHC Desmin
Figure 5: IHC MyoD1
Figure 6: IHC CD163

Which is the most common genetic abnormality associated with this tumor?

  • MYOD1 pLeu122Arg gene mutation
  • Loss of function mutations in PTCH1 
  • Near haplodization (LOH for all autosomes except for 5, 20, and 22)
  • t(12;22)(q33;q12) translocation resulting in an EWSR1-CREB1 fusion 

The correct answer is ...

The correct answer is: near haploidization (LOH for all autosomes except for 5, 20, and 22)

The pattern of near haploidization with retention of disomic chromosomes 5, 20, and 22 is a highly characteristic genetic feature of inflammatory rhabdomyoblastic tumor (IRMT). This is an uncommon skeletal muscle tumor of borderline malignancy (locally recurring, rarely metastasizing) (1, 2). Cases of IRMT have previously been reported as both “inflammatory leiomyosarcoma” (ILMS) (3) and “histiocyte-rich rhabdomyoblastic tumor” (HRRMT) (1) .

IRMT occurs most often in young to middle-aged adults in the soft tissues of the extremities and trunk. Microscopically, it is characterized by a circumscribed growth pattern, often with features of chronicity, including a fibrous capsule, peripheral lymphoid aggregates, calcifications, and cholesterol deposition. The lesional cells themselves are often largely obscured by a striking infiltrate of foamy macrophages and multinucleated giant cells. Close inspection, however, disclosed small aggregates of pleomorphic, eosinophilic, spindled to epithelioid cells, sometimes with enlarged, hyperchromatic, bizarre-appearing nuclei. Mitotic activity is extremely low and tumor cell necrosis is absent. The lesional cells are diffusely desmin-positive, much more variably MyoD1-positive, and may be largely negative for myogenin. Smooth muscle actin expression may be seen, but caldesmon is negative. The non-neoplastic histiocytes are diffusely CD163/CD68-positive.

At the genetic level, IRMT are characterized by a near haploid genotype with or without subsequent genome doubling (2). Identical changes are seen in cases previously reported as “ILMS” and “HRRMT,” strongly supporting the concept that tumors reported under these different names represent the same entity. Some cases harbor pathogenic inactivating NF1 mutations (1, 4).

Based on relatively limited data, the prognosis for patients with IRMT is quite favorable, with only a low risk for metastases. To date, all reported patients are alive and without disease (1, 2). An exceptionally unusual example of a morphology and genetically typical IRMT showing progression to high-grade rhabdomyosarcoma has recently been reported, however (in press).

Incorrect answers

  1. t(12;22)(q33;q12) translocation resulting in an EWSR1-CREB1 fusion

    This rearrangement is seen in the majority of angiomatoid fibrous histiocytomas (AFH), in addition to a variety of other mesenchymal and non-mesenchymal neoplasms (see below). Less often, AFH harbor EWSR1-ATF1 or FUS-ATF1 fusions (7, 8). AFH is a rare mesenchymal tumor of borderline malignancy that typically occurs in the superficial soft tissues of the extremities, trunk, head, and neck in children. It follows an indolent clinical course (3). These tumors share several histologic features with IRMT, including a thick fibrous pseudocapsule, lymphoid aggregates, and variably pleomorphic, desmin-positive tumor cells. However, AFH usually show a distinctive whorling pattern of growth and lack expression of MyoD1 and myogenin. The finding of EWSR1/FUS-CREB1/ATF1 fusions is diagnostic in the appropriate morphologic context (1, 7, 8). These fusions are also, however, found in wholly dissimilar tumors (e.g., clear cell sarcoma of soft tissue, malignant gastrointestinal neuroectodermal tumor, clear cell salivary gland carcinoma, others).
  1. MYOD1 pLeu122Arg gene mutation

    Spindle cell/sclerosing rhabdomyosarcoma (S/SCRMS) harbors mutations in the DNA-binding domain of MYOD1, leading to a reduced transcriptional activation at MYOD1 sites with enhanced binding to MYC (9-12). Similarly to IRMT, S/SCRMS tends to occur in the head and neck as well as in the extremities. It affects infants, children and adults and has an equal sex distribution. However, S/SCRMS is morphologically quite different from IRMT, consisting of clearly malignant spindled and round cells, arranged in fibrosarcoma-like fascicles, and unusual nests of cells surrounded by vaguely chondroid, hyalinized stroma. S/SCRMS are typically diffusely positive for MyoD1, with much more limited expression of desmin and myogenin (3).
  1. Loss of function mutations in PTCH1

    These mutations are characteristic of adult rhabdomyoma. PTCH1 encodes for a sonic hedgehog signaling pathway member and loss of function mutations result in inactivation of the pathway (3). These tumors are slow growing and frequently occur in the head and neck of older males. However, microscopically they are quite different from IRMT, being composed of sheets of polygonal or round cells with abundant eosinophilic cytoplasm, large nuclei, and prominent nucleoli. So-called “spider cells” may be prominent. Mitotic activity is absent. Adult rhabdomyomas express various skeletal muscle markers, as expected (1, 3).


  1. Martinez AP, Fritchie KJ, Weiss SW, Agaimy A, Haller F, Huang H-Y, et al. Histiocyte-rich rhabdomyoblastic tumor: rhabdomyosarcoma, rhabdomyoma, or rhabdomyoblastic tumor of uncertain malignant potential? A histologically distinctive rhabdomyoblastic tumor in search of a place in the classification of skeletal muscle neoplasms. Modern Pathology. 2019;32(3):446-57.
  2. Cloutier JM, Charville GW, Mertens F, Sukov W, Fritchie K, Perry KD, et al. “Inflammatory Leiomyosarcoma” and “Histiocyte-rich Rhabdomyoblastic Tumor”: a clinicopathological, immunohistochemical and genetic study of 13 cases, with a proposal for reclassification as “Inflammatory Rhabdomyoblastic Tumor.” Modern Pathology. 2020.
  3. WHO Classification of tumors of soft tissue and bone. 4 ed. Board WCoTE, editor. Lyon, France 2020.
  4. Bourgeau M, Martinez AP. Histiocyte-rich rhabdomyoblastic tumor: a report of two cases and a review of the differential diagnoses. Virchows Archiv. 2020.
  5. Nord KH, Paulsson K, Veerla S, Wejde J, Brosjö O, Mandahl N, et al. Retained heterodisomy is associated with high gene expression in hyperhaploid inflammatory leiomyosarcoma. Neoplasia. 2012;14(9):807-12.
  6. Uhlen M, Zhang C, Lee S, Sjöstedt E, Fagerberg L, Bidkhori G, et al. A pathology atlas of the human cancer transcriptome. Science. 2017;357(6352).
  7. Fanburg-Smith JC, Miettinen M. Angiomatoid "malignant" fibrous histiocytoma: a clinicopathologic study of 158 cases and further exploration of the myoid phenotype. Hum Pathol. 1999;30(11):1336-43.
  8. Smith ME, Costa MJ, Weiss SW. Evaluation of CD68 and other histiocytic antigens in angiomatoid malignant fibrous histiocytoma. Am J Surg Pathol. 1991;15(8):757-63.
  9. Agaram NP, Chen CL, Zhang L, LaQuaglia MP, Wexler L, Antonescu CR. Recurrent MYOD1 mutations in pediatric and adult sclerosing and spindle cell rhabdomyosarcomas: evidence for a common pathogenesis. Genes Chromosomes Cancer. 2014;53(9):779-87.
  10. Alaggio R, Zhang L, Sung YS, Huang SC, Chen CL, Bisogno G, et al. A Molecular Study of Pediatric Spindle and Sclerosing Rhabdomyosarcoma: Identification of Novel and Recurrent VGLL2-related Fusions in Infantile Cases. Am J Surg Pathol. 2016;40(2):224-35.
  11. Szuhai K, de Jong D, Leung WY, Fletcher CD, Hogendoorn PC. Transactivating mutation of the MYOD1 gene is a frequent event in adult spindle cell rhabdomyosarcoma. J Pathol. 2014;232(3):300-7.
  12. Rekhi B, Upadhyay P, Ramteke MP, Dutt A. MYOD1 (L122R) mutations are associated with spindle cell and sclerosing rhabdomyosarcomas with aggressive clinical outcomes. Mod Pathol. 2016;29(12):1532-40.

Luisa Ricaurte Archila, M.D.

Resident, Anatomic and Clinical Pathology
Mayo Clinic


Andrew Folpe, M.D. 

Consultant, Anatomic Pathology
Mayo Clinic

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

An asymptomatic 41-year-old man presented for evaluation for a kidney transplant. He has a history of end-stage renal disease of unknown etiology and has been on hemodialysis for the past five years. On imaging, a 7.3 cm complex solid cystic mass (Bosniak IV) with thickened, irregular septations and soft tissue nodule was seen in the lower pole of the right kidney. Multiple bilateral renal cysts and renal atrophy were also noted. The patient underwent right radical nephrectomy. Grossly, 7.0 cm multiseptated encapsulated cystic mass with a solid soft tan brown nodule was seen in the lower pole. The rest of the kidney had multiple cysts. See below for microscopic images.

Figure 1
Figure 2
Figure 3
Figure 4

What is your diagnosis?

  • Clear cell renal cell carcinoma (CCRCC)
  • Acquired cystic disease-associated renal cell carcinoma (ACD-RCC)
  • Clear cell papillary renal cell carcinoma (CCPRCC)
  • Papillary renal cell carcinoma (PRCC)

The correct answer is ...

The correct answer is: acquired cystic disease-associated renal cell carcinoma (ACD-RCC).

Microscopically, sections from the cystic mass showed a thick fibrous capsule and tumor arising from the capsule and filling up the cyst (Figure 1). The tumor showed variegated architecture with papillary and tubulocystic areas. Prominent intracellular and intercellular spaces imparting a distinct cribriform appearance were seen (Figure 2). The tumor cells are predominantly large, with abundant granular eosinophilic cytoplasm, ill-defined cell membranes, and Fuhrman grade 3 nuclei with prominent nucleoli (Figure 3). Refractile intratumoral calcium oxalate crystals with no foreign body giant cell reaction were present (Figure 4). The histological findings were consistent with the diagnosis of acquired cystic disease-associated renal cell carcinoma (ACD-RCC).

Because papillary architecture can be variably present in cases of ACD-RCC, these tumors are commonly misdiagnosed as type 2 papillary renal cell carcinoma (PRCC). Separating ACD-RCC from type 2 PRCC based on morphology can be challenging, as both have papillary architecture and large eosinophilic cells with high-grade nuclei. Helpful features to distinguish are the presence of foamy macrophages, psammoma bodies, and glassy hyaline globules in PRCC but are not seen in ACD-RCC. Papillary RCC also lacks the cribriform appearance and is not associated with polarizable calcium oxalate crystals.

The presence of clear cell areas with solid and acinar architecture may lead to confusion with clear cell renal cell carcinoma (CCRCC). The combination of papillary, cribriform, and/or tubulocystic features of ACD-RCC is more complex than in classic CCRCC, and the eosinophilic cells and high-grade nuclei are uncharacteristic of classic CCRCC.

Clear cell papillary renal cell carcinoma (CCPRCC) is an important differential diagnosis because of the variable papillary and tubulocystic features. Despite the architectural similarities, the papillary cores of CCPRCC are lined by low-grade cells with a characteristic subnuclear vacuolar appearance due to the reversed polarity of nuclei away from the basement membrane.

Although CCRCC, type 2 PRCC, and clear cell PRCC can occur in the same clinical setting of acquired cystic kidney disease with ESRD, and the morphologies of these entities overlap, careful attention to subtle histologic and cytologic details, such as the presence of cribriform architecture and intratumoral calcium oxalate crystals, is essential in deciphering the correct diagnosis. The key defining features of ACD-RCC lacking in the other entities is the mixture of eosinophilic and clear cells, cribriform morphology, and presence of polarizable calcium oxalate crystals.


  1. Tickoo SK, dePeralta-Venturina MN, Harik LR, Worcester HD, Salama ME, Young AN, Moch H, Amin MB. Spectrum of epithelial neoplasms in end-stage renal disease: an experience from 66 tumor-bearing kidneys with emphasis on histologic patterns distinct from those in sporadic adult renal neoplasia. Am J Surg Pathol. 2006 Feb;30(2):141-53.
  2. Foshat M, Eyzaguirre E. Acquired Cystic Disease-Associated Renal Cell Carcinoma: Review of Pathogenesis, Morphology, Ancillary Tests, and Clinical Features. Arch Pathol Lab Med. 2017 Apr;141(4):600-606.
  3. Przybycin CG, Harper HL, Reynolds JP, Magi-Galluzzi C, Nguyen JK, Wu A, Sangoi AR, Liu PS, Umar S, Mehra R, Zhang X, Cox RM, McKenney JK. Acquired Cystic Disease-associated Renal Cell Carcinoma (ACD-RCC): A Multiinstitutional Study of 40 Cases With Clinical Follow-up. Am J Surg Pathol. 2018 Sep;42(9):1156-1165.

Lagnajita Datta, M.B.B.S.

Resident, Surgical Pathology
Mayo Clinic

Yajue Huang, M.D., Ph.D. 

Consultant, Anatomic Pathology
Mayo Clinic

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

An 82-year-old woman presented with abnormal vaginal bleeding and pelvic pain. The ultrasound showed a 12.3 cm polypoid mass occupying the endometrial cavity. The patient underwent a total hysterectomy with bilateral salpingo-oophorectomy. Representative sections from the mass are submitted. 

Figure 1
Figure 2
Figure 3

What is the most likely diagnosis?

  • Undifferentiated uterine sarcoma
  • Endometroid carcinoma with corded hyalinized and spindle cell areas
  • Low grade Mullerian adenosarcoma
  • Carcinosarcoma (malignant mixed Mullerian tumor) with heterologous elements (rhabdomyosarcomatous differentiation)

The correct answer is ...

The correct answer is: carcinosarcoma (malignant mixed Mullerian tumor) with heterologous elements (rhabdomyosarcomatous differentiation).

Carcinosarcoma (malignant mixed Mullerian tumor) is a malignant biphasic tumor (carcinomatous and sarcomatous elements, arising from the same malignant clone) that are intimately admixed (at least focally) (1). The incidence is less than 5% of all uterine malignancy, typically affects postmenopausal women (mean age: 65 years) with slight predilection in African American women. The clinical picture is abnormal vaginal bleeding, enlarged uterus by imaging, polyploid mass (might protrude through cervical os), and pelvic pain. Recurrence and metastases are often that of the carcinomatous element in 70% of the cases (2). Some studies mentioned that the risk factors are similar to that of endometrial carcinoma, including obesity, smoking, nulliparity, estrogen exposure, tamoxifen therapy, and pelvic irradiation (3).

The core treatment is total hysterectomy with bilateral salpingo-oopherectomy with biopsy staging, followed by chemotherapy and/or radiotherapy. The prognosis is worse than that of patients with high-grade endometrial carcinoma (particularly high stage). An adverse outcome in the stage I disease might be associated with one of the following: deep myometrial invasion, lymphovascular invasion, serous and clear cell type carcinomatous elements, extensive sarcomatous elements, and presence of heterologous elements (4,5). The molecular studies showed frequent PIK3CA, FBXW7, KRAS, and TP53 mutations (6). 

Grossly, the tumor presents as a polypoid mass filling the endometrial cavity, often protrude from the cervix (measures from 1.8 cm -17 cm; mean 6.6 cm). Necrosis and hemorrhage are common findings. Cystic degeneration is rarely seen. Microscopically, the carcinomatous component (typically predominant) is usually high-grade endometrioid, serous or clear cell. It might be hard to classify if poorly differentiated carcinoma. Immunohistochemical stains will be positive for cytokeratin and EMA. ER and PR are positive in endometroid and negative in serous carcinoma. The sarcomatous component is either homologous or heterologous (mesenchymal components that are not normally present in the uterus) in descending order (rhabdomyosarcoma, chondrosarcoma, osteosarcoma, and liposarcoma). Immunohistochemical stains will be positive for cytokeratin, vimentin, desmin, actin, CD10, and CD34. Myogenin and MyoD1 stain the rhabdomyosarcomatous component. SATB2 could identify the osteosarcomatous elements. Mutant-pattern P53 expression and diffuse p16 staining are usually present in both carcinomatous and sarcomatous elements. 

Low-grade Mullerian adenosarcoma is a biphasic tumor with benign or low-grade epithelial component and low-grade malignant stroma showing phyllodes growth pattern and periglandular condensation. Sarcomatous overgrowth and heterologous elements can occur in this tumor as well.

Undifferentiated uterine sarcoma is a high-grade sarcoma arising from the endometrium or myometrium with no specific differentiation. Usually, it is a diagnosis of exclusion. 

Endometrioid carcinoma with corded hyalinized and spindle cell morphology with areas of dense hyalinization, calcification, and metaplastic bone formation can mimic carcinosarcoma. However, the glandular component is usually low-grade, and squamous metaplasia could help to render the lesion's endometrioid nature. The spindle cell component of this tumor also shows bland morphology, and gradual transition from epithelial areas to spindle cell areas are notable (versus usually abrupt transition in the carcinosarcoma).


  1. Denschlag D, Ulrich UA. Uterine Carcinosarcomas – Diagnosis and Management. Oncol Res Treat. 2018;41(11):675-679. doi: 10.1159/000494335. Epub 2018 Oct 13. PMID: 30317231.
  2. Abdulfatah E, Lordello L, Khurram M, Van de Vijver K, Alosh B, Bandyopadhyay S, Oliva E, Ali-Fehmi R. Predictive Histologic Factors in Carcinosarcomas of the Uterus: A Multi-institutional Study. Int J Gynecol Pathol. 2019 May;38(3):205-215. doi: 10.1097/PGP.0000000000000497. PMID: 30958427.
  3. Zelmanowicz A, Hildesheim A, Sherman ME, Sturgeon SR, Kurman RJ, Barrett RJ, Berman ML, Mortel R, Twiggs LB, Wilbanks GD, Brinton LA. Evidence for a common etiology for endometrial carcinomas and malignant mixed mullerian tumors. Gynecol Oncol. 1998 Jun;69(3):253-7. doi: 10.1006/gyno.1998.4941. PMID: 9648597.
  4. Matsuo K, Takazawa Y, Ross MS, Elishaev E, Podzielinski I, Yunokawa M, Sheridan TB, Bush SH, Klobocista MM, Blake EA, Takano T, Matsuzaki S, Baba T, Satoh S, Shida M, Nishikawa T, Ikeda Y, Adachi S, Yokoyama T, Takekuma M, Fujiwara K, Hazama Y, Kadogami D, Moffitt MN, Takeuchi S, Nishimura M, Iwasaki K, Ushioda N, Johnson MS, Yoshida M, Hakam A, Li SW, Richmond AM, Machida H, Mhawech-Fauceglia P, Ueda Y, Yoshino K, Yamaguchi K, Oishi T, Kajiwara H, Hasegawa K, Yasuda M, Kawana K, Suda K, Miyake TM, Moriya T, Yuba Y, Morgan T, Fukagawa T, Wakatsuki A, Sugiyama T, Pejovic T, Nagano T, Shimoya K, Andoh M, Shiki Y, Enomoto T, Sasaki T, Fujiwara K, Mikami M, Shimada M, Konishi I, Kimura T, Post MD, Shahzad MM, Im DD, Yoshida H, Omatsu K, Ueland FR, Kelley JL, Karabakhtsian RG, Roman LD. Significance of histologic pattern of carcinoma and sarcoma components on survival outcomes of uterine carcinosarcoma. Ann Oncol. 2016 Jul;27(7):1257-66. doi: 10.1093/annonc/mdw161. Epub 2016 Apr 6. PMID: 27052653.
  5. Ferguson SE, Tornos C, Hummer A, Barakat RR, Soslow RA. Prognostic features of surgical stage I uterine carcinosarcoma. Am J Surg Pathol. 2007 Nov;31(11):1653-61. doi: 10.1097/PAS.0b013e3181161ba3. PMID: 18059221.
  6. Cherniack AD, Shen H, Walter V, Stewart C, Murray BA, Bowlby R, Hu X, Ling S, Soslow RA, Broaddus RR, Zuna RE, Robertson G, Laird PW, Kucherlapati R, Mills GB; Cancer Genome Atlas Research Network, Weinstein JN, Zhang J, Akbani R, Levine DA. Integrated Molecular Characterization of Uterine Carcinosarcoma. Cancer Cell. 2017 Mar 13;31(3):411-423. doi: 10.1016/j.ccell.2017.02.010. PMID: 28292439; PMCID: PMC5599133.

Hayder Abdulwahid, M.B.Ch.B.

Fellow, Surgical Pathology
Mayo Clinic

Maryam Shahi, M.D.

Senior Associate Consultant, Anatomic Pathology
Mayo Clinic

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

A female patient in her 80s presented from an outside institution with a recurrence of a parotid mass after resection one year prior. The new mass was gradually increasing in size and associated with ear pain and facial paralysis. Grossly, the 12.2 cm mass was ill-defined and multinodular, invading the overlying dermis and encasing auricular cartilage. Microscopic examination showed basophilic cells with prominent nucleoli in a combination of architectural patterns, from an open cystic pattern to solid sheets of cells. 

Figure 1: Gross Photo
Figure 2: Low Power to Dermis
Figure 3: Medium Power Solid Pattern
Figure 4: High Power with Necrosis
Figure 5: High Power Solid Pattern
Figure 6: High Power Open Cystic Pattern

Which immunohistochemical stain would be positive in this entity?

  • p63
  • Mammoglobin
  • Synaptophysin
  • DOG1

The correct answer is ...

The correct answer is: DOG1.

The entity shown above is high-grade acinic cell carcinoma, a malignant epithelial neoplasm of serous acinar cells and other cell types. This tumor often features a combination of architectural patterns, including solid, microcystic, papillary cystic, and follicular. Most of the cells seen in this case were serous acinar cells, but acinic cell carcinoma can also contain intercalated duct cells, vacuolated cells, and clear cells. Acinic cell carcinoma generally has a good prognosis, with a 5-year survival rate of 90%, and complete surgical excision is the treatment of choice. However, as in our patient, local recurrence can occur in approximately 35% of cases. 

Immunohistochemistry specific for acinic cell carcinoma include DOG1 and NR4A3. DOG1 has a delicate membrane reaction, and NR4A3 has highly specific and strong nuclear staining. In fact, the most common oncogenic driver of acinic cell carcinoma is the overexpression of NR4A3, which can result from the t(4;9)(q13;q31) translocation. This translocation (which occurs in 80% of cases) moves the enhancer region from the SCCP gene to upstream of NR4A3, resulting in its overexpression. Another newly identified mechanism of NR4A3 overexpression is a result of the upregulation of the MYB gene, which mostly occurs in high-grade acinic cell carcinoma. Acinic cell carcinoma can also show patchy PAS+ and diastase-resistant zymogen granules.

Positive staining for mammoglobin occurs in secretory carcinoma. This entity can have a variety of architectural patterns (cystic to microcystic) and intraluminal secretions, as in acinic cell carcinoma, but typically the cytology is very uniform and the cytoplasm is much more pale. Acinic cell carcinoma is mammoglobin negative.

Positive staining for synaptophysin occurs in neuroendocrine carcinoma. Like our high-grade acinic cell carcinoma, this entity often forms sheets and nests. However, acinic cell carcinoma lacks the cytologic features that we would expect from a neuroendocrine tumor and is negative for synaptophysin. Positive staining for p63 occurs in adenoid cystic carcinoma and mucoepidermoid carcinoma. Like our high-grade acinic cell carcinoma, adenoid cystic carcinoma is very basaloid and can show cribriform or solid architecture, but we would expect to see myoepithelial cells with angulated nuclei, which are not present. Mucoepidermoid carcinoma can display a microcystic pattern, like our tumor, but would be composed of a mix of squamous, mucinous, and intermediate cells, not serous acinar cells. 


  • Haller, F., Bieg, M., Will, R. et al. Enhancer hijacking activates oncogenic transcription factor NR4A3 in acinic cell carcinomas of the salivary glands. Nat Commun. 2019;10(1):368.
  • Haller, F., Skálová, A., Ihrler, S., et al. Nuclear NR4A3 Immunostaining Is a Specific and Sensitive Novel Marker for Acinic Cell Carcinoma of the Salivary Glands. Am J Surg Pathol. 2019;43(9):1264-1272. 
  • Lee, D. Y., Brayer, K. J., Mitani, Y., et al. Oncogenic Orphan Nuclear Receptor NR4A3 Interacts and Cooperates with MYB in Acinic Cell Carcinoma. Cancers. 2020;12(9):2433.
  • Thompson L. D. Salivary gland acinic cell carcinoma. Ear, nose, & throat journal. 2010;89(11):530–532. 

Clarissa Jordan, M.D.

Resident, Anatomic and Clinical Pathology
Mayo Clinic

@ pathcej_md

Jennifer Boland Froemming, M.D.

Consultant, Anatomic Pathology
Mayo Clinic

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


A man in his 70s presented with persistent leukocytosis, thrombocytopenia, anemia, and splenomegaly. The findings of the laboratory workup are outlined in the table and figure below.

Figure 1: Table
Figure 2: Figure

What is the best diagnosis?

  • Chronic neutrophilic leukemia
  • Chronic myelomonocytic leukemia
  • Chronic myeloid leukemia, BCR-ABL1-positive
  • Atypical chronic myeloid leukemia, BCR-ABL1-negative

The correct answer is ...

The correct answer is: Atypical chronic myeloid leukemia, BCR-ABL1-negative.

Atypical chronic myeloid leukemia (CML), BCR-ABL1-negative, is categorized under myelodysplastic/myeloproliferative neoplasms in the current World Health Organization (WHO) classification. The typical clinical presentation is a combination of leukocytosis, anemia, thrombocytopenia, and splenomegaly in the seventh or eighth decade of life. It is characterized by an aggressive clinical course, with leukemic transformation in a subset of patients.

On microscopic examination, the peripheral blood leukocytosis is due to an increase of neutrophils as well as granulocyte precursors (promyelocytes, myelocytes, and metamyelocytes) that comprise ≥10% of the leukocytes. By definition, blasts constitute less than 20% of peripheral blood and bone marrow cellularity. Myelodysplasia is most prominent in the granulocytic lineage, manifesting as hypersegmented nuclei with clumped chromatin or cytoplasmic hypogranularity (subtle but present in this case) among other morphologies. However, dyserythropoiesis and dysmegakaryopoiesis also may be seen. The latter is exemplified in this case by a mixture of hypogranular and large/oblong platelets, indicated by the blue arrows in the figure, in addition to the small and hypolobated megakaryocytes and megakaryocytes with abnormally disjointed nuclei in the patient’s bone marrow. The bone marrow is typically hypercellular, with an increased myeloid-to-erythroid ratio frequently exceeding 10:1.

Per WHO diagnostic criteria, BCR-ABL1 fusion is not present. Similarly, cases with rearrangements of PDGFRAPDGFRB or FGFR1, or PCM1-JAK2 are not included within the category of atypical CML, BCR-ABL1-negative. In this case, fluorescence in situ hybridization was utilized to rule out CHIC2 deletion as a surrogate for the cytogenetically cryptic FIP1L1-PDGFRA fusion. The most common karyotypic abnormalities in this entity are trisomy 8 and deletion 20q.   

In contrast to atypical CML, BCR-ABL1-negative; CML, BCR-ABL1-positive is a myeloproliferative neoplasm characterized by t(9;22)(q34.1;q11.2), leading to the formation of the Philadelphia chromosome. The latter entity is relatively more common and lacks significant granulocytic dysplasia. Chronic neutrophilic leukemia is another myeloproliferative neoplasm that is devoid of significant granulocytic dysplasia. It is characterized by <10% immature myeloid cells in the peripheral blood, unlike atypical CML, BCR-ABL1-negative. Chronic myelomonocytic leukemia (CMML) is another condition in the differential diagnosis. Persistent monocytosis in the peripheral blood (≥1 x 109/L, comprising 10% or more of the leukocytes) is an important feature of CMML, and is used to distinguish it from CML, BCR-ABL1-negative.


  1. Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: International Agency for Research on Cancer; 2017.
  2. Schwartz LC, Mascarenhas J. Current and evolving understanding of atypical chronic myeloid leukemia. Blood Rev. 2019;33:74-81.
  3. Sadigh S, Hasserjian RP, Hobbs G. Distinguishing atypical chronic myeloid leukemia from other Philadelphia-negative chronic myeloproliferative neoplasms. Curr Opin Hematol. 2020;27:122-127. 
Photo of Burak Tekin, M.D.

Burak Tekin, M.D.

Resident, Anatomic and Clinical Pathology
Mayo Clinic

Adam Wood, D.O., M.S.

Consultant, Hematopathology
Mayo Clinic

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

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