Richard Judelson, MD, Wafaa Elatre, MD, MPH

Clinical History

59 year-old female who was recently diagnosed with solid papillary carcinoma of the left breast and is status post lumpectomy, adjuvant radiation and hormone therapy. Surveillance MRI identified a 2.9 cm left supraclavicular mass just below the thyroid gland, which was suspicious for lymphadenopathy vs a thyroid or parathyroid nodule. Follow up ultrasound of the head & neck confirmed an ovoid shaped, solid mass inferior to the thyroid gland which appears to be contiguous with the left thyroid and devoid of calcifications.  This mass measures 2.4 cm and is consistent with TIRADS 4. The patient subsequently underwent ultrasound-guided fine needle aspiration of the neck mass.

Cytomorphologic findings

Cellular Diff-Quik and Papanicolaou stained smears showed abundant mature squamous cells with associated bacterial organisms. Rare bland follicular cells admixed with watery and thick colloid and mixed inflammatory cells were present in the background. The cell block showed mature squamous cells, bacterial organisms and mixed inflammation.

Discussion

Suspected thyroid nodules consisting almost entirely of mature squamous epithelial cells is rare. The differential diagnosis of benign appearing squamous epithelium in the thyroid includes squamous metaplasia, thyroglossal duct cyst, thymic/lymphoepithelial/ultimobranchial body remnants, epidermoid/dermoid cysts or esophageal tissue (accidental esophageal sampling vs esophageal diverticula). Any squamous atypia should raise suspicion of a malignant entity such as papillary thyroid carcinoma with squamous changes or a metastatic squamous cell carcinoma.

Differentiating between the various benign squamous lined cystic lesions in and around the thyroid is challenging and definitive diagnosis is best reserved for excisional biopsy.

Of note, the presence of mostly bland, mature squamous epithelium associated bacteria and mixed inflammation is highly suspicious for sampling of esophageal mucosa. In such a case, recommending radiologic follow up with barium studies may be helpful to rule out the possibility of an esophageal diverticula.

Reference

Chen AL, Renshaw AA, Faquin WC, Alexander EK, Heller HT, Cibas ES. Thyroid FNA biopsies comprised of abundant, mature squamous cells can be reported as benign: A cytologic study of 18 patients with clinical correlation. Cancer Cytopathol. 2018 May;126(5):336-341. doi: 10.1002/cncy.21976. Epub 2018 Apr 10. PMID: 29634853.

CLINICAL HISTORY:

The patient is 65-year-old male with no past medical history who presented with anorexia and intermittent back and abdominal pain for few weeks. No other symptoms, such as nausea or vomiting, were reported. Physical examination did not reveal any specific findings. There was no family history of gastrointestinal diseases. The computed tomography (CT) scans showed 3.4 cm infiltrative pancreatic uncinate mass. No other masses or metastasis were observed on the scan. The patient was scheduled for endoscopy to perform endoscopic ultrasound fine-needle aspiration (EUS-FNA) to the mass.

The Diff-Quik and Pap-stained smear preparations were cellular, showing Irregularly sized and shaped cohesive cluster and singly discohesive, dispersed cells. The clusters showed uneven distribution of cells. The cells showed irregular nuclear contours, nuclear enlargement, hypochromasia and hyperchromasia, anisonucleosis (greater than 4:1 variation in diameter within a single cluster), irregular chromatin distribution, and focal vacuolated cytoplasm. Few clusters showed focal dense blue cytoplasm in Diff-Quik and blue to red dense cytplasim in Pap stain. The H&E sections from cell block showed clusters with dense pink cytoplasm intimately associated with disorganized angulated glands and single cells in desmoplastic and myxoid stroma. The cells in H&E show similar cytomorphologic findings to smear preparations.

The initial differential diagnosis was pancreatic ductal adenocarcinoma (PDAC) & its variants/subtypes, reactive/reparative atypia, chronic pancreatitis, radiation changes, and metastatic carcinoma.

Immunohistochemical stains were performed and showed positive for CK7, p63 (focal, see fig 5), and CK20 (rare cells). The cells were negative for TTF-1, SATB2, and CDX2.

Diagnosis:

The histomorphology and immunohistochemical findings fit Adenocarcinoma with focal area of squamous differentiation consistent with adenosquamous carcinoma of the pancreas.

The patient underwent pancreaticoduodenectomy (Whipple procedure). The resection showed similar histology to cell block H&E and was ultimately diagnosed as Adenosquamous carcinoma of the pancreas.

Discussion:

Pancreatic adenosquamous carcinoma is a rare aggressive subtype of ductal adenocarcinoma and accounts for 1-4% of all exocrine malignancies of the pancreas. Also referred to as mucoepidermoid carcinoma and adenoacanthoma in older literature, adenosquamous carcinoma demonstrates both malignant squamous cell and glandular differentiation. In surgical pathology and per WHO 5ed, the squamous component arbitrarily should account for ≥ 30% of the neoplasm in order for it to qualify as adenosquamous. Squamous metaplasia of the pancreatic ductal epithelium occurs most commonly in the setting of chronic pancreatitis but is noted in the adjacent ducts of only about 4% of adenocarcinomas. Squamous metaplasia of pre-existing adenocarcinoma has been suggested by some authors as a mechanism underlying the histogenesis of pancreatic adenosquamous carcinoma. Making a diagnosis of adenosquamous carcinoma on fine needle aspiration before surgery can be difficult and it is possible when aspirates show evidence of both squamous and glandular differentiation. Adenosquamous carcinoma also may represent a metastasis to the pancreas arising from lung, colon, esophagus, salivary glands, and female reproductive organs. Pure squamous cell carcinomas of pancreas are exceedingly rare and findings of malignant squamous cells in FNA should prompt the pathologist to search for glandular differentiation for adenosquamous carcinoma. The adenosquamous carcinoma could be recognized/suggested in cytology by unique cytological features that recapitulate the histology. The squamous component often expresses p63, p40, and low-molecular-weight cytokeratins. Almost all cases harbour KRAS mutations at codon 12, and they show highly enriched TP53 mutations, along with 3p loss and mutations in the RNA surveillance gene UPF1. Immunohistochemically, they show loss of p16 (CDKN2A) protein expression, loss of SMAD4 (DPC4) protein, and strong nuclear p53 immunoreactivity, which is similar to the molecular signature found in Pancreatic ductal adenocarcinomas (PDACs). Adenosquamous carcinomas appear to have a worse prognosis than pure ductal adenocarcinomas even when resected, with a median survival time of about 9 months. The presence of any squamous component in the neoplasm appears to portend a worse prognosis.

REFERENCES:

1. WHO Classification of Tumours Editorial Board. Digestive system tumours. Lyon (France): International Agency for Research on Cancer; 2019. (WHO classification of tumours series, 5th ed.; vol. 1). https://publications.iarc.fr/579.
2. Skafida E, Grammatoglou X, Glava C, Zissis D, Paschalidis N, Katsamagkou E, Firfiris N, Vasilakaki T. Adenosquamous carcinoma of the pancreas: a case report. Cases J. 2010 Feb 1;3:41. doi: 10.1186/1757-1626-3-41. PMID: 20205828; PMCID: PMC2825199.
3. Cibas ES, Ducatman BS. Cytology: Diagnostic Principles and Clinical Correlates. Philadelphia, PA: Elsevier; 2021.
4. Paramythiotis, D., Kyriakidis, F., Karlafti, E. et al. Adenosquamous carcinoma of the pancreas: two case reports and review of the literature. J Med Case Reports 16, 395 (2022). https://doi.org/10.1186/s13256-022-03610-5.
5. Aşkın OÇ, Adsay NV. Adenosquamous carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/pancreasadenosquamous.html. Accessed March 25th, 2023.

Luna Li, MD, PhD, Wafaa A. Elatre, MD, MPH

History

– 59 year old male with medical history of diabetes mellitus, hypertension, heart failure with reduced ejection fraction, and possible malignancy.

Patient found to have pleural effusion as well as possible mass in bronchus and diffuse lymphadenopathy in mediastinum.

Had diagnostic thoracentesis on 10/28/22. Diagnosis “positive for carcinoma” with unknown origin on cytology

Immunoreactivity for GATA3, CK7 and mammaglobin are in favor of a breast primary, while a urothelial cell origin cannot be entirely ruled out.

Biopsy of right bronchus intermedius mass on 11/1/2022 was performed. Pathology diagnosis was well-differentiated squamous carcinoma with an atypical immuophenotype. The cells express GATA-3 which is a marker or urothelium.

• Patient developed pericardial effusion one month later. Patient also reports cough productive of white sputum, bilateral extremities swelling x1 week, and 20 lb weight loss over 1 month with decreased appetite. His shortness of breath is aggravated by ambulation. Patient has worked in construction for many years.

•Immunohistochemical staining were performed on the cell block to further characterize the lesion. CK7, GATA3, BRST-2, and Androgen Receptor were positive on tumor cells, CK5/6 and p16 were focally positive, while CK20, Mammaglobin, S100, SOX10, Uroplakin II, Calretinin, TTF-1 and Napsin A showed negative staining on tumor cells. Special staining for Mucicarmine was essentially negative.

Molecular testing

•Tempus Labs xT 648 gene panel performed on surgical biopsy specimen Right bronchus intermedius mass.

•xT 648 gene panel focused on actionable mutations by DNA sequencing.

•PIK3CA mutation p.I102_P104delinsKS with an inframe deletion – GOF (exon 1) was identified.

Discussion

•Primary pulmonary salivary gland–type cancer is rare and comprises less than 1% of all lung tumors.

•This group of tumors derives from small salivary glands in the respiratory system and mainly include two common histological subtypes of mucoepidermoid carcinoma and adenoid cystic carcinoma.

• Like salivary duct carcinoma, pulmonary salivary gland–type carcinoma is positive for androgen receptor (AR), GATA 3 is usually positive, and most cases are also positive for GCDFP-15 (BRST-2).

•HER2/neu expression is usually seen but diffuse strong membranous staining or HER2 amplification on FISH is seen in only 25% of cases. 

A novel mutation in a pulmonary salivary-type duct carcinoma with a PIK3CA mutation was identified which could guide treatment options for this rare cancer

Clinical History

• A 69-year-old African male who presented with leg pain, chest pain radiating to the back, and recent significant weight loss.
• CT imaging showed a soft tissue mass anterior to the mid sternum (5.8 cm) and a conglomerate, ill-defined retrosternal soft tissue mass extending to involve the mid to distal sternum (6.9 cm).
• There were also numerous lytic lesions throughout spine , bilateral ribs, and scapulae.
• Imaging also reported suspicion for pathologic fracture with expansile lytic lesions and osseous destruction of multiple ribs. X-ray imaging of pelvis and hip also showed lytic lesions in right femur, left iliac wing, and pubic rami.
• PET imaging mirrored the X-ray and CT imaging findings also highlighting the cardiac involvement.
• Fine needle aspiration was performed on the anterior sternal mass.

Figure 1. The cellular smear preparation demonstrates singly dispersed and clustered large immature plasma cells with eccentric nuclei, coarse chromatin, prominent eosinophilic nucleoli, high nuclear-to-cytoplasmic ratio, and scant to moderate amounts of cytoplasm. Admixed with smaller mature plasma cells and normal blood elements (Diff-Quik, 40X).

Figure 2. The cellular smear preparation demonstrates mostly clustered immature plasma cells, coarse chromatin, prominent eosinophilic nucleoli, high nuclear-to-cytoplasmic ratio, and scant to moderate amounts of cytoplasm. At the periphery of this grouping are smaller mature plasma cells. The Pap stain highlights the prominent eosinophilic nucleoli and the granularity of the coarse chromatin (Pap stain, 40X).

Figure 3. The cell block redemonstrates features seen in the smear preparations with more variably sized plasma cells and blood elements including neutrophils (A: H&E, 10X; B: H&E, 20X).

Figure 4. Immunohistochemical studies confirm plasma cell lineage with CD138 (A) strongly positive in both the larger immature and smaller immature plasma cells (10X). Kappa (B) highlights a majority of the plasma cells (20X). While lambda (C) is positive in only a few plasma cells. CD30 (D) is completely negative as is c-Myc (not pictured) (20X).

Figure 5. The proliferation rate via Ki-67(MIB-1) within the plasma cells is exceedingly high approximating >80-90% (10X).

Discussion

The cytologic features of mostly immature plasma cells (Figures 1-3) as confirmed by ubiquitous CD138 positivity points towards a plasma cell dyscrasia (Figure 4). A high number of the plasma cells show positivity by kappa immunostaining as compared to a significantly lower number of few plasma cells showing positivity by lambda immunostaining; thereby proving kappa restriction (Figure 4). Not pictured in our treatise, but associated with plasma cell dyscrasias, are Russell bodies (hyaline cytoplasmic inclusions containing immunoglobulin) and Dutcher bodies (intranuclear cytoplasmic invaginations). Russell bodies are seen in both benign and malignant plasma cells. Yet, Dutcher bodies are more common in neoplastic plasma cells. CD30 was negative, but expression can be used to decide anti-CD30 targetability in multiple myeloma. c-Myc, which is negative, is assessed as overexpression is associated with adverse clinical outcomes. Ki-67(MIB-1) is high (Figure 5), which is indicative of the aggressive proliferation of the plasma cell neoplasm. Table 1 summarizes interpretation of the immunostains.

The final diagnosis is plasma cell dyscrasia, kappa restricted.

The clinical history combined with the cytology and the histopathology of the follow-up bone marrow biopsy are indicative of an active multiple myeloma.

The bone marrow biopsy was used for further molecular and cytogenetics testing which allowed for stratification of risk, prognosis, and treatment.

Molecular Studies/Cytogenetics

Molecular studies/cytogenetic testing from subsequent bone marrow biopsy of the same site showed the following:

Positive for IGH/FGF3 rearrangement [FISH].
Positive for IGH/CCND1 rearrangement [FISH].
Positive for 1q gain, gain of 9 and 13q deletion/monosomy 13 [FISH].
Negative for TP53 (17p13) deletion, and for rearrangements in IGH/MAF or IGH/MAFB [FISH].

Prognosis

Multiple myeloma has a poor prognosis especially with TP53(17p13) deletion (a high risk chromosomal abnormality). From diagnosis, most patients live from less than 6 months to 10 years with the median survival of 5.5 years. Prognosis is determined by the combination of two risk stratification components: genetics and revised multiple myeloma staging system. The Revised International Staging System (R-ISS) for Multiple Myeloma was devised by the International Myeloma Working group incorporating these two risk stratification components to categorize multiple myeloma patients into three (3) major stages. These were later recommended by NCCN and are standard of practice.

Stage I criteria include (1) beta-2 microglobulin ≤3.5 g/dL and albumin ≥3.5 g/dL, (2) standard risk for chromosomal abnormalities (CA), and (3) normal lactate dehydrogenase (LDH) levels. Stage II is an intermediate category for patients whose clinical and cytogenetic profile are do not meet criteria for either Stage I or Stage III. Stage III criteria include (1) having a beta-2 microglobulin ≥ 5.5 g/dL and (2) being high risk for CA or having a high LDH.

From diagnosis, most patients live from less than 6 months to 10 years with the median survival of 5.5 years. The R-ISS further stratifies this by associating each stage with a specific median progression-free survival (PFS). Patients in Stage I have a median PFS of 66 months. Median PFS for Stage II and Stage III are 42 months and 29 months, respectively. The patient is Stage II based on his beta-2 microglobulin levels and standard/intermediate risk for chromosomal abnormalities.

References

Cibas ES, Ducatman BS. Cytology: Diagnostic Principles and Clinical Correlates. Philadelphia, PA: Elsevier; 2021.

DeMay RM. The Book of Cells: A Breviary of Cytopathology. American Society of Clinical Pathology: 2016.

Callander NS, Baljevic M, et al. NCCN Guidelines® Insights: Multiple Myeloma, Version 3.2022. J Natl Compr Canc Netw. 2022;20(1):8-19.

Palumbo A, Avet-Loiseau H, et al. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol. 2015;33(26):2863-9.

Swerdlow SH, Campo E, Seto M, et al. (eds). WHO classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. International Agency for Research on Cancer: 2017.

Clinical history

• 51 years old female presented for follow up on liver lesions seen on CT scan . ​
• Patient has a complicated past medical history including, Cushing’s Disease, due to ACTH-secreting pituitary adenoma, status post transsphenoidal resection (1990), with refractory hypercortisolism, and chronic adrenal insufficiency, status post bilateral adrenalectomy, showing incidental metastatic renal cell carcinoma/ clear cell type (2011), status post left nephrectomy (2013). ​
• Patient also has a history of papillary thyroid carcinoma with pulmonary metastasis, status post total thyroidectomy (2014), with multiple following neck dissections showing metastatic PTC on (2014 & 2015) with radioiodine treatment (2016), leading to postsurgical hypothyroidism, ​
• Other medial problems include type II diabetes, hypertension, osteopenia, and seizure.

                                           Initial workup

• The previous CT scan showed a 2 cm hypoenhancing lesion at the liver dome. ​
• Following Multiphase liver CT scan with contrast showed Interval increase in size of the lesion to 22.45 mm hypodense mass in the medial hepatic dome, highly suspicious for metastatic disease in this patient with history of papillary thyroid cancer (figuer1).​
• There was also a new 14 mm hypodense in the lateral left hepatic lobe which was also suspicious for metastatic disease. The patient was referred for fine needle aspiration.

                          Fine Needle aspiration findings

• Smear preparations were cellular showing numerous singly dispersed large cells with bizarre appearing multilobulated, hyperchromatic nuclei but with variable N:C ratio, admixed with pleomorphic population of lymphocytes and granulocytes. The background consists of aggregates and small sheets of hepatocytes, macrophages, and red blood cells. The cell block is less cellular but otherwise shows similar findings (figure 2-4).

IHC Stains 

• Immunohistochemical stains were performed on the cell block and show the following results: Pancytokeratin, TTF-1 and HepPar1 were negative in the atypical cells but positive in hepatocytes. PAX8 and CD45 are negative in the atypical cells and positive in small lymphocytes. CD31 is positive in the atypical cells (figure 5 & 6).

                          Final Cytologic diagnosis

• The overall cytomorphology and Immunohistochemical pattern of staining were consistent with the presence of polymorphic lymphoid/granulocytic population and megakaryocytes.
• This may be seen in extramedullary hematopoiesis or in myelolipoma, both of which may be included in the differential diagnosis. Definitive cytologic features of malignancy are not identified.

                                        Discussion

• Hematopoiesis usually occurs in bone marrow in adults and when it occurs at sites except for bone marrow, it is known as extramedullary hematopoiesis (c). It is typically seen in organs that are vigorously involved in fetal hematopoiesis, including liver, spleen, and lymph nodes. Seldom, it has also been recognized in other sites for instance mediastinum, paraspinal/paravertebral region, adrenal, lung, pleura, gastrointestinal tract, kidney, prostate gland, breast, and so forth1.
• EMH is a compensatory mechanism that is closely related to inadequate functioning of medullary hematopoiesis, especially myeloproliferative disorders and hemolytic anemia. However, there have also been reports of EMH in cases of malignant solid tumors, including breast cancer, lung cancer, and Kaposi’s sarcoma2
• EHM is rarely presents in the liver, especially as liver mass and only very few liver nodules of EMH have been described in the literature.
• The etiology of EMH in patients with solid tumors remains unclear. Granulocyte colony-stimulating factor (G-CSF) may be an inducing factor of EMH2.
• Screening the smear at low power is crucial in such cases, as megakaryocytes are more readily seen at low power. These cells are so peculiar that they “stare at” the cytopathologists. Though megakaryocytes have distinct morphology still they can be confused with atypical cells. Therefore, awareness of their morphology is critical for the basic diagnosis1.
• Our case presented with a complicated past medical history including pituitary adenoma, metastatic renal cell carcinoma/ clear cell type and papillary thyroid carcinoma with pulmonary metastasis.
• The patients 2.2 mm liver nodule was thought to be a result of metastasis for one of the mentioned tumor. During rapid on-site evaluation, the presence of the large atypical cells on the Diff Quick stained concluded the specimen as adequate.
• Our smear and H & E slides showed numerous singly dispersed large cells with bizarre appearing multilobulated, hyperchromatic nuclei but with variable N:C ratio. These cells were the clue for the diagnosis as they showed significant similarity to Megakaryocytes seen usually in the bone marrow.
• Above finding also seemed sensible to the cells presented in the background, which included pleomorphic population of lymphocytes, and granulocytes, macrophages, and red blood cells
• Multiple sheets and singly dispersed population of bland appearing hepatocytes were also present in the background, and they look very district form the atypical cells.
• Immunohistochemical stains were performed to exclude any poorly differentiated carcinoma (Pancytokeratin), including papillary thyroid carcinoma (TTF-1), renal cell carcinoma/ clear cell type (PAX8) and primary hepatocellular carcinoma (HepPar1), and all were negative in the atypical cells. Also, (CD45 ) was performed to exclude any lymphoma (CD45) and results are also negative in the atypical cells, but positive in the background small lymphocytes.
• CD31 was the only positive stains (granular, membranous expression) in the atypical cells which confirmed our cytomorphological impression.
• It is usually unnecessary to treat asymptomatic patients with EMH, whereas there are several options for the treatment of symptomatic patients, including hydroxyurea, transfusion, radiotherapy, and surgery.(2)
• Our patient did get any further treatment for the liver lesion, as the lesion did not case any symptom.

                                             References

1.Kapatia G, Kaur A, Rastogi P, et al. Extramedullary hematopoiesis: Clinical and cytological features. Diagnostic Cytopathology. 2020;48:191–196. https:// doi.org/10.1002/dc.24353

2.Bao Y, Liu Z, Guo M, Li B, Sun X, Wang L. Extramedullary hematopoiesis secondary to malignant solid tumors: a case report and literature review. Cancer Manag Res. 2018;10:1461-1470
https://doi.org/10.2147/CMAR.S161746

 

Clinical History

• The patient is a 45 y/o gentleman with PMHx of Non-Hodgkin’s Lymphoma in remission and significant tobacco use who presented to the emergency department with 1 week of worsening abdominal pain. The abdominal pain was described as sharp and radiating to the left flank.
• Initial lab work showed hypercalcemia with CT Abdomen and Pelvis showing a 10.2 cm mass in the tail of pancreas, diffuse retroperitoneal and mesenteric lymphadenopathy, inguinal lymphadenopathy, and a 3.0 x 2.9 x 2.3 cm solid mass in the right inferior thyroid.
• At the time, the thyroid mass was favored to possible represent a possible focus of metastatic carcinoma vs nodal disease vs primary thyroid lesion.

FNA of the thyroid nodule was planned and performed.

Cytology

• The Diff-Quik and Pap-stained preparations were highly cellular, showingcohesive sheets, ribbon-like and corded structures, crowded trabeculae, and both macrofollicular- and microfollicular-like arrangements of cells with round to oval nuclei, mild anisonucleosis, granular chromatin, small and conspicuous nucleoli and moderate amounts of fine cytoplasm. There were admixed inflammatory cells, single and dispersed and naked nuclei and anucleated squamous in a bloody background. Although somewhat less cellular, the cell block showed similar findings.

• The initial differential diagnosis included a follicular neoplasm, metastatic adenocarcinoma, and sampling of the parathyroid gland.

Diagnosis

• The histomorphology and immunohistochemical findings from the left thyroid FNA best fit as hypercellular parathyroid tissue, with a differential diagnosis of hyperplasia vs neoplasm with clinical correlation required for distinction.

                                                   Discussion

Parathyroid tissue on FNA can be difficult to identify due to overlapping features with thyroid neoplasms, particularly follicular neoplasms.  Parathyroid tissue has been misdiagnosed as follicular thyroid carcinoma, papillary thyroid carcinoma, and medullary thyroid carcinoma on FNA. The sensitivity of FNA in the diagnosis of parathyroid tissue has been reported to be between 40% and 86%. The previous literature regarding FNA of the parathyroid gland has only characterized the cytomorphology on FNA smears. Characteristics such as high cellularity, the presence of naked nuclei, loose 2-dimensional clusters, and papillary architecture on FNA smears are suggestive of parathyroid tissue.

• Ultrasound has no specific findings to distinguish parathyroid, thyroid, and lymph nodes.
• Serum PTH level or hypercalcemia can be used as an important clue.
• Overall, Parathyroid FNAs show intermediate-to-high cellularity, occasional papillary fragments, tight clusters, and microfollicular patterns with numerous naked nuclei in background.
• They tend to have more stippled/hyperchromatic nuclei than thyroid follicular cells.
• Bethesda IV tends to have more prominent nucleoli.
• Anisonucleosis also tends to suggest Parathyroid as opposed to Bethesda IV.

 

References

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430501/
• https://pubmed.ncbi.nlm.nih.gov/19283690/
• Cibas, Edmund S., and Barbara S. Ducatman. Cytology: Diagnostic Principles and Clinical Correlates.Elsevier, 2021.

Clinical History

A 58-year-old male was referred to ENT clinic due to facial nerve paralysis for about 10 months. He stated that he had gradual onset of right facial paralysis about 10 months prior to presentation that was not improved. He also had noticed a mass in the right pre-auricular region 6 months before presentation that had continuously grown since. He endorsed 40lb weight loss over 6 months. On physical examination he had a 3-4cm right firm parotid mass as well as a right level II cervical lymphadenopathy. There were no pre-auricular masses or lymphadenopathy.

Initial Work Up

The neck CT scan with contrast showed a large bulky ill-defined heterogeneously enhancing mass measuring 4.7 x 4.2 x 4.2 cm, associated with the superficial lobe of the parotid gland extending medially behind the ramus of the mandible into the deep lobe of the parotid. A portion of the mass was extending to the level of the skin in the postauricular region. The mass appeared to invade the posterior aspect of the masseter muscle. The adjacent right cervical lymph nodes were pathologically enlarged.

Fine needle aspiration of the mass performed in the FNA clinic.

Cytologic Findings

Diff-Quick and Pap-stained smears showed numerous variably sized clusters and sheets of markedly atypical cells displaying pleomorphism, hyperchromatic nuclei with irregular nuclear contours, occasional conspicuous nucleoli, moderate amount of cytoplasm, and occasional well defined cellular membranes. Necrotic debris and blood elements as well as extracellular proteinaceous material were seen in the background. The cell block showed variably sized fragments of epithelial cells with well-defined cell borders, focally arranging in a microcystic to cribriform pattern. Cytoplasmic vacuoles were occasionally seen. Mitotic figures were readily identified.

Immunohistochemical staining were performed on the cell block to further characterize the lesion. CK5/6, S100, DOG1 and p63 were negative on tumor cells, while Mammaglobin, GATA3, and Androgen receptor showed positive staining. Special staining for Mucicarmine was essentially negative.

Final Cytologic diagnosis

The overall immunohistochemical pattern of staining and morphological features were consistent with a salivary duct carcinoma. Focal presence of magenta color extracellular proteinaceous material was suggestive of a carcinoma ex-pleomorphic adenoma with salivary duct carcinoma as carcinoma component, although a distinct component of pleomorphic adenoma could not be identified.

Surgical management

The patient underwent radical parotidectomy with right levels I-V modified radical neck dissection.

Surgical Pathology Findings

On parotidectomy specimen the tumor shows an infiltrative pattern consisting of island, trabeculae, and sheets of malignant cells, some forming cribriform architectures. In areas, the solid architecture contains central necrosis (comedonecrosis) resembling a high-grade ductal carcinoma in-situ of breast. The cells display high grade morphology with pleomorphism, high N:C ratio, prominent nucleoli, moderate amount of eosinophilic cytoplasm and distinct cell borders. On the resection specimen, the tumor cells were negative for CK5/6 and p63, however, they were positive for CK7, AE1/AE3 and EMA. HER2 showed a 2+ membrane staining (utilizing breast cancer grading criteria). p53 immunohistochemical staining showed a wild type pattern of expression.

Treatment

After surgery, the patient underwent 60Gy radiation therapy. At the time of this case presentation, he is under close surveillance and the plan is to consider adjuvant systemic treatment if the tumor recurs. Since the tumor is positive for androgen receptor (AR) androgen deprivation therapy is offered to him as well. If the tumor is positive for HER-2 overexpression on FISH, anti-HER2 therapy will also be considered as a potential treatment.

Discussion

Salivary duct carcinoma is a high grade malignant salivary gland tumor which constitute approximately 10% of all malignant salivary gland tumors. At least half of salivary duct carcinomas arise as carcinoma ex-pleomorphic adenoma. It usually occurs in older individuals with peak incidence in 6^th or 7^th decade and are much more common in men. The parotid gland is the most common site (80%). This tumor usually presents as a rapidly growing mass with symptoms of nerve involvement. They are usually large and show an infiltrative growth pattern with foci of necrosis resembling mammary ductal carcinoma. Regional or distant metastasis may be present at time of presentation. The patients are usually managed with radical surgery with ipsilateral neck dissection followed by adjuvant radiation therapy.

On cytology, salivary duct carcinoma presents as a cellular aspirate consisting of three-dimensional crowded and cribriform groups of cells with overt malignant features displayed as medium to large polygonal cells with well-defined cell borders and abundant eosinophilic cytoplasm. Frequent mitosis and necrotic background are usually seen. The most common high-grade tumors that are among the differential diagnosis with salivary duct carcinoma, high grade mucoepidermoid carcinoma, oncocytic carcinoma and metastatic carcinoma from the breast, prostate, or lung. To distinguish these tumors, a panel of immunohistochemical stains is usually required. Salivary duct carcinoma is positive for androgen receptor (AR), whereas expression of ER and PR is rare. GATA 3 is usually positive, and most cases are also positive for GCDFP-15. HER2/neu expression is usually seen but diffuse strong membranous staining or HER2 amplification on FISH is seen in only 25% of cases. The tumors that arise as carcinoma ex-pleomorphic adenoma may overexpress translocation proteins PLAG1 or HMGA2 and more likely to express HER2.

References

1. William C. Faquin, Esther Diana Rossi, Zubair Baloch, Güliz A. Barkan, Maria P. Foschini, Daniel F.I. Kurtycz, Marc Pusztaszeri, Philippe Vielh. The Milan System for Reporting Salivary Gland Cytopathology. Springer International Publishing AG 2018. Chapter 7. ISBN 978-3-319-71284-0.
2. Edmund S. Cibas, Barbara S. Ducatman. Diagnostic Principles and Clinical Correlates, 5th Edition. Chapter 11. ISBN 978-0-323-63636-0

 

 

 

 

 

Clinical History

The patient is a 34 year old male who presented with to the ED with a left calf mass. The patient first noticed the mass 3 years ago and it had been slowly increasing in size. Recently it had become more painful.

Physical exam demonstrated a large nontender calf mass with no overlying skin changes, induration or fluctuance. The patient was referred by MRI evaluation.

Initial Work Up

MRI of the lower extremity showed a 5.2 x 6.6 x 19.3 cm mass centered in the lateral (peroneal) muscular compartment of the left calf. The lesion abutted, but did not encircle, the anterior neurovascular bundle. The mass abutted the fibula but did not involve the osseous structures. Biopsy of the lesion was recommended for further evaluation.

The patient was sent for ultrasound guided biopsy with cytopathology at bedside for rapid on-site evaluation.

CYTOLOGY (Touch preparations of 14G core needle biopsy of the left calf mass)

The Diff-Quik stained touch preparations showed large clusters and numerous singly dispersed cells with large pleomorphic hyperchromatic nuclei, irregular nuclear contours, densely granular chromatin, prominent irregular macronucleoli and moderate to abundant amounts of vacuolated granular cytoplasm.

Many of the nuclei have no cytoplasm and are naked. The background is predominantly blood elements.

Figure 1. Touch Preparation with clusters of malignant cells with pleomorphic nuclei and abundant fragile, granular and vacuolated cytoplasm (Diff-Quik stain, 20X).

 

Figure 2. Many of the surrounding nuclei have irregular macronucleoli and are naked as the cytoplasmic contents have spilled into the background (Diff-Quik stain, 20X).

 

Figure 3. Some of the naked nuclei are markedly pleomorphic and surrounded by abundant granular disrupted cytoplasmic contents (Diff-Quik stain, 40X).

 

Figure 4. The tumor cells are arranged in aggregates which form dense trabeculae (Hematoxylin and eosin, 20X).

 

Figure 5. The tumor cells are large with distinct cell borders, ovoid nuclei, prominent nucleoli and abundant granular, eosinophilic and sometimes vacuolated cytoplasm (Hematoxylin and eosin, 40X).

 

Figure 6. TFE3 Immunohistochemistry shows strong nuclear staining in the tumor cells

The tumor cells were immunohistochemically NEGATIVE for CK AE1/AE3, EMA, Vimentin, Glypican-3, Synaptophysin, SMA, Myo D1, S100, CD34, and PAX-8. Ki67 was positive in 20% of the cells.

 

Discussion

The final diagnosis for the touch preparation was malignant cells present (correlate with the concurrent surgical pathology case for further characterization). The final diagnosis for the 14G core needle biopsy was Alveolar soft part sarcoma.

Alveolar soft part sarcoma (ASPS) is a soft tissue sarcoma with distinct clinical and morphological features which accounts for approximately 0.4% to 1.0% of all soft tissue sarcomas

Clinical Features

ASPS usually occurs in adolescents and young adults and is most common in patients between the ages of 15 and 35. The tumor commonly occurs in different anatomic sites based on age. In infants and children the most common site is the head and neck region. In adults the most common site is the lower extremities. The tumor is slow growing and presents as a painless mass. The mass lesion usually does not cause functional impairment and can be overlooked resulting in many cases where metastasis to the lung and/or brain is the first manifestation of disease.

Pathologic Findings

Grossly ASPS tends to be a soft, friable and poorly circumscribed tumor. The cut surface is usually yellow-white to gray-red. Areas of necrosis and hemorrhage are common.

Microscopically the tumor is divided into compartments by thick fibrous trabeculae. The compartments are further subdivided into aggregates of tumor cells by sinusoidal vascular channels that are lined by endothelial cells. Necrosis and loss of cohesion between tumor cells is common. The tumor

cells are usually large, round to polygonal shaped with distinct cell borders, prominent irregular macronucleoli and abundant granular, eosinophilic and sometimes vacuolated cytoplasm. Mitotic figures are uncommon. Vascular invasion is a frequent finding.

PAS histochemical staining highlights intracellular glycogen and PAS-positive, diastase-resistant rhomboid or rod shaped crystals. Immunohistochemically the tumor cells are sometimes positive for MyoD1 and desmin (~50%).

The tumor cells are generally negative for keratins, EMA, neurofilaments, GFAP, HMB-45, melan-A and synaptophysin.

Cytogenetic and Molecular Findings

ASPS has a characteristic genetic alteration, der(17)t(X;17)(p11.2q25).

This alteration results in a fusion gene, ASPSCR1-TFE3, which encodes for a fusion protein that functions as an aberrant transcription factor leading to activation of MET signaling.

Prognosis

ASPS has a poor prognosis with an overall 5-year overall survival of around 20%. Metastatic disease usually occurs early with pulmonary, brain and skeleton metastases being the most common presentations.

However, metastatic disease may also occur years later in some cases. Older age at diagnosis, large tumor size, and the presence of metastatic disease at presentation are adverse prognostic parameters.

Treatment

Treatment of ASPS usually consists of radical resection of the primary tumor and metastatic lesions in addition to radiotherapy and/or chemotherapy.

References

1.Cibas, Edmund S., and Barbara S. Ducatman. Cytology: Diagnostic Principles and Clinical Correlates. Elsevier, 2021.

2.Goldblum, John, et al. Enzinger and Weiss’s Soft Tissue Tumors. 7th ed., Elsevier, 2019.

Clinical History:

29-year-old female presented to the ED for 2-3 months of worsening lower abdominal pain. She had a lifelong history of monthly menses, previously lasting 6-7 days with moderate flow, but noticed that her periods became lighter and shorter the past 2-3 months as well. She reported a 12-pound weight loss over the last month but associated this with increased exercise. She also endorsed worsening dyspareunia, and denied abnormal vaginal discharge, constipation, blood in the stools, hematuria, nausea and vomiting.

Initial Work-Up:

CT revealed innumerable heterogeneously enhancing and centrally necrotic soft tissue masses and nodules scattered throughout the abdominal cavity and pelvis, involving the peritoneum, omentum, and left ovary, with the largest mass (10.2 x 9.3 x 8.0 cm) in the right lower quadrant adjacent to the right adnexa and possibly arising from the right ovary.

CA125 was elevated to 258 and CEA, CA19-9, AFP, estradiol, and testosterone were within normal limits. An endometrial biopsy (EMB) and pap were performed. The EMB showed benign proliferative endometrium and PAP was negative for intraepithelial lesion.

The patient then underwent ultrasound-guided biopsy of the right adnexal mass with adequacy evaluation performed by cytopathology at time of the procedure.

Cytology (touch preparations of the right adnexal mass core biopsy):

The Diff-Quik stained preparations showed a relatively monotonous population of moderately atypical cells with eccentric nuclei with increased nuclear to cytoplasmic ratios, occasional prominent nucleoli, smooth nuclear contours, and finely vacuolated cytoplasm, occurring singly and in few loosely cohesive groups (Fig. 1-3). Occasional binucleated forms were identified. In the background were numerous mixed inflammatory cells.

The touch preparation was called adequate with lesional cells present at time of procedure.

Figure 1: Diff Quik stained touch preparation showing numerous plasmacytoid cells (100x).

Figure 2: Diff-Quik stained touch preparation showing cells with eccentric nuclei, increased N:C ratio, and occasional prominent nucleoli occurring singly (400x).

Figure 3: Diff-Quik stained touch preparation showing loosely cohesive group of cells with mild anisonucleosis and smooth nuclear contours (400x).

Figure 4: Core biopsy showing tumor cells arranged in nests and trabeculae (100x).

Figure 5: Core biopsy (400x)

Figure 6: CD117 (200x)

Figure 7: DOG1 (200x)

Core biopsy of right adnexal mass:

The core biopsy showed monotonous plasmacytoid cells with minimal pleomorphism, increased N:C ratios, and dense to flocculant cytoplasm, organized in nests and trabeculae (Fig. 4,5). Several mitotic figures were identified.

Diagnostic considerations included PEComa, ovarian sex cord or germ cell tumor, renal tumor, and lymphoma; however, PanCK, HMB45, S-100, PAX-8, CD45, Inhibin, SALL-4, and OCT-4 were negative. The tumor was also negative for desmin, synaptophysin, chromogranin, calretinin and p63. SMA was focally weakly positive, and Vimentin was positive. At this point, a gastrointestinal stromal tumor entered the differential, and the tumor showed positive expression for CD34, CD117 (Fig. 6), and DOG1 (Fig.7).

The case was signed out as predominantly epithelioid gastrointestinal stromal tumor.

Given the clinically malignant behavior of the tumor, the final touch preparation diagnosis was malignant cells present (correlate with the surgical pathology report for definitive characterization).

Patient Follow-Up:

The primary site remained indeterminant. The patient was re-admitted a couple months after initial presentation with imaging showing progression of disease. SDH mutational testing was requested and is pending.

Discussion:

Gastrointestinal stromal tumors (GISTs) are uncommon tumors of the GI tract that originate from the interstitial cells of Cajal, with a median age at presentation of 65 years. They typically arise in the stomach (56%), small bowel (32%), and colon and rectum (6%). Rarely, extra-gastrointestinal GIST can arise in the omentum, mesentery, retroperitoneum or pleura. Majority have activating mutations of c-kit. Those arising in younger individuals may  contain mutations in one of the subunits of SDH, which can be seen in the setting of Carney Triad and Carney-Stratakis syndrome.

GISTs have three main histologic subtypes: spindled (most common), epithelioid, or mixed.  The cytology generally shows spindled to epithelioid cells with bland chromatin and wispy cytoplasm arranged as large, crowded clusters of cells or occurring singly. Some cells may show perinuclear vacuoles (especially in gastric GISTs) . Definitive diagnosis is aided by IHC stains: about 95% show expression of CD117 and 88% show expression of DOG-1. SMA is generally negative but can be positive. S100 is negative. In SDH deficient GISTs, there is loss of SDHB expression.

Up to 40% of small intestinal GISTs and 25% of gastric GISTs behave malignantly. Prognosis depends on tumor size, site of origin, mitotic rate and presence or absence of intraoperative tumor rupture. Treatment generally entails surgical resection with tyrosine kinase inhibitors indicated in metastatic/recurrent GISTs.

References:

• Bell P, Findeis-Hosey J. GIST. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stomachGIST.html. Accessed March 4th, 2021.
• Cibas ES, Ducatman BS. Cytology: Diagnostic Principles and Clinical Correlates. Fifth Edition.
• Trisha M. Parab, et. Al. Gastrointestinal stromal tumors: a comprehensive review. Journal of Gastrointestinal Oncology. 2019; 10(1):144-154. doi: 10.21037/jgo.2018.08.20

• 56-year-old male with past medical history of Diabetes Mellitus, T2a cutaneous T cell lymphoma/mycosis fungoides, and stage III clear cell renal cell carcinoma status-post left nephrectomy in December 2018. Pathology report of the nephrectomy specimen revealed an 8 cm mass with clear cell renal cell carcinoma, histologic grade 4 with about 10% sarcomatoid features. Thyroid ultrasound showed mixed cystic and solid, isoechoic nodule measuring up to 1.5 cm (TIRADS 4).
• Ultrasound-guided fine needle aspiration of right thyroid nodule was performed.
• Diff-Quik preparation and pap stained smears showed pauci-cellular specimen with rare bland thyroid follicular cells arranged singly and in small groups with Hurthle cell changes, in a background of scant colloid, few macrophages, blood cells and debris. No malignant cells identified in the smears.
• Cell Block: showed two group of cells with irregular nuclei, prominent nucleoli, eosinophilic cytoplasm and cytoplasmic clearing.
• Cell Block: showed two group of cells with irregular nuclei, prominent nucleoli, eosinophilic cytoplasm and cytoplasmic clearing.
• Cell Block: showed two group of cells with irregular nuclei, prominent nucleoli, eosinophilic cytoplasm and cytoplasmic clearing.Positive RCC, CD10 and vimentin staining: compatible with RCC origin
  • • Negative staining for TTF1 (specific stain for primary thyroid carcinomas and negative in metastatic RCC)
      

                        Discussion

      Clear cell renal cell carcinoma comprises 75%-80% of all RCCs and is strongly associated with a variety of deletions on chromosome 3p, the site for VHL gene. Size is not a determinant of malignancy, but the frequency of metastases does correlate with increasing size of the primary tumor. Cytomorphologic features of clear cell renal cell carcinoma include: large cohesive cell groups, abundant wispy cytoplasm with ill-defined edges, cytoplasmic vacuoles, large, round, eccentrically placed nucleus, nucleoli (vary in size depending on WHO/ISUP grade), and blood.

      Despite its robust vascularity, metastases to the thyroid gland only account for a small proportion of benign and malignant thyroid entities diagnosed. The possibility of metastasis should be considered whenever the cytologic picture does not conform with common thyroid neoplasms or the patient has a history of cancer elsewhere in the body.

      Definitive diagnosis of metastatic RCC to the thyroid can only be confirmed by immunohistochemical staining and histologic examination. FNA with ultrasound guidance is the most common approach. FNA sensitivity and specificity for diagnosing metastases to the thyroid have been reported to be as high as 94% and 100%.

      When a metastasis is suspected, comparing the aspirated specimen to previous histologic or cytologic material is very helpful, as is immunohistochemistry. Immunohistochemical staining for markers specific to RCC are utilized including CD10, vimentin, cytokeratin 7, and renal cell carcinoma marker. It is also helpful to use staining markers for thyroglobulin, calcitonin, and thyroid transcription factor 1 (TTF-1), which are specific to primary thyroid carcinomas and negative with metastatic RCC.

                   References

  • Cibas ES, Ducatman BS. Cytology: Diagnostic Principles and Clinical Correlates. Fifth Edition.
  • Thomas Rand Geisbush, Zaneta Dymon, Medhat Sam Gabriel, and Vivek Yedavalli. A Multimodal and Pathological Analysis of a Renal Cell Carcinoma Metastasis to the Thyroid Gland 11 Years Post Nephrectomy. J Radiol Case Rep. 2019 Apr; 13(4): 1–9.Published online 2019 Apr 30. doi: 10.3941/jrcr.v13i4.3497