Take a closer look at the cases that will be discussed at this year's conference. Here you'll find the Case History of each with links to their biopsies.
L. Priya Kunju / GU Pathology
Andy Sciallis / Breast Pathology
Henry Appelman / Gastrointestinal Pathology
Sara Abbott / Breast Pathology
Karen Choi / Gastrointestinal Pathology
Carol Farver / Thoracic Pathology
Richard Cantley / Cytopathology
Kristine Konopka / Thoracic Pathology
Sarah Choi / Hematopathology
Scott Bresler / Dermatopathology
Daniel Boyer / Hematopathology
Paul Harms / Dermatopathology
DIAGNOSIS: Adjacent, clonally distinct borderline melanocytic tumors
Tumor 2: At her 12-month follow-up visit, the dermatologist noticed another lesion in proximity to the excision scar, of uncertain duration. Shave biopsy was obtained.
Tumor 2: At low magnification, the shave biopsy demonstrated an asymmetric, inflamed predominantly dermal melanocytic proliferation extending to margins. Lesional melanocytes displayed a spitzoid morphology characterized by large spindled to epithelioid cells with abundant amphophilic cytoplasm. Marked cytologic atypia was present in the form of pleomorphism and hyperchromasia. A rare dermal mitotic figure was identified. No aberrancy was identified by HMB45, p16, and Ki67/MART1 immunohistochemistry. The findings raised a differential diagnosis of inflamed atypical Spitz nevus, atypical Spitz tumor, spitzoid melanoma, or a satellite metastasis from Tumor #1.
Melanomas display chromosomal instability, resulting in the presence of multiple segmental chromosomal gains and losses in the majority of cases. In addition, melanomas may display specific oncogene amplification events (RREB1, CCND1, MYC) or tumor suppressor losses (homozygous CDKN2A deletion) not observed in nevi. In contrast, nevi demonstrate few or no chromosomal numerical abnormalities. Molecular tests for melanoma diagnosis have hence predominantly focused on chromosomal copy aberrations, either genome-wide by array comparative genomic hybridization (aCGH)/SNP analysis, or changes specific to melanoma by fluorescence in situ hybridization (FISH). Molecular risk stratification has been further refined in atypical Spitz tumors (ASTs), which are indeterminate melanocytic proliferations sharing features of Spitz nevi and spitzoid melanoma. In ASTs, homozygous CDKN2A deletion and TERT promoter mutation have been associated with an aggressive course; gains in RREB1 or CCND1 are also associated with risk of adverse outcome. Based on the results of molecular analysis, challenging melanocytic tumors may be classified as low/no risk (similar to nevi) or high risk (similar to melanoma). However, molecular results must always be considered in the context of clinical, microscopic, and immunohistochemical features of a lesion.
In addition to risk stratification, our case also demonstrates a second utility for molecular analysis: evaluation of tumor clonality for staging purposes. In melanoma, primary-metastasis pairs demonstrate shared chromosomal copy number changes in the majority of cases. When present, NRAS mutation is also shared between primary and metastasis in 92% or more of cases. Likewise, BRAF mutations are also shared in the majority of cases, although the exact frequency has been debated. This evidence suggests that aCGH/SNP analysis may be useful in evaluating the likelihood that two melanocytic lesions are related.
Riccardo Valdez / Hematopathology
Diagnosis: Atypical Chronic Myeloid Leukemia
Microscopic Description and Ancillary Testing
The peripheral blood smear revealed a granulocytic left-shift with 2% circulating blasts and occasional nucleated red blood cells. Blasts with Auer rods were not found. Dysgranulopoiesis and thrombocytopenia with few hypogranular platelets were present.
The bone core biopsy was nearly 100% cellular due to a prominent myeloid expansion. The aspirate smears confirmed an increased myeloid to erythroid ratio and showed a myeloid left-shift without an increase in blasts. Dysmorphic changes were found in all three cell lines, including dyserythropoiesis with few ringed sideroblasts, and notably, prominent dysgranulopoiesis. Conventional cytogenetics revealed the following karyotype: 46,XY,del(20)(q11.2q13.3)/46,XY. Interphase fluorescence in-situ hydridization (FISH) showed no abnormalities of BCR/ABL1, PDGFRA/FIP1L1, PDGFRB, or FGFR1. Molecular testing was negative for mutations in JAK2 V617F, JAK2 exon 12, MPL, and CALR. Next-generation sequencing revealed a gain-of-function mutation in SRSF2 and loss-of-function mutation in ASXL1.
There is a paucity of epidemiological data on aCML. The incidence is estimated to be approximately 1–2% of BCR-ABL1-positive CML, with a median survival of 15 months (range 12.4–37 months). The median age at diagnosis is in the sixth and seventh decade of life with several studies demonstrating a slight male predominance. In the largest series of WHO-defined aCML, shorter survival was associated with older age (>65 years), female gender, leukocytosis >50 K/uL, and the presence of circulating precursors. The natural history of aCML is characterized by increasing leukemic cell burden, organomegaly, anemia, and bone marrow failure with transformation to acute myeloid leukemia (AML) in 30–40% of cases.
The following are the current WHO-defined diagnostic criteria for atypical CML:
These diagnostic criteria help distinguish aCML from other entities in the differential diagnosis, which should include a leukemoid reaction in addition to the neoplastic entities listed above. The minimal absolute monocytosis and presence of >10% immature myeloid cells with dysplasia in aCML helps to distinguish aCML from CMML and CNL, respectively.
As noted above, the diagnostic evaluation of patients with suspected aCML should include conventional cytogenetics (karyotype), fluorescence in situ hybridization (FISH), and mutational analysis. The frequency of chromosomal abnormalities in aCML is widely variable, ranging from 20-88% in several series. Recurrent karyotypic abnormalities include aneuploidy in one third of patients. Trisomy 8 is most commonly found, but loss of chromosomes 5 and 7, del (20q), and isochromosome i(17)(q10) may also be seen. Driver mutations associated with MPNs (including mutated JAK2, CALR, and MPL) are typically absent in the MDS/MPN disorders, with the exception of JAK2V617F which has been reported in approximately 4–8% of aCML cases. Given the low incidence, JAK2V617F is unlikely to be a driver mutation in the pathogenesis of aCML. The largest category of somatically mutated genes in MDS/MPN, especially in aCML, are mutations that activate signaling pathways and likely drive pathogenesis. The earliest mutations identified were those involving RAS (KRAS and NRAS), which mediate the MAP kinase signaling cascade, and are seen in about 10–30% of patients with aCML.
Technologic advances in mutational profiling and next-generation sequencing have begun to reveal several molecular distinctions further differentiating aCML from its MDS/MPN overlap and MPN counterparts. The molecular fingerprint of aCML appears to be heterogeneous, including recurrent somatic mutations affecting genes involved in growth factor signaling and epigenetic regulation of DNA methylation and histone modification. The most common mutations detected in aCML include ASXL1 (20–70%), SETBP1 (25–30%), and TET2 (43%). SETBP1 mutations show a preference for MDS/MPN overlap syndromes, especially those with del(20q), −7, and iso-chromosome i(17)(q10) abnormalities, suggesting its use as a biomarker for these syndromes. There is a strong correlation of mutated SETBP1 with mutations involving ASXL1 (a histone modification gene), suggesting a potential cooperative role in leukemic progression in aCML. Multiple studies have shown that mutated SETBP1 is associated with a more adverse clinical profile (higher WBC count, lower hemoglobin level, thrombocytopenia) and overall worse prognosis in both aCML and CMML patients, perhaps indicating this mutation is not only relevant to leukemogenesis but also an important prognostic factor for clinical decision making in these diseases. A high frequency of SRSF2 mutations (40%) was reported among a cohort of 60 patients with aCML, while its frequency has been reported variably in other studies. SRSF2 mutation appears more frequently associated with ASXL1 and SETBP1 mutations in aCML as compared to other MPN/MDS entities, including CMML. Mutations in the granulocyte-colony stimulating factor 3 receptor (CSF3R), an important cellular signaling pathway oncogene, are mostly associated with chronic neutrophilic leukemia, but also rarely present in aCML (less than 10%). Mutations in ETNK1 (ethanolamine kinase 1) have been recently described in approximately 9% of aCML patients. These mutations are less commonly found in closely related clonal diseases such as CMML, and absent in healthy donors, MPN, and MDS/MPN overlap syndromes. This recurrent somatic mutation has never before been reported in cancer and its mutated locus is highly conserved across many species suggesting a critical, yet unknown, functional role in the pathogenesis of aCML. The presence of this molecular heterogeneity may provide pathogenetic insight and a rationale for development of novel therapeutic agents against these targets in patients with aCML.
There is currently no standard of care for the treatment of aCML. The challenges in the management of this relatively rare MDS/MPN stem from its heterogeneous clinical and genetic features, high rate of transformation to AML, and absence of sufficient randomized clinical trial data to support treatment recommendations. As with other MDS/MPN entities, participation in therapeutic clinical trials whenever possible is recommended given the absence of established treatment guidelines. When clinical trials are unavailable, the current treatment approach incorporates current strategies used for MDS and MPN including use of hematopoietic stem cell transplantation, conventional chemotherapy, and adjunctive agents for disease cytoreduction.
Several experimental targeted therapies have emerged based on insights from NGS data. Given the poor prognosis of aCML, eligibility for allogeneic HSCT should be one of the first considerations in the treatment algorithm as this is the only potentially curative treatment strategy for this disease. Current data supporting the use of HSCT remains extremely limited due to the low disease incidence. Until recently, most of this data was based on series of patients with heterogeneous MDS/MPNs showing overall survival (OS) and disease free-survival (DFS) rates at 2–5 years of 42–47%, and 37–52%, respectively. For those ineligible for HSCT or clinical trials, or those in need of immediate treatment from highly symptomatic disease (e.g. leukocytosis, anemia, splenomegaly, constitutional symptoms), strategies used previously in MDS and/or MPN hydroxyurea, interferon-alpha, erythropoiesis stimulating agents, and hypomethylating agents (e.g. azacitidine and decitibine), have been adopted to induce palliative disease cytoreduction in aCML. The most commonly administered adjunct therapy is hydroxyurea typically utilized to control leukocytosis or symptomatic splenomegaly. There have been multiple reports of both hydroxyurea and IFN-α inducing complete and partial hematologic response in aCML; however, the duration of response is usually limited to months.
Angela Wu / GU Pathology
Drew Pratt / Neuropathology
Jiaqi Shi / GI Pathology
Kathleen Cho / Gynecologic Pathology
Julia Dahl / Gynecologic Pathology
Andy Sciallis / Gynecologic Pathology
Stephanie Skala / Gynecologic Pathology
Robert H. Young / Gynecologic Pathology
Sara Abbott & Andy Sciallis / Breast Pathology
Case 1 / Clinical History: 51F with a right breast mass.
Jeffrey Myers / Thoracic Pathology
Case 1 / Clinical History: Pre-operative diagnosis: Cancer of bronchus right upper lobe.
Case 2 / Clinical History: A 68-year-old woman was referred for ongoing care for stage IIIB (cT4 N3 MO) lung adenocarcinoma. Her story began in January 2016 when a CT scan of her chest showed a 3.2 cm right upper lobe lung mass with tracheal invasion. A core needle biopsy showed a TTF-1 positive adenocarcinoma. She underwent concurrent chemoradiation resulting in a partial response (RUL mass reduced to 1.8 cm with no adenopathy). Follow-up CT at 2 years was stable showing no significant change. Follow-up PET/CT scan performed 5 months later showed an FDG-avid enlarging RUL mass (4.7 cm) and an FDG-avid LUL nodule. Biopsy of her RUL mass (slide A) showed only apical cap and was negative for malignancy. Repeat PET/CT scan 3 months later (January 2019) showed interval progression of her right apical opacity for which she underwent wedge resection (slide B).
Case 3 / Clinical History: A 66-year-old man with radiologic findings consistent with interstitial lung disease. His past medical history is significant for right-sided spontaneous pneumothorax in December 2018 for which he underwent VATS with blebectomy and talc pleurodesis. He also has a history of tobacco abuse. On physical examination, his lungs were described as clear to auscultation. A CT scan of his chest reported, "Findings consistent with chronic interstitial lung disease with bilateral bulla and peripheral honeycombing in both lung bases."
Case 4 / Clinical History: A 44-year-old man presented with abdominal pain, weight loss, and abdominal distention. His past medical history includes no previous malignancies. A CT scan of his chest, abdomen and pelvis showed adenopathy throughout with omental caking and a small right pleural effusion. He had no masses in his organs.
Case 5 / Clinical History: A 31-year-old woman presented with exertional dyspnea. Her past medical history is most significant for common variable immunodeficiency (CVID), managed with IVIG. She is a former smoker. A CT scan of her chest performed with contrast was described as showing "patchy interstitial alveolar nodular type infiltrates" and splenomegaly.
Case 6 / Clinical History: A 42-year-old woman presented for ongoing management of multiple lung nodules. Her past medical history is significant for previous resections of histologically similar tumors from her uterus and elsewhere for which she carried a diagnosis of a leiomyoma with disseminated leiomyomatosis. Others had proposed a diagnosis of metastatic low-grade leiomyosarcoma. Her oncologist was requesting comprehensive molecular profiling of her lung tumors.
Case 7 / Clinical History: A 78-year-old man presented with new-onset seizures and was discovered to have clinical stage IV lung cancer with brain metastases. A CT scan of his chest showed a 4.4 cm spiculated lesion in his right upper lobe and 1.1 cm. spiculated nodule in his left upper lobe.
Case 8 / Clinical History: A 55-year-old woman initially presented in February of this year with increasing shortness of breath. She was diagnosed with interstitial lung disease for which she was started on steroids. Serologic studies were negative for connective tissue disease-associated markers. Her symptoms progress and were not relieved by supplemental oxygen. Her chest x-ray and CT scan confirmed extensive chronic interstitial lung disease with marked progression.
Scott Owens / GI Pathology
Case 1 / Clinical History: 42-year-old man with a history of fatigue, hepatitis C, elevated liver enzymes, and a liver lesion.
Case 2 / Clinical History: 62-year-old man with multiple polyps found on screening colonoscopy.
Case 3 / Clinical History: 55-year-old man with abnormal MRI findings in the abdomen, suggestive of “mesenteric panniculitis”. Patchy abnormalities found in jejunal mucosa on endoscopy.
Case 4 / Clinical History: 61-year-old man with rectal polyp found on screening endoscopy.
Case 5 / Clinical History: 40-year-old woman with chronic diarrhea and an endoscopically normal colon.
Case 6 / Clinical History: 41-year-old woman with diabetes and gastroparesis, found to have elevated liver enzymes (AST 156, ALT 206, alkaline phosphatase 442). Weakly positive ANA.
Case 7 / Clinical History: 54-year-old woman with a rectal mass.
Case 8 / Clinical History: 69-year-old man with a history of prostate cancer and obstructive jaundice found to have a mass around the bile duct.
Case 9 / Clinical History: 66-year-old man with abnormal CT findings in the GI tract. There were ulcers in the cecum and at the splenic flexure. Past history of a lung transplant.
Case 10 / Clinical History: 83-year-old woman who presented with gastric outlet obstruction. An antral mass was found and resected. This is a regional lymph node from that resection.
Case 11 / Clinical History: 80-year-old man with gastric resection for an invasive adenocarcinoma found in a polyp in the gastric body. These sections are from the stomach around the polypectomy site.
Case 12 / Clinical History: 90-year-old woman with a “slowly growing anal polyp.”
Case 13 / Clinical History: 59-year-old man with vague right lower quadrant and pelvic pain, cramping, diarrhea, weight loss, and anemia. Abdominal lymphadenopathy and splenomegaly were seen on CT scan and the duodenum appeared “inflamed” on endoscopy.
Case 14 / Clinical History: 53-year-old woman with a history of colon polyps and perianal inflammation. Rectal biopsy.
Douglas Fullen / Dermatopathology
Cutaneous Adnexal Tumor Case Histories
Case 1 / Clinical History: 42 y.o. female with papule on her nose. DDx: R/O BCC
Case 2 / Clinical History: Nodule on the flank of a 63 y.o. man. DDx: Cyst, R/O malignancy
Case 3 / Clinical History: Nodule on the eyelid of a 65 y.o. female. DDx: Cyst vs Neoplasm
Case 4 / Clinical History: Nodule on the cheek of a 55 y.o. male. DDx: R/ONMSC
Case 5 / Clinical History: Lesion on the cheek of a 42 y.o. female. DDx: SK, R/O BCC
Case 6 / Clinical History: Tumor on the trunk of a 75 y.o. female. DDx: BCC vs SCC vs other
Case 7 / Clinical History: Yellowish papueon the left cheek of a 59 y.o. male. DDx: Sebaceous hyperplasia vs sebaceous neoplasm vs BCC vs nevus
Case 8 / Clinical History: Nodule on the finger of a 47 y.o. male. DDx: NUB, cyst
Case 9 / Clinical History: Scalp tumor nodule in a 77 y.o. woman. No prior history of cancer. DDx: R/O malignancy
Case 10 / Clinical History: Long-standing nodule on the scalp of a 38 y.o. male. DDx: R/O neoplasm or cyst.
Lauren Smith & Anamarija Perry / Hematopathology
Case 1 / Clinical History: 23-year-old male with cervical lymphadenopathy
Case 2 / Clinical History: 31-year-old male with cervical lymphadenopathy
Case 3 / Clinical History: 34-year-old male with an axillary mass
Case 4 / Clinical History: 23-year-old male with inguinal lymphadenopathy
Case 5 / Clinical History: 3-year-old female with cervical lymphadenopathy
Case 6 / Clinical History: 67-year-old male with diffuse lymphadenopathy and pancytopenia
Case 7 / Clinical History: 31-year-old male with nasal mass
Case 8 / Clinical History: 68-year-old female with axillary lymphadenopathy
Case 9 / Clinical History: 55-year-old female with diffuse lymphadenopathy
Case 10 / Clinical History: 82-year-old male with hepatosplenomegaly and pancytopenia; splenectomy performed
Case 11 / Clinical History: 59-year-old female with cervical lymphadenopathy
Case 12 / Clinical History: 80-year-old male with inguinal lymphadenopathy
Case 13 / Clinical History: 58-year-old female with a mediastinal mass
Tao Huang / GYN Pathology
Case 1 / Clinical History: A 56-year-old woman presented with a left ovarian mass. On gross examination, the left ovary measures 13.5 cm and is multicystic with multiple papillary excrescences on the surface and cyst lining.
H&E slides: A-Representative section of left ovarian mass B-Section of the uterine serosa C-Biopsy of peritoneum D-Biopsy of pelvic lymph node
Case 2 / Clinical History: 58-year-old woman presented with right-sided abdominal pain. A CT scan revealed a right adnexal complex cystic mass measuring 9.4 cm. She underwent TAH, BSO, pelvic and para-aortic lymphadenectomy, omentectomy, and implant biopsies.
H&E slides: A-Representative section of right ovarian mass (frozen section control) B-Representative section of right ovarian mass C-Section of uterine serosa D-GBiopsies of implants H-J Representative sections of omentum K-Section of the right fallopian tube L-Biopsy of pelvic lymph node
Case 3 / Clinical History: 57-year-old woman presented with increasing abdominal pain and MRI demonstrated a complex left ovarian complex cystic mass measuring 11 cm. She underwent TAH, BSO, pelvic and para-aortic lymphadenectomy, omentectomy.
H&E slides: A-B: Representative sections of the left ovarian mass
Case 4 / Clinical History: 49-year-old woman presented with menorrhagia and a pelvic ultrasound demonstrated multiple large fibroids with the largest one measuring 10 cm as well as a 6.5 cm right ovarian cyst. She underwent TAH and BSO. Intraoperatively, an enlarged, irregular, 20-week size uterus with normal ovaries and fallopian tubes wasnoted.
H&E slides: A-Section of the left fallopian tube and ovary B-Section of the right fallopian tube and ovary C-Additional section of the right ovary
Case 5 / Clinical history: A 63-year-old woman presented with a pelvic mass and underwent TAH/BSO with a tumor staging procedure
H&E slides: A-Representative section of the pelvic mass
Case 6 / Clinical History: 36-year-old woman underwent TAH for abdominal/pelvic pain and menorrhagia. She continued to have abdominal/pelvic pain after TAH. Two years later, she underwent a diagnostic laparoscopy, lysis of adhesions, and peritoneal biopsies. Intraoperatively, numerous peritoneal implants were found, for which pathology showed low-grade serous neoplasm. Two months later, she underwent exploratory laparotomy, BSO, omentectomy, pelvic and para-aortic lymphadenectomy with optimal debulking to no measurable disease. Intraoperatively, the fallopian tubes and ovaries were both noted to be in situ with small surface excrescences. There were also multiple small, firm peritoneal implants in the cul-de-sac extending onto the pelvic sidewalls, rectal serosa, mesorectum, and serosal surface of the distal ileum.
H&E slides: A-Section of left ovary B-Section of left ovary C-Biopsy of pelvic implant D-Biopsy of small bowel serosal implant
Case 7 / Clinical history: 71-year-old woman presented with ascites and pelvic mass. Histologically, it is a low-grade serous carcinoma, arising from a serous borderline tumor with micropapillary architecture, involving bilateral ovaries and fallopian tubes.
H&E slides: A-Sections taken from a well-circumscribed nodule of the ovarian low-grade serous carcinoma
Case 8 / Clinical history: 46-year-old woman presented with an abdominal mass. She underwent TAH, BSO, and omentectomy. On gross examination, the bilateral ovarian surfaces show multiple implants measuring up to 3 cm. Omentum also shows multiple nodules measuring up to 7 cm.
H&E slides: A-Representative section of the ovary