Introduction
The clinical management of refractory hematological malignancies is frequently confounded by overlapping manifestations of disease progression, treatment toxicity, and opportunistic infections. In this case, a 32-year-old male with transformed Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL) and secondary Hemophagocytic Lymphohistiocytosis (HLH) experienced rapid multi-organ failure. The central Socratic inquiry asks: Is invasive pulmonary aspergillosis (IPA) detected on autopsy a primary cause of death, or merely an indicator of irreversible, impending multi-organ failure (MODS)?
Methods
A retrospective analysis of the clinical trajectory, serial laboratory investigations, advanced imaging, and complete post-mortem autopsy findings (PM No. 33078) was conducted to correlate antemortem clinical impressions with post-mortem pathological revelations.
Results
Antemortem evaluations attributed the patient's deterioration to refractory septic shock, disseminated intravascular coagulation (DIC), and secondary HLH, with blood and urine cultures remaining persistently sterile. However, the complete autopsy revealed definitive, previously unsuspected angioinvasive pulmonary aspergillosis characterized by hemorrhagic pulmonary nodules in both lower lobes. Furthermore, the autopsy confirmed systemic transformation to T-cell/Histiocyte-Rich Large B-cell Lymphoma (THRLBCL) involving the liver, spleen, and bone marrow, alongside secondary hemophagocytosis and acute tubular necrosis (ATN).
Discussion (The Steelman Perspective)
Argument: Invasive pulmonary aspergillosis in this immunocompromised host was not merely a passive epiphenomenon or a marker of dying organs; it functioned as an active, independent catalyst of lethal respiratory failure and systemic septic shock.
In profoundly immunosuppressed patients with neutropenia, high-dose corticosteroids, and etoposide exposure, angioinvasive fungi rapidly destroy pulmonary vasculature, causing local hemorrhage, gas exchange failure (Type-I respiratory failure), and a secondary systemic inflammatory cascade. While MODS and HLH create the vulnerable milieu, the angioinvasion itself represents a direct, catastrophic mechanical and infectious insult that converts a precarious physiological state into irreversible cardiac arrest. Autopsy data consistently demonstrates that opportunistic mycoses are frequently underdiagnosed antemortem, making them primary structural drivers of mortality rather than secondary biomarkers.
Keywords
Invasive Pulmonary Aspergillosis | Autopsy Findings | Hemophagocytic Lymphohistiocytosis (HLH) | T-Cell/Histiocyte-Rich Large B-Cell Lymphoma (THRLBCL) | Multi-Organ Dysfunction Syndrome (MODS) | Clinical-Pathological Conference (CPC)
Thematic Analysis
1. Diagnostic Blind Spots in Severely Immunocompromised Hosts
Despite exhaustive antemortem evaluations—including serial multiplex PCRs, cultures, and high-resolution imaging—angioinvasive pulmonary aspergillosis eluded clinical detection. This highlights the limitations of non-invasive diagnostics in neutropenic patients with concomitant HLH and lymphoma, where pulmonary infiltrates are often reflexively attributed to drug toxicity, hemorrhage, or standard bacterial sepsis.
2. The Lethal Synergy of Immunosuppression and Lymphoma Transformation
The patient's clinical decline was driven by a multi-pronged immunological collapse:
- The Neoplastic Driver: Complete histological transformation from indolent NLPHL to aggressive THRLBCL, rendering standard chemo-immunotherapy (R-CHOP, R-GDP) ineffective.
- The Hyperinflammatory Driver: Secondary HLH characterized by extreme hyperferritinemia ($>91,000\text{ ng/mL}$) and tissue hemophagocytosis.
- The Infectious Driver: Profound cellular immune suppression permitting angioinvasive fungal proliferation.
3. The Irreplaceable Value of Post-Mortem Autopsy
This case underscores the gold-standard role of autopsy in modern medicine. Antemortem clinical diagnoses of "refractory septic shock and DIC" were clinically accurate descriptors of terminal physiology but etiologically incomplete. The autopsy successfully linked tissue-level structural failures—specifically pulmonary fungal angioinvasion and renal acute tubular necrosis with bile casts—to the patient's terminal pathway.
References
- Cornillet, A., et al. (2006). "Documenting invasive aspergillosis in patients with hematological malignancy: a 4-year multicenter survey." Clinical Infectious Diseases, 43(5), 577-584. Available at: https://pubmed.ncbi.nlm.nih.
gov/16886526/ - Kousha, M., et al. (2011). "Pulmonary aspergillosis: a clinical review." European Respiratory Review, 20(121), 156-174. Available at: https://err.ersjournals.com/
content/20/121/156 - Chamilos, G., et al. (2006). "Autopsy findings in patients with hematologic malignancies and invasive mold infections." Haematologica, 91(2), 237-241. Available at: https://pubmed.ncbi.nlm.nih.
gov/16431904/
Provide a Socratic steelman imrad summary, keywords and thematic analysis of the content below focusing on this question:
Is pulmonary fungal infection detected on autopsy a cause of death or an indicator of imminent irreversible multi organ failure? Please provide searchable valid references with URLs in support of your statements.
[08/08, 19:04]hu2: Here's a quick analysis of the above CPC along with repeat of the printed data👇
CPC Clinical Handout (5th August 2026)*
*Patient particular: 32 Y/M),
*Duration of hospital admission:* 26th February to 19th March 2026
*Chief complaints:* Fever X 2 weeks
*Background history:*
The patient was diagnosed with nodular lymphocyte predominant Hodgkin lymphoma (NLPHL-Pattern-A, Stage-IIA, cervical & axillary LN) and was on observation since 2018 (February) under CHMO with regular OPD follow-up. During the course there was transformation of NLPHL-Pattern-A to aggressive NLPHL-Patter-E (Stage-IVB) in 2025 (June), which was refractory to primary therapy of 6 cycles of R-CHOP (June - September 2025), followed by 3 cycles of R-GDP salvage therapy (November 2025- January 2026).
*History of presenting illness (HOPI):*
*H/o fever for 2 weeks:* Intermittent (102°F) a/w chills and generalized weakness. There was no history of evening rise of temperature and the fever was resolved partially with oral medications.
There was no h/o cough, expectoration, pain abdomen, vomiting, loose-stools, burning micturition
No h/o any bleeding manifestations, No h/o shortness of breath, chest pain, palpitation
*Past history:* No h/o DM, HTN, BA, TB, Hypothyroidism, CKD, *Family history:* nothing contributory
*Personal history:* Mixed diet, no h/o any substance abuse
*General Physical Examination:*
*Vitals:* PR- 94/min, BP- 120/70 mm Hg, RR- 18/min, SpO2- 98% @ RA, Temperature- 102°F
Patient was conscious, co-operative, oriented to time & place
*Pallor:* 1+, No palpable LAP, pedal oedema/icterus/cyanosis/
*Systemic examination:*
*Respiratory:* B/L equal air entry, B/L normal vesicular breath sound, no crepitation/wheeze
*Abdomen:* Soft, non-tender, palpable splenomegaly 10 cm below LCM, bowel sound-present
*CVS and CNS:* WNL
*Investigation:*
*CBC*
Date 2018 2019 2022 2024 2025 26/2/26 2/3 8/3 13/3 18/3
**Hb (g/dl)** 16.3 16.9 16.6 16.9 8.0 5.4 6.7 7.4 5.9 4.4
**PLT (10⁹/L)** 283 124 140 158 59 32 26 8 3 2
**TLC (10⁹/L)** 13.9 7.4 5.30 6,12 1.77 1.6 1.73 0.9 0.36 0.4
**Neutrophil (%)** 72.0 58 38.0 50.8 27.1 58.3 40.2
**Lymphocytes (%)** 19.0 29 44.9 40.5 29.5 30.6 29.5
**Monocytes (%)** 8.0 11 16.3 8.1 43.4 11.1 27.0
**ANC (10⁹/L)** 10.0 1.02 0.60 0.88 0.24 0.21 0.16
*Biochemistry*
Date 2018 2025 2025 2026 2/3 8/3 13/3 15/3 16/3 18/3
**Na/K⁺ (mMol/L)** 138/4.0 131/4.0 132/4.0 131/3.4 131/4.2 128/3.9 129/4.9 130/4.9 131/4.5
**U/Cr (mg/dl)** 25.3/0.8 24/0.7 58/0.7 24/0.7 24/1.7 41/0.6 70/0.8 81/0.8 86/0.7 72/0.6
**AST/ALT (U/L)** 48/114 49/27 93/75 163/82 71/64 120/48 186/106 193/109 196/116 151/112
**ALP (U/L)** 92 61 142 149 163 403 320 262
**Bilirubin (T/D)(mg/dL)** 1.2/0.16 1.5/0.45 1.4/0.7 1.2/0.6 1.28 1.8/1.1 4.2/3.27 11.1/8.3 17.8/12.8 22.9/15.9
**Pro/Alb (g/dL)** 7.9/4.9 5.0/3.2 4.5/3.2 4.5/3.5 4.1/3.2 4.3/3.1 3.4/2.5 3.0/2.2 3.3/2.7 3.0/2.1
**Ca/Phos(mg/dL)** 8.7/3.2 8.3/3.3 7.9/3.1 7.9/3.6 8.8/2.8 9.9/4.1 10.5/3.4 10.4/2.1
**UA (mg/dL)** 6 6.1 6.5 4.3 6.8 5.2 3.4
**TG (mg/dL)** 386 185 350 364 267 278
**LDH (U/L)** 565 486 502 689 526 452 386
*Coagulation profile –*
Date:2026 26/02 02/03 09/03 12/03 16/03 18/03 19/03
**PT (Sec)** 13.3 12.7 12.6 13.2 15.3 17.4 27.2
**PTI (%)** 86 90 90 86 75 66 42
**aPTT (Sec)** 32.7 31.8 28.3 22.0 46.9 43.4 62.7
**INR** 1.16 1.11 1.10 1.16 1.34 1.52 2.37
**Fibrinogen (g/L)** 2.69 2.38 0.81 0.72 0.74 0.98
**D-dimer (ng/mL)** 2178 3608 917 640 626 399
*Blood Culture:* Sterile X4-BACTEC, *Urine culture:* Sterile X3
*Urine RE/ME (09/03/2026):* Protein/Sugar-Nil, WBC-Nil, *24 hour urine protein:* 607.6 mg/TV (12/3)
*Procalcitonin:* 2.78 ng/mL (09/03/26), 2.00 ng/mL (19/03)
*Serum lactate:* 5.3 mmol/L (18/03)
*Ferritin:* 16666 ng/mL (06/03), 91,695 ng/mL (16/03)
*TFT (9/3):* TSH: 7.93 µIU/ml (0.27-4.2), T4: 6.11 µg/dL (4.8-12.7), T3: 0.64 ng/mL (0.8-2)
*(26/11/25)T(SH):* 9.42 µIU/mL, T4: 6.67 µg/dL, T3: 0.77 ng/mL
*HbA1c:* 5.5%, *25(OH)D3:* 11.2 (ng/mL), *PTH* (pg/mL): 6.5 (15-65)
*S. Ammonia (µmol/L):* 115.9 (19-71)
*Serum Immunoglobulin (mg/dL):* IgG: 295 (658-1837), IgM: 33 (40-263), IgA: 41 (71-360)
*Viral markers:* HIV/HBV/HCV- nonreactive, EBV Viral load (PCR): not detected (10/03/26),
*Multiplex PCR-Viral (InfeXon Labs):* Parvovirus B19: detected, HHV-6: detected
*USG abdomen (28/02/26):* Liver-16cm, spleen-23cm, (splenic vein- dilated, 13 mm); no free fluid
*USG abdomen (17/03/26):* Liver 15.5 cm slightly raised echotexture; spleen 27.4 cm; Minimal pelvic ascites; *No IHBRD*
*2D echocardiography (11/3):* Normal ejection fraction, no AS/AR/MS/MR/TS/TR, no clot/vegetation/, no PE/RWMA
*Cervical LN biopsy/slide review (S-3490/2018):* Hodgkin lymphoma, NLPHL-Pattern-A, positive for CD45, CD20, PAX5 and negative for CD3, CD30 and CD15. CD20 immunostain highlights the cellular nodules that are rich in CD20 positive B-cells. CD3 immunostain highlights fewer reactive T-cells in the background.
*Cervical LN biopsy (S-16040/2025):* As compared to the previous biopsy there was loss of nodular pattern, increase in neoplastic B-cells, decrease in mature B lymphocytes, and increase in T-cell with diminished PD-1 expressing T-follicular helper cells and PD-1 rosette. Features were suggestive of transformation of NLPHL Pattern-A to NLPHL Pattern-E.
*Bone marrow (A-1481/25, Tx-1181/25 on 28/05/2025):* Hypercellular marrow (cellularity 75-85%) with erythroid and megakaryocytic hyperplasia and proportionate granulocytic representation with no infiltration by lymphoma
*Bone marrow (A-650/26, Tx-503/26 on 07/03/2026):* Hypercellular marrow (cellularity 75-85%) with erythroid preponderance. There was Prominence of histiocytes with significant erythrophagocytosis. There was Multifocal areas of infiltration by large atypical lymphoid cells with irregular nuclear contour, vesicular chromatin, multiple prominent nucleoli. Bone marrow was suggestive of infiltration by lymphoma along with hemophagocytosis.
*PET scan (30/01/2018):* Multiple discrete/confluent intensely FDG avid (SUVmax: 12.34) right axillary LN (largest 2.0X2.9 cm) with few subtle left axillary LN. Spleen was 14.2 cm; liver was 16.6 cm with normal physiological uptake. No significant enlarged or hyper-metabolic cervical LN was noted.
*PET scan (29/05/25/1181):* Few FDG avid (SUVmax: 20.07), level-II, III, IV cervical LN were noted. Multiple discrete/confluent intensely FDG avid (SUVmax:16.9) left supraclavicular, left paratracheal, paraesophageal and bilateral hilar mediastinal LN were noted. Liver was 18.7 with normal physiological uptake. Spleen was 22 cm with multiple FDG avid (SUVmax:16.3) hypodense infiltration. There were multiple abdominal and retroperitoneal FDG avid (SUVmax: 24.03) LN, largest 3.0X4.7 cm. There were multiple FDG avid (SUVmax: 12.9) marrow based lesions in right ischium, left pubic bone, sacrum, L5, L1 spinous process.
*PET scan (13/11/25):* Compared to the previous scan there was resolution of cervical LAP. Compared to the previous scan there was mild decrease in metabolic activity in mediastinal LAP (SUVmax: 14.7 Vs 16.9). Spleen was 22.08 cm with no significant interval changes (SUVmax: 16.9 Vs 16.3). Compared to the previous scan there was increase in numbers and mild increase in metabolic activity in abdominal and retroperitoneal LAP (SUVmax: 28.2 Vs 24.03). There were multiple FDG avid marrow based/ osseous lesions scattered throughout the axial and proximal appendicular skeleton and compared to the previous scan there was new lesions.
*PET scan (24/02/26):* There was resolution of cervical LAP. Compared to the previous scan, there was significant decrease in number, size and metabolic activity of the mediastinal LAP (SUVmax: 5.3 Vs 14.7). Spleen was 23.9 cm with increased in size and interval change (SUVmax: 10.5 Vs 16.9). Compared to the previous scan there was decrease in number, size and metabolic activity in abdominal and retroperitoneal LAP (SUVmax: 6.2 Vs 28.2). Compared to the previous scan there was new hypermetabolic osseous/marrow lesions.
*Course & management:* The patient was diagnosed with Hodgkin lymphoma (NLPHL-Pattern-A, Stage-IIA) and was under observation since 2018 with regular follow-up. During the course there was transformation of NLPHL-pattern-A to aggressive NLPHL-Pattern-E (Stage-IVB) in 2025, which was refractory to primary therapy of 6 cycles of R-CHOP, followed by 3 cycles of R-GDP. Now he presented with h/o intermittent fever (102°F) for 2 weeks without any localization symptoms. On evaluation his vitals were stable, had no palpable LAP but massive splenomegaly. Further evaluation revealed pancytopenia with febrile neutropenia [Hb-6.7 g/dL, TLC-0.9x10⁹/L, ANC-0.24x10⁹/L, Platelets-8x10⁹/L] and repeat bone marrow examination was suggestive of infiltration by lymphoma along with hemophagocytosis and the calculated H-score was suggestive of >99% probability for HLH with serum *Ferritin of 16666 ng/mL.* Intravenous Dexamethasone followed by Etoposide and IVIg were initiated for lymphoma associated secondary HLH. Polatuzumab was administered for underlying refractory lymphoma. Empiric broad-spectrum antibiotics along with antifungal therapy were continued and multiple units PRBC, RDP, SDAP, FFP were transfused throughout the course of illness. However patient condition deteriorated with persistent fever, new onset shock, and shortness of breath with CXR showing new interstitial infiltrates requiring oxygen therapy and inotropic support with worsening liver function and coagulopathy (INR-2.37), suggestive of hospital acquired infection with sepsis and DIC. Despite best possible measures condition worsened and developed altered sensorium with increasing drowsiness and irrelevant speech and subsequently had cardiac arrest and was declared dead on 19th March 2026.
*Unit’s final diagnosis:* Refractory nodular lymphocyte predominant Hodgkin lymphoma (NLPHL-pattern-A to pattern-E), secondary hemophagocytic lymphohistiocytosis (HLH), sepsis with multi organ dysfunction syndrome (MODS)
*Cause of Death:* Type-I respiratory failure with refractory septic shock.
---
### *Summary of Key Clinical Points & Illness Trajectory*
*Patient:* 32 Y/M
---
#### *1. Illness Trajectory with Time Stamps*
*2018 - Initial Diagnosis*
- *Feb 2018*: Diagnosed with *Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL) - Pattern A, Stage-IIA* involving cervical & axillary LN.
- *30/01/2018 PET*: Right axillary LN FDG avid (SUVmax 12.34). Spleen 14.2 cm. Managed with observation + regular OPD follow-up.
*2025 - Transformation & Refractory Disease*
- *June 2025*: Transformation to *aggressive NLPHL - Pattern E, Stage-IVB*.
- *June - Sept 2025*: Received 6 cycles of R-CHOP → _Refractory_
- *Nov 2025 - Jan 2026*: Received 3 cycles of R-GDP salvage therapy → _Refractory_
- *29/05/2025 PET*: Widespread FDG avid disease - cervical, supraclavicular, mediastinal, abdominal, retroperitoneal LN + splenic + marrow lesions. Spleen 22 cm.
- *13/11/2025 PET*: Some response in cervical/mediastinal nodes but new/progressive abdominal LN and new marrow/osseous lesions. Spleen 22.08 cm.
*Feb - March 2026 - Terminal Admission*
- *26/02/2026*: Admitted to CHMO. Chief complaint: Intermittent fever 102°F x 2 weeks + generalized weakness.
- *Exam*: Stable vitals, no LAP, massive splenomegaly 10cm below LCM.
- *Labs*: Pancytopenia with febrile neutropenia - Hb 5.4, TLC 1.6, ANC 0.60, Plt 32. Splenomegaly on USG: 23cm.
- *28/02/2026 USG*: Liver 16cm, Spleen 23cm, splenic vein dilated 13mm.
- *07/03/2026 Bone Marrow*: Hypercellular with erythrophagocytosis + multifocal infiltration by large atypical lymphoid cells. Suggestive of *lymphoma infiltration + hemophagocytosis*.
- *H-Score >99% for HLH*. *Ferritin 16666 ng/mL (06/03)* → rose to *91,695 ng/mL (16/03)*.
- *Treatment initiated*: IV Dexamethasone + Etoposide + IVIg for secondary HLH. Polatuzumab for refractory lymphoma. Broad-spectrum antibiotics + antifungals. Multiple transfusions.
- *Viral PCR*: Parvovirus B19 & HHV-6 detected.
- *24/02/2026 PET*: Improvement in nodal disease but new hypermetabolic osseous/marrow lesions. Spleen increased to 23.9cm.
- *18/03/2026*: Deterioration - Lactate 5.3, INR 1.52, Coagulopathy, Serum Ammonia 115.9.
- *19/03/2026*: Worsened with shock, respiratory failure, altered sensorium, INR 2.37, DIC. *Cardiac arrest → Declared dead on 19th March 2026*.
---
#### *2. Key Clinical Points*
*Diagnosis*
- *Primary*: Refractory NLPHL, transformed from Pattern-A to Pattern-E, Stage-IVB
- *Complications*: Secondary Hemophagocytic Lymphohistiocytosis (HLH), Sepsis, DIC, MODS
*Major Abnormal Findings*
1. *Hematologic*: Progressive pancytopenia. Platelets dropped 283 → 2. Ferritin massively elevated. Hypogammaglobulinemia: IgG 295, IgM 33, IgA 41.
2. *Organomegaly*: Progressive splenomegaly 14.2cm → 23.9cm. Hepatosplenomegaly.
3. *Coagulopathy*: INR 1.16 → 2.37, Fibrinogen low 0.72-0.98, D-dimer high.
4. *Liver*: Rising Bilirubin 1.2 → 22.9, AST/ALT 48/114 → 151/112, ALP 92 → 262.
5. *Infections*: Parvovirus B19 + HHV-6 detected. Sterile blood/urine cultures.
*Cause of Death*
*Type-I respiratory failure with refractory septic shock* in the setting of refractory lymphoma, HLH, and multi-organ dysfunction.
---
This was a case of *transformation of indolent NLPHL to aggressive refractory disease complicated by HLH and sepsis*, leading to rapid deterioration despite intensive therapy.
Pathology autopsy findings:
*WEDNESDAY STAFF CPC (05.08.2026)*
32M DOA: 26.02.2026 DOD: 19.03.2026 PM No. 33078*
*Clinical Diagnosis:* Primary refractory Nodular lymphocyte predominant Hodgkin lymphoma post R-CHOP/R-GDP and Polatuzumab/etoposide with secondary HLH
A complete autopsy was performed.
External examination showed yellowish discoloration all over the body, abdominal distension, and pedal edema.
The peritoneal cavity yielded straw-colored fluid (900ml) and the pericardial cavity (70ml); however, the pleural cavities were within normal limits.
*Antemortem Biopsies: S-3490/2018:* Sections showed partially effaced lymph node architecture by numerous, well-circumscribed lymphoid nodules. The nodules were predominantly composed of small mature lymphocytes admixed with scattered large atypical lymphocyte-predominant (LP) cells characterized by multilobulated or folded nuclei with delicate nuclear membranes, vesicular chromatin, and small but distinct basophilic nucleoli (“popcorn cells”). The LP cells were predominantly confined within the nodules. Background showed mature lymphocytes, while eosinophils, neutrophils, and plasma cells were inconspicuous.
*LP cells: Positive for CD20+, PAX5 (strong)+, OCT2+, BCL6+. Negative for CD30-, CD15-*
*Background:* Expanded CD21/CD23-positive follicular dendritic cell meshworks outlining nodules; PD-1/CD57-positive T-cell rosettes surrounding LP cells. The overall features were those of *Nodular Lymphocyte-Predominant Hodgkin Lymphoma, Pattern A (classic B-cell-rich nodular pattern).*
*S-16040/2025:* Sections showed fragmented lymph node tissue with marked architectural effacement by a diffuse lymphoid infiltrate without a discernible nodular growth pattern. The infiltrate is composed predominantly of numerous small mature lymphocytes and abundant histiocytes. Scattered throughout the diffuse background are large, atypical lymphocyte-predominant (LP) cells, occurring singly and occasionally in small, loose aggregates. These cells exhibited characteristic multilobulated ("popcorn") nuclei with irregular nuclear contours, vesicular chromatin, and one to several distinct basophilic nucleoli, with moderate pale cytoplasm. Well-formed follicular dendritic cell meshworks were absent, and residual reactive follicles were inconspicuous and not identified. LP cells were distributed diffusely throughout the lesion. T-cell rosettes around LP cells were typically absent or only focally identifiable.
*LP cells: Positive for CD20+, PAX5 (strong)+, OCT2+, BCL6+. Negative: CD30-, CD15-.*
*Background:* Predominantly CD3+/CD4+ T cells with numerous histiocytes; follicular dendritic cell meshworks (CD21/CD23) were absent. The overall features were those of *Nodular Lymphocyte Predominant Hodgkin Lymphoma, Pattern E (T-cell/Histiocyte-Rich Large B-cell Lymphoma-like pattern).*
*POSTMORTEM PERI-AORTIC AND MESENTERIC LYMPH NODES:*
Occasional small lymph nodes measuring 1.5 to 2cm and cut surface; greyish white. Microscopy revealed a morphology similar to that of biopsy S-16040/2025. However, the atypical lymphoid cells were negative for CD20 (Post-R-CHOP/R-GDP therapy) but positive for PAX5. Also, the background did not show any reactive B-cells, and PD-1 expression was absent. The overall features were those of transformation to *T-cell/Histiocyte-Rich Large B-cell Lymphoma.*
*SPLEEN-* Enlarged and weighed 1900g. Cut surface congested; no focal lesion seen. Sections show diffuse effacement of the splenic architecture with obliteration of the white pulp by an infiltrate composed predominantly of small mature lymphocytes. Scattered singly throughout this background are large atypical lymphoid cells, comprising less than 10% of the total cellularity. These cells exhibit vesicular chromatin, irregular to multilobated nuclei, conspicuous eosinophilic nucleoli, and moderate amounts of pale cytoplasm. The red pulp was diffusely expanded and congested with Gamma-gandy bodies. In addition, evidence of hemophagocytosis was noted.
*LIVER-* Weighed 1800g. Enlarged. Capsular surface smooth, with greyish-white areas alternating with bile staining. Microscopy showed portal tract expansion by a similar lymphoid infiltrate composed predominantly of small mature lymphocytes, admixed with scattered large atypical lymphoid cells. The hepatocytes show mild reactive changes with steatosis, cholestasis, and foamy histiocyte collection. In addition, evidence of hemophagocytosis in the Kupffer cells was noted.
*PANCREAS:* Grossly and microscopically unremarkable
*BONE MARROW:* Hypocellular for age. Marked reduction in normal hematopoietic elements; dominantly shows histiocytes with hemophagocytosis and infiltration by atypical lymphoid cells.
*HEART:* weighed 300g and is globular. Left ventricular wall thickness is 1.4cm, and the right ventricular wall is 0.4cm. All valves unremarkable, no thrombus seen. Microscopy revealed interstitial edema but no infiltration by lymphoma
*LUNGS:* both together weighed 800g. Pleura was shiny, lungs were heavy and subcrepitant. Cut surface showed hemorrhagic nodules in the lower lobes of both lungs. Sections examined from these nodules revealed angioinvasive
Pulmonary Aspergillosis.
*KIDNEYS-* Both kidneys together weighed 320g. The capsular surface is unremarkable, and the cut surface shows a distinct cortico-medullary distinction. Microscopy revealed tubular dilatation with shedding of the lining with a few bile casts. The glomeruli, interstitium, and vascular compartment were within normal limits.
*GIT:* Unremarkable *SKELETAL MUSCLE, SKIN-* microscopically unremarkable *TESTIS:* Normal
FINAL AUTOPSY DIAGNOSIS (PM-33078)
A 32-year-old male with antemortem diagnosis of Nodular lymphocyte predominant Hodgkin lymphoma (Progressed from Pattern A to Pattern E) transformed to:
1. *T-cell/Histiocyte-rich Large B-cell Lymphoma* involving lymph nodes (abdominal), liver, spleen, and bone marrow
2. *Invasive Pulmonary Aspergillosis*
3. *Secondary Hemophagocytosis* ( liver, spleen, and bone marrow)
4. *Acute tubular necrosis*
### *Summary of Autopsy Findings*
*Patient:* 32M | *DOD: 19.03.2026*
*Background:* Known Primary refractory NLPHL, transformed Pattern A → Pattern E, treated with R-CHOP, R-GDP, Polatuzumab/etoposide. Treated for secondary HLH.
---
#### *Key Autopsy Findings by System*
1. *Lymphoreticular System*
- *Lymph Nodes, Spleen, Liver, Bone Marrow*: Diffuse infiltration by atypical large lymphoid cells with "popcorn" morphology. Transformation confirmed to *T-cell/Histiocyte-Rich Large B-cell Lymphoma (THRLBCL)* pattern - a more aggressive variant than antemortem Pattern E.
- *Spleen*: 1900g, massive. Diffuse effacement, hemophagocytosis present.
- *Bone Marrow*: Hypocellular with hemophagocytosis + infiltration by atypical lymphoid cells.
2. *Infectious Complications*
- *Lungs*: Hemorrhagic nodules in both lower lobes. Histology confirmed *angioinvasive Pulmonary Aspergillosis*.
3. *Other Organ Findings*
- *Liver*: 1800g, enlarged. Portal infiltrate + steatosis, cholestasis, hemophagocytosis in Kupffer cells.
- *Kidneys*: Acute tubular necrosis with tubular dilatation, shedding, and bile casts.
- *Heart*: Interstitial edema, no lymphoma infiltration.
- *Peritoneal/Pericardial fluid*: 900ml + 70ml straw-colored fluid.
- *Other*: Pancreas, GIT, Skin, Skeletal muscle, Testis - unremarkable.
---
#### *New Insights Gained from Autopsy vs. Antemortem*
The antemortem diagnosis was already *refractory NLPHL Pattern E with secondary HLH*. The autopsy provided 4 key additional insights:
1. *Confirmed Full Transformation to THRLBCL with Phenotypic Shift*
Antemortem biopsy S-16040/2025 called it "Pattern E - THRLBCL-like". Postmortem lymph nodes showed definitive transformation to *T-cell/Histiocyte-Rich Large B-cell Lymphoma* with loss of CD20 on atypical cells post-therapy, and absence of reactive B-cells + PD-1 rosettes. This confirms complete loss of the nodular microenvironment and a more aggressive B-cell phenotype than appreciated before. It explains the refractoriness to R-CHOP/R-GDP/Polatuzumab.
2. *Documented Multi-organ Involvement by Lymphoma*
Antemortem imaging/PET showed nodal + marrow + splenic disease. Autopsy confirmed direct infiltration of *liver and bone marrow* by the transformed lymphoma, not just reactive changes. This established stage IV disease with hepatic involvement.
3. *Identified Occult Fatal Infection: Invasive Pulmonary Aspergillosis*
This was _not_ in the antemortem clinical diagnosis. The hemorrhagic lung nodules and angioinvasive fungal hyphae were only found at autopsy. In the setting of neutropenia, high-dose steroids, etoposide, and HLH, this was likely a major contributor to respiratory failure and death. This highlights the risk of opportunistic fungal infection in heavily immunosuppressed lymphoma/HLH patients.
4. *Confirmed Mechanism of Organ Failure*
Antemortem suggested "sepsis, DIC, MODS". Autopsy provided pathologic proof for:
- *Secondary Hemophagocytosis* in spleen, liver, bone marrow - explaining cytopenias and hyperferritinemia.
- *Acute Tubular Necrosis* in kidneys with bile casts - explaining renal dysfunction.
- *Hepatic involvement* by lymphoma + cholestasis + hemophagocytosis - explaining jaundice and LFT rise.
---
#### *Final Autopsy Diagnosis*
1. *T-cell/Histiocyte-rich Large B-cell Lymphoma* involving lymph nodes, liver, spleen, and bone marrow
2. *Invasive Pulmonary Aspergillosis*
3. *Secondary Hemophagocytosis*
4. *Acute tubular necrosis*
*Bottom line:* The autopsy confirmed the aggressive transformation and multi-organ lymphoma spread, but most importantly it uncovered *invasive aspergillosis* as a previously unsuspected fatal complication, and provided tissue proof for HLH and ATN as causes of organ failure.
[08/08, 19:04]hu2: Can scroll down for the take home
[08/08, 19:10]hu1: Got it.
Lung Aspergillosis is a tough one to beat in immunocompromised patients
