Clinical Presentation:

An 82-year-old male patient arrived at the emergency department with shortness of breath, a dry cough that improved with rest, and swelling of his left leg. A CT pulmonary angiography was performed to rule out pulmonary embolism, revealing no signs of thrombosis; however, bilateral pleural effusions were detected. Additionally, a CT scan of the abdomen and pelvis was performed, but no tumor mass was found. The clinicians performed a therapeutic pleural puncture and sent the pleural fluid for cytological analysis.

A cytological smear was prepared from the pleural fluid sediment. Microscopic examination revealed numerous large atypical lymphoid cells with irregular nuclear contours, prominent nucleoli, and abundant basophilic cytoplasm. Some cells displayed plasmacytoid features with occasional vacuolization.

Highly cellular pleural fluid sediments showed large atypical lymphoid cells with prominent nucleoli and abundant cytoplasm.

High magnification view highlighting plasmacytoid morphology and mitotic activity.

Prominent nucleoli, abundant basophilic cytoplasm.

Cytoplasmic vacuoles, multinucleation.

A cell block was prepared from the pleural fluid sediment for further analysis.

Immunohistochemical (IHC) staining was performed on the cell block sections to reveal the immunophenotype of the atypical lymphoid cells. The tumor cells were negative for CD20 and CD3, while showing positive staining for CD30, CD138, HHV-8 and MUM 1.

CD3 (200x magnification): Demonstrating T-cell marker expression.

CD20 (200x magnification): Demonstrating B-cell marker expression.

CD30 (400x magnification): Demonstrating variable CD30 expression in lymphoma cells.

CD138 (400x magnification): Demonstrating plasma cell differentiation marker.

HHV-8 (400x magnification): Demonstrating HHV-8 positivity in tumor cells.

MUM1 (400x magnification): Demonstrating MUM1 expression in tumor cells.

Flow cytometry: Analysis of the cells within the lymphocyte gate shows 72% T lymphocytes and 3% B lymphocytes. The B cells are mature monoclonal B cells (CD19+CD20+CD22+) that express lambda light chains on their surface (kappa/lambda ratio: 1.2; normal range = 0.5-

4.0). The T cells are of mature phenotype and have a normal ratio of helper and cytotoxic T lymphocytes (CD4/CD8 = 1.0; normal ratio = 0.9-3.4). The majority of cells in the sample (60%) are mononuclear cells of the phenotype CD45+CD19-CD3-CD38+CD138+, which most closely corresponds to plasma cells.

A bone biopsy and puncture were also performed, revealing no evidence of infiltration from the underlying disease.

Antibody testing was conducted for Epstein-Barr virus, cytomegalovirus, human immunodeficiency virus, and hepatitis B and C. The test results were positive for EBV IgG and CMV IgG.

Discussion:

This case highlights the importance of considering Primary Effusion Lymphoma in the differential diagnosis of unexplained pleural effusions, particularly in elderly or immunocompromised patients. Primary Effusion Lymphoma is a rare and aggressive B-cell non-Hodgkin lymphoma associated with Human Herpesvirus 8 (HHV-8) infection. It is typically seen in immunocompromised patients, particularly in those with HIV/AIDS, but can also occur in elderly individuals with age-related immunosenescence. The differential diagnosis includes malignant mesothelioma, metastatic carcinoma, and other lymphomas (such as large B-cell lymphoma with plasmablastic features). The absence of CD20 expression and positivity for HHV-8 are key distinguishing features.

Key Learning Points:

1. PEL presents as a malignant effusion without a detectable tumor mass.
2. HHV-8 positivity is a defining feature and aids in diagnosis.
3. It primarily affects immunocompromised individuals but can also occur in elderly patients.
4. The prognosis remains poor despite chemotherapy, highlighting the need for novel therapeutic approaches.

Author of the case:

Ena Holjević, MD; Special thanks to assistant professor Christophe Štemberger,MD, PhD and assistant professor Irena Seili-Bekafigo, MD, PhD for their support in the developing of this case.

References:

Cesarman, E., Mesri, E. A., & Gershengorn, M. C. (2023). Primary Effusion Lymphoma. Diagnostics, 13(3), 370.

Coyle, T., Xie, Y., & Shergill, A. (2021). Primary Effusion Lymphoma: Current Perspectives. Frontiers in Oncology, 11, 33669719.

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Jerzy Klijanienko,

Beatrix Cochand-Priollet,

Olivier Choussy,

Wojciech Golusinski

(Editors),

Springer Nature, 2024.

ISBN: 9783031676741

The ENT region is of great anatomical complexity. The proximity of tissues of different origin, a specific clinical terrain and the presence of organs exposed to viruses and other aggressive agents mean that this region presents a great variety of lesions of different nature: inflammatory, benign tumors and malignant tumors can present overlapping clinical, radiological and pathological characteristics.

In addition, this richness (diversity) of presentation is the source of “hyperspecialization” in the involved medical specialties. There are specialists for the thyroid gland, salivary glands, connective tumors or, finally, the upper aero-digestive tract. As much as some chapters of this pathology can be quite common, others can be extremely rare and therefore more difficult to diagnose.

There is a simple explanation for this: the diagnosis of rarer, more complex and more difficult lesions is more easily managed by centers specialized in this field. In an attempt to cover this complicated field of pathology, we have invited leading specialists engaged in diagnosis to cooperate.

First, the former President and the former General Secretary of the European Federation of Cytology Societies, the former President of the European Head and Neck Society and the current head of oncological surgery at the Institut Curie in Paris represent the four Editors. The introduction was written by Prof Andrew S. Field, from the University of New South Wales, former President of the International Academy of Cytology as well as Prof Fernando Schmitt, from the Medical Faculty, University of Porto, current president of the International Academy of Cytology, both widely implicated in the IAC WHO IARC Joint Standing Editorial Board for the publication of the so-called “Blue Books” (i.e international systems for reporting cytologies).

The chapters were entrusted to specialists in the different fields coming from numerous Centers and prestigious universities. Chapters in clinical, radiology, nuclear medicine, virology, immunohisto/cytochemistry, molecular biology, dermatology, and ophthalmology offer an original scientific approach of these Head and Neck lesions. In seeking the objective of clinical objectivity and usefulness, we treated classical pathology and cytopathology techniques equally. Scientific arguments in favor of one technique or the other were shown and discussed. We are aware that different oncological centers have their own diagnostic methods and we tried to unite them, discussing and showing the advantages of other experiences.

In hopes that all of this will serve our patients and that they will benefit from modernity and efficiency in medicine in 2025.

Prof J Klijanienko

Ass Prof B Cochand-Priollet

Dr Olivier Choussy

Prof W Golusinski

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CaseReport:

Rebuilding a Diagnostic Puzzle: Integrating History and Morphology

An 82-year-old male, who was asymptomatic, underwent follow-up for a simple kidney cyst by magnetic resonance imaging (MRI). A tumor on the lower lobule of the left lung was detected. A thoracic computed tomography showed the following findings:

inthelowerlobeoftheleftlung

A full-body positron emission tomography (PET) scan was performed, revealing only the two previously mentioned lesions.

At this point, the patient denied any previous history of malignancy, so the clinician decided to perform an Endobronchial Ultrasound with Bronchoscope-Guided Fine-Needle Aspiration from the hilar adenopathy, under the suspicion that this would be a primary lung tumor. Aspirate smears and a cell block were obtained from the EBUS-B-FNA. Rapid On-Site Evaluation (ROSE) was performed.

A poorly differentiated tumor, suspected of being a primary pulmonary neoplasm, was observed, so, initially, the following immunohistochemical studies were requested:

• TTF1
• Napsin A
• CK7
• CKAE1/AE3
• p40

All these markers where negative.

So, if you were thinking it was a poorly differentiated adenocarcinoma, and you see all these negative markers, you might be feeling a bit lost at this point, probably thinking of requesting a SMARCA4 determination.

But sometimes, it’s more important to review the clinical background before going further and requesting new immunohistochemical markers. So, we decided to ask the clinicians for further clinical details, including whether the patient was a smoker. They revealed that the patient had never been exposed to tobacco.

With this new information, we re-evaluated our diagnosis: what if this is not a primary tumor of the lung, but actually a metastasis?

So, we started to look carefully at our cytological features:

Given these cytological findings, we decided to request two other immunohistochemical markers:

The final diagnosis was of metastasis of melanoma. The patient was referred to dermatology for a general examination, but only four nevi were identified, with no lesions consistent with melanoma. Although primary pulmonary melanoma is recognized in the 2021 WHO classification of pulmonary tumors, we believe this is most likely a metastasis from skin melanoma that has regressed.

Comment:

The clinical history of a patient is a fundamental aspect of pathological diagnosis. When working with pathological samples, understanding the patient’s medical background, symptoms, and risk factors provides crucial context for interpreting the findings. Without this information, it is easy to misinterpret or overlook certain diagnostic clues. Clinical history helps guide the differential diagnosis and ensures that all possible conditions, including rare or atypical ones, are considered. Therefore, a thorough review of the patient’s history is essential to reach an accurate diagnosis and provide the best possible care.

When working with our pathological samples, morphology should always be our first biomarker, before requesting any unnecessary immunohistochemical studies. Melanoma is the eternal mimic, the tumor that should consistently be considered in our differential diagnosis, as it can exhibit a wide range of nuclear patterns. However, it often presents with distinct features, such as prominent nucleoli, intranuclear cytoplasmic inclusions, binucleation, and may also contain cytoplasmic pigment.

Primary pulmonary melanoma (PPM) is an entity recognized in the 2021 World Health classification of lung tumors, which has been described in multiple publications dating from 1916, and is classified in a group termed “tumors of ectopic origin”, which encompass tumors that are more common presented in other sites, but sometime can arise as primary pulmonary tumors. The actual existence of this entity is doubted, and the most accepted theory to this day attempting explain these tumors is that they are a metastases from a primary cutaneous melanoma with regression, a well-described phenomenon.

Author of the case

Allan Argueta, MD Special thanks to M.D. Lozano M.D., Ph.D. for her support in the developing of this case.

REFERENCES

Nicholson AG, Tsao MS, Beth Beasley M, Borczuk AC, Brambilla E, Cooper WA, et al. The 2021 WHO Classification of Lung Tumors: Impact of Advances Since 2015. J Thorac Oncol [Internet]. 2022 [cited 2023 Jan 20];17(3):362–87. Available from:

Yang C, Sanchez-Vega F, Chang JC, Chatila WK, Shoushtari AN, Ladanyi M, et al. Lung-only melanoma: UV mutational signature supports origin from occult cutaneous primaries and

argues against the concept of primary pulmonary melanoma HHS Public Access. Mod Pathol [Internet]. 2020 [cited 2023 Jan 20];33(11):2244–55. Available from:

Sekine I, Kodama T, Yokose T, Nishiwaki Y, Suzuki K, Goto K, et al. Rare pulmonary tumors – a review of 32 cases. Oncology [Internet]. 1998 [cited 2023 Jan 21];55(5):431–4. Available

from: https://pubmed.ncbi.nlm.nih.gov/9732221/

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